Clinical Drug Investigation

https://doi.org/10.1007/s40261-019-00862-w

ORIGINAL RESEARCH ARTICLE

Fetal Safety of Dydrogesterone Exposure in the First Trimester

of Pregnancy
Gideon Koren1,2,3   · Daniella Gilboa3 · Rachel Katz3

© Springer Nature Switzerland AG 2019

Abstract
Background  The progestin dydrogesterone (DYD) is widely used for threatened and recurrent miscarriages, as well as for
dysfunctional bleeding, infertility and other obstetric and gynecological indications. While its apparent efficacy has been
compared to other progestins, its fetal safety has been only sparsely investigated.
Objectives  To follow up fetal outcome after gestational exposure to DYD and compare it to a non-exposed comparison group.
Objectives  To follow up fetal outcome after gestational exposure to DYD and compare it to a non-exposed comparison group.
Patients and methods  Using the 2.5 million patient database of Maccabi Health Services, we compared rates of congenital
malformations among babies exposed in utero during the first trimester of pregnancy to DYD between Jan 1999 and Decem-
ber 2016, to a comparison group not receiving this medication. From the DYD group we excluded all cases with concomitant
exposure to in vitro fertilization (IVF) and other forms of assisted reproductive technology (ART).
Results  There were 8508 children exposed to DYD during the first trimester of pregnancy (4417 males, 4091 females) out
of 777,422 cases in the database. After excluding from the DYD group cases with concomitant exposure to IVF and other
ART, DYD exposure was associated with increased risk for hypospadias [OR 1.28 (95% confidence interval 1.06–1.55)],
for overall cardiovascular malformations [OR 1.18 (91.06–1.33)], spina bifida [OR 2.29 (1.32–3.97)] and hydrocephalus
[OR 2.04 (1.28–3.25)]. In a sensitivity analysis, including also cases exposed to IVF and ART in addition to DYD, there
were also increased risks for cryptorchidism [1.37 (1.19–1.58)] and congenital dislocation of the hip [OR 1.58 (1.42–1.78)].
Conclusions  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. Some of these adverse fetal effects appear to be further augmented by concomitant use of IVF and ART.

Key Points 
In a large cohort study, dydrogesterone conferred terato-
genic effects after exposure to the recommended doses in
pregnant women.
There was increased risk for hypospadias, cardiovascular
malformations, spina bifida and hydrocephalus.
These malformations are consistent with the known
biological effects of progestins.
The paper was presented at the 17th meeting of the European
Society for Developmental Perinatal and Pediatric Pharmacology,
May 28–30, 2019, Basel, Switzerland.
* Gideon Koren
gidiup_2000@yahoo.com
1
Adelson Faculty of Medicine, Ariel University, 40700 Ariel,
Israel
1 Introduction
Dydrogesterone (DYD) is a widely used progestin indi-
cated 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 [1]. Since its introduction in
1961, the drug has been used worldwide, with repeated stud-
ies documenting efficacy equivalent to micronized vaginal
progesterone [2–4]. While the drug has been shown to have
mostly mild adverse maternal effects, its fetal safety has been
only sparsely investigated.
2
Motherisk Israel Program, Zerifin, Israel
3
Kahn-Sagol-Maccabi Institute for Research and Innovation,
Tel Aviv, Israel

Vol.:(0123456789)

The introduction of the oral contraceptive pills in the
1960s has led to concerns regarding sexual changes in male
fetuses; however, numerous studies and several meta analy-
ses have confirmed the safety of the “pill” [5, 6]. 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 [7].
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 deter-
mine whether this removal was based on safety concerns. In
its official response, the FDA determined that the withdrawal
from sale of oral 5 mg and 10 mg tablets of DYD, was not
due to safety or effectiveness concerns [8]. In its analysis
the FDA declared that its review has failed to show safety
concerns. However, the apparent lack of fetal safety studies
of DYD raises questions about the validity of such state-
ment [8].
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.
2 Methods
2.1 Settings
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 pro-
viding 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.
3 Study Population and Design
Maccabi Healthcare Service maintains central computer-
ized databases containing demographic and medical data,
including hospitalizations, diagnoses, drug purchases,
laboratory data and physician visits [9]. In this retro-
spective cohort study, we identified all cases of pregnant
women receiving DYD during the first trimester of preg-
nancy between January 1, 1990 and December 31, 2016.
All mothers were members of Maccabi continuously dur-
ing the year preceding and following the date of birth of
the child. We identified all purchases of DYD from par-
ticipants’ medical records, including the number of packs
during the 9 months preceding the birth date of the index
G. Koren et al.
child, and identified those receiving the drug during at
least the first 3 months of pregnancy. We collected infor-
mation on primary physician and obstetric visits and the
following maternal conditions, habits and status: diabe-
tes mellitus, hypertension, cardiovascular diseases, epi-
lepsy, cancer and subfertility, smoking and socioeconomic
class. We searched whether in addition to DYD the woman
underwent in vitro fertilization (IVF) and/or other meth-
ods of assisted reproductive technology (ART), as these
procedures have been associated with increased risks for
birth defects [10–12]. 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 comparison 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 Inter-
national Classification of Diseases (ICD 9) system [13]
and extracted from the electronic computerized database
of MHS.
4 Statistical Analysis
Differences between cases and controls in rates of major
malformations were compared by logistic multivariable
analysis, adjusting for diabetes mellitus, hypertension, car-
diovascular diseases, epilepsy, cancer, maternal weight,
socioeconomic status and smoking.
Statistical analyses were performed using SPSS Statis-
tics for Windows, Version 21.0, 2012 (IBM Corp Armonk,
NY, USA).
5 Results
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 777,422 children were born in MHS (399,391
boys and 378,031 girls). Women receiving DYD were
twice more likely to had undergone IVF than in the com-
parison group (9.16% vs 4.39%, p < 0.0001). Children
exposed in utero to DYD had a slightly lower mean birth
weight (3222 ± 536 g vs 3096 ± 631 g, p < 0.0001) and a
shorter mean gestation (38.5 ± 2.6 wk vs 39.0 ± 1.95 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 over-
all cardiovascular malformations [OR 1.18 (1.06–1.33)],
Dydrogesterone and Congenital Malformations

congenital aortic insufficiency [OR 1.65 (1.008–2.71)] 6 Discussion

patent ductus arteriosus [OR  1.27 (0.96–1.67)], spina
bifida [OR 2.29 (1.32–3.97)] and hydrocephalus [OR 1.75 Our study, based on a very large sample size of exposed fetuses,
(1.03–1.96)] (Table 2). In a sensitivity analysis, including has detected increased teratogenic risk among DYD-exposed
also those exposed to IVF and ART in addition to DYD, offspring. Unlike other progesterone derivatives, which have
there were additional increased risks for cryptorchidism been widely studied for fetal safety when used as oral con-
[OR 1.37 (1.19–1.58)] and congenital dislocation of the hip traceptives, DYD has been very sparsely investigated. It is
[OR 1.58 (1.42–1.78)] (Table 2). not clear whether this lack of fetal safety studies was due to
extrapolation from the safety profile of progesterone as an oral
Table 1  Characteristics of women and children exposed in utero to contraceptive, however such extrapolation may not be valid as
DYD and the control group DYD is far more potent in vivo then progesterone [7]. In the
Characteristic Dydrogesterone Whole ­populationa p vast majority of studies investigating DYD in pregnancy, the
primary endpoint of interest was the success in commencing
Numbers 8508 777,422 pregnancy, and fetal malformations were rarely reported. In a
Boys 4417 399,391 small study of birth defects between 1977 and 2005, 28 poten-
Girls 4091 378,031 tial links to birth defects were reported, leading the authors to
Exposed to IVF/ART 9.16% 4.39% < 0.001 conclude there was no evidence for teratogenicity [14]. In a
(%)
Phase 3 trial in Singapore, the rate of reported malformation
Numbers after 7742 746,325
excluding IVF/ART​
with DYD was 1.9% among 1050 pregnancies [3]. In a recent
Birth weight (g) 3095 ± 631 3222  ± 537 < 0.001
study comparing 1429 DYD exposures in pregnancy to GnRH-
Gestational age 38.5  ± 2.6 39.0  ± 1.9 < 0.001
agonist (n = 2127) there were no differences in malformation
(weeks) rtaes, but the study did not have a healthy control group, and
Prevalence the malformation analysis is short and not sufficiently spe-
 Epilepsy 0.35% 0.32% N.S. cific [15]. In contrast, in a case–control study, there was an odds
 Type 2 diabetes 3.2% 3.5% N.S ratio of 2.71 for cardiac malformations among babies exposed
mellitus in utero to DYD, as compared to unexposed controls [16].
 Hypertension 4.2% 3.7% N.S Despite these very limited data, the FDA declared in 2016
that it has found “no information that would indicate that this
ART​assisted reproduction technology, IVF in vitro fertilization
a
drug product was withdrawn from sale for reasons of safety
 Excluding cases receiving IVF or other forms of ART​
or effectiveness” [8]. This declaration was not supported by
any data to justify it.

Table 2  Odds ratios (95% confidence interval) of selected congenital or when combined with those exposed to IVF/ART, and after adjust-
malformations in children exposed in utero to DYD, versus an unex- ing for potential confounders (see Sect. 2)
posed control group, after excluding those exposed also to IVF/ART,
Congenital malformation Dydrogesterone DYD + IVF/ART​

Hypospadias 1.28 (1.06–1.55) 1.56 (1.31–1.85)

Undescended testis/cryptorchidism 1.0 (0.85–1.19) 1.37 (1.19–1.58)
Congenital 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)
Congenital pylorus stenosis 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)
Congenital aortic insufficiency 1.65 (1.008–2.71) 1.96 (1.25–3.1)
Pulmonary stenosis 0.95 (0.81–1.48) 1.21 (0.81–1.81)
Congenital cataract 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)
Congenital hydrocephalus 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 malformations 1.18 (1.06–1.33) 1.31 (1.12–1.42)

DYD dydrogesterone, PDA patent ductus arteriosus, TGA​transposition of great arteries, VSD ventricular septal defects

The present study, based on a very large number of preg-
nancies exposed to DYD, and a comparison group of over
770,000 births, has identified increased risk for several seri-
ous congenital malformations. The increased risk of hypo-
spadias 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 agree-
ment 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 showing that the use of oral
contraceptives leads to reduction in blood folate concentra-
tions, and hence may increase the risk for spina bifida [18].
We also detected increased risk of hydrocephalus without
evidence of neural tube defects.
Because DYD is used to support women exhibiting sub-
fertility, 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 consen-
sus that IVF/ICSI are associated with increased teratogenic
risk [10–12]. 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 dis-
location 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.
The recent assessment by the FDA, concluding that there
is no apparent evidence of adverse fetal effects of DYD [13]
may lead to false reassurance of physicians, women and
their families regarding the potential fetal risks of this drug.
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–ben-
efit assessment should be conducted to select the optimal
choice.
7 Conclusions
DYD appears to confer teratogenic effects after exposure to
the recommended doses in pregnant women. The risks of
hypospadias and cryptorchidism have biological plausibility
G. Koren et al.
by the known effects on male genitalia, as is the risk for
spina bifida, by the proven decrease in folic acid levels.
Some of these adverse fetal effects appear to be further aug-
mented by concomitant use of IVF and ART. More studies
on the fetal safety of DYD are needed.
Compliance with Ethical Standards 
Funding  No source of funding.
Conflicts of interest  None of the authors have a conflict of interest to
declare.
Ethics approval  The study was approved by Assuta Hospital Research
ethics committee, Tel Aviv.
Informed consent  Being an anonymous database research, informed
consent was waivered.
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