Oral contraceptives and congenital limb defects During 1973 a number of papers appeared in The Lancet in which an association was claimed between congenital malformations in the fetus and exogenous exposure to sex steroids during pregnancy. The steroid might have been supplied to the mother in the form of a pregnancy test or as supportive hormone therapy during pregnancy, or the mother might have experienced a breakthrough pregnancy while using an oral contraceptive. This association has been examined retrospectively by Janerich, Piper and Glebatis' from the Birth Defects Institute in Albany, New York, by comparing 108 children with congenital limb-reduction defects with a corresponding number of normal children. Data were obtained from birth certificates and subsequent interviews with the parents, and the parents were matched for race and maternal age. There are no striking features in the two series to account for the presence of limb defects in the proband series except for exposure to exogenous sex hormones. In their report Janerich and colleagues note that 15 of the series of mothers with malformed children had a history of exposure to sex steroids, whereas only 4 of the mothers of normal children were so exposed. Of the 15 mothers with affected children 11 had received hormones by mouth. Six of the mothers with affected children and one mother with a normal child had become pregnant while using a contraceptive pill. There is no reason to attribute any of these failures, mostly associated with a combination-type preparation, to improper use of the contraceptive pill. In two cases twins were born and one twin in each case
was malformed. The authors also note that mothers of affected children tended to become pregnant immediately after discontinuation of the pill, that is, during a period when effects of the contraceptive were persisting. This finding might, on the other hand, mean that mothers of affected children rapidly recovered from the influence of oral contraceptives and were therefore more likely to become pregnant. A most striking finding is that six affected infants whose mother had a history of "pill failure" and five affected infants exposed to other types of orally administered sex steroids during pregnancy were all males. Among the affected infants exposed to parenterally administered sex steroids there were three females and one male. It seems that there is a sex-specific effect limited to cases in which the hormones are taken orally during pregnancy. Since orally ingested progestins are believed to have different effects on developing male and female fetuses, this may be the basis of the sex-specific effect. If oral contraceptives can cause limbreduction deformities, the frequency of such deformities should have increased during recent years. A scrutiny of the records by the authors suggested that the frequency has indeed increased in recent years, gradually and irregularly, with the highest rate in 1973 (0.24 per 1000 births). However, this secular eftect should be interpreted with caution until it is confirmed elsewhere. It is still an open question whether such an association, if proved, is causal or secondary. Obviously the great majority of pregnancies preceded by use of oral contraceptives do not result in defective offspring, so that some type
of maternal predisposition is probably necessary before malformation can occur. In an accompanying editorial2 Nora and Nora, who have previously discussed the relation between birth defects and oral contraceptives,3 summarize their data, in which a preponderance of affected males after exposure to progestogen-estrogen was also found. Their list of anomalies associated with the use of these hormones includes vertebral, anal, cardiac, tracheal, esophageal, renal and limb (VACTERL group) defects. Again we are dealing with a relatively uncommon effect, and the only positive action recommended by both the Noras and Janerich and colleagues is to discontinue the use of hormonal pregnancy tests. In addition, further research is needed to develop oral contraceptives for which the breakthrough pregnancy rate is minimized. References 1. JANERICH DT, PIPER JM, GLEBATIS DM: Oral
contraceptives and congenital limb-reduction defects. N Engi I Med 291: 697, 1974 2. NORA JJ, NORA AH: Can the pill cause birth defects? (editorial). Ibid, p 731 3. Idem: Birth defects and oral contraceptives (correspondence). Lancet 1: 941, 1973
Erratum In the article "Hepatitis B antigen in Montreal blood donors: childhood institutionalization as an epidemiologic factor" by Richer et al in the Jan. 11 issue of the Journal (112: 49, 1975) line 34, column 2, page 51 should read "One donor could not be confirmed by us to be HBAg-.
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was malformed. The authors also note that mothers of affected children tended to become pregnant immediately after discontinuation of the pill, that is, during a period when effects of the contraceptive were persisting. This finding might, on the other hand, mean that mothers of affected children rapidly recovered from the influence of oral contraceptives and were therefore more likely to become pregnant. A most striking finding is that six affected infants whose mother had a history of "pill failure" and five affected infants exposed to other types of orally administered sex steroids during pregnancy were all males. Among the affected infants exposed to parenterally administered sex steroids there were three females and one male. It seems that there is a sex-specific effect limited to cases in which the hormones are taken orally during pregnancy. Since orally ingested progestins are believed to have different effects on developing male and female fetuses, this may be the basis of the sex-specific effect. If oral contraceptives can cause limbreduction deformities, the frequency of such deformities should have increased during recent years. A scrutiny of the records by the authors suggested that the frequency has indeed increased in recent years, gradually and irregularly, with the highest rate in 1973 (0.24 per 1000 births). However, this secular eftect should be interpreted with caution until it is confirmed elsewhere. It is still an open question whether such an association, if proved, is causal or secondary. Obviously the great majority of pregnancies preceded by use of oral contraceptives do not result in defective offspring, so that some type
of maternal predisposition is probably necessary before malformation can occur. In an accompanying editorial2 Nora and Nora, who have previously discussed the relation between birth defects and oral contraceptives,3 summarize their data, in which a preponderance of affected males after exposure to progestogen-estrogen was also found. Their list of anomalies associated with the use of these hormones includes vertebral, anal, cardiac, tracheal, esophageal, renal and limb (VACTERL group) defects. Again we are dealing with a relatively uncommon effect, and the only positive action recommended by both the Noras and Janerich and colleagues is to discontinue the use of hormonal pregnancy tests. In addition, further research is needed to develop oral contraceptives for which the breakthrough pregnancy rate is minimized. References 1. JANERICH DT, PIPER JM, GLEBATIS DM: Oral
contraceptives and congenital limb-reduction defects. N Engi I Med 291: 697, 1974 2. NORA JJ, NORA AH: Can the pill cause birth defects? (editorial). Ibid, p 731 3. Idem: Birth defects and oral contraceptives (correspondence). Lancet 1: 941, 1973
Erratum In the article "Hepatitis B antigen in Montreal blood donors: childhood institutionalization as an epidemiologic factor" by Richer et al in the Jan. 11 issue of the Journal (112: 49, 1975) line 34, column 2, page 51 should read "One donor could not be confirmed by us to be HBAg-.
CMA JOURNAL/MARCH 8, 1975/VOL. 112 551
