ICP/MCH/002(VII) (UNFPA No. RAS/71/P08)
~GIONAL f
SEMINAR ON
NEW DEVELOPMENTS IN FERTILITY REGULATION
Sponsored by the
WORLD HEALTH ORGANIZATION REGIONAL OFFICE FOR THE WESTERN PACIFIC
Manila, Philippines 28 November - 3 December 1977
FINAL REPORT
Not for Sale Printed and Distributed by the Regional Office for the Western Pacific of the World Health Organization Manila, Philippines February 1978
The views expressed in this report are those of the consultants and partioipants in the seminar and do not necessarily reflect the policy of the World Health Organization.
This report has been prepared by the WHO Regional Office for the Western Pacific for governments of Member States in the Region and for the participants in the Seminar.
CONTENTS
1.
INTRODUCTION
....................................................................................................
2.
TOPICS AND DISCUSSIONS Agenda items 1 and 2 A review of the techniques of fertility regulation used in the Region by Dr E. Hyock Kwon •..•.••.••..•..•..... Advantages and disadvantages of different fertility regulating methods by Dr Takashi Wagatsuma. . ..........•••... 5 13
Agenda item 3 - New developments in methods and research in fertility regulation and family planning .. . . . .. . . .. . .. . . .. .. . . . .. . . . .. . . . .. . .. . . . . . . .. . . . . . . . . . . . . . . . . 15
-
Research trends in human reproduction with implications for fertility regulation by Dr E. Diczfalusy •••••••••••.•• New developments in combination oral contraception by Dr J .. W.. Goldzieher by Dr G.. Benaglano
15 18 20
. .. . . .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. . .. .. .. .. .. .. .. .. .. .. .
Long-acting systemic contraceptive agents .. .. .. .. .. . .. .. .. .. . .. .. .. .. .. .. .. . . .. .. .. .. .. .. .. . . . .. .. .. .. .. .. .. .. .. .. ..
Non-medicated and medicated intra-uterine contraceptive devices by Dr Takashi Wagatsuma Sterilization technology by Dr Ruben A. Apelo Methods of fertility cQntrol in the male bJ Dr- I.. Potherby .................................................... r.Bunological approaches by Dr E. Diczfalusy ,e .. .. .. .. .. .. .. .. .. .. .. .. .. .. ..
24
28 30
32 36
-
Determination of the fertile period by' Dr G.. Benagiano
. .. .. . .. .. . .. .. .. .. .. . .. . . . .. .. .. .. .. .. . .. .. .. . .. .. .. . . . .. . . . . .
Iaduced abortion: health aspects of various teobnlques by Dr I. Edstrom •.••••••••••••.•••.•.•......... Long-term or late effects of induced abortion by Dr 'tIIa.rk A. Belaey
42 48
............................. ". . . . . . . . . . . . . . . . .
Prostaglandin in human reproduction by Professor S.S. Ratnaa and Professor S.H.H. Karim •••••••••
49
- ii -
Contents
3.
CONCLUSIONS ANNEXES
53
Annex 1 Annex 2 Annex 3 -
List of participants, observers, consultants and secretariat.................................. Programme
65 75 75
.........................................
List of materials distributed to the participants •. . . •. . •. . . . . . . . . . . . . ••••••••. . . . . . . . .
TABLES AND FIGURE Table A1 Table 12 Prevalence of use of family planning methods, Western Pacific Region ....••....••...... Annual acceptor rate of family planning methods (Government supported), Western Pacific Region ................... ". . . . . . . . . . . . . . . 9
8
Table B -
Legislation or regulations affecting use or distribution and source of fertility regulating methods, Western Pacific Region Quoted cost and cost to the user in the family planning programme, Western Pacific Region Maternal, infant and child mortality and total fertility in the Western Pacific Region .••....... Relative effectiveness and short-term safety of some common methods of induced abortion Prostaglandins and their inhibitors: Modulation and mediation of reproductive processes ..........
10
Table C -
11
Table D Table E Figure 1 -
12
47 50
1.
INTRODUCTION
The Regional Seminar on New Developments in Fertility Regulation was held in Manila from 28 November to 3 December 1977. The meeting was convened under WHO sponsorship with funds provided by UNFPA. The objectives of the seminar were: (a) (b) (c) (d) (e) to review teohniques of fertility regulation used in the Region; to exchange experiences gained with reference to effects, advantages and disadvantages in the use of these techniques; to apprise participants of new developments in methods and research in fertility regulation and family planning; to consider the implications of introducing these developments into existing family planning activities; to formulate practical guidelines for national family planning programmes in the Region based on the above innovations and developments.
In his opening remarks, the Acting Regional Director, Dr J.H. Hirshman, noted that just last year a regional seminar was devoted to the issue of the delivery of maternal and ch1ld health and family planning within primary health care. An important conclusion of that seminar was that family planning care is integrally related to the rest of health care, particularly maternal and child health, in both its rationale and in most of the means by wh1ch family planning oan be provided to a community. In his comments, the Acting Regional Director noted that the initial optimism following each new teohnological advance in fertility regulation subsequently has been tempered by the realization that many constraints still exist to safe, effective, acceptable and convenient fertility regulation by couples despite the technological advances. Many of the constraints reflect the lack of acceptance of the method by the couple, a lack of acceptability by the clinicians for fear of long-term complications or risks, or the unavailability of facilities and skilled personnel. One major constraint in many areas is the lack of a health infrastructure with sufficient trained manpower capable of providing a variety of fertility regulating methods. Another obstacle to effective family planning practice in a community is the great attention given by the media to the presumed adverse effects of different fertility regulating methods as opposed to the advantages of these methods. Both the public and the health sectors have looked towards the advances in research to overcome the limitations of current methods and to come up with new methods.
- 2 -
Well over a decade ago, the World Health Assembly recognized the need for the encouragement and promotion of research in human reproduction, and in 1972, the Organization greatly expanded its programme of research and training in human reproduction. Many exciting developments have taken place during the last decade. At the same time, a greater understanding of existing methods and human reproduction function has enabled us to better understand the limitations and health service requirements and clinical procedures needed to ensure safe, effective and satisfied use of the different fertility regulating methods. In view of the accumulated experience of the past few years, it is now considered appropriate to review the recent developments in fertility regulating methods; to examine these new developments in terms of the current experiences and problems of the methods presently used in the family planning programmes of oountries and areas in the Western Paoifio Region; aznd to discuss the implications of these new developments in terms of their implications for maternal and child health and family planning programmes. The Seminar Direotor, Dr Mark,A. Belsey, thanked the Acting Regional Director for personally welooming the seminar participants and for placing the seminar objectives within the context of the improvement of MeH and family planning services. He noted in his remarks the importance of health workers being fully informed on the new developments in fertility regulation. It was also pointed out that the family planning programme experiences and problems encountered by health workers represented an important guide in the setting of directions and priorities for research. In response to the recognition of insufficient scientific knowledge of the biology of human reproduction and the medical aspects of fertility regulation, WHO initiated a programme of research and research training in human reproduction. Over the past five years, this programme has grown considerably so that today it constitutes a special programme in WHO and is regarded now as one of the leading programmes in this field internationally. The fundamental objectives of this" programme are as follows: (1) (2) (3)
to provide Member States with a variety of safe, effeotive and aooeptable fertility regulating methods; to assist national authorities in devising the best ways of providing fertility regulating methods on a oontinuing basis; to assist national authorities in determining the magnitude and causes of infertility and to promote research of its prevention and treatment; "to strengthen the resources for research in this field, particularly in developing countries, and also to strengthen on a world-wide basis the needed discipline.
(4)
- 3 These fundamental objectives are then translated into priority areas for research: (a) (b) (c) (d) The health rationale for family planning Technology of fertility regulation Acceptability and service delivery Infertility
Inherent in some of the discussions on research priorities has been the set of underlying principles that guides the setting of those priorities. Seven main principles are followed in this programme. First and foremost, the research activity must meet the needs of developing countries. It is not enough to undertake that research, but by doing so the research resources of the country must be strengthened, be this by increasing the skills and experience of the researcher through training, collaboration and exchange of experiences with other scientists or through improvement in facilities. The research must be mission-oriented with respect to the formulation of health policies, to assess, improve and develop new health technologies or to improve health services. The research must be international in scope. Women differ from one area of the world to another, even from one country to another. Body sizes differ and there may be genetic differences which could result in marked differences in the rate of metabolism of hormones. Communities differ widely in their nutritional and dietary patterns. Anaemia may be common and may be aggravated with increased blood loss associated with some fertility regulating methods, but improved with others. The applicability of some research to entirely different settings remains to be confirmed. Research must also be collaborative. Much confusion and uncertainty has been generated in scientific circles with the appearance of apparently contradictory results. Yet it often is not possible to determine whether the apparently contradictory results are real and reflect different situations, or merely represent differences in the research methods used. The research programme is planned and coordinated with other agencies. The programme is built on existing institutions and on national expertise, and finally, but not least, the programme must be scientifically feasible. The means by which the priorities are set and the feasibility is judged are found within the structure of the programme. The WHO Special Programme in Human Reproduction is supported by contributions to the WHO Voluntary Fund for Health Promotion by the governments of Canada, ,Denmark, Finland, India, Mexico, Norway, Sweden and the United Kingdom, and from the United Nations Fund for Population Activities. Overall research direction and priorities are recommended by an advisory group composed of leading scientists.
- 4 -
The scientific feasibility as well as the ethical acceptability of eaoh and every research projeot is examined by a review group. The activities of the programme are listed under the following Research and Training Centres (RTC) Collaborating Centres for Clinical Research (CCCR) Task Forces Others The CCCRs number some 22, four of which - Manila, Sydney, Seoul and Singapore - are found in the Western Paoifio Region. The baokbone of the programme in research is found in the Task Forces and in the collaboration between the Task Forces and the CCCRs. TaskForoes are goal-oriented in their research, answering specific, well-defined Questions with respeot to specifio fertility regulating methods, reproductive processes or such aspeots as acceptability and the delivery of services. The Task Forces establish the priorities and strategies for answering the order of priorities that have been established by the advisory group. Having presented the principles and organization of the WHO Special Programme in Human Reproduction, the Seminar Director briefly underlined the importance of this mechanism for the improvement of family planning servioes. Working papers prepared specifioally for the seminar are compiled in a document issued as an appendix to this report. Additional background documentation included the Sixth Annual Report of the Special Programme of Research, Development and Research Training in Human Reproduction. Tables prepared beforehand and updated by the governments in the Region included: Prevalence of Use of Family Planning Methods; Annual Acceptor Rate of Family Planning Methods (Government Supported); Legislation or Regulations Affecting Use or Distribution and Source of Fertility Regulating Methods; Quoted Cost and Cost to the User in the Family Planning Programme; and Maternal, Infant and Child Mortality and Total Fertility in Western Pacifio Region. Additional reference materials were provided by the library and available in the conference room. Following the opening ceremony, the seminar group elected Dr F.B. Spooner as chairman for the first day's plenary session, and Dr G. Koteka as rapporteur. The chairmen for each of the subsequent plenary sessions were Professor R.J. Seddon, Dr Nora Ignacio-Silao, Hme Chang Chih-Fen, Dr Nguyen Thi Xiem and Dr R.L. Evans; the rapporteurs were Dr Luk Kwok-Fai, Dr Sinniah Dharmalingam, Dr Tanny Chan Tan Lai, Dr J. Leeton and Dr MYon Woo Shin. The seminar was divided into three main components: the presentation of the epidemiological overview, the advantages and disadvantages of the respective methods, and workshop discussions of individual country and area headi~:
- 5 -
experiences; the presentation of the new developments as related to specific methods of fertility regulation; and workshop discussions of the implications of these new developments for the family planning programmes in the respective countries and areas. The consolidated report of the first working group discussions and the highlights of the second working group discussions were reviewed and discussed further. The Assistant Director of Health Services, Dr S.T. Han, in his closing statement noted that the seminar group had successfully deliberated on the most essential problems of the implications of introducing the development of methodology into their existing family planning activities. He cited also the considerable amount of discussion on such relevant subjects as research on long-acting and short-acting steroid contraceptives, non-medicated and medicated intra-uterine devices, immunological approaches, male and female sterilizations, induced abortion and prostaglandins. These subjects he saw as important areas for the development of research and training in the Western Pacific Region considering the magnitude of the Region's need for fertility regulation and the capability of manpower and resources in Member countries and areas. He was also pleased to note that the group focused discussions on future collaboration with the Organization in research projects which would be oriented towards the improvement of contraceptive methods in national family planning programmes. This seminar should have a multiplier effect. The countries can now begin to plan for and conduct national seminars or workshops to review the recent developments in research on fertility regulation related to their own needs. The Organization will support a country's request to assist the government in developing and strengthening research fertility regulation. 2. 2.1 TOPICS AND DISCUSSIONS
Agenda item 1 - A review of the techniques of fertility regulation used in the Region, and Agenda item 2 - Advantages and disadvantages of the fertility regulating methods currently in use Fertility regulation methods in the Western Pacific Region: epidea1ological overview: presented by Dr E. Hyock Kwonan
2.1.1
The following is a brief summary of the results of a study on the pattern of contraceptive practices, services, production and methods of supply commonly used in countries or areas of the Western Pacific Region. The study has been conducted by comparing all the characteristics and phenomena of contraceptive services of one country or area with another, as far as data are available.
-Director, Institute of Reproductive Medicine and Population and Dean, School of Public Health, Seoul National University, Seoul, Republic of Korea.
- 6 (a) Demographical view
Demographically, it is obvious that most countries or areas in the Western Pacific Region, excluding a few such as Australia, Japan, New Zealand and Singapore, are suffering critically from population problems generated by persistently high fertility and mortality rates. It cannot be denied, however, that the fertility rate of each country or area has declined remarkably during the past ten years, largely due to the early adoption and positive implementation of family planning programmes as integral parts of population control policies (declined by 45% in Hong Kong, 37% in the Republic of Korea, 40% in Singapore). (b) Tendency of contraception
The present tendency is for most countries to make every effort to increase the contraceptive acceptance rate by the utilization to the maximum extent of available contraceptive methods such as oral pills, intra-uterine devices, sterilization and all other conventional methods. Induced abortion is also becoming an accepted, legali·zed means of population control policy exoept in oountries or areas such as Australia, Hong Kong, Malaysia and the Philippines. (c) Methods of contraception
It is observed that the family planning practice rate remains at above 60% of all eligible women in Australia, Hong Kong, Japan and Singapore. On the other hand, in Papua New Guinea, the Philippines, Samoa and Solomon Islands, it remains below 30%. Examining popular methods of contraception in the Western Pacific Region, Hong Kong depends largely on the oral pill and sterilization; Japan on the condom and the rhythm method. The oral pill and the condom are popular in Australia and Malaysia and the oral pill in the Philippines. In the Republic of Korea, the oral pill and intra-uterine devices are mostly used and sterilization is well accepted in Singapore as well as the oral pill. Therefore, the most common methods used in the Western Pacific Region are the oral pill, intra-uterine devices, the condom and sterilization. (d) Characteristics of acceptors
The average age of family planning acceptors remains somewhere between 25 and 34 in most countries or areas of the Region. The average age in Singapore is 25.5 years which is the lowest age of aoceptors for the Region. The Republio of Korea reoords the highest average age in the Region at 36.6. One reason for this high mean age is that the purpose of 86% of family planning aoceptors is not to space births but to prevent pregnancy. A second re~son is that a large percentage of acceptors are highly educated and a third is that marriage takes place at a later age. The mean number of children of family planning acceptors living was carefully examined. In Malaysia, among IUD acceptors, there is an average of 4.5 children which is the highest in the Region and there are 2.9 children in Hong Kong and 3.6 in the Republic of Korea in each IUD-user group. Among oral pill takers, the Republic of Korea has the highest number of living children at 3.9; Hong Kong has 2.9.
- 7 -
(e)
Cost of oontraoeption .ethod
Comparing the cost of contraoeption by method, the oral pill is available free in Malaysia and the Philippines. The Republic of Korea utilizes a system of charging one-fifth of the market value of the oral pi 11. as a nominal fee. Except in Hong Ions and Singapore, the condom and IUDs are known to be supplied free of ohar.. in most of the countries or areas of the Region. (f)
Legal status of induoed abortion
It is known that in China, Japan and Singapore, induoed abortion is practised lel&lly. In all otber countries, it is not legal exoept for ..dioal reasons or where tbe life of the mother is threatened. In the Republic of Korea, the induced abortion rate in women between the ages of 15 and ,_ is 50.3 per thousand per year and the average frequency of induced abortion performed per woman is 1.65. (g) Status of supply and manufacture ot oontraoeptives
With regard to the ourrent status of the supply and manufacture of oontraoeptives used in the Western Paoifio Region, exoept in Japan and in the Republio of Korea, supply of the oral pill and the condom is believed to depend a great deal on produots imported from other countries. Those produced in Japan and the Republio of Korea are known to exoeed the entire amount consumed in those countries, a considerable amount being exported to neighbouring countries. Another supply source of the oral pill and the condom is through international donor agencies. In some countries, most of the condolll8 and oral pills produced are manufactured from raw materials imported from well-known manufacturers in other oountries. Because the nu~er of users of the oral pill and the condom is rapidly inoreasing, especially those who purohase them oo. .eroially rather than receive them through government programmes, it is desirable that a more effective scheme be systematioally developed to supply quality contraceptives inexpensively by making them more readily available on the commercial market. (h) Conolusions
Present researoh must continue in order to improve the defects and shortcomings remaining in the oontraoeptive services and the supply systems currently employed by countries or areas in the Region. More positive efforts must be made towards better ooor-dination in exchanging new theoretical and teohnioal knowledge based on the results of research which is greatly needed for the attainaent of population control not only in a national but also in a regional context.
I
CouDt.a7 _ in b
Area
Population
W ..tem
or marrlecl
l'ao1t1olles101l
_D
_I'
TABlE Al
TOrAL lI9IRS
15-411
(thowlanda )
..-r1ed
" or
-.
_I' -
PREVAID«'!E OF USE OF FMILY PLANNIICl IIE'l1IOIlB
USERS OF ORAL COIIDIACIPI.'IV
tm:RII OF
(thouaIIDde )
(thowoanda )
15-44
Auav.ua
1 JU9" .862 .~
26
" of
-.,.
lI&l'I'1eel
(thowlanda )
..
IWm1'AIItII9
USI!IIS OF lUDB _bel'
HAVDIJ
" of
1"-411
0
....neel
(thowlanda )
" or
......sec! L~
a-r
S'l'I!RILIZATICli
or (UM'''._.) " _eel
15-44
-
"""1' (thoua.ncla) .UT
USI!IIS OF 0'lHIII IB'DlOOO
15-411
16 80
" of _eel'
15-411
ou_ fiJi
Cook lalanda
.126
82 :r.lIIDdtI
::2
5 •.Jl7 61 124
2 1."dI
.
.)Zt>
.0lI5 III
2.511
5 .617 24 5 9.1 0.7
5
.0::2
I!onI IfGIIII (1976) 01_ (1975) ~(lm) ~ ~
(1Q'1~ 26~
290
60.5 541.8
,., n ....
66
1'.75 5.' •• 0
76
..
(78.90_)
1575
".11 5.'1T 2l.1 ".2 12.8
264.6
16.8
0.5
11.0
6, 5.00\ 116 ,
20,.21.0 316 J9'I 81.8-
12.9-
561500
Papa . . . CIIdMa
(196'1414 1m)
29.80\ 1 10\9
6 522 472
1.2 9.6 9.7 ~.o
I
2.8
.56
15,
,"0
1.0 2.1 3.9
0.2 5.8 8.0
ftdUppl .... (1m)
~1~l II 900
195 615 ~.o
,.6 12.6 !6.0 2.8 2.1
-
~~)orr81nppoN
(1975) ~.2'n
1670
189
(1975)
(l~ill 2lj.~ 9.~
3.891 212.,
.m 48.0 .121
77.1 6.6 ~.7
74.8 .826
27.2
8ol_IalllDds '1'anp
1.6)1 11.25'
,.,
7.7 .091 .129
2.5 17.4 0.5
29.70.,
0.' 1.11
.509
.080
...
- 'I'otal _
15-" (l'1fO) '
PlSW'8" tor other than orsl OCIIl_pUvea
Ino1ud1ng injeoteble oontraaepti_ 1. 2.
110ft:
Data tor _ratio aa._ _• _ . r- '*'Ple'a _ratie lIepubl.1c _ _ llebri_ .... not available. About ~ or Oh _ _ _ wllb OCIIItIWIeptian - . . IIIlIL. ,. In 1976 0"''' 35lI 000 IUDo .... _ in SOCialist IIapubl10 or Viet _ .
CCIuD\rJ _ _ in _ _I'll
I'opIlaUan ot 1I&ft'1...
_r 10.5 750.8
TABIE A2
-
ANNUAL ACCEPl'OR RA're OF FAMILY PLANNING ME'DiOOoS (00VEIIIM!Hl' SUPFaI'D!D)
'l'01'AL 1EIiRS
(thOuaaIIda )
Pao1tt. II1II1_!;<!Qk
_15-411 (~)
-
" ot 1I&ft'1e<1
_r
\lSIIIIS OP CJIAL cotmIACEP'1'lVE
(t.IIou-.)
15-44 .1'16
-,. lI&ft'1ed
Im:R8 OP III.JIi£TAIIU!S
" or
(thawI-.)
...-ri...
15-44
..
" or
_r 0.2 1.1 2.,
08IRS OF IIIDII
(-)
...-ri...
" or
~
Ial.dIo 119'T6) 1!2
PU1
Gilbert Ialama (1976) ~ Boas IraoI& (1915) IIelqala ~ (1976) 1515
.J30 0.4 .441 22.4 75. 2
.007
.0tS, .oar 0.04 0••
-
.l.5-"
511
IlAYllQ S'BIIIILIZA1'ICIf
" or (fln,csm_) arrlecl ~
..
0.7
.O'R '.7 4.11
.'J12
15.9 65.0
J.J 4.1J 0.7b 7.1 2.0 ,.4 2.4 1.8
.04
0.7 2.0
o.ar 0.46 1.0 6.8
... ~
i~-75 to -7f» ftIll1pp1Me (1915) ~1o or _ (1915) (1975)
hpIa"~
500 5100 4900
2.1 14.7
,.8.
1., 9.6
.014 0.5 .oeM 0.7'.9
0.25 0.211>
\lSIIIIS OP ontIIR IIIftH<lDS
(tbO"· __ )
..
_e<I " or .~
.021
1.2 6.7 '.5 1.1 1 •• 0.29 0.22
"".6 'R 9.'
If ....' " .
275.4
"'.255 9.?#(
51.2 ". 0.1
311.0-
., ,.4 0.4
".1 1'R 7.(10.7 100 1.00Ii!
5.9 4.0 2.6 6.5
4.656
J&.9 1.500 2
1,.• 6.1
.oi 0.8 1.98
a:
abortion) (0GIIb~) ~l8l.-I8
24.458
.6 .lbb
.08 .567
21.5
0., 6.1
.2
.185
100 .CIIIo
.86
0.4 10.8
-1111. . . ~ 8Wr1lJaU0II Data till' _
DOt
d1tte~_. Auatral1a. China. _raUo KaallQChea. . . S001al1at IIapubl10 ot net _
"IIIolud2JIs 1I\,Ieot.Ul. 00II\ra0apt1.... . tIIUoodQs ~ri...... not available.
aua..
Japen. Lao ....pl••• _raUO Re1'Ub11o. _
llebrides. . . Zealand
'"
TABLE B
-
LEGISLATION OR REGUIATIONS AFFF.X:TIt-li USE OR DISTRIBIlI'ION
AND SOUJK:E OF F£RTILITY REGULATING ME'mOOO
Country and Area in the Weatem
Oral contraceptives
InJeetables
I1JIlo
Indu.ced. Abortion-
Sterilization
other
Paclts.c -:ReSton Cb1Da
On requeat Ott101ally supported by
OlD. request Officially alpported by aove .......t Propopllda of Boll1Ds ...thod 18 doDo by R •• pono1ble Parent.boOd As8001atiCID
P1Jl
ao...."..,t
0t't101a11y supported by Goven.ent
Oftoia11y sa_by
ao.e......t
Abortion ......1ble !'or me41cal ftUOD. PeDal Code Chapter n. Section 165-7 _ _ COl 2&.>
oubold1_ b 1 _
aove.....t ..... 1!aIs ~ ~.-
L1bonl - .-Idle fOr~ bulth _ W i... ~t_~
J_
r..
_ _0 Peop1.e'.
1IopIbl1c
"'- _
IIIdMa
_
On_~(tor
.. -
-"pt:I..1 but _ ~tlltoft.
Sale by
~1. .
111_ bo
On n...t .-dulo (tor Mle by pronar1pt1...l. but _ ~• • GIl
- ~
1'bJ8101aD
lID lopalat1ca
0nl1
hpllJ ....u.a.J.
-
I'Ne17 &ft1loblo ~lIl'1t_
_~to
cIoctor'.
_~byllMlth _t1_~~
bultbDr _ _
---~
...
'l'ooo
_oted. l'b111pp1Du ~11_
HoaltbDo_ Ston' ~tStorf
troel1by
-(-I
OCIIIHIlt ot _ 10 botb
C-rc1a1 d1atzo1but1 _ __
_NC!.
~11_
Ayailable ... IWIItr1OU. .
Import 110 .... _ _ tor d1a~_
requ1red
81"OUftIU - ........... approYal _
_(_,..,1a1 cI1atr1IIut1_ 1Iopoob1S0
or _
~11_
_NC!.
IIoport 1 1 _
~11_
L1bonl - _lable tor~bul"
~~
U_ IDoal
-
~lea1alated ~Dr
NqU1NcI.
I.ocal
...
......zo1_1 Iaport 1 1 _ ...qu1recI tor _
produotlon
re...... 28 _ . 1Ioz. pat.
_'s
approval neecIad All other aethocb haw not _
(or _ t )
Fb1 _ _ _ Zeal_
-
dlo~
r..wt.latfon. AYa1l.abl. an request. Mu. _to 24_ wU.u~
S~
On
request
thre.t.eaa I1te. SolCDrEI Islands Re,;ul.atlon that only JDed.ical offioers can prescribe As
.ou.r". Done on consent a f' husband and wlCe (Signatures
tor arab
Regulation tr..at any doctor can
The U.K. law on abortion (probably that or 1898) 10 still followed here
insert Ulough in practice nurses
necessary)
do.
.
~oet!"11"lt Ik'\)'lbll'~
I
I
legal status .. 1.e. IndiGationa when abortion 1s penaitted.
Data for the f'ollowing oountries an! not available:
Australia. Cook Islands, Democratic K.a.rapuohea .. Gilbert Islands. GWUII, Ma..laysla. New !-iee, ides, New Zealand. 0:' V1,·t. ';.. ';'o~,-,
C'
TABIB C -
QUO'mD COS'!' AND COS'l' '10 '!lIB USI!R IN 'DIE PMIIN l'LAIIHIIIO l'ROGIIMME
Couatry aDd Area io the W •• tern Pacific ReliOR
Oral CoIrtraceptive. Coat to User Quoted Coat
IlIlII Quoted Cost
Coat to User
auat:.d
InJeotable. Cost Coat to UNr
CondGu Quoted Coat
ftJl
W
par ..,.,le 10,1' per 0701" If unable to tree $0.-'0/07018 JlII;l',
$,.211 .ach $2.00
Prea I t unab1ll to ~,
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- 13 -
2.1.2
Advantages and disadvantages of different fertility regulating methods: presented by Dr Takashi Wagatsuma i
Since there is no single and ideal contraceptive method available today which can be applicable to everybody, a decision should be made as to which methods would be suitable for people in a certain country or area. In order to evaluate the suitability of each currently available contraceptive method, advantages and disadvantages of different methods of fertility regulation should be carefully examined from various angles as well as from different points of view. The following is an overall schema for examining the advantages and disadvantages of different methods of fertility regulation. (a) Sex of user Female Male Both
(b)
Effectiveness Overall: high, moderate, low Duration: temporary, permanent Reversibility Appropriateness to stage of life cycle: lactating women
nullipara, multipara,
(c)
Acceptability and motivation (i) Mode of action (ii) Pre-conceptive Post-conceptive
Mode of use Simplicity and ease of use Circumstance of use: coital, post-coital or non-coital Timing of use Frequency of use Duration of use Protection of privacy
( 11i )
Sexual Effects on libido and pleasure
·Chief ConSUltant and Head, Department of Obstetrics and Gynaecology, National Medical Center Hospital, Tokyo.
- 14 -
(iv) (v) (vi)
Suitability to local customs, modesty, resistance to superstition, concern with menses Suitability to cultural, religious, ethical and legal differences Route of administration Local or general Pain of discomfort at use Self-administration or non-self-administration
(vii)
Motivation Sustained Temporary
(d)
Health safety (i)· User Presence of contraindioations Side effeots: iamediate, local,general, late Positive effects on normal physiological functions Long-term safety Effects on future fertility (ii) Fetal -Effects in case of aooidental pregnancy Long-term effects on the future oonoeptus
(e)
Mode of distribution (i) (11)
(111) (iv) (v)
Skill and knowledge of providing Positive diffusibility through word of mouth Relianoe on supply lines Sources Medical personnel, clinics and instruments
(f)
Economics (i) (11) Shelf-life Cost
It should be borne in mind that it would sometimes be neoessary to change the value of some factor shown in this schema, when an assessment is carried out from different points of view, such as from the standpoint of users, health workers, physicians or administrators. Examples of the assessment from the perspective of the user of seven different fertility regulating methods c~rrently available were shown (see Appendix to this report).
- 15 -
2.2 2.2.1
Agenda item 3 - New developments in methods and research in fertility regulation and family planning Research trends in human reproduction with implications for fertility regulation: presented by Dr E. Diczfalusy'
One of the objectives of the WHO Special Programme of Research, Development and Research Training in Human Reproduction is to develop a variety of safe, acceptable and effective methods for the regulation of human fertility that can be easily provided in settings which differ socially, culturally and in terms of the services available. The first question is: Why do we need several methods? We need several methods because there are major differences in acceptability due to cultural, socio-economic and religious heterogenicity; because the needs of couples change during various phases of their reproductive life; because there ~re major differences in the services available; because of the possibility of unexpeoted appearanoe of adverse reaotions with long-term use of any method; because there are ethnic and geographic differences in the frequency of adverse reactions; and finally, because of the polymorphism of human populations. A reoent Ford Foundation study noted that what is needed is a broad array of fertility regulating methods which require a simple distribution system, which are safer and more convenient than those that are presently available and used, which have a high acceptability and high oontinuity of use, and which are suited to diverse requirements. The importance of research centred on the determination of the fertile period is obvious. It is well established that the fertilizable life of the human ovum is limited to a few hours, whereas the fertilizing life span of sperm deposited in the female organism is at least a few days and up to five days. therefore, prediction or detection of OVUlation by some simple means would be a major achievement. Efforts are under way to identify a few -.rkers from Which a simple assay kit could be developed using enzyme-assay metbods with a kind of dip-stick technique. The most promising appears to be estrone-3-glucuronide, which shows a significant rise some three-four days prior to the LH peak. Among the methods which are unrelated to the sex act are: intra-uterine devices (IUDs), oral contraceptives, long-acting steroidal contraceptives, sterilization and abortion. There are a number of problems associated with IUDs. There is an increased menstrual blood loss with the copper devices and the non-medicated devices but this is not the case with devioes releasing progesterone or progestational agents. Another problem is the frequency of inter-menstrual bleeding. There are reports on an increased frequency of an ectopic pregnancy, of pelvic inflammatory disease. There are complications in terms of pain and expulsion and their efficacy is lower than that of the combined oral contraceptives. Attempts are under way to develop so-called "post-placental" devices which could be inserted immediately after the delivery of the placenta. There appears to be a major need for devices of this type.
-Director, Reproductive Endocrinology Research Unit, Karolinska Sjukhuset, Sweden.
- 16 Some of the problems associated with the use of steroidal contraceptives include: the much publicized, but rarely occurring complications of thromboembolic disease; a tendency to develop increased blood pressure, both systolic and diastolic; changes in sugar, fat and vitamin metabolism; a few women experience cycle irregularities and in rare cases, there is interference with subsequent fertility; and, there is a problem of possible carcinogenicity. The most important studies in the WHO programme are related to finding optimal estrogen-progestogen ratios, finding progestogen only formulations with a bleeding pattern which is more acceptable than the presently available ones, and assessing the possible advantages of natural estrogens that are estradiol rather than synthetic ones like ethinyl-estradiol in contraceptive combinations. There are some studies on the acceptability of the "paper pill" which was developed by colleagues in the People's Republic of China. The metabolic effects of oral contraceptives are also under study. Lactation is a problem not only in terms of the effect of contraceptives upon the quality and quantity of milk but also the transfer of steroid with the mother's milk to the newborn and whether it has any possible side-effects. Malnutrition and its relation to oral contraception and endemic diseases such as liver fluke diseases, schistosomiasiS and their relationship to oral contraceptives are also under study 1a a number of centres. A number of governments have indicated to WHO that in those countries, it would be important to have long-acting injectable formulations. There are very few preparations available for the time being. Indeed, with the exception of Depo-Provera and norethisterone aenanthate, only the estrogen-progestogen combination monthly injectables are available. The programme tries to develop injectable preparations for one month, two months', three months' use before moving to preparations of longer duration. Long-acting formulations are also under study in the form of vaginal rings. The major problems with long-acting formulations can be summarized in that either one gives too much steroid which inhibits the pituitary ovarian system with amenorrhoea as a result, or that one does not completely inhibit the pituitary ovarian function in which case inter-menstrual bleeding is the major problem. Intra-cervical devices are still at an early stage of development and the prototype device is still under study. The idea here is to release very small quantities of spermicidal agents into the cervical mucus. The so-called post-coital contraception or intraception is an area in which most of the work has been conducted in the United States of America and in the People's Republic of China. As it is known, large doses of estrogen such as 5 milligrams ethinyl-estradiol for three days are given. The feeling is that very large doses of estrogen are really an emergency type of treatment which cannot be repeated frequently and which should be reserved to certain cases. An interesting development is in norethinyl which is anordrin, a steroid with ring A containing 5 carbon atoms. This has been extensively studied in the People's Republic of China as a so-called "vacation pill". Vasectomies are carried out on a large scale in a number of countries. The possible consequences could be classified as morphological, immunological, endocrinological and possibly behavioural. There are
- 17 relatively few studies on the sequelae of vasectomy. It is known that there is an increase in different types of circulating antibodies. The problem is to know what that increase really means. The steroidal contraception for men is still in its infancy. The problem is that in order to induce azoospermia or at least severe oligospermia the human male requires much larger steroidal dose than does the female in order to inhibit pituitary ovarian function. Therefore,.the steroid load to which the organ will be exPosed during a prolonged per~od of time is very considerable. The other problem is that it is difficult indeed to induce complete azoospermia. In the WHO programme, there is an assessment of the safety and short-term sequelae of the popular surgical techniques for female sterilization such as mini-incision laparotomy, laparoscopy, culdoscopy and colpotomy techniques. Among the long-term sequelae, menorrhagia has been singled out as a possible complication. Some psychological effects are under study and attempts are being made to improve the techniques for restoration of the tube for reversal of sterilization. In other programmes there are a number ot clips and plugs under study. The non-surgical method for female sterilization may also deserve coument. After the early report on the use of quinacrine, some other studies were also conducted mostly in subhuman primates with methylcyanoacrylate. There are a number of groups working also on hysteroscopic electro-coagulation of the tubes. Cilne problem in this field is a report of increased frequency of intramural pregnancies, which suggest that one should move cautiously in this field.
On the use of prostaglandins for fertility regulation, the Task Force on Prostaglandins for Fertility Regulation has conducted a number of studies on the termination of very early stages of pregnancy with apparent success. It seems that one can terminate pregnancy by vaginal suppositories of one of the long-acting prostaglandins analogUes such as 15-methyl prostaglandin F2a or the 16-16 dimethyl-prostaglandin E2. This Task Force now tries to do two new things: to find delivery systems from which prostaglandins could be released at a constant rate and to look into the role of prostaglandin inhibitors in counteracting the normal ovulatory mechanism. Indigenous plants are a recently revived interest which has developed satisfactorily. The Task Force has completed a computer search for ethno botanical and pharmacological information - on a large number of indigenous plants used by indigenous population in different parts of the world. There are already three plants which show definite promise. One is the Mexican plant montanoa tomentosa which is also called zoapatle. Zoapatle is an orally active uterotonic agent and as such would seem to offer certain advantages compared to prostaglandin since it has a very specific uterotonic effect with few side-effects. Some Paraguayan plants have also been identified and are now under study in the Research and Training Centre in Buenos Aires. They certainly interfere with the ovulatory process. In Hong Kong, leonorus artemesia or the Chinese mothewort has been studied and appears to be an orally active uterotonic agent.
- 18 -
ol is great The inter est in immunological methods of ferti lity contr . lastin g long a be would The pay-o ff would be consi derab le since there the nnel perso h healt effec t; it could be admin istere d by auxil iary at a'low cost synth etic antige n could be produced on a large scale and of the sperm . Some nes. The.m ost advanced leads are the place ntal hormo menti oned. ant~gens, and the zona pellu cida antig ens shoul d also be ved There are obsta cles to the development of a varie ty of impro us serio a sent repre metho ds. In addit ion to gaps in knowledge, which s. It is d:awback, one cruci al problem is the scarc ity of anima l model extra polat e iably d~fficult to find an anima l model from which one can invar assess ment of to condi tions in the human being . This means then that the term studi es in longsafet y creat es a major demand. Safet y must be shown in speci ally seriou s sever al anima l speci es which are time-c onsum ing. What is somewhat reluc tant is is that studi es on safet y are rathe r costl y. Indus try and the likeli hood to under write such activ ity becau se of the cost involv ed That is why publi c . that they may never be able to recov er their inves tment s. diture secto r agenc ies must take on addit ional expen 2.2.2 New develo pment s in comb inatio n oral contr acept ion: Dr J.W. Goldz ieher* prese nted by
h for new There are sever al impor tant reaso ns for contin uing the searc ed to in adher iple princ al gener modi ficati ons of oral contr acept ives. The table accep and tive effec is that pharmacology holds that the lowes t dose based are ives acept contr oral of s shoul d be used. Host curre nt formu lation in ences differ nal regio be may on tests among Western women, where as there both t affec to known is t body weigh t and hormone metab olism . Body weigh acept ives (in case symptom freque ncy and even effec tiven ess of hormonal contr ning speci al desig in tages advan of injec table s). There may there fore be also show ethni c formu lation s on a natio nal basis . Stero id metab olism may Sri Lanka and the pore, Singa ia, varia tions as evide nced by studi es in Niger Unite d State s of America. side- effec ts Anoth er reaso n for contin uing resea rch is the reduc tion of rates . There on nuati conti and ty which are assoc iated with lower accep tabili ts withi n the is a wide varia tion in subje ctive and objec tive side- effec effec ts and sideof sment Asses Unite d State s and in diffe rent count ries. in diffe rent es studi d e-blin doubl disco ntinu ation requi re local , rando mized , other s. It in cable appli not count ries, and data from one count ry are often months three first the g durin shoul d be noted that many side- effec ts occur ant const fairly a ain maint of use (naus ea, etc.) while other s (head ache) freque ncy with time. initi al The altere d menst rual patte rn that may be seen durin g the est inter of be may It use. ued cycle s usual ly stabi lizes with contin ize minim to doses h enoug high with s there fore to start with formu lation e, enanc maint for doses lower to go to later break throu gh bleed ing and then incide nce of where as starti ng with the lower dose would cause a highe r bleed ing proble ms. for -Dire ctor, Divis ion of Clini cal Scien ce, South west Found ation ca of Ameri Resea rch and Educa tion, San Anton io, Texas , Unite d State s
- 19 -
Some cultures may find non-monthly bleeding pattern acceptable, e.g. the "tricycle" pill appears to be acceptable to some women in Scotland - 84 days of oral contraceptives, six days off. Similarly, in some cultures total amenorrhoea from injectable may be acceptable. As before, the acceptability of altered menstrual patterns requires careful, individual acceptability studies at the local level. A final reason for continued research is the need to reduce health hazards the presence of which is suggested by epidemiological studies (e.g. cardiovascular disease, liver tumors, etc.). Some of the problems with epidemiological research are noted as follows: retrospective studies do not prove causality, but show associations that may later be attributed to other confounding factors; if not carefully standardized and controlled, they are open to many methodological biases; and they are applicable only to the population studied, requiring further replication before being applicable to other countries. For example, the incidence of thromboembolic diseas.e in Thailand is at least one tenth or less than the levels in the United States and the United nngdom. The initial rarity of many health hazards associated with oral contraceptives may be negligible when compared to their health benefits and when compared to the benefits of committing these same resources to avoiding other more frequent health hazards (e.g. is it worth the cost and effort to screen for hepatomas which appear to occur in the United Kingdom, an incidence of less than 1/500 000 subjects/year). Finally, the clinical significance of the reported metabolic side-effect requires asseSSMent; for example, changes in carbohydrate and/or lipid metabolism. Carbohydrate intolerance is not equal to the disease condition of diabetes, and lipid levels may vary with population. It is necessary to document the relationship of oral contraceptive hazard to local health factors such as parasitism and nutritional deficiency status. Results of studies in India, Sri Lanka and Thailand show changes in riboflavin levels; those women who were initially deficient showed no further deterioration, while those not deficient showed some biochemical evidence of deterioration. The clinical significance of this observation is not yet clear.
The approaches to oral contraceptive modifications include: alterations of type and dose of estrogen (natural versus synthetic estrogen, and ethinylestradiol versus mestranol since side-effects may relate to the rate and levels of uptake systematically); and progestational compound selection. Finally, it is necessary to keep in mind the interaction of oral contraceptives with other drugs, e.g.rifamipicin - in perspective of other drugs used for endemic disease chemoprophylaxis or therapy.
- 20 2.2.3 Long-acting systemic contraceptive agents: Dr G. Benagiano. presented by
During the last decade a great variety of long-acting fertility regulating agents have been investigated, which could be delivered systemically as well as at the level of the vagina, cervix, uterus and fallopian tubes. The duration of action of these agents ranges between one week and several years. For the systemic administration of long-acting compounds, the oral, intra-muscular and subcutaneous routes have been utilized. Injectable systems have become popular in several parts of the world because they do not rely upon women's compliance with the administration schedule; they are simple to administer by auxiliary health personnel and their absorption is not dependent upon normal gastrointestinal functioning. Two major types of injectable preparations have been utilized clinically. The first one is intended to provide protection during one month and contains both a long-acting estrogen and progestin. The second type of medication contains a long-acting progestogen alone and has been used to provide contraceptive protection of either three or six months. (a) Monthly injectables
Since 1963 several estrogen-progestogen combinations have been tested clinically. The first attempts to obtain long-acting preparations were made by administering esters of synthetic progestogens alone; although these compounds can easily inhibit ovulation for long periods of time they almost inevitably produce severe cycle disturbance. The addition of a long-acting estrogen allows a much better cycle control. (i) Deladroxate
The preparation tested more extensively to date is the combination of 150 mg of dihydroxy-progesterone aceptophenide and 10 mg of estradiol oenanthate, which is known as "Deladroxate". It offers complete protection against unwanted pregnancies: of the more than 15 000 women-months of experience published to date, not a single pregnancy has ever been reported. Cycle control seems reasonable. Reported dropout rates for bleeding irregularities range between 7.5 and 24.4 per cent. Other adverse reactions are of minor importance with this preparation. Return of fertility seems assured within a two- to three-year period. Evaluation of hepatocellular integrity, metabolic status and hepatic excretory function in subjects treated with this monthly injectable has failed to reveal any increase to abnormal values in any of the tests performed. In conclusion the injectable preparation containing dihydroxy-progesterone acetophenide and estradiol oenanthate has proved to be an adequate monthly contraceptive in terms of efficacy and clinical .Scientist, Special Programme of Research, Development and Research Training in Human Reproduction, WHO, Geneva.
- 21 -
side-effects. Nevertheless, before extensive use of this preparation can be advocated, the question of its long-term safety must be resolved. It seems that in the beagle bitch it causes breast nodules and cancer and pituitary hyperplasia in rats. (ii) Cycloprovera
Another monthly preparation which deserves attention is the combination of depot-medroxyprogesterone acetate (25 mg) and estradiol cypronate (5 mg) commercially known as cycloprovera. The WHO Task Force on long-acting systemic agents has just favourably completed phase I studies with this preparation. Phase II trials will be initiated during 1978 to evaluate its effectiveness. (b) Three-monthly injectables
The observation that it is relatively simple to inhibit ovulation with high doses of long-acting progestins given alone, has led to a series of investigations aimed at selecting compounds which could be used clinically without provoking too serious menstrual disorders. Three progestational steroids with a possible duration of action of three months have been tested clinically: chlormadinone acetate (250 mg), depot-medroxyprogesterone acetate (150 mg) and norethisterone oenanthate (200 mg). (i) Chlormadinone acetate
Experience with chlormadinone acetate covers over 30 000 women-months. Drug failure is low (a Pearl Index of 0.5 with 150 mg and of 0.1 with 250 mg). Unfortunately, use of chlormadinone acetate had to be discontinued as a precaution following the report of breast nodules in beagle bitches treated chronically with the steroid. (ii) Depot-medroxyprogesterone acetate
Medroxyprogesterone acetate in its depot-microcrystalline form, known commercially as Depo-Provera (DMPA) , has been used since 1960 for the treatment of a variety of pathological conditions. The optimum contraceptive regimen is yielded by injecting 150 mg of DMPA intra-muscularly every three months. Reported pregnancy rates range between o and 1.2, with a majority of studies indicating a rate below 0.5 per hundred women-years. . One of the most disturbing features of this medication is the high frequency of severe cycle abnormalities, which can be attributed to the marked influence of the steroid on the endometrium. During the first months of medication an irregular and unpredictable bleeding pattern is observed, in as much as one-third of all subjects. Following prolonged treatment, however, there is an increasing frequency of amenorrhoea. By the end of the second year of treatment its incidence may climb up to 60-70%.
- 22 Amenorrhoea is probably the principal cause of a delay in the return of fertility observed with this drug. By the end of the second year following discontinuation, however, the great majority of subjects who wished to become pregnant will conceive. There is evidence that DMPA given to nursing mothers may promote milk production and the duration of lactation. In this event, though, the possibility of a hazard to the infant caused by the steroid transferred ~ the milk has not been ruled out. In the early seventies, studies conducted in the United States showed that beagle bitches treated chronically with high doses of DMPA developed breast tumours. The relevance of these findings for the human situation is questionable because the human organism seems to handle 17-acetoxy progestogens in a different way. The issue of a possible association between frequency of an increased cervical carcinoma and use of DMPA remains unresolved, especially in view of the observation that there is apparently less tendency of carcinoma in situ to develop among women who have extended exposure to Depo-Proveri.---(iii) Norethisterone oenanthate
The only other long-acting injectable compound available today is norethisterone oenanthate (NET-DEN). This ester was originally given at a dose of 200 mg every three months. From the early studies, however, it became apparent that the contraceptive effectiveness of NET-OEN declines rapidly during the last days of the third month following an injection. In view of this most investigators have given NET-OEN every 12 weeks (84 days) instead of three months (90 days). Even this regimen though does not provide full contraceptive protection. In recent WHO-sponsored multicentre comparative study of DMPA and NET-OEN a pregnancy rate of 3.6 per 100 women-years was observed for the latter compound. For this reason the Organization is testing at present a new regimen where the drug is administered every 60 days during the first six-month period and every 84 days thereafter. Preliminary results are very encouraging. With NET-OEN ovulation may resume as rapidly as two months following injection, which explains the relatively high number of pregnancies during the third month following an injection. Cycle disturbances are observed with norethisterone oenanthate as well. However, the incidence of amenorrhoea is greatly lower with this drug ~-!-vis DMPA. With the exclusion of mentrual abnormalities no other major side-effects have been observed with this preparation. (c) Sustained release preparations
The serious cycle irregularities observed with long-acting injectable preparations have been, at least in part, attributed to the very high plasma concentration of the active steroid immediately after injection; these levels usually falloff markedly during the treatment period.
- 23 For this reason some 10 years ago it was suggested administering fertility regulating agents through delivery systems capable of achieving a sustained zero-order release of the active compound. (i) Non-biodegradable systems
The first delivery system developed for fertility-regulating purposes consisted of a polydimethylsiloxane (PDS) capsule filled with a variety of synthetic progestational steroids. This system was extensively investigated under the auspices of the Population Council, New York, USA. Permeation of steroids through PDS membranes follow Fick's law of diffusion; it is inversely proportional to the polarity of the steroid and the thickness of the membrane. PDS has also been utilized as a solid del! very system; in this case steroid particles are finely dispersed in the polymer matrix. With systems of this nature constant zero order in vitro release can be achieved from the beginning of the experiment. -The human pharmacokinetic profile of steroids released from PDS implants shows that - similarly to the in vitro s1tuation - in vivo release is not constant during the first one or-rwo months after insert~ After this initial period, however, diffusion becomes constant throughout the entire life-span of the system. (ii) Biodegradable systems
More recently biodegradable delivery systems have been obtained for the sustained administration of fertility regulating agents. Two such systems have already been the subject of extensive experiments in animals and are quickly reaching the stage of human experimentation. These systems constitute one of the main features of the work sponsored by the WHO Task Force on long-acting systemic agents for the regulation of fertility. The first consists of a polymeric biodegradable rod containing homogeneously dispersed contraceptive steroids. The polymeric matrix and steroid diffusion occurs only at the erosion surface. The polymer is eroded through hydrolytic cleavage which can be controlled to achieve the desired duration of action. The second system consists of biodegradable polymeric micropellets made of polylactic-polyglycolic acid co-polymers, containing homogeneously dispersed contraceptive steroids. Diffusion of the steroid occurs in this case through both permeation across the pellet solid phase and by surface erosion of the polymer. Both these systems have been tested in several animal models, and their'ability to release steroids at constant zero-order rates has been extablished. (iii) Programmed release systems
Clinical data obtained from PDS implants indicate that cycle control is definitely better than that.achieved with classical injectable preparations. However, available information points to the fact that more
- 24 -
sophisticated delivery systems are needed to mimic hormonal plasma levels obtained during the cycle. For this reason the WHO Special Programme of Research, ,Development and Research Training in Human Reproduction is considering at present the development of programmed-release systems where the drug will be diffused only during given times of the female cycle. This could be achieved for instance by triggering the release through the appearance in the circulation of an enzyme. If such systems could be developed a major advance towards more acceptable long-acting fertility regulating systems could be attained. 2.2.4 (a) Non-medicated and medicated intra-uterine contraceptive devices: presented by Dr Takashi Wagatsuma. History
A brief history of the invention and development of intra-uterine devices (IUDs) was reviewed. (b) Advantages of the IUD (i) Motivation
One of the most important aspects of IUDs is the fact that it is the sole fully reversible method of fertility control which requires only the decision to have the device inserted, rather than the sustained motivation of one or both sexual partners. (ii) Coital independence
The IUD is free from the aesthetic disadvantage of some other methods of contraception. Non-cooperation of the male partner does not interfere with contraceptive effectiveness. (iii) Effects on general health
Unlike the steroidal contraceptives, there has been no report of any possiblity of the IUD exerting hazardous effects on blood coagulability, blood pressure, glucose metabolism, or endometrial malignancy. The method is especially recommendable for women who have any contra-indications for the use of steroidal contraceptives. (iv) Contraceptive effectiveness
The pregnancy protection provided by IUDs is surpassed only by the disciplined use of combined type oral contraceptives. For long-term protection from a single procedure, only surgical sterilization can claim superiority over the IUD .
• Chief Consultant and Head, Department of Obstetrics and Gynaecology, National Medical Center Hospital, Tokyo, Japan.
- 25 -
(v)
Cost and distribution problems
The recurring cost of oral contraceptives remains a factor inhibiting the use of this method in the many areas of the world with rapidly expanding populations. On the other hand, IUDs are inexpensive and do not require any recurrent supply. (c) Disadvantages of the IUD (i) Expulsion
A troublesome problem associated with the use of IUDs is their spontaneous expulsion from the uterus. The majority of expulsions take place within three months after insertion. Sometimes the woman is unaware that an expulsion has taken place. Such unnoticed expulsions are usually followed by conception. (ii) Bleeding
Inter~menstrual bleeding, usually in the form of spotting or a serosnaguinous discharge, may occur during the weeks after insertion. Such small amount of bleeding should not lead to the removal of the device unless it continues for more than two or three months, but such bleeding often upsets a patient and constitutes medical reason for removal. Qccasionally, the menstrual abnormality may last indefinitely, but seldom becomes frankly haemorrhagic. Anemia due to the excessive menstrual blood loss among IUD wearers may create serious health problems in certain countries.
(iii)
Pain
Pain, usually in the form of uterine cramps, and occasionally as a low backache, may occur after insertion, although the only complaint may be of some discomfort. (i v) Infection
There is evidence that the insertion of the device can entail some degree of uterine contamination. Nevertheless, when an appropriate sterile technique is followed, and strictly sterilized devices are used, septic complications related to the insertion procedure are exceedingly rare. Recently, some reports suggested that the incidence of pelvic inflammatory disease (PID) and that of ectopic pregnancy among IUD users are higher than those of control. (v) Perforation
The incidence of perforation varies considerably with the skill and experience of the inserting physicians. Observance of technical precautions will contribute to safe and correct placement of the device in the uterine cavity.
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(d)
Contra-indications to insertion
The generally recognized contra-indications to the use of IUDs include the following: (i) (ii) (iii) (iv) (v) (vi) (vii) (viii) (ix) (x) (xi) (xii) (xiii) (e) Known or suspected pregnancy Acute or sub-acute PID A history of recurring pelvic inflammatory disease A history of septic abortion within a three-month interval Post-partum endometritis within three months Spacial and/or configurational abnormality of the endometrial cavity incompatible with the structure and shape of the IUD Stenosis of the cervical canal A history of an ectopic pregnancy Genital bleeding of unexplained etiology A history of incapacitating dysmenorrhea or menorrhagia Known or suspected cervical or uterine malignancy Acute cervicitis Repeated expulsion of IUD
Non-medicated IUDs (i) Material
Most devices now in use are made of plastic, moulded in many different forms and shapes. The materials used are co-polymers such as polyethylene, polypropylene or ethylene vinyl acetate, which contain barium sulphate to render them opaque to X-rays. The shape and stiffness of a device have a close relationship to its expulsion rate, that is, when a device is made with soft material, it tends to have a higher expUlsion rate. (ii) The marker tail
In 1959, J. Lippes first invented a loop-shaped device with a monofilament of plastic as a tail. The marker tail made confirmation of the presence of the device and easy removal possible, without causing ascending endometritis or salpingitis. In some cases, husbands complain of discomfort due to the presence of the marker.
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(iii)
The size and shape of IUD in relation to its anti-fertility effect and complications
In his Cooperative Statistical Programme, C. Tietze found that the smaller sizes of all types of IUDs tend to have higher pregnancy and expulsion rates than the larger sizes. The same programme disclosed a relationship between the pregnancy rates and the total surface area of non-medicated devices in contact with the endometrium. The larger the IUD size, the higher the anti-fertility effect it exerts. On the other hand, there is a direct association between removals for medical reasons (mostly bleeding and pain) and the size of the IUD. The larger the size of the IUD, the higher the rate of the devicets untoward effects. (f) Medicated IUDs
The logic of using an IOU as a vehicle or carrier for an active anti-fertility agent was conceived independently in 1968 by Zipper et al., who used metallic copper, and Doyle and Clewe, who used a synthetic-- -progestin. (i) Copper loaded IUDs
At present there are two copper-bearing IUDs which have had extensive clinical evaluation and which are available commercially in most countries of the world. These are the Copper T (T Cu.200) and the Copper 7 (Gravigard). Recently, several different types of Copper-loaded IUDs, such as ML-250 Cu-Ypsilon, have been clinically tested in some countries. (ii) Progesterone IUD
Scommegna et al. in 1974 published the first clinical report on the use of the T shape-aS-a platform for the intra-uterine administration of progesterone for contraception. While the clinical effects were encouraging, the relatively rapid release of the progesterone by the Silastic capsule make impractical this specific mode of delivery of the steroid. Working independently, Pharris ~ al. were given a license by the Population Council to utilize the T shape as a vehicle for their slow-release system for the delivery of progesterone to the intra-uterine cavity. This IUD, Progestasert, releases 65 Ug of progesterone per 24 hours. (iii) Advantages of medicated IODs Higher contraceptive effectiveness Clinical trials with copper IUDs and Progestasert have shown that these medicated IUDs have higher contraceptive efficacy than that of non-medicated IUDs. Lower incidence of side-effects These medicated IUDs have lower incidence of removal for medical reasons especially due to bleeding and pain because of its smaller size and well-fitted shape. Progestasert is the only IUD which decreases the menstrual blood loss due to its suppressing effect on the endometrium.
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Higher acceptability (iv) Disadvantages of medicated IUDs Limited duration of use Cu-7 and Copper T have to be changed two-three years after the insertion while the Progestasert must be replaced after one year. Clinical trials of several new medicated IUDs with longer effective-life have been conducted. Expensive cost Medicated IUDs are more expensive than non-medicated IUDs. Unknown effects of long-term use and possible teratogenicity in case of pregnancy in situ. (g) Present and future research in the field of regulation of implementation
Various research projects under the Task Force on Methods for the Regulation of Implantation: Intra-uterine medication section will be explained and discussed. 2.2.5 Sterilization technology: presented by Dr Ruben A. Apelo-
Around 75 million men and women allover the world have undergone sterilization, and there are strong indications that the acceptance will continue to .ultiply. The popularity of sterilization is undoubtedly due to the simplicity and safety of the process, the fact that it is a one-time procedure, the awareness that it takes only 15 minutes to perform a tubectomy and even less time to do a vasectomy, and the consolation that neither operation entails hospitalization. In this paper, sterilization is discussed in the light of the following: that it is a method (1) which is simple; (2) which does not change the anatomy and physiology of the human reproductive system; and (3) which is generally performed for family planning and population control purposes. The different methods of sterilization are taken up: laparoscopy demands supplementary apparatuses to get the intestines out of the way and even greater demands on the part of the surgeon. Even in the hands of the
-Director, Reproductive Biology Center, Department of Obstetrics and Gynaecology. College of Medicine, University of the Philippines, Manila.
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rigidly trained obstetrics-gynaecology specialists, complications can never be ruled out. On the other hand, culdoscopy has not become very popular because of the uncomfortable position that the patient has to assume during surgery and the physician's preference for the abdominal route. There is doubt whether minilap will be acceptable in the more affluent sectors of society. Colpotomy can be considered safe, simple and economical for certain women although it requires the services of a highly trained obstetrician-gynaecologist. (a) Sterilization techniques
The Pomeroy technique has stood the test of time but with the coming of the laparoscope, the electrocoagulation technique was born. However, extra-tubal burns occurred, so the use of clips was resorted to. Unfortunately, clips present higher technical failure and difficulty, not to speak of their bringing about a high pregnancy rate. Hysteroscopy enables the reaching of the fallopian tubes through the cervix. Through this process, plugs may be applied to the tubes. Chemicals like silver nitrate, Quinacrine, formaldehyde, and methylcyanoacrylate can also be used for tubal occlusion. Other methods under study are the use of plugs ooated with chemicals and the insertion into the uterine cavity of an inflatable balloon through which the freezing medium circulates. (b) Irreversibility of the procedure
The methods of sterilization are varied and many but up to this time, this surgical method of contraception is still irreversible in spite of allegations from some quarters to the"contrary. This fact should be stressed to everyone interested in undergoing the process. (c) Sterilization for men
All studies on male sterilization boil down to two aspects - an attempt to make vasectomy reversible and the effort to bring about immediate sterility in the men. Plugs, devices, chemicals and clips or a combination of these, which are used for closing the fallopian tubes are also used for occluding the vas. Identical problems arise, foremost of which is the problem of keeping the things in place. Bio-materials in the form of plastic, metals, ceramics, dacron and teflon are used as plugs. Other methods possible are the use of intravasal devices, of vas valves, of clips and the transplantation of the vas into the bladder.
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II "'11
(d)
Vasovasostomy
Surgeons use different operative techniques. But so far, thf' av" percentage of successful restoration in terms of reappearance of sper~ ;, the semen is 64% and only 33% on the basis of impregnations. (e) How to achieve immediate sterility 'I;
II
This is still a problem where vasectomy is concerned. The flushi'i!' spermicidal solutions toward the seminal vesicular direction dud ng Lh., operation might be helpful for the purpose. Other studies on the matter, like the use of chemicals, androgen,3, ultrasonic rays to weaken or reduce sperm count are presently going on. (f) Conclusion
Time, effort and resources are being spent to bring about re-canalization. There are and there will be instances where men and W0mp.n will ask that they be rendered capable of reproduction once again. On the other hand, we have zealous crusaders who are bent on doing their bit to curb population growth. A word of advice to them is: let not the burning desire for more acceptors prod them to give would-be patients false hopes of guaranteed reversibility. 2.2.6 Methods of fertility control in the male: Dr K. Fotherby* presented by
Three methods are in use: the condom, coitus interruptus and vasectomy. A fourth approach involving the pharmacological control of fertility is currently being investigated. (a) The condom
m~l~
Provides an effective, simple, inexpensive, non-clinical method or family planning which is free of side-effects. It is a popular meth0d ," family planning in many countries. With present day manufacturing :ot'1:"j",;,' the theoretical effectiveness of the condom is high (a failure rate )r probably less than 2 per 100 years of exposure). However, use-effect.l'!' iI" is variable and Tietze quotes failure rates ranging from 3 to 36 per 10D years of exposure. Service implications: manufacture, import and distribution.
*Reader in Biochemistry, Royal Postgraduate Medical School, Uni V e.,," -' i , ' of London, Hammersmith Hospital, London.
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(b)
Coitus interruptus
A simple, inexpensive, effective, non-clinical method of family planning which is free of any undesirable side-effects. It is widely used in many countries and its failure rate appears to be no higher than that of many barrier methods of contraception. Service implications: (c) Vasectomy adequate explanation of the technique.
A highly effective permanent method with a failure rate of less than one hundred procedures. It requires the services of clinically trained personnel and is associated with a low incidence of side-effects. Most failures are due either to re-canna1ization of the vas or sexual intercourse before the reproductive tract is clear of sperm. Disadvantages are (a) that it is not immediately effective, a period of about three months should be allowed for sperm to disappear from the ejaculate; (b) occurrence of side-effects. Short-term ones are usually minor in nature (slight pain, possibly post-operative bleeding, bruising). Under proper conditions, infection should be rare. Well-designed studies are needed to assess the long term effects. Antibodies to sperm are found in up to 50% of vasectomized men and the antibody titre appears to increase with time. Service implications: proper counselling of men for vasectormy thus avoiding inclusion of men with conditions which might preclude outpatient operation, availability of facilities and personnel, follow-up procedures. Whereas vasectomy is a simple operation, reversal is much more complicated and demanding in terms of time and skill. Vasectomy should therefore be regarded at present as an irreversible operation. It is not clear yet whether in those cases where reversal is anatomically successful this is also successful in terms of function. (d) Pharmacological control
Introduction of a pharmacological method for controlling fertility in the female, the oral contraceptive pill, quickly gained widespread acceptance. The lack of pharmacological method for the male stems partially from the meagre state of our knowledge of male reproductive physiology. The approach to the pharmacological control of fertility in men has been an empirical one. Four types of compounds have been tested. (i) Estrogens
These are potent inhibitors of gonadotropin release, both FSH and LH being affected. Thus they will inhibit spermatogenesis and reduce testosterone secretion. The use of estrogens alone to produce an azoospermia was accompanied by undesirable side-effects such as reduction in libido and the development of gynaecomastia. Whether these disadvantages can be overcome by the concommitant administration of an androgen remains to be determined.
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(ii)
Androgens
The ability of androgens to suppress spermatogenesis has been known for almost 30 years. Injection of testosterone esters will suppress spermatogenesis without altering libido. So far high doses have been necessary and it is conceivable that undesirable side-effects would occur in a long-term treatment. An exception may be the use of the compound Danazol; when used in combination with an androgen, a severe oligospermia or ozoospermia can be produced within eight weeks without any decrease in libido or sexual potentia. Studies with this combination have now been extended to include more than 100 men with satisfactory results. (iii) Gestagens
The use of gestagens is more attractive since the metabolic effects are likely to be less widespread than those of either estrogens or androgens. A large number of synthetic geatac_ns have been tested. The administration of the gestagens either orall,.~ intra-muscularly in a sufficient dose will inhibit gonadotropin secretion and lead not only to a suppression of spermatogenesis but also to a suppression of androgen production. To overcome this a suitable androgen must be administered with the gestagen. (iv) Anti-androgens
Trials have also been carried out with the steroid cyproterone acetate which has strong anti-androgenic activity. Administration of small doses daily (5 to 20 mg orally) will cause a decrease in the sperm count, oligospermic levels being after about 10 weeks of treatment. The studies which have been carried out so far are short-term ones involving only small numbers of men. Extrapolation of the findings to a wider use of the preparations must be made with caution. So far the efficacy of the compound has been determined on the basis of semen analysis and it is not known whether this is a reliable means of assessing efficacy unless an azoospermia or severe oligospermia is produced. The investigation of non-steroidal compounds for controlling fertility in men has not been rewarding. Although a number of non-steroidal compounds, of which a-chlorohydrin and its analogues appeared the most promising, will suppress spermatogenesis in many animal species, they have undesirable side-effects which preclude their use in man. 2.2.7 Immunological approaches: presented by Dr E. Diczfalusy·
Immunological fertility control has a great appeal because if achieved with active immunization, one could get long-lasting effect. It could be administered by auxiliary health personnel and the immunogenes, if a synthetic compound, could be manufactured on a large scale at a low cost .
• Director, Reproductive Endocrinology Research Unit, Karolinska, Sjukhuset, Sweden.
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First, active or passive immunization. When the Special Programme in Human Reproduction started, there were a number of consultations of leading immunologists and the conclusion at that time was that passive immunization was not a feasible proposition for a variety of reasons, mainly because of the questions where to find women who would be willing to be immunized and how to provide enough serum. Passive immunization would not be a feasible proposition for a large-scale fertility control. Speaking of active immunization, the problem that enters immediately is the kind of immunogene. Presently, peptide chemistry is advanced enough to produce compounds with a molecular weight of 3000 to perhaps 7000 but it is not yet possible to produce protein synthetically. Therefore any approach based on an active immunization process with a specific immunogene has to be based necessarily on a low molecular weight polypeptide, which raises the problem of weak immunogenecity of such small-sized molecules. Such molecules would have to be coupled to a large protein carrier or an adjuvant. It is obvious that one has entered a high-risk field with some major problems. Among the problems mentioned is the possibility of adverse reactions. The major problems are that once people are immunized there will be a major variation in duration of the effect, and reversibility. What antibody titre has one to achieve in order to control fertility and what is going to happen in the presence of declining antibody titre? Do you possibly induce malformations and how can you assess that risk? There remains the rather remote but still possible chance that one might in a few generations' time select out a group of non-reactors. One has to consider the potential adverse reaction of anti-fertility vaccines and of course the auto-immune reactions represent a major danger. This danger will occur when one shared antigenic determinants. It will be difficult to show or to disprove that there is cross reaction because of the so-called immunological escalation which then brings in also the unpleasant problem of cell medicated immune reaction. Immune complex disease which one finds in a very high concentration of antigen/antibody circulation may happen if at a re-immunization the organism is charged with a new and large amount of antigen. Anaphylactic reaction has to be conSidered, as well as endocrinological/metabolic disturbances and possibly embryonic damage. What the Organization did was to try to develop in collaboration with a number of national drug regulatory agencies guidelines for testing such vaccines and hopefully, new guidelines together with a detailed assessment of the potential complications will be published. If it is assumed then that the present approach should be active immunization to induce antibodies in the organism against specific antigens, then the present approaches can be described under placental hormones and other placental antigens, sperm antigen, zona pellucida antigen and experiments of nature. Among sperm antigenS, five have been identified with a suffiCiently high specificity. These are LD-X or lactic dehydrogenase-x which have certain very favourable characteristics since they are sperm specific but not species specific. It is present in several animals, at least to have been seen and thus there is a good animal model on which to assess the efficacy. It can be disassociated into four sub-units but these sub-units are too big to be synthesized chemically. It has a certain anti-fertility effect and mice and rabbits were successfully immunized with highly purified LD-X. For the time being experiments with baboons are in progress in the Organization to
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explore the feasibility of this approach. This is considered as a back-up method in case development does not proceed with placenta antigen. The sperm immobilizing antibodies represent another class of antigens which induce antibodies which then immobilize sperms. It seems that there is a great similarity in the different antigens. These are really sperm specific again and represent a third line of attack. The T-antigens, the sperm specific acrosin, that is the proteolytic enzyme, and the sperm specific hyluvandase have been tested and work on them has been discontinued. They are considered either non-effective and non-feasible for the time being. The zona pellucida antigen represents another class of antigen where there is organ specificity but not species specificity. It is present in marmoset, baboons, and pigs. Antisera produced from antigens from these species cross react with the human zona pellucida. In a number of cases, the zona antibody has been found in the plasma of women living in a barren marriage, but whether this is associated with infertility is difficult to say. There is a report for instance that in a !eries of nine women with such antibodies, there are two pregnancies. Obviously more information is still ne~ded. Dr Lederberg who proposed the term experiments of nature and suggested that if one analysed carefully serum from sterile women one might discover antibodies which react with certain specific antigens. Previously antibodies to LDH-X and zona pellucida were unknown in human sera. For the time being there are some reference sera maintained in a serum bank in Denmark. More than 20 laboratories are collaborating with the group in Denmark where they are trying to assess antisera and establish their profile against well-characterized antigens. The placenta is perhaps the most suitable organ which contains a fairly large number of specific proteins. Among these are hormonal proteins, like human chorionic gonadotropin, and the human placental lactogen. There are a few specific enzymes which occur only in. the placenta and there are a number of secreted or structural protein. Among hormones, the human placental lactogen rises very slowly during pregnancy and reaches its highest level towards the end of the pregnancy. Although immunization using this protein can be used in terminating pregnancy in baboons, it does so as a late abortion. It therefore does not seem to be a suitable method which one could, with a good conscience, recommend for development because what will be achieved will be a late abortion but not an interference with the early phases of pregnancy. Most pituitary hormones such as luteinizing hormones, or LH, follicle stimulating hormones, or FSH, or thyroid stimulating hormones, or TSH, can be disassoc~ated into two sub-units - alpha sub-unit which is for all practical purposes common, and the sub-unit which carries a specificity of the hormone. The same applies to human chorionic gonadotropin which can also be disassociated into two sub-units, alpha and beta sub-units; whereas the alpha sub-unit is again closely related to the alpha unit to luteinizing hormones. The beta sub-unit shows certain differences. So in most immunological systems chorionic gonadotropin and luteinizing hormone will cross react. However, there will be much less or no cross reaction if one takes only the beta sub-unit. The problems are again many. When we speak
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of luteinizing hormone, we should not forget that we are talking about large varieties of different molecules where the carbohydrate, molecular weight and the biologic activity in relation to immunological activity may be different. We enter into an entirely new phase when Dr Stevens in Ohio showed that one can use beta sub-unit of human gonadotropin for immunization. Its immunogenecity can be enhanced by so-called haptene coupling. The advantage of this work is that the sequence analysis disclosed that both luteinizing hormones and human chorionic gonadotropin hormones have the beta sub-unit and in this beta sub-unit there is a portion of chorionic gonadotropin of 35 amino acids. Such a peptide can be synthesized. So, during the early 1970's, ~ch effort had been centered on the synthesis of these peptides. Some of the problems have to be considered. First is that these peptides have a weak antigenecity. They have to be coupled to large carrier molecules called the conjugation process. In addition, one has to use an adjuvant in order to enhance the immuno reaction. In the past, the adjuvant mostly used in the immunological studies was the Freund's adjuvant which is related to tubercle bacilli, and which obviously could not be used in clinical studies. There came a breakthrough when Dr Talwar and his group in New Delhi showed that one could use a conjugation procedure by which one conjugates the peptide to toxoid, a large carrier protein which could be either tetanus toxoid or diphtheria toxoid used under normal circumstances for immunization. Also, a group at the Institut Pasteur in Paris obtained synthetic adjuvants which are components of microbacteria and can be used safely in humans. These two breakthroughs seem to open the way to vaccine development provided there is absolute specificity. Dr eben and his colleagues at the National Institute of Health found a ohorionio-gonadotropin-like material in the pituitary tissue and in urinary extracts obtained from non-pregnant women. It is present admittedly in very small quantities but it is there. Antisera which have been raised against the synthetic fragments, the 35 and 32 amino acid fragments, do cross react with this material. Antiserum prepared against this synthetic material did indeed react with the international reference preparations for both urinary and pituitary gonadotropins. The question is: Will there be any problem? So. our group in Stockholm has been asked to reconfirm the findings of Dr Chen and Dr Ross. Our conclusion is that there is some material in pituitary tissue and urine which in non-pregnant women will behave like chorionic gonadotropin. The questions may be asked: Is it an aggregated form? Is it a metabolized form during the metabolism? Well, it could be, since it has been shown that luteinizing hormone prepared from baboons, from humans and from other species will cross react with antisera if they are digested by some enzymes. So that what one has to find out is whether this cross reaction, which can only be demonstrated when the material is concentrated, is present really in minor quantities. Will this cause any problem when people will be immunized with it? Dr Talwar and his the tetanus toxoid was group suggest that the and that they may have
group in New Delhi have developed a method in which coupled to the beta sub-units. Dr Talwar and his vaccine is relatively safe, immunologically speaking, a major promise.
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To sum up the situation, by far the best chance today to develop an immunological method is active immunization, and by far the best chance is a synthetic peptide of the beta sub-unit of chorionic gonadotropin. Since this is a new field where a number of unexpected complications may occur, one has to proceed very carefully and slowly and has to conduct an unusually large number of safety studies. It is hoped that if these safety studies are going satisfactorily, then perhaps by the end of the next year or so the first clinical studies can be commenced in the WHO programme. Now, if that approach should fail for any reason, the other approaches which we have will then take a much longer time to develop because we do not have the necessary methods of protein chemistry. With the synthetic peptide prepared from beta sub-units, we might have a vaccine within the next 10 years or so. Otherwise, my personal estimate would be more pessimistic and I would say that maybe we need 15-20 years. 2.2.8 Determination of the fertile period: presented by Dr G. Benagiano·
Methods based on periodiC abstinence a~ indicated for persons who wish to take advantage of knowledge of the fertile and infertile phases of their aenstrual oycle to regulate their fertility, or for couples who do not wish to use drugs or devices either because they are concerned about their side-effects or for ethical or religious reasons. There is still controversy on the usefulness and effectiveness of methods based on the determination of the fertile period even by well-motivated couples who received appropriate teaching and training. Thus, family planning administrators have hesitated to include them in national programmes despite their apparent advantages in terms of cost and simplicity of delivery. The appeal of such methods would increase if techniques were developed to pera1t women to determine objectively and preCisely the fertile and inf~tile phases of the menstrual cycle. The development of such techniques should: (1) (2) enhance the effectiveness and perhaps simplify the use of methods based solely on periodic abstinence; allow couples who use certain methods of fertility regulation such as the condom, diaphragm and coitus interuptus to limit these to the days of the fertile period; allow the use of other new methods which are being developed, e.g. post-coital agents, to be restricted to the ovulatory period; improve the timing of intercourse for conception when pregnancy is desired.
(3)
(4)
There are at present four methods of fertility regulation based on the identification of the fertile period: (a) the calendar method (also called rhythm);
.Scientist, Special Programme of Research, Development aznd Research Training in Human Reproduction, WHO, Geneva.
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(b) (c) (d)
the temperature method (usually abbreviated as the BBT method); the cervical-mucus method (also called the ovulation or the Billings method); the sympto-thermal method.
Promoters have advocated modifications for each of these methods, to improve either effectiveness or users compliance. (a) The calendar period
This method is considered today obsolete by most workers in this field because it does not take into consideration normal biological variation and hence does not offer a satisfactory level of protection against unplanned pregnancies. Also the method, if applied strictly, allows intercourse on very few days each month. In brief, early days when sex relations can be considered safe are calculated by subtracting 21 to the number of days of the shortest menstrual cycle in the last six months (e.g. if.the shortest oyole was 26 days, intercourse will be allowed on 1 to 5). Post-ovulatory safe days are identified by subtracting to the number of days of the longest menstrual cycle in the last six months (e.g. if the longest cycle was 32 days intercourse can be resumed on day of the cycle. (b) The temperature (BBT) method
The temperature method alone is relatively effective if intercourse is confined to the post-ovulatory phase of the menstrual cycle. However, the degree of abstinence required, especially during long or anovulatory cycles, detracts from its use and acceptability. The use of the temperature method to prevent pregnancy is based on the fact that there has never been a conception reported to have occurred from intercourse taking place from the third day of the hyperthermic phase of the cycle until the following menstruation. Experts throughout the world confirmed this experience at a WHO scientific meeting in 1966. Unfortunately, not all BBT curves show an easily recognizable rise. the 1966 Expert Meeting the following definition was adopted: "The change from the hypothermic to the hyperthermic phase is spoken of as the 'shift'. A significant shift is one that occurs in 48 hours or less, and in which three consecutive daily temperatures are at least 0.2 degree centigrade higher than the last six daily temperatures prior to the shift." It is useful to distinguish between two forms of the temperature method. The "strict form" of the method uses only the infertile time from the third day of the hyperthermic phase until the following menstruation. Although this method is very reliable it is often not accepted because it allows only some 10 days for sexual intercourse. The so-called "combined temperature method" recognizes a further infertile post-menstrual phase right at the beginning of a cycle. This second infertile phase is less reliable. At
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(c)
The cervical-mucus (or ovulation) method
This technique is based on the assumption that well-trained women are capable of subjectively "feeling" changes during the mentrual cycle in the quantity and quality of their cervical secretions, as distinct from other pseudo-secretions, such as vaginal discharge due to infection. This method has received wide publicity and attention recently, particularly in the Western Pacific area, since its originators Dr and Mrs J. Billings come from Australia. In order to attempt an independent assessment of the cervical-mucus method, the WHO Special Programme of Research in Human Reproduction began in 1976 subject recruitment for a multi-centre clinical trial of the ovulation method. Specifically, the study is attempting to: (1) (2) determine the percentage of women who are capable of recognlzlng changes in cervical mucus during the menstrual cycle; correlate in selected number of cycles the changes in cervical mucus with an objective parameter of ovulation, namely progesterone levels; correlate the ability or inability of women to observe cervical mucus changes with social and medical data available for the subjects; determine the theoretical effectiveness and use-effectiveness of the method in subjects who are capable of detecting changes in the cervical mucus.
(3)
(4)
In order to enable a cross~cultural assessment of this method, centres were seleced in El Salvador, India, Ireland, New Zealand and the Philippines. The centres were chosen from among those which had previous experience in the method being studied and available qualified teachers. At this stage in the study there are not enough data available to report statistically significant pregnancy rates, especially in terms of life tables. Nevertheless, it appears that almost all of the women recruited into the study are able to observe changes in the quality and quantity of cervical mucus throughout the menstrual cycle compatible with their ovulatory status. (d) The Sympto-thermal method
The sympto-thermal method basically relies on a variety of indications of ovulation including cervical mucus changes, mittleschmerz, calendar calculations, etc., combined with BBT measurements. In certain circumstances the sympto-thermal method may be more suitable for a given woman than a cervical mucus method alone, e.g. when difficulty in assessing the changing characteristics of the mucus is experienced. On the other hand, for women using a sympto-thermal method who find that the mucus symptom and BBT end points which signal the beginning of the post-OVUlatory
- 39 -
infertile phase coincide perhaps the somewhat tedious task of temperature taking and recording can be abandoned. Nevertheless, the effectiveness of these methods has not yet been unequivocally determined, although it appears to depend greatly upon the motivation of the couple, the quality of the teaching of the methods and the regularity of the phenomena monitored in different women. In order to attempt a comparison between the simple cervical mucus and sympto-thermal methods, the WHO Task Force on Methods for the Determination of the Fertile Period, initiated a year ago a study in Colombia which aims at comparing in 400 randomized subjects the effectiveness of the ovulation method ~ith that of one form of the sympto-thermal method in two cities (Bogota and Cali) and through different health service channels. The investigators in Colombia have experienced more difficulty than they anticipated in recruiting couples for this study. Again, at present there are insufficient data available to calculate pregnancy rates. This study is being conducted in close collaboration with a similar study in Los Angeles, United States of America, supported by the National Institute of Health. (e) 'Research to improve presently available techniques (i) Evaluation of physiological events relating to the fertile period
During the past several years researchers in human reproduction have assumed, primarily from circumstantial evidence, that ovulation occurs approximately 18-24 hours after the LH peak. Aside from a few isolated projects on small groups of women there has not been any major study performed to obtain a truly accurate estimation of the occurrence of ovulation in relation to changes in several hormonal parameters. Such information would, of course, be extremely useful to all areas of laboratory and clinical research in human reproduction concerned with ovulation. The WHO Task Force on Methods for the Determination of the Fertile Period initiated in 1975 a multi-centre study to correlate ovulation, as observed at laparotomy, with steroid and gonadotropin plasma concentrations. A total of 140 subjects were analysed. Preliminary results from 99 cases suggest that the median time interval between ovulation and the LH, FSH and estradiol peaks is 17.5 hours (S.B. = 4.0) 17.3 hours (S.B. = 4.2) and 32.6 hours (S.E. = 5.3), respectively. In determining the duration of the fertile period one must also take into account the fertilizing life span of spermatozoa since viable sperm may still be present from coitus which occurred before the immediate periovulatory period. Relatively little is known about the fertile life span of the gametes in humans and there is no practical way of ascertaining it precisely for the individual couple. A possible approach is to evaluate the fertilizing life span of spermatozoa and the fertilizable life span of ova by retrospective analysis of charts obtain from women who became pregnant while practising methods of family planning which require temperature recording.
- 40 -
(ii) Developments of simple "do-it-yourself" methods to predict or
detect ovulation The development of assay-kits, suitable for home use, of the "test-tape" or "dip and read" stick kind, which measures the concentril t, i ()n of a specific compound in urine or other body fluids and signals whether a woman is entering a fertile period, represents a major goal of research in this field. At present research to identify potential markers is ongoing with regard to several body fluids. Urine It has been recently ascertained, through WHO-sponsored researoh, that to prediot ovulation exoretion patterns of estriol-16~ gluouronide were more consistent and had better defined peaks than those of estradiol-3-g1ucuronide, estradiol-17 J!-glucuronide and estriol-3-g1uouronide. The ooncentrations of estriol-16«-glucuronide and estrone-3-g1ucuronide significantly increase above baseline values aproximately three to four days before the LH peak, repeotively, i.e. approximately four to five days before ovulation. Pregnanediol-3~ -glucuronide is the most significant urinary metabolite of progesterone. Preliminary data from WHO-sponsored research indicate that a significant rise above mean baseline values occurs around two days after the LH peak, that there is a reasonable correlation between the values obtained for the 24-hour collection and the early morning speoimens. Finally, there seems to be a good possibility to define "universal" threshold values indicative of ovulation. The mean values of pregnanediol-3 a( -glucuronide during the follicular luteal phase of the menstrual cycle were found to be approximately 3 nmol/24 and 17 nmol/24h, respectively. Thus, there appears to be at least five-fold increase in the oompound after ovulation. These findings indioate that the measurement of pregnanediol-3o( -glucuronide may provide a practical means for detecting the end of the fertile period and the beginning of the post-ovulatory infertile phase of the menstrual cycle.
Luteinizing hormone It is well established that LH reaches its peak concentration in blood or urine before ovulation. However, the measurement of this hormone would not operationally permit the prediction of ovulation as the peak does not occur early enough to allow for the fertilizing life span of spermatozoa.. Determination of LH could be nevertheless utilized as an indication of impending ovulation and to calculate the time when free intercourse can be resumed. A method which shows promise in this respect is a modification of the radio-receptor assay. An enzyme-receptor assay for instance would give as the end point of colour reaction which can conceivably be applied to simple kits.
- 41 -
Saliva Saliva is probably the most easily accessible body fluid which can be obtained and handled by women themselves for analysis purposes. However, the work on developing a saliva test for hormones as a means of predicting or detecting ovulation did not produce appreciable results, since concentrations of both pituitary and ovarian hormones in saliva are very low and do not show any meaningful cyclical variation. In spite of this, researchers in several parts of the world continue the search for other types of salivary compounds, such as enzymes, which could be used to predict ovulation. Cervical mucus At mid-cycle, prior to the plasma LH surge, there is a significant decrease in the concentration of cervical mucus alkaline phosphatase activity. Based on this observation a simple test has been developed utilizing a colorimetric reaction on a tampon. Because of difficulties experienced in collecting samples of cervical mucus, this technique does not yield satisfactory results. (iii) Development of devices to predict ovulation
Bio-engineering techniques can be applied to investigate the menstrual cycle in search for indicators of impending ovulation. Some of these techniques can, in fact, measure changes in vaginal blood flow, light reflectance and impedance which precede ovulation. Whether instruments to detect such changes can be transformed into devices suitable for home use remains to be established. A method which received publicity in the press utilized a biopotential meter to measure changes in polarity and magnitude of electrical potential of the body, around ovulation. A recent WHO-sponsored clinical testing of this instrument failed to demonstrate any usefulness of this gadget; in only one out of 35 ovulatory cycles monitored was a change in polarity recorded around the time of ovulation. More promising is the research aimed at replacing the need for tedious basal body temperature recording. Advances in "pocket calculator" technology are such that it now appears feasible to make simple inexpensive instruments which could, for example, instantaneously take a temperature recording, automatically record it, and, at the push of a button, display a sequence of previous eight recordings, plot a graph, or indicate, with a red or green light, if the temperature shift has occurred. (iv) Improvement of the service delivery of methods based on periodic abstinence The educational component of methods based on periodic abstinence plays an even more important role than in other methods of family planning. The extremely wide range of unplanned pregnancies reported for these methods (approximately 0.3-26 pregnancies per 100 years as calculated by the Pearl Index) may be due in part to the quality of the instruction provided.
- 42 -
In order to improv'~ "Tl.-ltural" family planninp r>r>rf'rorrn:lrl"'. 'I ::llnol~r(li.z0rj curriculum for instructing non-physician teach(!r:; :In,1 II;:' I -r:"'Jplr>~3, is b~in~ prepared by the WHO Task Force on Methods for the Determ i '1'1 t ion of thp. Fertile Period. A "learning package" is being prepared. The pr0totype package was developed by the British Life Assurance Trust, which is the Centre for Health and Medical Education of the British Medical Associ.ation and a WHO Collaborating Centre for Educational Technology. Beginninp, in 1979 it will be pre-tested and evaluated in a number of centres with wid€ geographical distribution. 2.2.9 Induced abortion: Dr K. Edstrt$m' health aspects of various techniques: presented by
In most countries of the world, induced abortion whether legal or illegal plays an important role in fertility regulation. The health effect of illegal abortion, or clandestine abortion, are well known to all medical professionals. In countries where it is legal, it places an increasing demand on the health services, and this has alerted both health planners and clinicians to discuss which are really the best choices of available abortion techniques in various clinical settings. This paper will attempt to discuss the abortion techniques most commonly employed in health services and some of the apparent advantages and disadvantages, mainly in relation to health. It is well known that the risk of complicaton after induced abortion, both the more serious ones and minor complications, does increase with advancing stage of pregnancy. The risk is approximately three to four times greater after the 12th week than during the first trimester. During the first trimester, for the most part, the only so-called one-stage methods are used, while in the second trimester both two-stage and one-stage methods are used. Methods of induced abortion (a) One-stage methods
These are abortion procedures which subject the woman to only one intervention, a procedure whereby all products of conception supposedly are completely removed before the woman leaves the operating table. The main procedures are: vacuum aspiration, classical D&C and hysterotomy. (b) Vaccum aspiration or suction curettage
This differs from the clinical D&C in that it uses no sharp instruments and gives less risk of trauma to the uterine wall.
'Medical Officer, Maternal and Child Health, WHO HeadqlJarters, Geneva.
- 43 This is a technique with an overall very low complication rate. Depending on the type and severity of complications registered the rates vary between 0.8 and 7.3 per cent in various reported studies. Perforation of the uterus is potentially the most dangerous complication and fortunately the most rare. The rate of perforation is usually reported to be around 0.1 to 0.3 per hundred abortions. Serious cervical laceration is reported around 10 times as often. Cervical laceration is particularly relevant in relation to the possibility of long-term sequelae such as premature delivery. Since dilatation of the cervix is normally not necessary in very early abortion, the danger for this complication is very much reduced during this period; on the other hand the failure rate is higher with the very early abortions. (c) Classical Ole
This method is also mainly used in the first trimester but has often been utilized at a later stage in pregnancy, that is 13 to 15 weeks. The serious complIcations are the same as described for vacuum aspiration. The overall complication rate is low. Compared to that of vacuum aspiration it is slightly higher up to and including 10 weeks' pregnancy, after the 10th week the complication rates (especially those of bleeding and re-curettage) are slightly higher with vacuum aspiration. The degree of dilatation of the cervix necessary with this method is higher than with vacuum aspiration, which potentially increases the risk of late sequelae. After the 12th week, this method requires a very high degree of skill, and even so the necessary degree of dilatation is Quite high. (d) HzsterotO!l7
This technique can be used in both the first and second trimesters, but the rate of complications is usually reported to be higher than with any other method. This higher risk indicates that it should preferably not be used as a primary method, but only if other indications for laparotomy are present. (e) Two-stage method or pharmacological method
There is a great variety of techniques and combinations of techniques belonging to this group of abortion methods. The cOlllllon feature is that they all imply an intervention (usually an intra-uterine injection or infusion of a pharmacological agent or solution) which is intended to induce uterine contractions which, after an interval of varying length, results in the secorid stage or the expUlsion of the fetus and placenta. The latter is often incomplete, and this requires instrumental intervention. These methods are practically confined to the second trimester of pregnancy. The main problems or drawbacks are the deiayed action, which requires hospitalization, and the relatively high frequency of failure to induce abortion.
- 44 -
(f)
Salin e
the secon d This method which is proba bly still the most widel y used iniotic -amn trim: ster.h as two basic varia tions , namely intra - and extra minor varia tions of r numbe The ion. solut e inst~llat~on of hyper tonic salin amount and in the techn ique is enormous; for instan ce, regard ing the fluid withd r tic amnio of t amoun the lled, conce ntrati on of solut ion insti awn, and the the techn ique of intra- amni otic insti llatio n of the solut ion, actio n. addit ion of other drugs or devic es to incre ase uterin e contr used The techn ique of intra- amni otic insti llatio n is the most often an~y. week of pregn althou gh it is more diffi cult to perfor m befor e the 16th larity , and it is popu in asing incre been has The extra -amn iotic techn ique , parti cular ly defin itely simpl er to carry out than the amnio centis es cases al between the interv in the perio d of 13 to 15 weeks of pregn ancy. The time be longe r than the to ed claim is fetus the of sion insti llatio n and the expul highe r. However, intra- amni otic techn ique, and the failur e rate seems to be contr olled studi es are lackin g. natrae mia A speci fic and poten tially dange rous comp licatio n is hyter can cause which usual ly is due to accid ental intrav enous infuS ion which Other . serio us haem olysis , anuri a, convu lsion and occas ional ly death n and chang es serio us speci fic comp licatio ns descr ibed are water intox icatio in blood coagu lation . (g)
'.:'he 40 per This techn ique is very simil ar to intra- amni otic salin e. dange rous than less cent. hyper tonic urea is often stated to be poten tially infus ion. On the 20 per cent salin e in the event of accid ental intrav enous n tlme inter val bortio other hand, the succe ss rate is low and the injec tion-a the , above is prolon ged. Of the speci fic comp licatio ns descr ibed is injury cal coagu lation changes have not been descr ibed, but cervi appar ently more frequ ent with this techn ique. (h) Prost aglan dins best This method is still under development with respe ct to the It has etc. tion, prepa ration to be used, the best route of admi nistra assoc iated is it ns: reaso gener ated a great deal of inter est mainl y for two other the than val with signi fican tly short er induc tion-a bortio n inter e. These two-s tage methods and it has been consi dered safer than salinnce of incide high advan tages are count er balan ced by the relati vely The comp arativ e uncom fortab le side- effec ts and the high cost of the drug. rapid effec t of more lly studi es recen tly publis hed confir m the subst antia ncy of the prost aglan din than of salin e, as well as the highe r freque licatio n rate comp the WHO by side- effec t. In a contr olled study condu cted bleed ing heavy of rate The was highe r for prost aglan din than for salin e. s of route new the and unds compo was three times as high. Newly develo ped in with dealt is this and admin istrat ion are still under inves tigati on, detai l later in this repor t.
-
Urea
- 45 -
(i)
Rivanol
This technique is similar to that of the extra-amniotic instillation of saline. An acridine derivate solution (ethacrine lactate), usually in amount 50-150 ml, is instilled through an indwelling catheter which is left in place for a few hours. Oxytocin is normally given in intravenous infusion. This method has not been tested on a large scale, but findings indicate that the complication rate, particularly infection, is slightly lower than with the previous two methods, but the success rate is said to be lower. (j) Specific technical aspect (i) Special eqUipment needed for vacuum aspiration
This method requires two types of special instruments in addition to those needed for D&C; a vacuum source and a perforated suction cannula. The vacuum source most commonly recommended is an electrical vacuum pump usually creating a negative pressure of 0.7 to 0.9 atmosphere. This equipment is dependent on availability of electriCity, and adequate maintenance. A number of mechanical vacuum sources have been developed such as foot-or hand-operated pumps, vacuum bottles and for the very early abortion, a 50 ml plastic syringe. The efficiency of mechanical pumps seems to be sufficient for most purposes although it has not been tested in controlled trial. A number of cannulas of various designs are available, flexible plastic ones, rigid plastiC and metal cannulas. They do not seem to differ very substantially in terms of risk of complication. Price and availability seem to be more important factors to consider. (ii) Pre-operative cervical dilatation
Cervioal incompetence and an increased risk for subsequent pre-term deliveries is often claimed to be the result of a previous induced abortion particularly in women whose first pregnancy is terminated by abortion. Cervical injury seems to be of particular importance if one is considering the use of D&C after the 12th week of pregnanoy, when extensive dilatation is necessary and the risk of clinically important cervical tears is inoreased. In order to reduoe this risk, various approaches have been tried to aohieve a more gradual and "physiological" dilatation over time and to reduce or completely abolish the need for rapid mechanioal dilatation. The most widely used approach is the insertion of laminara tents into the oervix up to 24 hours before the evaouation of the uterus. Recently, the availability of long-acting prostaglandin compounds in the form of vaginal suppositories have offered another approach to pre-operative dilatation. The effectiveness of both these regimens in achieving a sufficient dilatation seems to be without doubt. The studies so far performed are small, however, and further studies are required to assess the relative health risks attached to either of these two methods. The complications that might be expected to be influenced (decreased or increased) would be infection, uterine perforation and cervical laceration.
- 46 -
(k)
AUgmAnt~tion
of uterine contraction tn
two-3ta~c
abnrtion
Due to the often lon~ interval between the instillatLon of an intra-uterine solution and the expulsion of the fetus. it is common practice to trv to shorten this interval by stimulatinp, uterine contractLon~. The most commonly used ad.iunct is intravenous infusion of oxvt,o~in. which shoulrt be started immediately or within a few hours after the intra-uterine instillation in order to significantly shorten the interval. Similarly, intra-amniotic administration of prostaglandins simultaneously with that of hypertonic solution has also been successfully tried. Laminaria tents inserted before or at the instillaton of hypertonic solution have also been shown to reduce the time interval. So far, no controlled studies are available to evaluate whether the above combinations do decrease or possibly increase the risks of complications in terms of cervical laceration, hemorrhage or infection. (1)
Choice of methods at various stages
0.
)!i:Olp1ancy
The attached table, which describes the relative effectiveness and short-term safety of some common methods of induced abortion, was developed during the meeting of the Scientific Group on Induced Abortion in Geneva, 14-19 November 1977. In summary, the following statements were made: (i) 6 weeks or less: Vacuum curettage (suction curettage) seems to be the safest; the only problem is an increased risk of continued pregnancy. (ii) 7-10 weeks: Vacuum curettage, or D&C and in primigravida possibly combined with some methods of pre-operative cervical dilatation. (iii) 11-12 weeks: D&C seems slightly safer than vacuum curettage, but the safety might be more dependent on the skill of the operator. Pre-operative dilatation is recommended, particularly in primigravida. (iv) 13-15 weeks: Prostaglandins seem to be more effective than either instillation of hypertonic solution or rivanol, but the relative safety is not sufficiently assessed. There is some indication that D&C in combination with pre-operative cervical dilatation is safer in terms of immediate risks than abortion using saline, but this seems to apply only under the condition that the operator is very skilled and experienced. (v) 16 weeks or more: Prostaglandins are still more effective than saline but the latter might have a somewhat lower risk of complications. Vacuum curettage and D&C should not be routinely used. It was stated that the high complication rate of hysterotomy indicated that this method should not be used as a primary method of abortion without other indications for laparotomy existing simultaneously.
47 Table E
RELATIVE EFFECTIVENESS AND SHORT-TERM SAFETY OF SOME CGIMON METHODS OF INDUCED ABORTION
Gestation in weeks Method 6 or less a) Suction curettage only 7-10 11-12
13-15 High degree of manual dilatation 'necessary. In skilled and e~erienced
16 or more
Safe, simple Safest method, re- method quires no dilatation Not always effective Safe and Also very simple but safe does require a certain degree of dilatation Not applicable
Safe
b) D & Conly
Safe
hands safe and effective
Not used in most countries
c) Curettage (a) or (b) plus pre-operative Cx dilatation
Reduces or avoids need for manual dilatation. Desirable particularly In skilled and exin e.g. primigravidae 9-12 weeks, women with perienced tight Cx, etc. hands safe & effective Shorter. interval instillation ~ abortion than with (e) & (f) Extraamniotic technique simpler than intraamniotic Intra- amniot ic
d) Prostaglandin Currently available preparations. In some countries only
Vaginal sup- Currently less effectpositories ive than methods safe & sim- (a)- (c) pIe, not always effective.
& extrarunniotic both effective
I I ! I
e) Saline or other hypertonic solutions
Longer interval Not appropriate inst~llation ~
abortion
~
than with (d) Extraamniotic technique simpler than intra!1IIlIliotic
, Safer than , intra-amniotic pros taglandin. Not yet known for extraI amniotic PC-.
I I
f) Rivanol (ethacr ine lactate) extra-amniotic Not appropriate
Lower sepsis rate than (d) and (e)
(d), (e) and (f) can all be combined with e.g. oxytocin or with laminaria tents to increase effectiveness and reduce interval.
- 48 2.2.10 Long-term or late effects of induced abortion: Dr Mark A. Belsey' presented by
Since the early observation of Klinger in 1970 in Hungary, concern has been expressed as to the possible adverse attacks of induced abortion on subsequent pregnancy outcomes. Based on national data in Hungary, the overall prematurity rate defined as birth weight under 2500 gms rose from 7$ to 12% from 1954 to 1968. Half of this rise was attributed to an induced abortion effect, and the rest was attributed to changes in age, parity, employment, etc. Subsequently, a number of reports have been published on the problem. Several of these reports have confirmed the Hungarian observation while others have failed to establish any association between induced abortion and an adverse outcome of the subsequent pregnancies. What appear to be conflicting results between studies in reality may represent differences in the induoed abortion procedure in different settings among women with quite different characteristics. However, some of the differences in the results may also be attributed to differences in the research methods. There is ample evidence that the characteristics of the women affect the risks of short-term complications associated with abortion. It has also been widely shown that the characteristics of abortion-seeking women differ quite markedly in different countries from those of non-aborted women within the same country. Among the characteristics of abortion-seeking women which vary from those of the non-aborted women are smoking, contraceptive use, recall of the last menstrual period, use of health services, etc. Similarly so, the procedure for induced abortion varies widely between countries. Even the technique of dilatation and curettage (D&e) may be performed in a different manner in different countries or even clinics. The amount of dilatation varies as does the vigor with which dilatation is accomplished. These differences may affect the long-term sequelae risk. In view of the concern for this problem as expressed by many governments and the difficulty in interpreting existing data the WHO Task Force on the Sequelae of Induced Abortion initiated a collaborative investigation in nine cities in eight countries. A preliminary analysis suggests that in centres where smoking is common among women, this factor is far more important in affecting the birth weight of an infant. After adjusting for the duration of gestation, the birth weight of an infant born of a smoking mother is from 100 to 250 gms lighter than the infant of a non-smoking mother. This difference is important in interpreting the effect of abortion, since in nearly all centres studied, the frequency of smoking was significantly higher among women who had a previous induced abortion when compared with those who did not have an abortion. Once adjusting for the variety of compounding variables such as
-Medical Officer, SpeCial Programme of Research, Development and Research Training in Human Reproduction, WHO, Geneva.
- 49 smokin~, the time at which the women presented to the health services, age, educatlon, etc. nearly all of the differences in birth weight and duration of gestation disappeared between the different groups. It is not possible at present to conclude that induced abortion whether by vacuum aspiration or D&C results in any shortening of the duration of gestation or in increasing the risk of low birth weight. It does appear that the risk of spontaneous abortion in the second trimester of subsequent pregnancies is increased particularly in women whose termination was by D&C as compared with vacuum aspiration.
Few studies have been undertaken to examine the risk of infertility following an induced abortion. Most of these studies suffer either from inadequate number of subjects or a lack of controls. The result of studies that have been published in literature on the risk of infertility are somewhat contradictory. Only one study shows a definite marked increase in risk of infertility in women who had an induced abortion but this study was undertaken in a country where abortion was illegal and it is likely that many of these women have had complications such as infection following the illegal abortion. The World Health Organization is supporting two prospective studies currently under way in Hungary and in the Republic of Korea~
The problem of ectopic pregnancy following induced abortion is similar to that of infertility. Again the results of published studies are somewhat conflicting, probably because of problems of study design, inadequate controls or insufficient numbers of the women. It is hoped that studies that are ready to be started in both Cuba and Hungary will answer definitively the question as to whether D&C or vacuum aspiration has a greater or a lesser risk of an adverse outcome in subsequent pregnancies. One issue that is of particular importance in many countries but that is difficult to resolve methOdologically is the health consequences of repeated abortion. As noted previously, the characteristics of women who have had previous induced abortion differed from those who have not had an abortion. The characteristics of women who have multiple induced abortion differ even more markedly from those of women who have had only one induced abortion or no induced abortions. As such, many of these risks of adverse outcomes in pregnancy or other late sequelae may be risks inherent within this group of women and not related to the abortion per~. These issues are still under investigation. 2.2.11 Prostaglandin in human reproduction: ~resented by Professor 3.3. Ratnam and Professor 3. .M. Karimi
The" involvement of prostaglandins in various physiological and pharmacological processes associated with human reproduction is illustrated in Fig. 1. Clinical applications of prostaglandins are based on either mimicing these effects by exogenous prostaglandins or in some situations by preventing their synthesis.
-Department of Obstetrics and Gynaecology, University of Singapore, Kandang Kerbau Hospital, Singapore 8, Republic of Singapore.
50
MALE FERI'IUTY
FEMALE F£RTIUTY
PREGNANCY
eleCtion ejaculation lpenn motWty lleJOlclogeoe,"
sperm transport In (1) cervical muclII (2) utelU' and falloplan tubel uterine contractility tubal contractlllty and peristalsis ovarian contractlllty and lJVulatlOll luteolylts menstruation steroldogeneell Intrauterine contraceptive device
Ipontaneoul abortion prematu~ labour term labour
~ INVOLVEMENT IN PATHOLOGICAL (1) dyamenonbou.
~~
_ _ _ _- L_ _
~~~
PkOSTAGLA NDINSlh-------t1 LACTATION
I
SYNTHESIS INHIBITORS (1) ('2)
UMBIUCAL AND FETAL CIRCULATION
(2) aacwulatton
(3) toxaemia of pregDaacy (") habitual abortion
preventlOil of ovulation treatment of dysmenorrhea (3) Inhibition to premature labcu (4) prolong pregnancy (5) prolong labour
regulation of fetoplacental blood now (2) closure of umbilical blood veuell (3) potency of ductlll arteriosul (1)
PROSTAGlANDINS AND THEIR INHIBITORS: MODULATION AND MEDIATION OF REPRODUCTIVE PROCESSES
FIGURE 1
- 51 -
(a)
Female reproduction
. More work has been carried out to elucidate the role of prostaglandins 1n female reproduction than in any other area. The possibility that they could be used for the regulation and control of human fertility has been a great stimulus for research in this area. Prostaglandins have been isolated from all parts of the reproductive tract. The type and concentration of prostaglandins in each area and from different parts of the same structure vary. Investigations have been directed to demonstrate their role in sperm transport, tubal and ovarian contractility, luteolysis, menstruation, abortion, parturition and closure of umbilical blood vessels and ductus arteriosus. (b) Contraception
Theoretically, prostaglandins could act as contraceptives by a variety of mechanisms. These include: effect on egg or sperm transport altered tubal and uterine motility altered gonadotropin secretion interference with steroid hormone biosynthesis interference with ovum transport and implantation luteolysis interference with ovulation (synthesis inhibitors) However, clinical trials have so far not been carried out to establish whether prostaglandins could be utilized as contraceptives by any of the above mechanisms (except by luteolysis). (c) Menstrual regulation
The importance of the corpus luteum in the normal menstrual cycle and in the maintenance of early pregnancy (up to 7th week from last menstrual period) is well established. There has always been an interest in drugs which might inhibit corpus luteum function. Such a drug could be used as a post-coital contraceptive or an early abortifacient to be taken once a month or only when there is a delay in menstruation (suggesting early pregnancy) of two-three weeks. Such a drug could also be used as an alternative to abortion·performed later in pregnancy. Prostaglandins (particularly PGF o() have been shown to cause a regression of the corpus luteum in 2 several animal species but so far it has not been possible to convincingly demonstrate that prostaglandins given in pharmacological doses produce corpus luteum regression in the human female. In spite of the lack of direct effect of prostaglandins E and F c( on the human corpus luteum, 2 these compounds have been successfully used for inducing menstruation when this is delayed by up to two weeks. They are possibly acting by a myometrial stimulant action.
- 52 -
In early studies prostaglandins were administered by the vaginal route. This was associated with a high incidence of gastrointestinal side-effects and the efficacy was not always predictable. Preliminary results of more recent studies using 16, 16 dimethyl PGE 2 and its p-benzaldehyde semicarbazone esters have been encouraging. (d) Termination of first trimester pregnancy
For the purpose of present discussion only gestation of 7 to 12 weeks is included. Although prostaglandins have been successfully used for the termination of first trimester pregnancy they compare less favourably with the evacuation of the uterus by vaccum aspiration as shown below: Vacuum Aspiration (1) (2) (3)
Prostaglandins (1) (2) (3)
Can be performed within minutes. Can be performed in an outpatient clinic. Abortion oomplete.
Abortion process takes several hours. Requires overnight hospitalization of patients. Over 50% of abortions are incomplete and evacuation of the uterus by vacuum aspiration or curettage is necessary to complete the abortion. Most patients experience uterine cramps and gastrointestinal side-effects. No need to dilate the cervix.
(4)
Immediate side-effects are minimal.
(4)
(5)
It is necessary to mechanically dilate the cervix prior to vacuum aspiration of products of conception.
(5)
The main disadvantage of termination of pregnancy by vacuum aspiration is the need to mechanically dilate the cervix in almost all nulliparae and in most multiparae after the 8th week of gestation. Forceful dilatation of the cervix may lead to cervical incompetence resulting in a higher incidence of abortion and premature labour in subsequent pregnancy. (e) Pre-operative cervical dilatation with prostaglandins
Prostaglandins E2 and F2 and some synthetic analogues have been successfully used in several studies to gradually dilate the cervix in first trimester patients prior to evacuation of the uterus by vacuum aspiration or curettage. There are several disadvantages associated with the procedure and these include: (1) The time interval between prostaglandin administration and adequate cervical dilatation has been too long and has necessitated overnight hospital stay.
- 53 • f
(2) With the natural prostaglandins the dose has to be repeated periodically. (3) For acceptance rate of efficacy the drug has to be administered by the intra-uterine route. Although good efficacy by the vaginal route (using natural PGs and analogues) has been reported, the dose has to be repeated and adequate cervical dilatation takes several hours. (4) (f) The incidence of gastrointestinal side-effects is high.
Termination of second trimester pregnancy
Prostaglandins E2 and F2 o( given by intra-uterine routes (intra-amniotic and extra-amniotic) have proved superior to other methods (hypertonic saline or hysterotomy) of terminating second trimester pregnancies. Fifteen methyl analogues of these compounds administered intra-amniotically have shown better efficacy and fewer side-effects compared with the parent compounds in the termination of second trimester pregnancies. Further studies have been aimed at developing routes of administration which would avoid invasion of the uterus. Although both 15 methyl E2 and F20( show a good efficacy by the vaginal and intra-muscular routes, the incidence of nausea, vomiting, diarrhoea and pyrexia have been unacceptably high. Bygdeman and Bergstrom (1976) have reported good efficacy and low incidence of side-effects with 16, 16 dimethyl PGE (free acid) administered vaginally. We have used 16, 16 2 dimethyl PGE p-benzaldehyde semicarbazone ester (a stable crystalline 2 ester of 16, 16 dimethyl E2 ) by the vaginal and intra-muscular routes with good efficacy and low inciaence of side-effects. 3. CONCLUSIONS
3.1
Review of the techniques of fertility regulation used in the Region, and advantages and disadvantages of the fertility regulating methods currently in use During the group discussions, the following points were brought out:
The Pacific Islands have reasonably similar programmes. All types of methods are usually offered in the clinics. The client's own choice is the important denominator for the choice of method. All the countries have an active village distribution programme, mainly through community nurSes and midwives, and this seems to favour a selection of the pill by the health personnel since it is simpler to distribute to the clients than clinic-linked method. There appears to be a pattern of initial popularity with newly introduced methods followed either by a plateauing or a decline in use over time. There has been increasing interest in the injectable methods in the Pacific Islands but it has been noted that there are problems with the bleeding patterns. Proper case selection for the injectables is encouraging in terms of continuation.
- 54 -
The People's Republic of China seems to have a fai~ly similar,sy~tem in several ways. All methods are available in all th: :egl~ns, ,but ~lstlnct differences between the regions can be seen. Ster1l1zat1on 1S fa1rly popular; in some regions, vasectomy is more popular than tub~c~Omy~ but in the whole country, the overall preference is for female ster1l1zat1on. In China, the condom is freely available in both shops and clinics. All hormonal contraception products developed in China are supplied by health personnel, free of charge. Three forms were briefly mentioned: the long-acting once-a-month pill composed of a long-acting estrogen and progestogen and the short-acting combination pills provided in a 21- or 22-day cycles and the vacation pill. Hong Kong, Republic of Korea, Guam, New Zealand and Japan all have a system with a large private sector delivering family planning. As for the previously mentioned countries and areas, the patient's preference has high priority, but the providers do influence the choice of the pill since it is more easy to distribute. In the Republic of Korea, the IUD is the most preferred method, but the pill is second and has increased very sharply during the last 10 years. Sterilization is also very popular, but nearly exclusively females. In Hong Kong, the preferred method is the pill due to its easy distribution. In Japan, there is a preference among the clients of traditional methods combined with abortion in case of failure. Improvement in the quality of the condom has contributed to its acceptance and success in Japan although it is noted that there apparently is a high failure rate as evidenced by the very high abortion rate. Improvement in the condom technology was noted to be an important part of its acceptability. The second most popular single method is safe period, which is often followed in association with the condom. Use of the safe period may be due to the fact that the theory as to the timing of ovulation originally was found by famous Japanese doctors. The IUD is sanctioned by the Japanese Government only in the last three years, and its use has somewhat increased in popularity but still only accounts for 8-9~ of all users. Pills are not sanctioned as contraceptive method by the Government but are obtainable from physicians; 3.3% of contraceptive users are using pills, and 2.7% of women who know of the pill intend to use it in the future. In Malaysia, at one time, the large variety of oral pill preparations with different schedules was somewhat confusing to the clients. Distribution of all contraceptives by auxiliary health personnel is permitted in Malaysia and wri.tten instructions are also provided. Social stigma is attached to the use of condoms in Malaysia and Singapore and experience with the IUD was not too encouraging in either. However, recently there is an increasing acceptance in both of the newer IUD models. Injectable hormones are not particularly popular because of complications of menorrhagia and amenorrhea. In the Philippines, the programme is again dominated by the pill, but the rhythm method or the ovulation detection method is very acceptable to the patients. The family planning staff tries to promote the more effective methods in the Bohol MCH family planning project area.
- 55 simpl e In t~e Socia list Repub lic of Viet Nam, condoms are consi dered ol or contr to cult diffi are they and are w1dely used but it was noted that over that noted was it 1976, In to asses s the actua l number of users . exper ience d some 354 000 IUDs.were inser ted. Appro ximat ely 12% of the womeny the super -dana mainl is ry di:fic~lty w1th IUD. The IUD used in that count ssion that the ~h1Ch 1S produ ced in Czech oslov akia. It was the impre partic ipant s from the but e 1njec table methods would be effic ient and simpl with this ience exper no the Socia list Repub lic of Viet Nam have had acept ives are contr oral that prepa ration in their count ry. It was noted . accep table among some women users rate In New Zeala nd, the oral pill is the domin ating method, the ages of 15 the en betwe women of being the secon d highe st in the world , 35.3% eligib le of 4-5% ar, popul nably and 45 years for 1975. Injec table s are reaso ly asing incre be to rs appea tomy, women; while steri lizat ion inclu ding vasec able. avail not used, althou gh speci fic stati stics are r Contr acept ive use at diffe rent stage s of repro ducti ve caree gathe red In relati on to this pOint , it was noted that the stati stics only, since women ed marri ssed discu from count ries and areas shoul d not have des large numbers for sever al count ries and areas in the Regio n, this exclu ts in the count ries repor that sted of sexua lly activ e women. The group sugge not for ives, acept contr using and areas shoul d be given for all women marri ed women only. Pre-m arital contr acept ion by and given In New Zeala nd and Japan , contr acept ion is often reque sted the condom, respe ctive ly. to unma rried women, the choic e being the pill and acept ion to unmar ried contr give to al In the Philip pines , it is not illeg d for pre-m arital deman no is there , women irresp ectiv e of age. In China n, the demand on Regio the in areas and contr acept ion. In other count ries l press ure rathe r the whole seems to be low mainl y due to cultu ral and sociade contr acept ion. than to unwil lingn ess to pract ise family plann ing to provi n in some Pre-m arital sexua l activ ity seems to be incre asing ly commo count ries and areas . Cons traint s to contr acept ive method use methods of A number of const raints to the wider avail abili ty of these cular ly parti pill ferti lity regul ation were discu ssed. Side- effec ts of the to reduc e the d nause a, and with lower doses , break throu gh bleed ing tende bleed ing in part gh throu break The ives. acept accep tance of the oral contr gs, a great appea rs attrib utabl e to irreg ular pill-t aking . In some settin ion of how ehens deal of diffic ulty was encou ntered in obtai ning a full compr local ly with to take the oral contr acept ives on a regul ar basis . Even skept icism as some is there sion, provi ction instru adapt ed inform ation and In to the effec tiven ess of such instru ction s in some settin gs. labou r, some of the circum stance s where women were engaged in heavy physi cal of eithe r pain or partic ipant s noted that there were increa sed comp laints cramp ing assoc iated with the IUD. tages and There was a wide varia tion in the perce ption of the advan ries and count rent disad vanta ges of the diffe rent methods betwe en the diffe small of areas of the Region. Withi n the Pacif ic Islan ds, the case
- 56 populations that were widely dispersed presented a major problem of logistics for supply and close supervisory follow-up neces~ary for. some methods particularly the oral contraceptives. From the p01nt of V1ew of distribution, the injectable hormones were preferred since they all~wed f~r periodic visits of staff on a three-monthly basis . . Part of. the sa~lsf~ct1on with the IUD in the Socialist Republic of Viet Nam 1S assoc1ated w1th 1tS use at times other than the post-partum period thus avoiding the problems of expulsion and heavy post-partum bleeding. Part of the problem of the post-partum IUD was noted to be possibly attributable to the placement of the IUD in a still non-involuted uterine cavity. The groups discussed the importance of information, education and communication. There was talk about the need for guidelines for staff education and avoidance of self-preference on the part of the staff members providing family planning services in the clinics. It was pointed out that limited local demographic and family planning usage data in the Region make for much difficulty in extrapolating and accepting results from other countries or areas. Such local data is very much needed. Good information is available in some countries such as Singapore and Australia; but, on the other side, the participants from the New Hebrides and Tonga said that there was almost no socio-cultural demographic data available. It was also felt that the very marked differences between the countries and areas of the Region make for increasing difficulties in extrapolating or comparing data. One problem noted in the New Hebrides illustrates the difficulties in some of the other countries and areas. The New Hebrides has a population of only 80 000 on 53 populated islands and has 200 separate languages. Constantly stressed throughout the discussion were the differences between the States, the lack of data and the need for standardizing the reporting system. The participants expressed their hope for WHO assistance for developing such a system at the regional and national level. A range of views were expressed in the working groups. For example, it was pointed out that temporary methods by themselves may never be satisfactory for a rapid demographic effect that either abortion back-up and certainly sterilization should be considered and encouraged as part of a programme for rapid demographic effectiveness. Other discussions related to incentives; publicity in the mass media that would disseminate family planning information, as well as the problems of adverse publicity; and the need for multiple methods in a programme as a back-up in case of unforeseen or adverse publicity to anyone particular method. It can be stated that there were no trends emerging from this discussion, each country and area stating their own choice, their own present utilization, usage and delivery system, the differences being far more obvious than the similarities. But they all admit that valid data are scarce and especially that there are no data available on discontinuation. It was felt that the use of auxiliary workers should be stressed further.
- 57 -
3.2
Implications of the new developments and research for family planning programmes
The presentation on the new developments in fertility regulation and their implications for family planning programmes were discussed in terms of overall problems in family planning programmes and the specific fertility regulating methods. The discussion on the methods focused on guidelines for the continued provision of the method and research issues on the methods that were directly relevant to the family planning programmes of the participants' country or area. There is a clear need for family planning providers and administrators to be fully and accurately informed as to the most recent developments in fertility regulating research. In an era when the press and mass media often have more rapid but frequently incomplete access to the scientific developments in fertility regulation, it is essential that local authorities be even more informed of such developments. The local family planning authorities often are expected to comment on the popularized stories of scientific discoveries, and to advise the public and potential family planning clients on their concerns based on incomplete or inaccurate information. In this respect the family planning authorities needed to be better equipped to interpret and evaluate the sometimes controversial results of published research whether popularized or not in the local press 3.2.1 (a) General programme National or sub-regional seminars
National or sub-regional seminars are useful in the dissemination of information on contraceptive methods and at the same time provide an opportunity to exchange experiences and to find solutions to common problems. Seminars should be at national and local levels covering an exchange of experiences and technical advances. Even a pooling of experiences can be belpful in adapting solutions to the local problems. A "situation analysis" is required to adapt such seminars to local needs. Social scientists should be included in future seminars of this kind. Sociological aspects particularly those affecting the consumer (user) cannot be ignored. (b) Type of information and structure
The type of information and meeting structure that would be most effective varies from country to country. Documentation should be provided on a level that is appropriate to the participants and local needs. Furthermore, the summary information and conclusions from such meetings should be widely distributed to those that are involved in making changes. Quite often, it is the lack of information that makes the programme less successful. Members agreed on all points although the type of information and structure needed to be designed for the group it is intended. Not all types of information and techniques are suitable at different levels.
- 58 (c) Research
Research varies from place to place. Where a research capacity and need exists, the plan of research should be developed with the direct participation of the government to ensure its relevance to the national family planning programme. There should be good communication between various people such as the planners, administrators, field workers, the researchers, etc. Some comments were expressed to the effect that the seminar was strongly oriented towards technology and research. Strong feeling was expressed that there needed to be some acceptability and sociological studies in the field in the Region. (d) Obstacles to the wider use of methods
Obstacles encountered include lack of accurate knowledge by the consumer. Also, lack of understanding of the people's tradition and culture, in adapting methods to different communities. (e) Improvement of existing family planning programmes Discussions on this subject were summarized as follows: (i) (ii) (iii) (iv) (v) (vi) Motivation of family planning workers, and other health personnel who deliver health service. Special training, either long-term or short-term courses to family planning personnel and other health workers. Integration of family planning into the curriculum of medical schools and the training of other health workers. Involvement of community organizations, governments, women's groups into the family planning programme. Establishment by health authority of standard reporting techniques in order to both improve and rationalize reporting. Adjustment of government policies consistent with its health objectives to allocate resources as a high priority to family planning programmes. Exert pressure on lay publicity or press to avoid the provlslon of or mis-information of or mis-understanding by the public. Promote commercial advertising of family planning programmes where such promotion is consistent with the health and social objectives of the community. Education of suppliers of fertility regulating methods such as chemists.
(vii) (viii)
(ix)
- 59 -
(f)
Adolescent family planning needs
Adolescent sexual activity has become common in many countries in the Region. In some countries, marked increases were observed in teen-age abortion. Adolescent family planning service should be available. There are countries where using of contraceptives are prohibited to adolescents. In general, most adolescents prefer private clinio. It is reoo. .ended that contraceptives might be provided for all women at risk. (g) Sex education Sex
Sex education is part of the total programme of education. education is particularly related with adolescent problems.
Parental fear of sex education in sohool was likewise discussed. It was pointed out that sex education has tended to deal with reproductiye physiology and, accordingly, no development was observed with respect to human sexuality, contraception and responsible parenthood. In some countries, although parents were resistant to sex education in schools, Parents and Teachers Associations bave been able to discuss and develop programmes in stages. Problems of the connotation of sex eduoation terminology were also taken up witb a oonsensus suggesting tbe need for a more neutral terms, e.g. family life eduoation, reproductive health and education, etc. Participants reoommended a seminar on human sexuality and sex education whioh would inolude direotors of education as well as directors of health in the Region. 3.2.2 Information dissemination
There have been many research activities ooncerning both basic reproductive physiology and the practical fertility regulating methodology in many institutions throughout the world. Most of these results have been published in various periodical articles and journals. Unfortunately, however, only insufficient quantity of information reaches the personnel who are actively engaged in family planning programme activities. For example, many participants have never received such journals as "Studies in Family Planning" which is one of the most suitable references in this field. Therefore, some communication channels should be provided through which sufficient information concerning the present research activity and its future prospect should be provided to the health personnel in various countries and areas. At the same time, these channels should be utilized to send feedback of information to WHO Regional Headquarters staff concerning the programme needs for research on a particular subject in a certain country or area. It is important to encourage physicians, nurses and field workers that the ultimate aim of these research programmes are, however sophistioated they may seem to be, to achieve a success of their own work and that they themselves can actively partioipate in these researoh projects through their own work in the field.
- 60 -
3.2.3
Oral contraceptives
The discussion of the service implication on new developments related to oral contraceptive use may be oategorized as follows: records and information, screening of potential users, follow-up procedures, choice and seleotion of different oral contraceptives within a programme and the interval until conception might safely take place. The information obtained initially and collected in follow-up was not infrequently described as excessive for patient management, supervision and overall planning and evaluation. Among the data collected are: parity, number of marriages, number of living children, age of youngest child, method accepted, previous methods used, menstrual history, cycles of pills given, physical examination, pelvic examination, LHP, reason for dropout, complaints, date of visit, return visit, etc. A need for simplication and adaptation to local needs was urged in order that excessive paper work for staff and waiting time for clients be reduced. It was not possible to arrive at a consensus on the soreening procedures required for selection of woman suitable for oral contraception (combined pills). The differences in screening practices reflect the variations in the facilities, personnel and logistic support available in the different settings. Current practice on one hand consists of a checklist of questions related to age, parity and history of certain illnesses obtained by an auxiliary nurse or similarly trained individual. On the other end of the spectrum, qualified physicians undertake complete physical examinations including blood pressure, pelvic and breast examination; a papanicolau smear is obtained, urine examined for albumin and sugar. The screening procedUres of most of the countries lay somewhere between. On the whole, the screening procedures were less extensive in rural and widely dispersed populations, and in the case of Papanicolau smears, where facilities for their examination and follow-up treatment were not available. It was noted that no screening took place in circumstances where oral contraceptives were available from commercial sources without physician's prescription. Follow-up procedures vary as much as screening procedures. Where papanicolau smears are undertaken repeat examinations are done anywhere from every six months to two years. Blood pressure measurement and urine examination for sugar are frequently done for follow-up. However, it was noted in the discussion that the ohoice of screening and follow-up procedures was often based on experiences from other usually developed countries. Some procedures may be unnecessary from the point of view of either the absence or the law prevalence of the problem (e.g. thromboembolic diseases in some populations) while others not currently undertaken might be strongly indicated because of the looal health conditions. In only a few countries are specific recommendations made for deferring pregnancies six or twelve months following discontinuation of oral contraceptives after long-term use. The number of oral contraceptive preparations available in the different countries and areas varies. When a large proportion of pills are provided by either the private health sector or directly from the commercial
- 61 -
sector, a large, sometimes confusing array is presented. In the public sector, the number of preparations offered is more limited and may be as few as just one. It was suggested that at least several formulations be available in the public sector programmes in order to facilitate the clinical management of side-effects associated with one or another preparation. The once-a-month combination pill and the "vacation pill" were of interest to several of the participants. Where MCH and other health programmes, such as malaria, chemoprophylaxis are geared to monthly contact with households the once-a-month pill would be of definite advantage over the daily or "short-acting" pillS, assuming that the safety and effectiveness are established in different population groups. The "vacation pill" in certain l~mited circumstances also would be advantageous, such as when partners are exposed to pregnancy risk only periodically because of work patterns or other reasons. Areas of research that in the view of the participants would improve the provision of oral contraceptives in their family planning programmes were: the research necessary to rationalize the minimal screening and follow-up procedures for oral contraceptives; research on the safety, effectiveness and acceptability of both the once-a-month-pill and the "vacation pill". The development of a "morning-after" pill that was safe, effective and with low frequency of side-effects was thought to offer some advantages to certain groups, such as adolescents only periodically exposed to pregnancy. Under the heading of research to rationalize screening and follow-up procedures in different areas would be such issues as the need to perform urine examinations or to ask complicated screening questions for very uncommon diseases among populations whose understanding of the questions may be limited. 3.2.4 (a) Intra-uterine contraceptive devices (IUDs) General view
Several participants stressed that IUD was quite suitable to the people who belong to the agricultural group; therefore, this would be the most convenient, the safest and most economical method, which was now very popular among them. Higher acceptance rate of the IUD mainly depends upon client education, the detailed instructions as to what side-effects to expect, as well as the mode of its action. (b) Screening procedures before the insertion of IUD
Screening procedures mentioned during discussions were: clients' past history, pelvic examination together with pap smear to exclude the contra-indications. It was generally agreed that "method specific checklist" tailored to local situation and need should be developed in the Region to be used as a means of screening.
- 62 -
(c)
Training the personnel for the insertion
Much discussion took place as to the relevance of the insertion of the IUD by auxiliary health personnel such as field workers or nurses. Their training and utilization for this purpose depend mainly upon their respective governments, training background of the workers and demand for such services. In one group, an opinion was expressed that for the training of nurses and auxiliaries on the insertion of IUDs, 6-8 insertions under supervision would be sufficient to allow the workers to insert IUDs on their own thereafter. Certain guidelines on the training of auxiliaries on the insertion of IUDs should be established in the Region. (d) Follow-up of IUD users, detection of spontaneous expulsion or perforation of IUDs
During the follow-up period, when the thread of IUD is not visible, the next advisable step is to sound inside of the uterine cavity. Exclusion of a possibility of pregnancy should also be kept in mind. If the IUD is not detected by a sound, the next step would be either to wait for a next menstrual flow or to take a pelvic X-ray. During this period, the women must use other methods of contraception. Perforation of IUD is more related to both timing and technique of the insertion rather than to physical characteristics. The necessity of the immediate recovery of the perforated IUD of medicated or closed type was also discussed. (e) Post-partum IUD insertion
An active discussion was generated among the participants who have had different experiences on this subject. The experience on post-placental insertion in the Philippines did not show any increase in complications or pregnancy rate and even increased acceptance rate. The only problem was expulsion which usually occurred during the first three months. It was felt that if post-placental insertion technique were more accepted by the improvement of both IUD design and technique, it would have a real impact in any family planning programme. Whether this technique would become acceptable and practical in all countries would somewhat depend on existing local conditions. If IUD is planned to be inserted post-partum, it should be done either immediately after the explusion of placenta with a specially designed inserter or with fingers, or seven to eight weeks after the delivery to avoid a possibility of perforation of the involuting uterus.
- 63/64 -
This technique could be utilized by trained midwives and even in homp. settings. (f) Future research on the IUDs
Any improvement of the present IUDs, such as reduction of the incidence of side-effects like bleeding, excessive menstrual blood loss, infection, ~ramps, spontaneous expulsion, together with reduction or accidental pregnancy rate would certainly increase the acceptance rate of thi8 particular contraceptive method.
- 65 ANNEX 1 LIST OF PARTICIPANTS, OBSERVERS, CONSULTANTS AND SECRETARIAT LISTE DES PARTICIPANTS, OBSERVATEURS, CONSULTANTS ET SECRETARIAT 1.
PARTICIPANTS Dr John Leeton Associate Professor Obstetrics and Gynaecology Monash University Wellington Road, Clayton Victoria 3168 Australia Mme Chang Chih-Fen Professor of Obstetrics and Gynaecology Capital Hospital of Chinese Academy of Medical Sciences c/o Ministry of Public Health Peking China Mme Hsiao Pi-Lien Deputy Chief of Obstetrics and Gynaecology Department No. 3 People's Hospital Shanghai Second Medical College c/o Ministry of Public Health Peking China Dr Lei Hai-Peng Associate Research Fellow Pharmacology Department Institute of Medico Materia Chinese Academy of Medical Sciences c/o Ministry of Public Health Peking China
AUSTRALIA AUSTRALIE
CHINA CHINE
COOK ISLANDS ILES COOK
Dr George Koteka Director of Public Health Department of Health Rarotonga Cook Islands Dr Timoci Uluivuda Bavadra Family Health Officer Ministry of Health Government Buildings Suva Fiji
FIJI FIDJI
- 66 Annex 1 GILBERT ISLANDS ILES GILBERT Dr Terenganuea Taaram Family Planning Officer Ministry of Health and Community Affairs P.O. Box 268 Bikenibeu Tarawa Gilbert Islands Dr Leticia V. Espaldon Family Health Officer Department of Public Health and Social Services Government of Guam Mangilao Guam Dr Margaret Chan Kwan Shuk-wa Medical Officer-in-Charge Family Health Service Lee Gardens Hysan Avenue Hong Kong Dr Luk Kwok-Fai Medical and Health Officer Tsan Yuk Hospital Hospital Road Hong Kong JAPAN JAPON Dr Toshitaka Nakahara Deputy Director Maternal and Child Health Division Children and Families Bureau Ministry of Health and Welfare 1-2-2, Kasumigaseki Chiyoda-ku Tokyo Japan Dr Shanta Sokhalingam State Medical Officer National Family Planning Board P.O. Box 416 Kuala Lumpur Malaysia Dr Sinniah Dharmalingam Head of Department and Consultant Department of Obstetrics and Gynaecology General Hospital Ipoh, Perak Malaysia
GUAM
HONG KONG
MALAYSIA MALA ISlE
- 67 -
Annex 1 NEW HEBRIDES NOUVELLES-HEBRIDES Dr Frank B. Spooner Medical Superintendent Base Hospital Vila, New Hebrides Dr Michel DuCorps Medecin de l'~pital franc~is de Santo Residence de France Port-Vila Nouvelles-Hebrides Dr R. L. Evans Specialist/Surgeon/ Gynaecologist Vila Base Hospital New Hebrides NEW ZEALAND NOUVELLE-ZELANDE Professor Richard J. Seddon Head, Department of Obstetrics and Gynaecology Wellington Clinical School of Medicine Wellington Hospital Wellington .2. New Zealand Dr Henry Aikebuse Registrar, Obstetrics and Gynaecology Port Moresby General Hospital Free Mail Bag Boroko Papua New Guinea Sister Kolis Uramar Palanga Training Officer Family Planning Section Department of Health P.O. Box 5948 Boroko Papua New Guinea PHILIPPINES Dr Nora Ignacio-Silao Chairman Department of Obstetrics and Gynaecology Deputy Programme Director Population and Family Planning Center College of Medicine Philippine General Hospital University of the Philippines System Manila Philippines
PAPUA NEW GUINEA PAPOUASIE-NOUVELLE-GUINEE
- 68 Annex 1 Philippines (continued) (suite) Dr Rosario Isidro-Gutierrez Project Director Research in Reproductive Medicine Philippine General Hospital University of the Philippines System Taft Avenue Manila Philippines Ms Ester B. Sy-Quimsiam Officer-in-Charge Clinical Services Division Commission on Population South Super Highway Makati Philippines REPUBLIC OF KOREA REPUBLIQUE DE COREE Dr In Sou Park Head, Department of Obstetrics and Gynaecology National Medical Centre 18-79, 6-Ka Ulchi-Ro, Choong-ku Seoul Republic of Korea
--
Dr Myon Woo Shin Professor Department of Obstetrics and Gynaecology College of Medicine Seoul National University 28 YeonKun-Dong, Chongno-ku Seoul Republic of Korea SAMOA Dr Viopapa Edwina Annandale Medical Officer-in-Charge of Family Welfare Centre National Hospital Private Bag Apia Samoa Dr Tanny Chan Tan Lai Lecturer Department of Obstetrics and Gynaecology Faculty of Medicine University of Singapore 121-B, Rose Garden, Amber Road Singapore 15 Singapore
SINGAPORE SINGAPOUR
- 69 Annex 1
SINGAPORE SINGAPOUR (continued) (suite)
Dr Choo Hee Tiat Consultant, Obstetrics and Gynaeco1ogy Kandang Kerbau Hospital Hampshire Road Singapore 8 Singapore Dr Ann Sarah Lee Tse-Ai Acting Deputy Medical Superintendent Maternal and Child Health Service Ministry of Health 26 Dunearn Road Singapore 11 Singapore
SOCIALIST REPUBLIC OF VIET NAM REPUBLIQUE SOCIALISTE DU VIET NAM
Dr Nguyen Thi Ngoc Trung Mouvement de p1anification familiale Departement de prophylaxie et des h8pitaux Ministere de 1a Sante Hanoi Repub1ique socialiste du Viet Nam Dr Nguyen Thi Xiem Vice-Directrice de l'Institut de 1a Protection de la Mere et du Nouveau-ne 43 Trang Thi Hanoi R~publlque socia1iste du Viet Nam
SOLOMON ISLANDS ILES SALOMON
Dr Daniel Maemaruki Principal Medical Officer (Obstetrics and Gynaecology) Ministry of Health and Welfare P.O. Box 349 Honiara Solomon Islands Dr Mumui Tato1a Medical Officer-in-Charge Maternal Child Health and Family Planning Vaiola Hospital P.O. Box 59 Tofoa Tonga
TONGA
- 70 -
Annex 1 TRUST TERRITORY OF THE PACIFIC ISLANDS TERRITOIRE SOUS TUTELLE DES ILES DU PACIFIQUE Ms Augusta R. Salii Public Health Nurse Specialist, MCH/CCS/FP MCH/CCS Division Department of Health Services Saipan, Mariana Islands 96950 Trust Territory of the Pacific Islands 2. 2.
OBSERVERS OBSERVATEURS Dr Khoo Kim Eng Consultant in Obstetrics and Gynaecology Malacca General Hospital Malaysia Dr Gerard F. Rolland UNFPA Regional Coordinator c/o The Regional Representative of the United Nations Development Programme in the Far East G.P.O. Box 618 Bangkok 2 Thailand Dr Theresa H. Van der Vlugt Population Advisor United States Agency for International Development Ramon Magsaysay Center 1680 Roxas Boulevard Manila Philippines Dr Martin J. de la Rosa II Associate Professor of Public Health Administration Institute of Public Health University of the Philippines System P.O. Box EA-460 Manila Philippines
INTERNATIONAL PLANNED PARENTHOOD FEDERATION (IPPF) FEDERATION INTERNATIONALE POUR LE PLANNING FAMILIAL (FIPF) UNITED NATIONS FUND FOR POPULATION ACTIVITIES (UNFPA) FONDS DES NATIONS UNIES POUR LES ACTIVITES EN MATIERE DE POPULATION (FNUAP)
UNITED STATES AGENCY FOR INTERNATIONAL DEVELOPMENT (USAID), MANILA, PHILIPPINES AGENCY FOR INTERNATIONAL DEVELOPMENT DES ETATS-UNIS D'AMERIQUE (AID), MANILLE
INSTITUTE OF PUBLIC HEALTH, UNIVERSITY OF THE PHILIPPINES INSTITUT DE SANTE PUBLIQUE DE L'UNIVERSITE DES PHILIPPINES
- 71 -
Annex 1
3. SEMINAR DIRECTOR DIRECTEUR DU SEMINAIRE
SECRETARIAT Dr Mark A. Belsey Medical Officer Special Programme of Research, Development and Research Training in Human Reproduction WHO Headquarters Geneva Dr E. Hyock Kwon Director Institute of Reproductive Medicine and Population and Dean, School of Public Health Seoul National University 28 Yon Keun Dong Seoul Republic of Korea Dr Takashi Wagatsuma Chief Consultant and Head Department of Obstetrics and Gynaecology National Medical Center Hospital No.1, Toyoma-cho Shinjuku-ku Tokyo 162 Japan
CONSULTANTS
TEMPORARY ADVISERS CONSEILLERS TEMPORARIES
Dr Ruben A. Apelo Director, Reproductive Biology Center Department of Obstetrics and Gynaecology College of Medicine University of the Philippines System Philippine General Hospital Taft Avenue Manila Philippines Dr Rebecca M. Ramos Deputy Project Director Jose Fabella Memorial Hospital Comprehensive Family Planning Center Lope de Vega Street Sta. Cruz Manila Philippines
- 72 Annex 1 TEMPORARY ADVISERS CONSEILLERS TEMPORARIES (continued) (suite) Professor S.S. Ratnam Head, Department of Obstetrics and Gynaecology University of Singapore Kandang Kerbau Hospital for Women Singapore 8 Singapore Dr G. Benagiano Scientist Special Programme of Research, Development and Research Training in Human Reproduction WHO Headquarters Geneva Dr E. Diczfalusy Director Reproductive Endocrinology Research Unit Karolinska Sjukhuset 104 01 Stockholm 60 Sweden Dr K. Fotherby Royal Postgraduate Medical School University of London Hammersmith Hospital London, W. 12 United Kingdom Dr J.W. Goldzieher . Director, Division of Clinical Science Southwest Foundation for Research and Education P.O. Box 28148 7480 West Commerce Street San Antonio, Texas 78228 United States of America Dr R.A. Grossman Epidemiologist Research Team for Evaluation of Fertility Control Methods Institute of Health Research Chulalongkorn University Bangkok Thailand
RESOURCE PERSONS (MEMBERS, STEERING COMMITTEE ON TASK FORCE ON INJECTABLES) PERSONNEL D'APPOINT (MEMBRES DU COMITE DIRECTEUR DU GROUPE DE TRAVAIL SUR LES SUBSTANCES INJECTABLES)
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Annex 1 SECRETARY SECRETAIRE DE SEMINAIRE Dr T.C. Hsu Regional Adviser on MCH/Family Planning WHO Regional Office for the Western Pacific Manila Philippines Dr M. Kacic-Dimitri Regional Adviser on MCH WHO Regional Office for the Western Pacific Manila Philippines Dr K. Edstrom Medical Officer, MCH WHO Headquarters Geneva
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ANNEX 2 PROGRAMME Mon~ay,
28 November Registration Opening of the Seminar Address by the Aoting Regional Direotor, Dr J.H. Hirshman Address by the Seminar Director, Dr M.A. Belsey "The role of the WHO in research on human reproduction" Introduction of participants, observers, secretariat
0800 - 0830 0830 .. 1000
1000 - 1030 1030 - 1100
Coffee break Election of officers Adoption of agenda
1100 - 1230
Agenda item 1: A review of the techniques of fertility regulation used in the Region Plenary session Introduction of topic: "Fertility regulation methods in the Western Pacific Region: an epidemiological overview" by Dr Kwon Agenda item 2: Advantages and disadvantages of the fertility regulating methods currently in use Plenary session lntroduction of topic by: Dr Wagatsuma
1230 - 1330 1330 .. 1530
Lunch break Working groups
-
An exchange of experiences in the family planning prograllDl1es and clinical practice in the partiCipant's country
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Annex 2 Tuesday, 29 November 0800 - 1000 "
'"
Agenda item 3: New de:velopments in ;aethods~.nd research in fertility regulation and family planning "' , Plenary session Introduction of topic: "Research trends in human reproduction with implications for fertility regulation", by Dr Diczfalusy Discussion
1000 - 1030 1030 • 1230
I
Coffee break Plenary session Agenda item 3 (continued) 1. "Recent developments in research on oral hormonal contraceptives" (a) (b) by: estrogen-p~ogestogen
combined
progestogen only Dr Goldzieher
Discussion 1230 - 1330 1330 - 1530 Lunch break Plenary session Agenda item 3 (continued) 2. Wednesday,30 November 0800 - 1000 Plenary session Agenda item 3 (continued) "Long-acting injectable agents" by Dr Benagiano
Discussion
3. -
"Non-medicated and medicated IUDs" by Dr Wagatsuma
Discussion
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Annex 2 Wednesday, 30 November (cont'd) 1000 - 1030 1030 - 1230 Coffee break Plenary session Agenda item 3 (continued) 4. "Sterilization" by Dr Apelo
Discussion 5. "Male methods" by Dr Fotherby
Discussion 1230 - 1330 1330 - 1530 Lunch break Plenary session Agenda item 3 (continued) 6. "Immunological approaches" by Dr Diczfalusy
Discussion 7. "Determination of the fertile period" by Dr Benagiano
Discussion Thursday, December Plenary session Agenda item 3 (continued) 8. "Induced Abortion" Dr Belsey by Dr Edstrom and
0800 - 1000
Discussion 9. 1000 - 1030 1030 - 1230 "Prostaglandins" by Dr Ratnam
Coffee break Discussion Agenda item 4: Implications of the new developments and research for family planning programmes
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Annex 2 Thursday, 1 December (cont'd.) Working groups Discussions on the implications of the introduction of these methods into family planning programmes: The requirements for training (skill and knowledge), facilities or other means of provision or distribution, screening, follow-up care and evaluation of safety and effects 123(l - 1330 1330 - 1530 Lunch break Working groups Agenda item 4 (continued) Friday, 2 December 0800 - 1000 Working groups Agenda item 4 (continued) 1000 - 1030 1030 - 1230 Coffee break Working groups. Agenda item 4 (continued) 1230 - 1330 1330 1530 Lunch break Plenary session "The role and areas of research for the improvement of family planning programmes" by Dr Belsey Discussion Saturday, 3 December 0800 1000 Plenary session General discussion of the report on the country experiences. in respect to the "advantages and disadvantages of the fertility regulating methods currently in use"
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Annex 2 Saturday, 3 December (cont'd) 1000 - 1030 1030 - 1230
Coffee break Plenary session General discussion of the report on "the implications for the introduction of the fertility regulating methods into . family planning programmes" Closing
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ANNEX 3 LIST OF MATERIALS DISTRIBUTED TO THE PARTICIPANTS* Appendices to the Final Report Appendix Opening Address of the Acting Regional Director 2
Opening Address of the Seminar Director Fertility Regulation Methods in the Western Pacific Region: An Epidemiological Overview by Dr E.H. Kwon, Director, Institute of Reproductive Medicine and Population and Dean, School of Public Health, Seoul National University, Seoul, Republic of Korea Advantages and Disadvantages of Different Fertility Regulating Methods by Dr T. Wagatsuma, Chief Consultant and Head, Department of Obstetrics and Gynaecology, National Medical Center Hospital, Tokyo, Japan Research Trends in Human Reproduction with Implications for Fertility Regulation by Dr E. Diczfalusy, Director, Reproductive Endocrinology Research Unit, KarolinskaSjukhuset, Sweden Home-visiting Antifertility Pills by Dr Hsiao Pi-Lien, Deputy Chief of Obstetrics and Gynaecology Department, No.3 People's Hospital, Shanghai Second Medical College, China One-Pill-a-Month Contraceptive by Dr Lei Hai-Peng, Associate Research Fellow, Pharmacology Department, Institute of Medico Materia, Chinese Academy of Medical Sciences, China Non-medicated and Medicated Intra-uterine Contraceptive Devices by Dr T. Wagatsuma, Chief Consultant and Head, Department of ,Obstetrics and Gynaecology, National Medical Center Hospital, Tokyo, Japan.
3
4
5
6
7
8
*Compiled in a document issued as appendices to the final report. Copies are available on request from the World Health Organization Regional.Office for the Western Pacific.
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Annex 3 9 Fifteen Years of Use of Contraceptive Methods in Family Planning in Viet Nam: Impact on Demography by Dr Nguyen Thi Xiem, Assistant Director, Institute for the Protection of the Mother and the Newborn, Hanoi, Socialist Republic of Viet Nam Sterilization Technology by Dr R. Apelo, Director, Reproductive Biology Center, Department of Obstetrics and Gynaecology, College of Medicine, University of the Philippines, Manila, Philippines Techniques of Induced Abortion: Their Health Implications and Service Aspects by DrK. Edstrom, Medical Officer, Maternal and Child Health, WHO Headquarters, Geneva Prostaglandin in Human Reproduction by Professor S.S. Ratnam and Professor S.M.M. Karim, Department of Obstetrics and Gynaecology, University of Singapore, Kandang Kerbau Hospital, Singapore 8, Republic of Singapore
10
" 12