The research team, led by Alaa Baqer Alali and colleagues based in Al-Hasa, Saudi Arabia, followed PRISMA 2020 reporting guidelines and searched five major databases, including PubMed, Scopus, the Cochrane Library, Web of Science, and Google Scholar, up to November 25, 2025. Their screening process winnowed 181 initial records down to eight eligible studies, encompassing an extraordinary total of 3,632,118 pregnancies. Of these, 2,648 pregnancies involved documented exposure to topical retinoids such as tretinoin, adapalene, tazarotene, and topical isotretinoin, while more than 3.6 million served as unexposed controls. The studies spanned three decades of research, drawing on data from Nordic national registries, European teratology information services, California teratology counseling records, and United States health cooperative pharmacy databases.

The headline finding concerns the primary outcome of major congenital malformations, defined according to established classification systems including EUROCAT, the CDC Metropolitan Atlanta Congenital Defects Program, and the International Classification of Diseases. Across four studies contributing data to this outcome, the pooled risk ratio was 0.83, with a 95 percent confidence interval of 0.64 to 1.07 and a P-value of 0.14. In plain terms, the point estimate actually trended slightly below unity, suggesting marginally lower malformation rates among exposed pregnancies, but the confidence interval crossed the null value of 1.0, meaning the association could not be distinguished from no effect at all. Strikingly, statistical heterogeneity across studies was essentially absent, with an I-squared value of 0 percent, indicating remarkable consistency in the direction of findings.

The secondary outcome of spontaneous abortion, defined as pregnancy loss before 20 to 22 weeks of gestation, told an equally reassuring story. Two studies enrolling 341 exposed and 833 control pregnancies yielded a pooled risk ratio of 0.99, with a confidence interval of 0.68 to 1.43 and a P-value of 0.94. Again, heterogeneity was nil. Additional outcomes reinforced the null pattern: birth weight differed by a non-significant 33.7 grams between groups, gestational age at delivery showed no meaningful difference, and preterm birth rates were statistically indistinguishable between exposed and unexposed pregnancies.

What elevates this meta-analysis above a routine evidence synthesis is the sophistication of its statistical machinery. Beyond the conventional frequentist random-effects model using the DerSimonian-Laird method, the researchers deployed Bayesian hierarchical modeling under three distinct prior specifications: a weakly informative Half-Cauchy prior, a skeptical prior that penalizes large effects, and an empirical prior derived from pharmacological intervention meta-analyses. Posterior risk ratio estimates ranged narrowly from 0.86 to 0.89 across all three priors, and every credible interval crossed unity. The Markov Chain Monte Carlo sampling, run with four chains and 4,000 iterations, converged cleanly, with Gelman-Rubin statistics at 1.000 and divergence rates far below accepted thresholds.

The most technically ambitious component was the Robust Bayesian Model-Averaged analysis, or RoBMA, which simultaneously evaluates 36 competing models spanning three dimensions of uncertainty: whether a true effect exists at all, whether heterogeneity between studies is real, and whether publication bias distorts the observed literature. The verdict was unambiguous. The posterior probability for the null hypothesis of no effect reached 74.1 percent, yielding a Bayes factor of 0.35 in favor of no association. Intriguingly, the same analysis assigned a 75.2 percent posterior probability to the presence of publication bias in the evidence base, yet when the trim-and-fill method imputed two hypothetical missing studies, the adjusted estimate of 0.80 actually strengthened rather than weakened the protective direction of the point estimate.

Beneath the reassuring averages, however, lies a structural vulnerability the authors were careful to expose. A single study, the 2025 Nordic registry cohort by Refsum and colleagues, contributed 87.3 percent of the pooled weight for the malformation outcome, drawing on prescription dispensing records across Denmark, Iceland, Norway, and Sweden. Leave-one-out sensitivity analysis revealed that omitting this single study shifted the pooled risk ratio from 0.83 to 1.07, a change of nearly 30 percent. A Dirichlet Process Mixture clustering analysis confirmed the pattern statistically, isolating the Nordic estimate in its own cluster at a risk ratio of 0.80 while grouping the five remaining effect estimates near perfect nullity. The authors interpret this not as inconsistency but as the expected signature of one high-precision study, with a standard error of 0.138, dominating several smaller studies whose standard errors ranged up to 0.78.

The pharmacokinetic rationale for these findings has existed for years. Percutaneous absorption studies have repeatedly demonstrated that plasma concentrations of tretinoin after topical application remain within endogenous physiological ranges, a stark contrast to oral isotretinoin, whose pooled odds ratio for major malformations has been reported at 3.76 in meta-analysis. Yet regulatory agencies, including the European Medicines Agency and the Australian Therapeutic Goods Administration, continue to advise against topical retinoid use during pregnancy as a precaution, and the United States transitioned retinoid products from letter-based pregnancy categories to the more nuanced Pregnancy and Lactation Labeling Rule in 2014 without resolving the underlying uncertainty.

Perhaps the most sobering finding in the entire analysis concerns not fetal biology but human behavior. In the European multicenter prospective cohort, women exposed to topical retinoids underwent elective termination at more than three times the rate of unexposed controls, a risk ratio of 3.20 with a confidence interval of 1.70 to 5.90. The authors attribute this excess not to detected fetal abnormalities but to counseling-related decisions driven by fear of teratogenicity, amplified by precautionary labeling. Prescribing pattern surveys reinforce the point: in one United States study of women trying to conceive, retinoids were prescribed in zero percent of acne cases, and in a French dermatologist survey, only 45 percent of clinicians checked contraception status when prescribing acne treatments to women of reproductive age.

The authors conclude that the evidence supports reassurance for women with inadvertent first-trimester exposure, but stops short of endorsing intentional use during pregnancy, given that the pooled estimates rest heavily on a single registry study and the confidence intervals include the null. E-value analysis confirmed that the findings are not robust to unmeasured confounding, since the intervals already cross unity. The path forward, they argue, lies in larger prospective studies with detailed exposure characterization, formulation-specific analyses, and attention to minor malformations that registry data may under-ascertain. Until then, the study stands as a rare piece of good news in reproductive pharmacovigilance: the most feared creams in the dermatology cabinet appear, on current evidence, far less dangerous than their oral cousins, and the anxiety they generate may itself be the greater clinical hazard.

Subject of Research: Safety of topical retinoid exposure during early pregnancy

Article Title: Topical retinoids and risk of major congenital malformations and spontaneous abortion: a systematic review and meta-analysis

Article References: Topical retinoids and risk of major congenital malformations and spontaneous abortion: a systematic review and meta-analysis. (n.d.). https://doi.org/10.3389/fdsfr.2026.1864872

Image Credits: AI Generated

DOI: 10.3389/fdsfr.2026.1864872

Keywords: topical retinoids, pregnancy, congenital malformations, spontaneous abortion, teratogenicity, tretinoin, meta-analysis, Bayesian statistics, isotretinoin, dermatology, drug safety, acne