Motherisk Int J 2020;1:11
Gideon Koren MD(1-2),
From Ariel University Israel (1) and Motherisk Israel Program (2)
Daniella Gilboa MSc
Address for Correspondence:
Gideon Koren MD, FRCPC, FACMT
The paper was presented at the 17th meeting of the European Society for developmental perinatal and paediatric pharmacology, May 28-30, Basel, Switzerland
You presented results in the 2019 ESDPPP Basel meeting (1), suggesting that dydrogesterone (DYD) may cause malformations. The abstract naturally is short, and I could not figure out how did you address confounding by indication i.e. that the medical condition of these women with subfertilitydid cause the excess malformations, and not the drug itself?
Thank you, we are delighted to use this forum for this type of scientific exchange, and we shall present here the full results. It is correct that our study did not have a control group of sub-fertile women not receiving DYD. However, other studies on sub-fertile women did not show increase in these specific malformation – i.e. hypospadias, cardiovascular malformations and spina bifida, all of which having biological plausibility.
Dydrogesterone (DYD) is a widely used progestin indicated for threatened and repeated miscarriages, as well as for numerous other obstetric and gynecological indications, including luteal insufficiency, dysmenorrhea, premenstrual syndrome, to mention a few(2). Since its introduction in 1961, the drug has been used worldwide, with repeated studies documenting efficacy equivalent to micronized vaginal progesterone (3-5). While the drug has been shown to have mostly mild adverse maternal effects, its' fetal safety has been only sparsely investigated.
The introduction of the oral contraceptive pills in the 1960' has led to concerns regarding sexual changes in male fetuses , however numerous studies and several meta analyses have confirmed the safety of the "pill" (6-7). In contrast, no similar investigations had followed the introduction of DYD. DYD has been shown to be substantially more potent than other progestins, due to configuration at C9 and C10, and the enhanced rigidity due to the C6-C7 double bond(8). Hence one cannot extrapolate from the fetal safety of the oral contraceptive pill to DYD.
In August 2017, following removal of DYD from the American market, a citizen petition asked the FDA to determine whether this removal was based on safety concerns. In its official response, the FDA determined that the withdrawal from sale of oral 5mg and 10 mg tablets of DYD, was not due to safety or effectiveness concerns (9). In its analysis the FDA declared that its' review has failed to show safety concerns. However, the almost total lack of fetal safety studies of DYD raises questions about the validity of such determination (9).
The objective of the present study was to investigate the fetal safety of DYD based on analysis of electronic health records of a large health maintenance organization.
Maccabi Health Services (MHS) is Israel's second largest healthcare organization, serving as both insurer and health care provider to a population of 2.1 million members (25% of the Israeli population). MHS is one of four insurers providing equivalent, universal coverage mandated by Israel’s National Health Insurance Law. The present study was approved by Assuta Hospital Research Ethics Board in Tel Aviv.
Maccabi Healthcare Service maintains central computerized databases containing demographic and medical data including hospitalizations, diagnoses, drug purchases, laboratory data and physician visits(9). In this retrospective controlled cohort study, we identified all cases of pregnant women receiving DYD during the first trimester of pregnancy between January 1, 1999 and December 31, 2016. All mothers were members of Maccabi continuously during the year preceding, and following the date of birth of the child. We identified all purchases of DYD from participants’ medical records, including the number of packs during the 9 months preceding the birth date of the index child, and identified those receiving the drug during at least the first 3 months of pregnancy. We collected information on co-morbid maternal conditions: diabetes mellitus, hypertension, cardiovascular diseases, epilepsy, cancer and subfertility. We searched whether in addition to DYD the woman underwent in vitro fertilization (IVF) and/or other methods of assisted reproductive technology (ART), as these procedures have been associated with increased risks for birth defects (11-13). Women exposed to IVF or ART in addition to DYD were excluded from our primary analysis, however, were included in a secondary sensitivity analysis.
The control group consisted of all MHS women giving birth to children in the same time frame, who did not receive DYD, IVF or other forms of ART.
All major malformations were identified using the International Classification of Diseases (ICD 9) system (14).
Differences between cases and controls in rates of major malformations were compared by logistic multivariable analysis, adjusting for diabetes mellitus, hypertension, cardiovascular diseases, epilepsy and cancer.
Statistical analyses were performed using SPSS Statistics for Windows, Version 21.0, 2012(: IBM Corp Armonk, NY).
During the study period 8508 children were born after maternal use of DYD during at least the first trimester of pregnancy (4417 boys, 4091 girls). Overall, during this period 738,583 children were born in MHS. Women receiving DYD were twice more likely to had undergone IVF than in the control group (9.% vs. 4%, p<0.0001). Children exposed in utero to DYD had a slightly lower mean birth weight (3222+-537 g vs. 3095+-631 g, p<0.0001) and a shorter mean gestation (38.5 +- 2.6 wk vs.39.0+-1.9 wk , p<0.0001) (Table 1 ).
After excluding cases exposed also to IVF and ART in addition to DYD, there was increased risk for hypospadias [OR 1.28(95% confidence interval 1.06-1.55)], for overall cardiovascular malformations [ OR 1.18 (1.06-1.33)], congenital aortic insufficiency [OR 1.65(1.008-2.71) patent ductus arteriosus [OR 1.51(1.17-1.95), spina bifida [OR 2.29(1.32-3.97] and hydrocephalus [OR 2.04(1.28-3.25](Table 2 ). In a sensitivity analysis, including also those exposed to IVF and ART in addition to DYD, there were additional increased risks for cryptorchidism [1.37(1.19-1.58)] and congenital dislocation of the hip [OR 1.58(1.42-1.78)](Table 2 ).
Our study, based on a very large sample size of exposed fetuses has detected increased teratogenic risk among DYD- exposed offspring. Unlike other progesterone derivatives, which have been widely studied for fetal safety when used as oral contraceptives, DYD has been very sparsely investigated. It is not clear whether this lack of fetal safety studies was due to extrapolation from the safety profile of progesterone as an oral contraceptive, however such extrapolation may not be valid as DYD is far more potent in vivo then progesterone (8). In the vast majority of studies investigating DYD in pregnancy, the primary endpoint of interest was the success in commencing pregnancy, and fetal malformations were sparsely reported (4, 15- 16)
The present study, based on a very large number of pregnancies exposed to DYD, and a comparison group of over 770,000 births, has identified increased risk for several serious congenital malformations. The increased risk of hypospadias is consistent with the expected biological effects of a potent progestin on male genitalia (17), as is the increased risk for cryptorchidism seen in our sensitivity analysis. The overall increased risk of cardiac malformations is in agreement with the recent case control study from Gaza (16). The increased risk for spina bifida detected by us is consistent with a large number of studies and meta analysis showing that the useof oral contraceptives lead to reduction in blood folate concentrations, and hence may increase the risk for spina bifida (18). We also detected increased risk of hydrocephalus without evidence of neural tube defects.
Response to potential criticism:
Because DYD is used to support women exhibiting subfertility, confounding by indication is a major challenge that needs to be addressed before one can relate increased fetal risks to DYD. In particular, the use of ART, including IVF, has been the focus of numerous recent studies and meta- analyses investigating fetal safety. Overall, there is a consensus that IVF/ICSI are associated with increased teratogenic risk (11-13). To be able to separate potential adverse fetal effects of DYD from those of IVF/ART, we have elected for our primary analysis to exclude pregnancies where the women were exposed concomitantly to DYD and/or ART, avoiding their confounding effects. In a sensitivity analysis we calculated the fetal risk of the combined DYD plus ART cohort, showing a potential additive or synergistic adverse fetal effects, including cryptorchidism and congenital dislocation of the hip. Because these modalities are combined with DYD in 9% of women in our cohort, these additional teratogenic risks should also be considered in the overall risk-benefit assessment.
Importantly, the increased malformation rates described with sub-fertility are different from those found by us, which are biologically related to the effects of progestins.
Our study was also criticized for showing a malformation signal not detected by other studies. Yet, the other studies were all an order of magnitude smaller, lacking a power to discern the increased risk shown by us. It is important to remember that a sample size of only 1000 exposed cases has limited power to show even a twofold increased teratogenic risk. Our sample of almost 8000 DYD cases and 700,000 controls documented ORs of less than two folds, hence sample sizes of even 1000 cases would not be statistically significant. This type 2 statistical error may wrongly interpreted to be a “safe” signal. As important, the case control study by Zaqout et al (16) has shown, similar to us, an increased risk for cardiovascular malformations. Because of its potential importance this study was selected by Lancet to be republished to ensure it gets the visibility and attention. Indeed, it was the Zaqout study re published in Lancet that has prompted us to examine DYD, a progestin that has escaped below the radar for almost 70 years.
We were also criticized for extensive but not all inclusive correction for all possible confounders- however, the fact that the DYD-exposed group of infants had significant odd ratios for specific malformations dependent on progestin effects, and not just any malformations, provide biological plausibility which is a critical component in observational data.
Our data suggest that DYD exhibits independent teratogenic effects that may have important implications for the child and family. Because the efficacy of DYD for threatened and repeated miscarriages appears to be equivalent to that of micronized vaginal progesterone (2-4), a careful risk - benefit assessment should be conducted to select the optimal choice.
Till more studies are available, we believe it is important to advise parents about these potential fetal effects. DYD confers teratogenic effects after exposure to the recommended doses in pregnant women. The risks of hypospadias and cryptorchidism have biological plausibility by the known effects on male genitalia, as is the risk for spina bifida, by the proven decrease in folic acid levels. Clinically, it may be reasonable for fertility experts to perform tests to rule out fetal cardiovascular effects and spina bifida, which can be visualized prenatally.
1, Koren G, Gilboa D. Fetal Outcome following Dydrogesterone Exposure in Pregnancy. Arch Dis Child 2019: 104(6):004
2. Schindler AE. Present and future aspects of dydrogesterone in prevention or treatment of pregnancy disorders: an outlook. Horm Mol Biol Clin Investig. 2016 Aug 1;27 (2):49-53.
3. Tournaye H1, Sukhikh GT2, Kahler et al. A Phase III randomized controlled trial comparing the efficacy, safety and tolerability of oral dydrogesterone versus micronized vaginal progesterone for luteal support in in vitro fertilization. Hum Reprod. 2017 Oct 1;32(10):2152. doi: 10.1093/humrep/dex266.
4. Nadarajah R, Rajesh H, Wong KY,et al. Live birth rates and safety profile using dydrogesterone for luteal phase support in assisted reproductive techniques. Singapore Med J. 2017 Jun;58(6):294-297.
5. Siew JYS, Allen JC, Hui CYY, et al. The randomised controlled trial of micronised progesterone and dydrogesterone (TRoMaD) for threatened miscarriage.
Eur J Obstet Gynecol Reprod Biol. 2018 Sep;228:319-324
· Summary (text)
· Abstract (text)
· PMID List
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9. https://www.federalregister.gov/documents/2017/09/06/2017-18816/determination-that-gynorest-dydrogesterone-oral-tablets-5-milligrams-and-10-milligrams-were-not. Accessed May 26, 2019
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The authors report no conflict of interest.
No external funding was used for this research project.
Odds ratios (95% confidence interval) of selected congenital malformations in children exposed in utero to DYD, vs. an unexposed control group, after excluding those exposed also to IVF/ART, or when combined with those exposed to IVF/ART, and after adjusting for potential confounders
|Dydrogesterone DYD+ IVF/ART|
|Hypospadias 1.28(1.06-1.55) 1.56(1.31-1.85)|
|Undescended testis/ 1.0 (0.85 -1.19) 1.37 (1.19-1.58)|
|Cong. Hip Dislocation 0.9 (0.78-1.04) 1.58(1.42-1.78)|
|Fallot Tetralogy 1.1 (0.72-1.33) 1.35 (0.5- 3.62)|
|VSD 1.02 (0.91- 1.32) 1.07 (0.86-1.34)|
|Renal Dysplasia 1.04(0.85-1.33) 2.16(1.22-3.82)|
|Cong. Pylorus 1.04(0.84-1.18) 1.25(0.86-1.82)|
|PDA 1.27(0.96-1.67) 1.51(1.17-1.95)|
|Cong. Aortic 1.65(1.008-2.71) 1.96 (1.25-3.1)|
|Pulm. Stenosis 0.95(0.81-1.48) 1.21(0.81-1.81)|
|Cong. Catarct 1.52(0.84-2.76 1.52(0.84-2.76)|
|Spina Bifida 2.29(1.32-3.97) 2.29(1.32-3.97)|
|Cong. Hydocephalus 1.75 (1.03-1.96) 2.04(1.28-3.25)|
|TGA* 2.03(0.75-5.4) 2.03(0.75-5.4)|
|Overall cardiovascular 1.18 (1.06-1.33) 1.31(1.12-1.42)|
*Transposition of great arteries