MODERN TRENDS Edward Wallach, M.D. Associate Editor
Vol. 28, No.8, August 1977 Printed in U.S.A.
FERTILITY AND STERILITY Copyright © 1977 The American Fertility Society
ARE HORMONAL CONTRACEPTIVES TERATOGENIC?
LALIT M. AMBANI, M.D.* NARENDRA J. JOSm, M.Sc. RAMA A. VAIDYA, M.D., D.G.O., D.F.P. P. K. DEVI, M.S., F.R.C.S., F.A.M.S.t Institute for Research in Reproduction, Parel, Bombay-400 012, India
These two aspects of the teratogenicity of the hormonal contraceptive drugs are reviewed separately in this communication. The experimental teratologic work is also presented.
The introduction of sex hormones as oral contraceptive pills has been a revolutionizing factor in the field of family planning. The pill, 'Nhich contains either estrogens alone or an estrogenprogestogen combination, is the most effective method of contraception, and its wide use can reduce the growth of population considerably. An editorial in the Lancet! asserts that "Posterity may decide that the greatest contribution of the twentieth century to the health of mankind was not a vaccine, an antibiotic, or a transplant but the contraceptive pill." However, since the pill may be used by millions of women over many years, its safety must be ascertained. Many minor and major side effects have been ascribed to regular use of the pill. Of great concern, and the subject of this review, are the reports of the possible harmful effects on the offspring of women who receive hormonal contraceptives. The initial reports of teratogenicity mainly conconcerned the possibility of an increased rate of congenital malformations following the use of hormonal contraceptives during early pregnancy: first, as a therapy for threatened abortion; second, as a pregnancy test; and third, as oral contraceptives administered inadvertently to women who had just become pregnant or to some women who were already using these agents and continued to ingest them even after becoming pregnant. The later reports also considered the teratogenic potential of oral contraceptives when these agents were discontinued prior to pregnancy.
HORMONAL CONTRACEPl'IVES DURING PREGNANCY
Dubowitr reported a female with virilization and malformations of the urogenital sinus derivatives and internal genitalia. Since this report several isolated reports have appeared of females with virilized external genitalia. However, Smithells3 did not find any evidence of teratogenicity of the hormonal contraceptives. In 1967 Gal et al. 4 ascribed a congenital malformation, not related to the reproductive tract, to the use of hormonal contraceptives. Since then, a number of congenital malformations have been considered to increase in frequency in the offspring of women who had received contraceptive hormones during pregnancy.
Neural Tube Defects Gal et al. 4 reported that a significantly higher number of mothers of children with neural tube defects had received pregnancy test tablets as compared with control mothers. An epidemiologic survey in 1971,5 however, failed to reveal such an association. Gal 6 then reanalyzed her data and found that, even after excluding mothers with any predisposing factors such as advanced age and chronic infections, the difference was still significant. Again, Oakley et al. 7 failed to observe any increase in the frequency of use of pregnancy tests in mothers of children with neural tube defects as compared with controls. In all studies except those of Gal, the evidence is against such an association. On the basis of embryologic data,
Received May 18, 1977; accepted June 22,1977. *Reprint requests: Dr. Lalit Ambani, Senior Research Officer, Division of Genetics, Institute for Research in Reproduction, Jehangir Merwanji Street, Parel, Bombay-400 012, India. tPresent address: Postgraduate Institute of Medical Education and Research, Chandigarh-ll, Punjab, India.
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Sever" argued that, since the neural tube is formed and closed by the 4th week of gestation, open lesions of the spine such as myelomeningocele or spina bifida must develop at about that time. Since the average interval between conception and the pregnancy test was 5.6 weeks in the study by Gal et a1.,4 a large proportion of these mothers probably received the hormones after the complete formation of the neural tube. Congenital Cardiovascular Disease Levy et al.9 noted a high incidence of hormone treatment in pregnancies leading to the birth of infants with transposition of great vessels. Of 76 mothers interviewed, 7 gave a history of sex hormone ingestion during the first trimester: 6 had been treated for threatened abortion and 1 had had a pregnancy test. In the control group there was no history of administration of sex hormones. Nora and Nora10 reported progestogen-estrogen intake during pregnancy in 20 of 224 cases of congenital heart disease as compared with 4 of262 controls. They noted an apparent excess of malformations involving great vessels, most often a transposition. However, at the Johns Hopkins Hospital, Mulvhill et a1. 11 studied 88 patients with transposition of great vessels and compared them with those with ventricular septal defect. In each group, 4% to 5% of mothers had had firsttrimester exposure to sex hormones.
VACTERL Anomalies The defects described under the acronym VACTERL are: V for vertebral, A for anal, C for cardiac, T for tracheal, E for esophageal, R for renal or radial, and L for limb malformations. The anomalies of these simultaneously developing structures may remind one of the thalidomide syndrome. However, they present much less consistency of pattern. Nora and Nora 12 reported that of 15 patients with VACTERL syndrome, the mothers of 9 had received hormones during early pregnancy. This incidence was significantly higher than that for mothers in two control groups-those with chromosomally abnormal children and those with normal children. Two more mothers of patients with this group of anomalies have been reported to have ingested hormonal contraceptives during early pregnancy. Balci et a1. 13 had a patient with V ACTERL anomalies whose mother had ingested oral contraceptives 10 months before conception and 1 month into pregnancy. However, the patient's maternal
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grandmother was also affected, having had two siblings with spina bifida and sacralization of the 5th lumbar vertebrae. In a second infant with VACTERL anomalies, there was no history of the mother's having ingested sex hormones before or during pregnancy. These authors thought that the somewhat similar involvement of the grandmother in the first case indicated that exposure to oral contraceptives may have precipitated the syndrome in the first child who was genetically predisposed. Kaufmann14 reported one patient with VACTERL syndrome whose mother had received 'oral stilbestrol and parenteral progesterone for 2 months beginning 47 days after the last menstrual period. Cleft Lip/Cleft Palate Brogan15 reported that in 22 of 222 cases of cleft lip and/or cleft palate, the mothers had received pregnancy tests between the 5th and 8th weeks of gestation. Since the frequency of similar tests in controls was not determined, no conclusion can be drawn. No other study has indicated an increased incidence of this malformation following exposure to hormonal contraceptives. Limb Defects Janerich et a1}6 studied 108 mothers of patients with limb-reduction defects and compared them with mothers of normal infants. The defects were defined as absence of the whole or a part of any limb. The controls were matched for race and maternal age. A total of 15 mothers in the study group, compared with 4 in the control group, had received steroid hormones during pregnancy. All Malformations Unlike the studies referred to above, in which index patients were those who had a specific anomaly, in the Jerusalem perinatal study17 11,468 mothers were interviewed for history of drug ingestion during pregnancy. Malformations-minor and major-were found in 432 babies; 47 of these were born after exposure to sex hormones during early pregnancy. The incidence of ingestion of sex hormones during pregnancy was significantly higher in mothers of malformed babies (10.9%) than in the remainder of the women (7.8%). The question of sex hormone ingestion was not asked of mothers specifically; women with a "probable" history of having received sex hormones were also included, and the controls were not clearly defined.
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ARE HORMONAL CONTRACEPTIVES TERATOGENIC?
The prospective survey by Nora et aps of 100 liveborn infants exposed to hormonal contraceptives during the first trimester of pregnancy revealed 6 with "major" malformations. Of these, four had congenital cardiovascular disease and one had VACTERL anomalies. No controls were provided. A variety of malformations were arbitrarily defined as major or minor. Hence, the 2- to 4-fold increase does not seem to be meaningful. Thus far, the reports cited above have dealt with hormones given as a pregnancy test or for treatment of threatened abortion. There is very scant information on the outcome of pregnancy following inadvertent use of oral contraceptives during the early days of pregnancy. In a recent report by the Royal College of General Practitioners,19 136 women gave histories of receiving oral contraceptives inadvertently during early pregnancy. Of these pregnancies, 102 went to term. There were seven abnormal infants, of whom only two had obvious congenital malformations. This rate is the same as that found in other liveborns. Three of the pregnancies resulted in stillbirths. Since no details of postmortem studies of the stillborn infants are available, significant internal malformations may have been overlooked. The number of cases in this report is small and hence the role of pilIs unknowingly ingested during early pregnancy in causing congenital malformations is not yet clear.19
Comments There are many problems in documenting a definite increase in the frequency of the specific congenital malformations discussed above. First, all of these malformations are rare, and in order to detect a small increase the control and study populations must be large. Second, in retrospective studies such as most of those cited above, appropriate controls are difficult to obtain. Of course, these surveys, along with the case reports, serve as a warning signal. Appropriate prospective surveys to study the progeny of women who had used hormonal contraceptives during or before pregnancy could give us much more definitive data. Data collection along these lines is said to be in progress. 14 Many of the women in the above studies had received hormonal contraceptives as therapy for threatened abortion. If the threatened abortion is due to a chromosomal or genetic abnormality in the offspring, hormonal contraceptives may falsely be ascribed to be the cause of
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the congenital malformation. Hence, it is important to be aware of this potential bias in many studies reported above, which perhaps should have used untreated patients with threatened abortion as control. THE PILL AND THE OUTCOME OF SUBSEQUENT PREGNANCIES
Thus far we have reviewed the potential teratogenic effects of contraceptive hormones administered during early pregnancy. In the following section the literature is summarized regarding the outcome of pregnancies in women who had been - exposed to sex steroids prior to pregnancy.
Congenital Malformations Robinson20 conducted a controlled study in a maternity hospital in Halifax, Nova Scotia. He paired 1250 births in women who had previously used oral contraceptives with those in women who had never used the pilI; the women were matched for maternal age and parity. There were no significant differences in the rates of congenital malformations between the study group (36.2%) and the control group (31.1%). Janerich21 analyzed the same data according to maternal age and severity of defect. He concluded that a small increase in most of the study groups should not be considered as negative results. In two other studies,22. 23 the incidence of a specific malformation or of total congenital malformations in the former pilI-users was not found to be increased.
Abortion Rate In Robinson's study20 239 women gave a history of a previous pregnancy prior to which they had also used oral contraceptives. Of these , 22% ended in an abortion. No controls, however, were included. Peterson22 conducted a prospective survey of 442 pregnant women who had used oral contraceptives and compared them with 699 controls. The abortion rates of 9.2% and 8.6% in the two groups were not significantly different. In the study by the Royal College of General Practitioners23 a 20.9% spontaneous abortion rate was reported in the ex-pilI-taker group as compared with 12.3% among the non-pilI-users. The difference was attributed to an increased likelihood of ex-pilI-users having had an induced abortion if they became pregnant. To support this thesis the authors reported that the abortion rate in ex-pilI-takers who "desired pregnancy" was only 13.4%. However, the report failed to make
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a similar adjustment for nonusers. This defect of the study was rectified in the more recent report by the same group19 on the outcome of 3528 pregnancies following oral contraceptives as compared with 4551 controls. They divided both groups into young and old mothers. The rate of abortion was not significantly different between the two groups of younger mothers. The increased rate of abortion in older mothers (age 35 years or above) who had used oral contraceptives was due to a significantly higher rate of induced abortion in this group as compared with controls.19 Poland and Ash 24 studied spontaneous abortuses from former pill-users and compared them with abortuses from controls. They found that, whereas the systemic anomalies in the fetuses were comparable in the two groups, the incidence of severe growth disorganization was significantly higher in the former pill-users.
Cytogenetic Abnormalities
In Spontaneous Abortuses. Chromosome studies in 281 spontaneous abortuses from women who had conceived within 6 months of discontinuing oral contraceptives revealed a rate of 48% abnormal as compared with 22% in the control groUp.25 The increase in chromosomal aberrations was mainly accounted for by an increase in the incidence of triploidy. Trisomies and 45,XO karyotypes were found with equal frequency in both groups. Alberman et ap6 were able to karyotype 992 of 2620 spontaneous abortuses. They found an excess of approximately 20% in the proportion of abnormal karyotypes in the aborted fetuses of women who had used oral contraception for more than 18 months. The small increase in proportion of chromosomal anomalies applied to all types, viz., trisomy, triploidy, tetraploidy, and 45,XO. The chromosome study by Lauritsen 27 on products from 254 spontaneous abortions showed a 60% rate of abnormal karyotypes in the postoral contraceptive group as compared with 49% in the control group. The difference was not significant. There was, however, a highly significant. maternal age difference between the two groups. It is known that several karyotype abnormalities occur more frequently with age. The fact that the post-oral contraceptive group was younger than the controls could have masked the difference between the two. In Newborns. The only study which addresses itself to the relationship of a specific chromosomal anomaly in newborns and the ingestion of hor-
monal contraceptives is that of Janerich et ap8 One hundred and three mothers of patients with Down's syndrome were compared with normal matched controls. There was no increased incidence of pill usage among the mothers of patients with Down's syndrome. This finding suggests that nondisjunction does not increase following the use of hormonal contraceptives. In Cultured Lymphocytes. In vitro studies of the effect of synthetic hormonal contraceptives on the incidence of chromosome breakages in lymphocytes and fibroblasts from control women and women taking oral contraceptives demonstrated no difference in the two groupS.29 Cytogenetic studies of peripheral leukocyte cultures in seven women were performed prior to and after 1 and 2 months of oral contraceptive use. 30 No significant change in chromosome breaks or mitotic index was revealed when each of the seven women served as her own control. These results differ from other in vivo studies which did not use each patient as her own controJ.31. 32
Comments The weight of the evidence from the reports cited above suggests that the rate of occurrence of congenital malformations or a specific chromosomal abnormality in the newborns is not increased. However, the incidence of specific chromosomal abnormalities in the abortuses may increase. No effects on the chromosome morphology in vivo are found. EXPERIMENTAL TERATOLOGY
The reports on the effects of sex hormones on the development of embryos and fetuses appear to be focused mostly on the genital organs.
Estrogens Estrogen treatment during pregnancy causes masculinization of female offspring-their Wolman ducts differentiate partially and the typical female development ofthe urogenital sinus is partly inhibited. 33 On the other hand, in male fetuses, estrogen administration can have profound feminizing effects on sex differentiationtheir Mullerian ducts persist partially; Wolffian ducts are suppressed; and there is marked inhibition of epididymides, seminal vesicles, and ventral prostates. 33 In addition, estrogen administration during pregnancy can produce anomalies in mammary gland differentiation34 and cleft palate formation. 35
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ARE HORMONAL CONTRACEPTIVES TERATOGENIC?
Progesterone and Progestogens The virilizing activity of6-methyl-17-hydroxy36 (or -acetoxy37) progesterone acetate on female rat fetuses has been reported, although daily doses of 200 mg of progesterone had no masculinizing effects. 38 Progestogens such as cyproterone acetate with antiandrogenic activity, have been reported to cause virilization in female offspring and feminization in male offspring.39 Recently Andrew et al.4° reported that the administration of contraceptive progestins to one strain of mice results in clubfoot; cleft palate; exencephaly; hydrocephaly; abdominal hemorrhage; growth retardation; urogenital defects; abnormal ossification of ribs, sternum, and/or skull; cranioschisis; and partial duplication of kidney. However, in rats, exencephaly and cleft palate were not found. Cleft palate and stunning in fetuses of rabbits are noted with pretreatment by medroxyprogesterone acetate.
Combination of Estrogens and Progestogens The combinations of ethynodiol diacetate and mestranol were found to be nonteratogenic in rats and rabbits.41 Similarly, norethynodrel combined with mestranol did not show teratogenicity in rats.42
Comments From the experimental data it appears that genital anomalies due to the exogenous administration of estrogens and progestogens are welldocumented. Although progestogens may be weak in androgenic effects in terms of bioassays on adults,37 they may be sufficiently potent when they cross the placenta to masculinize the relatively sensitive end-organs of the developing fetus or they may be converted to androgens in mother or fetus. 43 The masculinization resulting from diethylstilbestrol therapy alone in some cases has been thought to be due to stimulation of adrenal androgen production. However, anomalies involving other organs do not seem to have been given proper attention in the experimental work in the past. A recent experiment40 indicates anomalies affecting various organs. Even though the frequency appears to be low, there is a need for more detailed studies under controlled conditions-particularly with combination agents. DISCUSSION
As yet, there is no clear and definitive evidence of teratogenic effects of oral contraceptives
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administered prior to or during pregnancy. The problem of conclusively proving a small increase in the incidence of rare abnormalities is very formidable. This may be due in part to the fact that the anomalies associated with hormonal contraceptives may occur primarily in those children who are predisposed genetically. A positive family history in two such cases lO • 13 supports such a hypothesis. There are two possible mechanisms by which some women may be genetically predisposed to having malformed children as a result of ex- posure to hormonal contraceptives: 1. The contraceptive hormones or their metabolic products may act in conjunction with the pool of abnormal genes to trigger the development of a specific malformation. 2. Low metabolic clearance of the hormones in some women may lead to abnormal accumulation of hormones and/or their metabolic products. T~ese s~bstances could be toxic to the embryo eIther dIrectly or by reducing the availability of vitamins crucial to fetal growth, such as folic acid. Various studies have demonstrated a significant decrease in the levels of vitamins B folic acid, and pyridoxal phosphate. 44 The m~;t consistent of these findings is reduced red cell folate. It is known that folate deficiency can cause several congenital malformations in experimental animals. 45 Indian women who are . malnourished and have low ' folate sometimes levels at the outset, may be even more susceptible. I~ addition to the predisposition through depletIOn of essential vitamin cofactors, various other environmental factors such as exposure to radiation, viral infection, or the use of certain drugs during early pregnancy may act synergistically with contraceptive hormones in genetically predisposed conceptuses and thus lead to congenital malformations. After an extensive review of the relationship of hormonal contraceptives and thromboembolism, a similar conclusion was reached by Goldzieher and Dozier. 46 From the numerous studies reviewed , "a profile of thromboembolic disease statistically associated in some studies with oral contraceptive use begins to emerge. The incidence of thromboembolism in users is not affected by duration of use and probably not by dosage level. An increased incidence is not found in users when the entire population sample is examined in most instances but appears consistently in the 'trohoc' studies when an 'idiopathic' group is selected." These authors believed that prior differences in
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susceptibility may have accounted for the observations. The use of hormones to prevent abortion has not been of proved value in threatened abortion, which may itself herald an abnormal pregnancy. Because of this bias the data do not clearly suggest a dermite increase in the incidence of congenital malformation. However, a small number of female fetuses so exposed do have masculinized genitalia. Hence, it would seem prudent not to use the hormones as therapy for threatened abortion.1. 47. 4S Hormonal contraceptives have also been used to determine whether or not a woman is pregnant. The absence of bleeding following withdrawal of the hormone signifies pregnancy. Since much simpler, more reliable, and noninvasive tests are available (e.g., through examination of the patient's blood or urine), the use of hormones as a pregnancy test is completely unjustified1. 47. 4S and may be medicolegally unsafe as well. 49 SUMMARY
August 1977 REFERENCES 1. Editorial: Are sex hormones teratogenic? Lancet 2:1489, 1974 2. Dubowitz V: Virilization and malformation of a female infant. Lancet 2:405, 1962 3. Smithells YRW: The problem of teratogenicity. Practitioner 194:107, 1965 4. Gal I, Kinnan B, Stern J: Hormonal pregnancy tests and congenital malformation. Nature 216:83, 1967 5. Laurence M, Miller M, Vowles M, Evans K, Carter C: Hormonal pregnancy tests and neural tube malformations. Nature 233:495, 1971 6. Gal I: Risks and benefits of the use of hormonal pregnancy test tablets. Nature 240:241, 1972 . 7. Oakley GP, Flynt JW, Falek A: Hormonal pregnancy tests and congenital malformations. Lancet 2:256, 1973 8. Sever LE: Hormonal pregnancy tests and spina bifida. Nature 292(5397):410, 1973 9. Levy EP, Cohen A, Fraser FL: Hormone treatment during pregnancy and congenital heart defects. Lancet 1:611, 1973 10. Nora JJ, Nora AH: Birth defects and oral contraceptives. Lancet 1:941, 1973 11. Mulvhill JJ, Mulvhill CG, Neill CA: Prenatal sex hormone exposure and cardiac defects in man. Teratology 9:A-30, 1974 12. Nora AH, Nora JJ: A syndrome of multiple congenital anomalies associated with teratogenic exposure. Arch Environ Health 30:17,1975 13. Balci S, Say B, Pirnar T, Hicsonmez A: Birth defects and oral contraceptives. Lancet 2:1098, 1973 14. Kaufmann RL: Birth defects and oral contraceptives. Lancet 1:1396, 1973 15. Brogan MF: Cleft lip and palate and pregnancy tests. Med J Aust 1:44, 1975 16. Janerich DT, Piper JM, Glebalis DM: Oral contraceptives and congenital limb-reduction defects. N Engl J Med 291:697, 1974 17. Harlap S, Prywes R, Davies AM: Birth defects and oestrogens and progesterones in pregnancy. Lancet 1:682, 1975 18. Nora JJ, Nora AH, Perinchief AG, Ingram JW, Fountain AK, Peterson MJ: Congenital abnormalities and first trimester exposure to progestagen-oestrogen. Lancet 1:313,1976 19. Royal College of General Practitioners Oral Contraceptive Study: The outcome of pregnancy in former oral contraceptive users. Br J Obstet Gynaecol 83:608, 1976 20. Robinson SC: Pregnancy outcome following oral contraceptives. Am J Obstet Gynecol 109:354, 1971
The widespread use of hormonal contraceptives for a prolonged time in women during the childbearing period necessitates that appropriate precautions be taken to ensure safety for the patient as well as for her progeny. Hormonal administration during or prior to pregnancy may be potentially teratogenic. Although there have been many reports during the last decade, it has been very difficult to document conclusively such a relationship. Over-all, it seems that hormonal use prior to pregnancy does not lead to an increase in the frequency of chromosomal aberrations or of congenital malformations. The use of certain hormones during pregnancy, on the other hand, may lead to an increase in the incidence of congenital malformations, probably in the genetically predisposed fetus. In view of this concept hormonal contraceptives should not be used to treat threatened abortion, and their use as a pregnancy test should be abandoned. Since the question of the safety of the inadvertent administration of pills during early pregnancy has not been resolved, the mother should be informed of the potential risks.
21. J anerich DT: The pill and subsequent pregnancies. Lancet 1:681,1975 22. Peterson WF: Pregnancy following oral contraceptive therapy. Obstet Gynecol 34:363, 1969 23. Oral contraceptives and health: Report of the Royal College of General Practitioners. London, Pittman Medical Publishers, 1974
Acknowledgments. The authors would like to thank Dr. Shanta S. Rao, Dr. Usha M. Joshi, and Dr. Ashok B. Vaidya for helpful suggestions and guidance in the preparation of this review.
24. Poland BJ, Ash KA: The influence of oral contraceptives on early intrauterine development. Am J Obstet Gynecol 116:1138, 1973 25. Carr DH: Chromosome studies in selected spontaneous abortions. 1. Conception after oral contraceptives. Can Med Assoc J 103:343, 1971
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26. Alberman C, Greasy M, Elliott M, Spicer C: Maternal factors associated with fetal chromosomal anomalies in spontaneous abortions. Br J Obstet Gynaecol 83:621, 1976 27. Lauritsen JG: The significance of oral contraceptives in causing chromosome anomalies in spontaneous abortions. Acta Obstet Gynecol Scand 54:261, 1975 28. Janerich DT, Flink EM, Keogh MD: Down's syndrome and pill usage. Br J Obstet Gynaecol 83:617, 1976 29. Littlefield LG, Mailhes JB: Comparison of chromosomal breakages in lymphocytes and fibroblasts from control women and women taking oral contraceptives. Fertil Steril 26:828, 1976 30. Shapiro LR, Graves ZR, Hirschhorn K: Oral contraceptives and in vivo cytogenetic studies. Obstet Gynecol 39:190, 1972 31. McQuarrie HG, Scott CD, Ellsworth HS, Harris JW, Stone RA: Cytogenetic studies on women using oral contraceptives and their progeny. Am J Obstet Gynecol 108:659, 1970 32. Carr DH: Chromosomes after oral contraceptive&. Lancet 2:830,1967 33. Greene RH, Burill NW, Levy AC: The effects of estrogens on the antenatal sexual development of rat. Am J Anat 67:305, 1940 34. Raynaud A, Raynaud J: La production experimentale de malformations mammaires chez les foetus de souris, par l'action des hormones. Ann Inst Pasteur 90:39, 1956 35. Gentaro N: Influence of sex hormones in experimental teratogenesis. Proc Soc Exp BioI Med 97:809,1958 36. Suchowsky GK, Junkmann K: A study of the virilizing effect of progesterone on the female rat fetus. Endocrinology 68:341,1961 37. Lyster SC, Lund GH, Dulin WE: Ability of some progestational steroids to stimulate male acceSBOry glands of reproduction in rat. Proc Soc Exp BioI Med 100:540, 1959
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38. Revesz C, Chappel CI, Gaudry R: Masculinization of female fetuses in the rat by progestational compounds. Endocrinology 66:140, 1970 39. Neumann F, Graf KJ, Elger W: Hormone-induced distubances in sexual differentiation. Adv Biosci 13:71, 1974 40. Andrew FD, Christensen HD, Williams TL: Comparative teratogenicity of contraceptives. Teratology 7:A-11, 1973 41. Saunders FJ, Elton RL: Effects of ethynodiol diacetate and mestranol in rats and rabbits on conception, the outcome of pregnancy and the offsprings. Toxicol Appl Pharmacol 11:229, 1967 42. Saunders Fl': Effects of norethynodrel combined with mestranol on the offspring when administered during pregnancy and lactation in rats. Endocrinology 80:447, 1967 43. Wilkins LJ: Masculinization ofthe female fetus due to use of orally given progestins. JAMA 172:1028, 1960 44. Prasad AS, Lei KY, Moghissi KS, Stryker JC, Oberleas D: Effect of oral contraceptives on nutrients. II. Vitamins B6 , B12 and folic acid. Am J Obstet Gynecol 125:1063, 1971 45. Nelson MM, Wright HV, Asling CW, Evans HM: Multiple congenital abnormalities resulting from transitory deficiency of pteryolglutamic acid during gestation in the rat. J Nutr 56:349, 1955 46. Goldzieher JW, Dozier TS: Oral contraceptives and thromboembolism: a reassessment. Am J Obstet Gynecol 123:878, 1975 47. Nora JJ, Nora AH: Can the pill cause birth defects? N Engl J Med 291:731, 1974 48. Editorial: Birth defects and oral contraceptives. Med J Aust 2:861, 1974 49. Mills DH: Medicolegal aspects of medical journal reports of drug harms. JAMA 234:536, 1975
Vol. 28, No.8, August 1977 Printed in U.S.A.
FERTILITY AND STERILITY Copyright © 1977 The American Fertility Society
ARE HORMONAL CONTRACEPTIVES TERATOGENIC?
LALIT M. AMBANI, M.D.* NARENDRA J. JOSm, M.Sc. RAMA A. VAIDYA, M.D., D.G.O., D.F.P. P. K. DEVI, M.S., F.R.C.S., F.A.M.S.t Institute for Research in Reproduction, Parel, Bombay-400 012, India
These two aspects of the teratogenicity of the hormonal contraceptive drugs are reviewed separately in this communication. The experimental teratologic work is also presented.
The introduction of sex hormones as oral contraceptive pills has been a revolutionizing factor in the field of family planning. The pill, 'Nhich contains either estrogens alone or an estrogenprogestogen combination, is the most effective method of contraception, and its wide use can reduce the growth of population considerably. An editorial in the Lancet! asserts that "Posterity may decide that the greatest contribution of the twentieth century to the health of mankind was not a vaccine, an antibiotic, or a transplant but the contraceptive pill." However, since the pill may be used by millions of women over many years, its safety must be ascertained. Many minor and major side effects have been ascribed to regular use of the pill. Of great concern, and the subject of this review, are the reports of the possible harmful effects on the offspring of women who receive hormonal contraceptives. The initial reports of teratogenicity mainly conconcerned the possibility of an increased rate of congenital malformations following the use of hormonal contraceptives during early pregnancy: first, as a therapy for threatened abortion; second, as a pregnancy test; and third, as oral contraceptives administered inadvertently to women who had just become pregnant or to some women who were already using these agents and continued to ingest them even after becoming pregnant. The later reports also considered the teratogenic potential of oral contraceptives when these agents were discontinued prior to pregnancy.
HORMONAL CONTRACEPl'IVES DURING PREGNANCY
Dubowitr reported a female with virilization and malformations of the urogenital sinus derivatives and internal genitalia. Since this report several isolated reports have appeared of females with virilized external genitalia. However, Smithells3 did not find any evidence of teratogenicity of the hormonal contraceptives. In 1967 Gal et al. 4 ascribed a congenital malformation, not related to the reproductive tract, to the use of hormonal contraceptives. Since then, a number of congenital malformations have been considered to increase in frequency in the offspring of women who had received contraceptive hormones during pregnancy.
Neural Tube Defects Gal et al. 4 reported that a significantly higher number of mothers of children with neural tube defects had received pregnancy test tablets as compared with control mothers. An epidemiologic survey in 1971,5 however, failed to reveal such an association. Gal 6 then reanalyzed her data and found that, even after excluding mothers with any predisposing factors such as advanced age and chronic infections, the difference was still significant. Again, Oakley et al. 7 failed to observe any increase in the frequency of use of pregnancy tests in mothers of children with neural tube defects as compared with controls. In all studies except those of Gal, the evidence is against such an association. On the basis of embryologic data,
Received May 18, 1977; accepted June 22,1977. *Reprint requests: Dr. Lalit Ambani, Senior Research Officer, Division of Genetics, Institute for Research in Reproduction, Jehangir Merwanji Street, Parel, Bombay-400 012, India. tPresent address: Postgraduate Institute of Medical Education and Research, Chandigarh-ll, Punjab, India.
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Sever" argued that, since the neural tube is formed and closed by the 4th week of gestation, open lesions of the spine such as myelomeningocele or spina bifida must develop at about that time. Since the average interval between conception and the pregnancy test was 5.6 weeks in the study by Gal et a1.,4 a large proportion of these mothers probably received the hormones after the complete formation of the neural tube. Congenital Cardiovascular Disease Levy et al.9 noted a high incidence of hormone treatment in pregnancies leading to the birth of infants with transposition of great vessels. Of 76 mothers interviewed, 7 gave a history of sex hormone ingestion during the first trimester: 6 had been treated for threatened abortion and 1 had had a pregnancy test. In the control group there was no history of administration of sex hormones. Nora and Nora10 reported progestogen-estrogen intake during pregnancy in 20 of 224 cases of congenital heart disease as compared with 4 of262 controls. They noted an apparent excess of malformations involving great vessels, most often a transposition. However, at the Johns Hopkins Hospital, Mulvhill et a1. 11 studied 88 patients with transposition of great vessels and compared them with those with ventricular septal defect. In each group, 4% to 5% of mothers had had firsttrimester exposure to sex hormones.
VACTERL Anomalies The defects described under the acronym VACTERL are: V for vertebral, A for anal, C for cardiac, T for tracheal, E for esophageal, R for renal or radial, and L for limb malformations. The anomalies of these simultaneously developing structures may remind one of the thalidomide syndrome. However, they present much less consistency of pattern. Nora and Nora 12 reported that of 15 patients with VACTERL syndrome, the mothers of 9 had received hormones during early pregnancy. This incidence was significantly higher than that for mothers in two control groups-those with chromosomally abnormal children and those with normal children. Two more mothers of patients with this group of anomalies have been reported to have ingested hormonal contraceptives during early pregnancy. Balci et a1. 13 had a patient with V ACTERL anomalies whose mother had ingested oral contraceptives 10 months before conception and 1 month into pregnancy. However, the patient's maternal
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grandmother was also affected, having had two siblings with spina bifida and sacralization of the 5th lumbar vertebrae. In a second infant with VACTERL anomalies, there was no history of the mother's having ingested sex hormones before or during pregnancy. These authors thought that the somewhat similar involvement of the grandmother in the first case indicated that exposure to oral contraceptives may have precipitated the syndrome in the first child who was genetically predisposed. Kaufmann14 reported one patient with VACTERL syndrome whose mother had received 'oral stilbestrol and parenteral progesterone for 2 months beginning 47 days after the last menstrual period. Cleft Lip/Cleft Palate Brogan15 reported that in 22 of 222 cases of cleft lip and/or cleft palate, the mothers had received pregnancy tests between the 5th and 8th weeks of gestation. Since the frequency of similar tests in controls was not determined, no conclusion can be drawn. No other study has indicated an increased incidence of this malformation following exposure to hormonal contraceptives. Limb Defects Janerich et a1}6 studied 108 mothers of patients with limb-reduction defects and compared them with mothers of normal infants. The defects were defined as absence of the whole or a part of any limb. The controls were matched for race and maternal age. A total of 15 mothers in the study group, compared with 4 in the control group, had received steroid hormones during pregnancy. All Malformations Unlike the studies referred to above, in which index patients were those who had a specific anomaly, in the Jerusalem perinatal study17 11,468 mothers were interviewed for history of drug ingestion during pregnancy. Malformations-minor and major-were found in 432 babies; 47 of these were born after exposure to sex hormones during early pregnancy. The incidence of ingestion of sex hormones during pregnancy was significantly higher in mothers of malformed babies (10.9%) than in the remainder of the women (7.8%). The question of sex hormone ingestion was not asked of mothers specifically; women with a "probable" history of having received sex hormones were also included, and the controls were not clearly defined.
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The prospective survey by Nora et aps of 100 liveborn infants exposed to hormonal contraceptives during the first trimester of pregnancy revealed 6 with "major" malformations. Of these, four had congenital cardiovascular disease and one had VACTERL anomalies. No controls were provided. A variety of malformations were arbitrarily defined as major or minor. Hence, the 2- to 4-fold increase does not seem to be meaningful. Thus far, the reports cited above have dealt with hormones given as a pregnancy test or for treatment of threatened abortion. There is very scant information on the outcome of pregnancy following inadvertent use of oral contraceptives during the early days of pregnancy. In a recent report by the Royal College of General Practitioners,19 136 women gave histories of receiving oral contraceptives inadvertently during early pregnancy. Of these pregnancies, 102 went to term. There were seven abnormal infants, of whom only two had obvious congenital malformations. This rate is the same as that found in other liveborns. Three of the pregnancies resulted in stillbirths. Since no details of postmortem studies of the stillborn infants are available, significant internal malformations may have been overlooked. The number of cases in this report is small and hence the role of pilIs unknowingly ingested during early pregnancy in causing congenital malformations is not yet clear.19
Comments There are many problems in documenting a definite increase in the frequency of the specific congenital malformations discussed above. First, all of these malformations are rare, and in order to detect a small increase the control and study populations must be large. Second, in retrospective studies such as most of those cited above, appropriate controls are difficult to obtain. Of course, these surveys, along with the case reports, serve as a warning signal. Appropriate prospective surveys to study the progeny of women who had used hormonal contraceptives during or before pregnancy could give us much more definitive data. Data collection along these lines is said to be in progress. 14 Many of the women in the above studies had received hormonal contraceptives as therapy for threatened abortion. If the threatened abortion is due to a chromosomal or genetic abnormality in the offspring, hormonal contraceptives may falsely be ascribed to be the cause of
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the congenital malformation. Hence, it is important to be aware of this potential bias in many studies reported above, which perhaps should have used untreated patients with threatened abortion as control. THE PILL AND THE OUTCOME OF SUBSEQUENT PREGNANCIES
Thus far we have reviewed the potential teratogenic effects of contraceptive hormones administered during early pregnancy. In the following section the literature is summarized regarding the outcome of pregnancies in women who had been - exposed to sex steroids prior to pregnancy.
Congenital Malformations Robinson20 conducted a controlled study in a maternity hospital in Halifax, Nova Scotia. He paired 1250 births in women who had previously used oral contraceptives with those in women who had never used the pilI; the women were matched for maternal age and parity. There were no significant differences in the rates of congenital malformations between the study group (36.2%) and the control group (31.1%). Janerich21 analyzed the same data according to maternal age and severity of defect. He concluded that a small increase in most of the study groups should not be considered as negative results. In two other studies,22. 23 the incidence of a specific malformation or of total congenital malformations in the former pilI-users was not found to be increased.
Abortion Rate In Robinson's study20 239 women gave a history of a previous pregnancy prior to which they had also used oral contraceptives. Of these , 22% ended in an abortion. No controls, however, were included. Peterson22 conducted a prospective survey of 442 pregnant women who had used oral contraceptives and compared them with 699 controls. The abortion rates of 9.2% and 8.6% in the two groups were not significantly different. In the study by the Royal College of General Practitioners23 a 20.9% spontaneous abortion rate was reported in the ex-pilI-taker group as compared with 12.3% among the non-pilI-users. The difference was attributed to an increased likelihood of ex-pilI-users having had an induced abortion if they became pregnant. To support this thesis the authors reported that the abortion rate in ex-pilI-takers who "desired pregnancy" was only 13.4%. However, the report failed to make
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a similar adjustment for nonusers. This defect of the study was rectified in the more recent report by the same group19 on the outcome of 3528 pregnancies following oral contraceptives as compared with 4551 controls. They divided both groups into young and old mothers. The rate of abortion was not significantly different between the two groups of younger mothers. The increased rate of abortion in older mothers (age 35 years or above) who had used oral contraceptives was due to a significantly higher rate of induced abortion in this group as compared with controls.19 Poland and Ash 24 studied spontaneous abortuses from former pill-users and compared them with abortuses from controls. They found that, whereas the systemic anomalies in the fetuses were comparable in the two groups, the incidence of severe growth disorganization was significantly higher in the former pill-users.
Cytogenetic Abnormalities
In Spontaneous Abortuses. Chromosome studies in 281 spontaneous abortuses from women who had conceived within 6 months of discontinuing oral contraceptives revealed a rate of 48% abnormal as compared with 22% in the control groUp.25 The increase in chromosomal aberrations was mainly accounted for by an increase in the incidence of triploidy. Trisomies and 45,XO karyotypes were found with equal frequency in both groups. Alberman et ap6 were able to karyotype 992 of 2620 spontaneous abortuses. They found an excess of approximately 20% in the proportion of abnormal karyotypes in the aborted fetuses of women who had used oral contraception for more than 18 months. The small increase in proportion of chromosomal anomalies applied to all types, viz., trisomy, triploidy, tetraploidy, and 45,XO. The chromosome study by Lauritsen 27 on products from 254 spontaneous abortions showed a 60% rate of abnormal karyotypes in the postoral contraceptive group as compared with 49% in the control group. The difference was not significant. There was, however, a highly significant. maternal age difference between the two groups. It is known that several karyotype abnormalities occur more frequently with age. The fact that the post-oral contraceptive group was younger than the controls could have masked the difference between the two. In Newborns. The only study which addresses itself to the relationship of a specific chromosomal anomaly in newborns and the ingestion of hor-
monal contraceptives is that of Janerich et ap8 One hundred and three mothers of patients with Down's syndrome were compared with normal matched controls. There was no increased incidence of pill usage among the mothers of patients with Down's syndrome. This finding suggests that nondisjunction does not increase following the use of hormonal contraceptives. In Cultured Lymphocytes. In vitro studies of the effect of synthetic hormonal contraceptives on the incidence of chromosome breakages in lymphocytes and fibroblasts from control women and women taking oral contraceptives demonstrated no difference in the two groupS.29 Cytogenetic studies of peripheral leukocyte cultures in seven women were performed prior to and after 1 and 2 months of oral contraceptive use. 30 No significant change in chromosome breaks or mitotic index was revealed when each of the seven women served as her own control. These results differ from other in vivo studies which did not use each patient as her own controJ.31. 32
Comments The weight of the evidence from the reports cited above suggests that the rate of occurrence of congenital malformations or a specific chromosomal abnormality in the newborns is not increased. However, the incidence of specific chromosomal abnormalities in the abortuses may increase. No effects on the chromosome morphology in vivo are found. EXPERIMENTAL TERATOLOGY
The reports on the effects of sex hormones on the development of embryos and fetuses appear to be focused mostly on the genital organs.
Estrogens Estrogen treatment during pregnancy causes masculinization of female offspring-their Wolman ducts differentiate partially and the typical female development ofthe urogenital sinus is partly inhibited. 33 On the other hand, in male fetuses, estrogen administration can have profound feminizing effects on sex differentiationtheir Mullerian ducts persist partially; Wolffian ducts are suppressed; and there is marked inhibition of epididymides, seminal vesicles, and ventral prostates. 33 In addition, estrogen administration during pregnancy can produce anomalies in mammary gland differentiation34 and cleft palate formation. 35
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Progesterone and Progestogens The virilizing activity of6-methyl-17-hydroxy36 (or -acetoxy37) progesterone acetate on female rat fetuses has been reported, although daily doses of 200 mg of progesterone had no masculinizing effects. 38 Progestogens such as cyproterone acetate with antiandrogenic activity, have been reported to cause virilization in female offspring and feminization in male offspring.39 Recently Andrew et al.4° reported that the administration of contraceptive progestins to one strain of mice results in clubfoot; cleft palate; exencephaly; hydrocephaly; abdominal hemorrhage; growth retardation; urogenital defects; abnormal ossification of ribs, sternum, and/or skull; cranioschisis; and partial duplication of kidney. However, in rats, exencephaly and cleft palate were not found. Cleft palate and stunning in fetuses of rabbits are noted with pretreatment by medroxyprogesterone acetate.
Combination of Estrogens and Progestogens The combinations of ethynodiol diacetate and mestranol were found to be nonteratogenic in rats and rabbits.41 Similarly, norethynodrel combined with mestranol did not show teratogenicity in rats.42
Comments From the experimental data it appears that genital anomalies due to the exogenous administration of estrogens and progestogens are welldocumented. Although progestogens may be weak in androgenic effects in terms of bioassays on adults,37 they may be sufficiently potent when they cross the placenta to masculinize the relatively sensitive end-organs of the developing fetus or they may be converted to androgens in mother or fetus. 43 The masculinization resulting from diethylstilbestrol therapy alone in some cases has been thought to be due to stimulation of adrenal androgen production. However, anomalies involving other organs do not seem to have been given proper attention in the experimental work in the past. A recent experiment40 indicates anomalies affecting various organs. Even though the frequency appears to be low, there is a need for more detailed studies under controlled conditions-particularly with combination agents. DISCUSSION
As yet, there is no clear and definitive evidence of teratogenic effects of oral contraceptives
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administered prior to or during pregnancy. The problem of conclusively proving a small increase in the incidence of rare abnormalities is very formidable. This may be due in part to the fact that the anomalies associated with hormonal contraceptives may occur primarily in those children who are predisposed genetically. A positive family history in two such cases lO • 13 supports such a hypothesis. There are two possible mechanisms by which some women may be genetically predisposed to having malformed children as a result of ex- posure to hormonal contraceptives: 1. The contraceptive hormones or their metabolic products may act in conjunction with the pool of abnormal genes to trigger the development of a specific malformation. 2. Low metabolic clearance of the hormones in some women may lead to abnormal accumulation of hormones and/or their metabolic products. T~ese s~bstances could be toxic to the embryo eIther dIrectly or by reducing the availability of vitamins crucial to fetal growth, such as folic acid. Various studies have demonstrated a significant decrease in the levels of vitamins B folic acid, and pyridoxal phosphate. 44 The m~;t consistent of these findings is reduced red cell folate. It is known that folate deficiency can cause several congenital malformations in experimental animals. 45 Indian women who are . malnourished and have low ' folate sometimes levels at the outset, may be even more susceptible. I~ addition to the predisposition through depletIOn of essential vitamin cofactors, various other environmental factors such as exposure to radiation, viral infection, or the use of certain drugs during early pregnancy may act synergistically with contraceptive hormones in genetically predisposed conceptuses and thus lead to congenital malformations. After an extensive review of the relationship of hormonal contraceptives and thromboembolism, a similar conclusion was reached by Goldzieher and Dozier. 46 From the numerous studies reviewed , "a profile of thromboembolic disease statistically associated in some studies with oral contraceptive use begins to emerge. The incidence of thromboembolism in users is not affected by duration of use and probably not by dosage level. An increased incidence is not found in users when the entire population sample is examined in most instances but appears consistently in the 'trohoc' studies when an 'idiopathic' group is selected." These authors believed that prior differences in
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susceptibility may have accounted for the observations. The use of hormones to prevent abortion has not been of proved value in threatened abortion, which may itself herald an abnormal pregnancy. Because of this bias the data do not clearly suggest a dermite increase in the incidence of congenital malformation. However, a small number of female fetuses so exposed do have masculinized genitalia. Hence, it would seem prudent not to use the hormones as therapy for threatened abortion.1. 47. 4S Hormonal contraceptives have also been used to determine whether or not a woman is pregnant. The absence of bleeding following withdrawal of the hormone signifies pregnancy. Since much simpler, more reliable, and noninvasive tests are available (e.g., through examination of the patient's blood or urine), the use of hormones as a pregnancy test is completely unjustified1. 47. 4S and may be medicolegally unsafe as well. 49 SUMMARY
August 1977 REFERENCES 1. Editorial: Are sex hormones teratogenic? Lancet 2:1489, 1974 2. Dubowitz V: Virilization and malformation of a female infant. Lancet 2:405, 1962 3. Smithells YRW: The problem of teratogenicity. Practitioner 194:107, 1965 4. Gal I, Kinnan B, Stern J: Hormonal pregnancy tests and congenital malformation. Nature 216:83, 1967 5. Laurence M, Miller M, Vowles M, Evans K, Carter C: Hormonal pregnancy tests and neural tube malformations. Nature 233:495, 1971 6. Gal I: Risks and benefits of the use of hormonal pregnancy test tablets. Nature 240:241, 1972 . 7. Oakley GP, Flynt JW, Falek A: Hormonal pregnancy tests and congenital malformations. Lancet 2:256, 1973 8. Sever LE: Hormonal pregnancy tests and spina bifida. Nature 292(5397):410, 1973 9. Levy EP, Cohen A, Fraser FL: Hormone treatment during pregnancy and congenital heart defects. Lancet 1:611, 1973 10. Nora JJ, Nora AH: Birth defects and oral contraceptives. Lancet 1:941, 1973 11. Mulvhill JJ, Mulvhill CG, Neill CA: Prenatal sex hormone exposure and cardiac defects in man. Teratology 9:A-30, 1974 12. Nora AH, Nora JJ: A syndrome of multiple congenital anomalies associated with teratogenic exposure. Arch Environ Health 30:17,1975 13. Balci S, Say B, Pirnar T, Hicsonmez A: Birth defects and oral contraceptives. Lancet 2:1098, 1973 14. Kaufmann RL: Birth defects and oral contraceptives. Lancet 1:1396, 1973 15. Brogan MF: Cleft lip and palate and pregnancy tests. Med J Aust 1:44, 1975 16. Janerich DT, Piper JM, Glebalis DM: Oral contraceptives and congenital limb-reduction defects. N Engl J Med 291:697, 1974 17. Harlap S, Prywes R, Davies AM: Birth defects and oestrogens and progesterones in pregnancy. Lancet 1:682, 1975 18. Nora JJ, Nora AH, Perinchief AG, Ingram JW, Fountain AK, Peterson MJ: Congenital abnormalities and first trimester exposure to progestagen-oestrogen. Lancet 1:313,1976 19. Royal College of General Practitioners Oral Contraceptive Study: The outcome of pregnancy in former oral contraceptive users. Br J Obstet Gynaecol 83:608, 1976 20. Robinson SC: Pregnancy outcome following oral contraceptives. Am J Obstet Gynecol 109:354, 1971
The widespread use of hormonal contraceptives for a prolonged time in women during the childbearing period necessitates that appropriate precautions be taken to ensure safety for the patient as well as for her progeny. Hormonal administration during or prior to pregnancy may be potentially teratogenic. Although there have been many reports during the last decade, it has been very difficult to document conclusively such a relationship. Over-all, it seems that hormonal use prior to pregnancy does not lead to an increase in the frequency of chromosomal aberrations or of congenital malformations. The use of certain hormones during pregnancy, on the other hand, may lead to an increase in the incidence of congenital malformations, probably in the genetically predisposed fetus. In view of this concept hormonal contraceptives should not be used to treat threatened abortion, and their use as a pregnancy test should be abandoned. Since the question of the safety of the inadvertent administration of pills during early pregnancy has not been resolved, the mother should be informed of the potential risks.
21. J anerich DT: The pill and subsequent pregnancies. Lancet 1:681,1975 22. Peterson WF: Pregnancy following oral contraceptive therapy. Obstet Gynecol 34:363, 1969 23. Oral contraceptives and health: Report of the Royal College of General Practitioners. London, Pittman Medical Publishers, 1974
Acknowledgments. The authors would like to thank Dr. Shanta S. Rao, Dr. Usha M. Joshi, and Dr. Ashok B. Vaidya for helpful suggestions and guidance in the preparation of this review.
24. Poland BJ, Ash KA: The influence of oral contraceptives on early intrauterine development. Am J Obstet Gynecol 116:1138, 1973 25. Carr DH: Chromosome studies in selected spontaneous abortions. 1. Conception after oral contraceptives. Can Med Assoc J 103:343, 1971
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26. Alberman C, Greasy M, Elliott M, Spicer C: Maternal factors associated with fetal chromosomal anomalies in spontaneous abortions. Br J Obstet Gynaecol 83:621, 1976 27. Lauritsen JG: The significance of oral contraceptives in causing chromosome anomalies in spontaneous abortions. Acta Obstet Gynecol Scand 54:261, 1975 28. Janerich DT, Flink EM, Keogh MD: Down's syndrome and pill usage. Br J Obstet Gynaecol 83:617, 1976 29. Littlefield LG, Mailhes JB: Comparison of chromosomal breakages in lymphocytes and fibroblasts from control women and women taking oral contraceptives. Fertil Steril 26:828, 1976 30. Shapiro LR, Graves ZR, Hirschhorn K: Oral contraceptives and in vivo cytogenetic studies. Obstet Gynecol 39:190, 1972 31. McQuarrie HG, Scott CD, Ellsworth HS, Harris JW, Stone RA: Cytogenetic studies on women using oral contraceptives and their progeny. Am J Obstet Gynecol 108:659, 1970 32. Carr DH: Chromosomes after oral contraceptive&. Lancet 2:830,1967 33. Greene RH, Burill NW, Levy AC: The effects of estrogens on the antenatal sexual development of rat. Am J Anat 67:305, 1940 34. Raynaud A, Raynaud J: La production experimentale de malformations mammaires chez les foetus de souris, par l'action des hormones. Ann Inst Pasteur 90:39, 1956 35. Gentaro N: Influence of sex hormones in experimental teratogenesis. Proc Soc Exp BioI Med 97:809,1958 36. Suchowsky GK, Junkmann K: A study of the virilizing effect of progesterone on the female rat fetus. Endocrinology 68:341,1961 37. Lyster SC, Lund GH, Dulin WE: Ability of some progestational steroids to stimulate male acceSBOry glands of reproduction in rat. Proc Soc Exp BioI Med 100:540, 1959
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38. Revesz C, Chappel CI, Gaudry R: Masculinization of female fetuses in the rat by progestational compounds. Endocrinology 66:140, 1970 39. Neumann F, Graf KJ, Elger W: Hormone-induced distubances in sexual differentiation. Adv Biosci 13:71, 1974 40. Andrew FD, Christensen HD, Williams TL: Comparative teratogenicity of contraceptives. Teratology 7:A-11, 1973 41. Saunders FJ, Elton RL: Effects of ethynodiol diacetate and mestranol in rats and rabbits on conception, the outcome of pregnancy and the offsprings. Toxicol Appl Pharmacol 11:229, 1967 42. Saunders Fl': Effects of norethynodrel combined with mestranol on the offspring when administered during pregnancy and lactation in rats. Endocrinology 80:447, 1967 43. Wilkins LJ: Masculinization ofthe female fetus due to use of orally given progestins. JAMA 172:1028, 1960 44. Prasad AS, Lei KY, Moghissi KS, Stryker JC, Oberleas D: Effect of oral contraceptives on nutrients. II. Vitamins B6 , B12 and folic acid. Am J Obstet Gynecol 125:1063, 1971 45. Nelson MM, Wright HV, Asling CW, Evans HM: Multiple congenital abnormalities resulting from transitory deficiency of pteryolglutamic acid during gestation in the rat. J Nutr 56:349, 1955 46. Goldzieher JW, Dozier TS: Oral contraceptives and thromboembolism: a reassessment. Am J Obstet Gynecol 123:878, 1975 47. Nora JJ, Nora AH: Can the pill cause birth defects? N Engl J Med 291:731, 1974 48. Editorial: Birth defects and oral contraceptives. Med J Aust 2:861, 1974 49. Mills DH: Medicolegal aspects of medical journal reports of drug harms. JAMA 234:536, 1975
