Administration of iodized oil during pregnancy: a summary of the published evidence.

Reviews/Analyses Administration of iodized oil during pregnancy: a summary of the published evidence* F. Delange1 This brief review of the available studies confirms that the administration of iodized oil before or during pregnancy prevents endemic cretinism and brain damage by correcting iodine deficiency and thyroid function in pregnant women, fetuses, neonates, infants and children. The potential benefits derived from using iodized oil immediately before or during pregnancy greatly outweigh the potential risks in areas of moderate and severe prevalence of iodine-deficiency disorders, where iodized salt is not yet available. The administration of iodized oil to entire popu- lations, and especially to women of childbearing age and during pregnancy, has been proposed as an emergency prophylactic and therapeutic approach in areas with severe iodine deficiency complicated by endemic cretinism where universal salt iodization has not yet been successfully introduced (1). This procedure prevents brain damage due to iodine defi- ciency in the fetus and the neonate. Findings Iodized oil programmes have conclusively been shown to be effective in preventing and treating endemic goitre, and also in preventing endemic cretinism (2-13) and the alterations of neuropsycho- intellectual development which are frequently en- countered in non-cretinous individuals (13-38). However, adverse side-effects have been reported in non-pregnant adults due to the administration of iodine far in excess of physiological need. For exam- ple, in a pilot study of 14 subjects in the Solu region of the Nepalese Himalayas, Croxson and colleagues (39, 40) reported a significant fall in serum T3 * This article in based on material presented at a WHO Consulta- tion on the Safety of Iodized Oil for Pregnant Women, Geneva, 13-14 September 1994. See also: Safe use of iodized oil to prevent iodine deficiency in pregnant women on pages 1-3 of this issue. Requests for reprints should be sent to Nutrition Unit, World Health Organization, 1211 Geneva 27, Switzerland. Department of Paediatrics, H6pital Saint-Pierre, Brussels, Belgium. Reprint No. 5679 (triiodothyronine) and a rise in serum TSH (thyroid- stimulating hormone) concentrations over a period of 4-10 days (mean, 6 days) in 8 subjects with small goitres soon after receiving intramuscular (IM) in- jections of 400mg of iodine in oil, which suggests an acute inhibitory Wolff-Chaikoff effect. In addition, three other subjects with large multinodular goitres developed biochemical hyperthyroidism. These findings in pilot studies are compatible with well- documented iodine-induced thyrotoxicosis which occurred in severely iodine-deficient populations fol- lowing the introduction of iodine prophylaxis by iodized salt (41-46). There are a few reports of iodiz- ed oil-induced hyper- or hypothyroidism in public health programmes, sporadic cases of hyperthy- roidism having been reported from Ecuador (47), Peru (48) and Argentina (49), but these were not detected in large-scale programmes in New Guinea (2,50), Zaire (6, 9,12,51), Nepal (38,40,52), Algeria (53), Indonesia (54, 55) and China (56, 57). Since many of these interventions were conducted under particularly difficult environmental conditions, ad- verse reactions to therapy could easily have escaped detection (58). In contrast, detailed studies have been carried out on the effects of iodized oil administered to women just before or during pregnancy with special attention to the short- and long-term side-effects of iodized oil on thyroid function in the mother, neonate, infant and child (59). In carefully executed studies in New Guinea on the effects of iodized oil administered before or during pregnancy to prevent endemic cretinism (4, 11), biological tests examining thyroid function were rarely available (20, 22) be- cause of particularly difficult environmental condi- Bulletin of the World Health Organization, 1996, 74 (1): 101-108 © World Health Organization 1996 101 0C a) c U) C ;D cEu a) CIO 0 'a cou 0. C E.: U5: O:acoo I ;-Z D E C) '. ..I HD 0) CE " U)o 0) )D C E -0c D C;) a) c E -ocD .C I.c c a) U) U) .C 0 E Cb 'a) .O CY) .C o Gr 0) Il S. a) Cl) a) C) C E -5C CH( C o) _ >25- Co a)~~~~~~-5 E N -° S -F o a) 0'- o . 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C. 0.LO +1 Cf) cl) m 0) C\j P- C.) co .0 IC -:i-: +1 C `< 1: 't (f) +1 +1 -.C U) +I (D , o Lo 'ra .- U) 'a .- co +1 N 70 +1U- 0 CD -0 "t 0 OD o (n LoQ) E 6 E c\i o c. co cts CM .Q) coS.) (q Ln ?-' 2 - c I Q) 2 E c\jV A Co 4)Ca co 4) ;r M cn -4 M cu cts :3(U C: C\l C Q) C.C F- F-Q, a U) (D 0 U) C/) co co C co CZ V 0 >(D Q. .N E N 0 CL 0 a &- E m 0 0 0 0C m cu > C (D wco +2 4 E 0 r- cq0 cq a) C/56 cD r-0 7. ct$ C U-) a) cn0 C co cou a. 0- CDE CL (D E0 o E CD 0 cn m +1 0 a) CDQ) m CDZ) C6 0 (D CUCD O E2CZ 0 0 CD C) 7E 0(D Co CD0 (D 4) =L- 0-0- Eco CU -o0,> 0) > C0 $D LO CD n a. 13"- WHO Bulletin OMS. Vol 74 1996 103 F. Delange tions. Pharoah (4) reported very low levels of serum protein-bound iodine (PBI) in untreated mothers who delivered cretins, whereas normal values were still found in treated mothers who delivered normal infants 3-4 years after receiving iodized oil injec- tions. Pretell and colleagues (60) reported that in an area of severe iodine deficiency in the Peruvian An- des (daily urinary excretion of iodine, 25 jg; preva- lence of visible goitre, 52-59%; and prevalence of cretinism, 1.0-3.6%), umbilical cord serum T4 (thy- roxine) and free T4 levels were much lower, and TSH levels higher, than in controls from an iodine-replete area. The results for the same variables were normal in neonates born to mothers injected with iodized oil before or during early pregnancy. No adverse side- effects were observed either in mothers or neonates. The most detailed studies of iodized oil given during pregnancy have been conducted in Zaire (7- 9,12,61-65), Algeria (66,67) and Malawi (65,68) in areas of severe iodine deficiency and endemic goitre, complicated by cretinism (Table 1). The doses of iodized oil were 1 ml IM (480mg I) in Zaire, and 0.5 ml IM or orally in Algeria and Malawi. Time of administration varied from just before pregnancy in Algeria to the third trimester of gestation in Zaire. The result was a systematic and dramatic increase in maternal iodine supply, with only occasional iodine overload (5% of treated women in Zaire had urinary iodine levels above 1000 ,ug/dl at the time of deliv- ery). Nevertheless, thyroid function in mothers, which frequently indicates hypothyroidism in the absence of therapy, was normal in all treated mothers at delivery; their serum TSH, T4 and T3 levels were similar to those observed in mothers in iodine-replete areas (69, 70). In addition, not a single woman exhibited biochemical evidence of hyperthyroidism and the prevalence of goitre markedly decreased in those who had been treated. In the absence of therapy for mothers, thyroid function was severely impaired in a large number of neonates (in the Ubangi area of Zaire, 14% of in- fants had cord serum TSH above 100 ,uU/ml and T4 below 4 ,ug/dl). The extent of deviation from normal values in infants was more severe than in mothers and was directly related to the severity of the iodine deficiency and hypothyroidism present in mothers. Once again, iodized oil administered to mothers en- tirely normalized the thyroid function in neonates, and the correction occurred regardless of the stage of pregnancy- from the first month to late in the third trimester - at the time of therapy. In seven years of follow-up after treatment of mothers with iodized oil, no case of hyperthyroidism was reported in either mothers or children. Depend- ing on the dose and the stage of pregnancy at which it was given, the status of iodine nutrition of infants and children (evaluated by ascertaining urinary iodine concentrations) progressively deteriorated with age, reverting to the degree of iodine deficiency found in untreated individuals from the age of 2 years onwards. Nevertheless, clinical and biochemi- cal hypothyroidism was largely prevented in infants born to treated women, and when they occurred, they were frequently transient in nature. Finally, treating pregnant women with iodized oil resulted in decreased incidence of abortions, prematurity and stillbirths, and an increased birth weight. These positive results stand out in contrast to the interpretation of the results of a single study, which has frequently been reported in the literature in the last decade (20, 71-74). The study was con- ducted in parts of Bhutan and India known for severe iodine deficiency (more than 50% of the population with urinary iodine/creatinine ratio be- low 25 gig/g creatinine and goitre prevalence varying from 60% to 80%). Iodized oil (1 ml IM) was admin- istered to schoolchildren, women of reproductive age, and pregnant women. Cord serum TSH and T4 were measured in a group of 154 neonates born to mothers who had been injected during the second half of the third trimester of pregnancy (mean of 3.5 weeks before delivery). Selection criteria for neonates and the range of the time interval between injection and delivery were not reported. Sixteen of the 154 infants (10.4%) had cord serum TSH above 50 mU/l and cord T4 below 3 gg/dl, indicating neonatal biochemical hypothyroidism. The investi- gators concluded that the iodized oil administered during pregnancy induced thyroid failure in the neonates, and consequently that oil therapy should be rejected as a prophylactic measure during preg- nancy. This interpretation is seriously to be questioned for two reasons. First, in the absence of results for urinary iodine in mothers, there is no evidence that the mothers were indeed injected and were iodine overloaded. Second, and more important, the same incidence of neonatal biochemical hypothyroidism (7.5-13.3%) was reported in the study areas in the absence of an iodized oil programme. Consequently, the study provides no evidence that the iodized oil administered to pregnant women had adverse effects on the neonates. Conclusion Detailed studies provide conclusive evidence that the administration of iodized oil prior to, or during, pregnancy prevents endemic cretinism and brain damage by correcting iodine deficiency and thyroid function in pregnant women, fetuses, neonates, in- WHO Bulletin OMS. Vol 74 1996104 Administration of iodized oil during pregnancy fants and children. To prevent neurological damage, it is crucial that iodine deficiency be corrected before or during early gestation. Correction of maternal, fetal and neonatal hypothyroidism can occur at any time during pregnancy, including the last trimester. The duration of postnatal correction of thyroid func- tion depends on the dose of iodized oil administered to the mother, e.g., about two years for 1 ml iodized oil administered orally or IM, but only 6 months for half this dose. Despite the massive doses of iodine administered, no iodine-induced thyroid function abnormalities have ever been conclusively demon- strated at the time of delivery or in the short- or long- term follow-up of pregnant women and their offspring. The potential benefits derived from using iodized oil immediately before or during pregnancy greatly outweigh the potential risks in areas of mod- erate and severe prevalence of iodine-deficiency dis- orders, where iodized salt is not available or unlikely to be available within 1-2 years. Resume Administration d'huile iodee pendant la grossesse: resume des etudes publiees Des 6tudes detaillees montrent de fa9on con- cluante que I'administration d'huile iod6e avant ou pendant la grossesse contribue a pr6venir le cr6tinisme end6mique et les I6sions c6r6brales en corrigeant la carence en iode et la fonction thyroTdienne chez la femme enceinte, le foetus, le nouveau-n6, le nourrisson et l'enfant. Pour pr6venir les lesions neurologiques, il est essentiel de cor- riger la carence en iode avant la grossesse ou au debut de celle-ci. La correction de I'hypothy- roidisme maternel, fcetal et n6onatal peut se faire a n'importe quel moment de la grossesse, meme au cours du dernier trimestre. La dur6e de la correction post-natale de la fonction thyroidienne d6pend de la dose d'huile iod6e administree a la mere; elle est par exemple d'environ deux ans apres administra- tion de 1 ml par voie orale ou intramusculaire, mais seulement de six mois pour 0,5 ml. En d6pit des doses massives d'iode qui ont ete administr6es, aucune anomalie de la fonction thyroTdienne in- duite par cet element n'a ete demontr6e de fagon concluante au moment de l'accouchement ou ult6rieurement chez les femmes enceintes et leurs enfants qui ont fait l'objet d'un suivi a court ou a long terme. Les avantages potentiels de I'administration d'huile iod6e imm6diatement avant la grossesse ou au cours de celle-ci compensent largement les risques potentiels dans les regions ou la pr6- valence des troubles dus a une carence en iode est mod6r6e a forte et ou l'on ne pr6voit pas de dis- tribution de sel iode avant un an ou deux. References 1. Dunn JT. The use of iodized oil and other alternatives for the elimination of iodine deficiency disorders. In: Hetzel BS, Pandav CS, eds. S.O.S. for a billion. The conquest of iodine deficiency disorders. New Delhi, Oxford University Press, 1994: 108-117. 2. Buttfield IH, Pharoah POD, Hetzel BS. 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