Dydrogesterone use after first-trimester not tied to additional risk of congenital anomalies, finds systematic review

Despite large clinical trials and meta-analyses that show no
association between dydrogesterone and congenital anomalies, some recently
retracted publications have postulated an association with teratogenicity.
Dydrogesterone is also often rated as less safe than bioidentical progestins. A
systematic review was conducted by Katalinic et al. according to a
pre-specified protocol with searches on Medline, Embase, Cochrane Central
Register of Controlled Trials (CENTRAL), and Clinicaltrials.gov. The search was
limited to human studies, with no restrictions on language, geographical
region, or date. The search algorithm used a PICO (Population, Intervention,
Comparison, Outcome)-style approach combining both simple search terms and
medical subject heading terms. As congenital anomalies are mostly reported as
secondary outcomes, the search term ‘safety’ was added.

Interventional study and observational study (OS) designs
were eligible for inclusion. Inclusion criteria were: women >17 years old
treated for threatened miscarriage, recurrent pregnancy loss, and/or ART; the
use of dydrogesterone in the first trimester compared with placebo, no
treatment or other interventions; and reporting of congenital anomalies in
newborns or infants ≤12
months old (primary outcome). Two authors (A.K., M.R.N.) independently
extracted the following data: general study information, study population
details, intervention and comparator(s), and frequencies of congenital
anomalies (classification, time of determination, and type).

Of the 897 records retrieved during the literature search,
47 were assessed for eligibility. Nine studies were included in the final
analysis: six randomized controlled trials (RCTs) and three OSs. Among the
RCTs, three had a low risk and three a high risk of bias. Two of the OSs were
considered to have a serious risk of bias and one with critical risk of bias
and was excluded for the evidence syntheses. The eight remaining studies included
a total of 5070 participants and 2680 live births from 16 countries. In the
meta-analysis of RCTs only, the overall risk ratio (RR) was 0.92 [95% CI 0.55;
1.55] with low certainty. When the two OSs were included, the overall RR was
1.11 [95% CI 0.73; 1.68] with low certainty.

Even though this systematic review, based on RCTs, gave no
hint for an increased risk for congenital anomalies, further evidence should be
generated to enhance the body of evidence. Pharmacovigilance data could be used
as a ‘sign giver’, but the evidence level of such data is limited due to
different reasons (such as incomplete reporting, missing risk factor
adjustment, etc.). More high-quality evidence is needed. However, as randomized
controlled reproductive medicine studies rarely focus on fetal safety as a
primary endpoint, there is no evidence at the highest level available for this
topic, and there probably never will be. Authors suggest that more new
randomized controlled studies in the field of threatened miscarriage or ART
involving dydrogesterone in the first trimester of pregnancy should include
standardized assessment of congenital anomalies as a secondary outcome.
Further, it should be discussed whether information on luteal supplementation
could be added to national and systematic registries for congenital anomalies
to be able to estimate the effects of these therapies and, if necessary, their extent
on a population basis. Authors believe that the systematic review and
meta-analysis provide the best possible reassurance to both clinicians and
patients alike that dydrogesterone adds no relevant additional risk for
congenital anomalies above the rate that might be expected for all progestogens
or environmental and genetic factors.

Source: Katalinic et al.; Human Reproduction Open, 2024, 2024(1),

hoae004 https://doi.org/10.1093/hropen/hoae004