Potential developmental effects of licit and illicit substances in humans: An approach to risk-specific dose and incidence.

Teratogens encompass any agent capable of causing a birth defect or elevating the incidence of defects within the population. This category includes substances like drugs, both legal and illegal. These substances cause congenital anomalies depending on the stage of development at the time of exposure, the dose, and the exposure time associated with the embryo. The most sensitive period is the embryonic stage, when the three leaflets give rise to tissues and organs. Susceptibility to teratogenesis decreases during the fetal phase but morphological and functional disturbance of the fetus may still occur. Substance use during pregnancy and its adverse effects are a public health problem and the lay population does not have access to this information. Particularly concerning is the period within the first six weeks of pregnancy, often before a woman realizes she is pregnant. Developmental data for many substances are simply not available, which makes the problem more serious. The aim of this study is to reflect on the teratogenic effects of licit and illicit substances in humans, focusing particularly on the dose that can induce malformations and their incidence in humans.

Comparative Safety of In Utero Exposure to Buprenorphine Combined With Naloxone vs Buprenorphine Alone.

Importance: Buprenorphine combined with naloxone is commonly used to treat opioid use disorders outside of pregnancy. In pregnancy, buprenorphine alone is generally recommended because of limited perinatal safety data on the combination product. Objective: To compare perinatal outcomes following prenatal exposure to buprenorphine with naloxone vs buprenorphine alone. Design, Settings, and Participants: Population-based cohort study using health care utilization data from Medicaid-insured beneficiaries in the US from 2000 to 2018. The cohort was restricted to pregnant individuals linked to their liveborn infants, with maternal Medicaid enrollment from 3 months before pregnancy to 1 month after delivery and infant enrollment for the first 3 months after birth, unless they died sooner. Exposure: Use of buprenorphine with naloxone vs buprenorphine alone during the first trimester based on outpatient dispensings. Main Outcomes and Measures: Outcomes included major congenital malformations, low birth weight, neonatal abstinence syndrome, neonatal intensive care unit admission, preterm birth, respiratory symptoms, small for gestational age, cesarean delivery, and maternal morbidity. Confounder-adjusted risk ratios were calculated using propensity score overlap weights. Results: This study identified 3369 pregnant individuals exposed to buprenorphine with naloxone during the first trimester (mean [SD] age, 28.8 [4.6] years) and 5326 exposed to buprenorphine alone or who switched from the combination to buprenorphine alone by the end of the first trimester (mean [SD] age, 28.3 [4.5] years). When comparing buprenorphine combined with naloxone with buprenorphine alone, a lower risk for neonatal abstinence syndrome (absolute risk, 37.4% vs 55.8%; weighted relative risk, 0.77 [95% CI, 0.70-0.84]) and a modestly lower risk for neonatal intensive care unit admission (absolute risk, 30.6% vs 34.9%; weighted relative risk, 0.91 [95% CI, 0.85-0.98]) and small for gestational age (absolute risk, 10.0% vs 12.4%; weighted relative risk, 0.86 [95% CI, 0.75-0.98]) was observed. For maternal morbidity, the comparative rates were 2.6% vs 2.9%, respectively, and the weighted relative risk was 0.90 (95% CI, 0.68-1.19). No differences were observed with respect to major congenital malformations overall, low birth weight, preterm birth, respiratory symptoms, or cesarean delivery. Results were consistent across sensitivity analyses. Conclusions and Relevance: There were similar and, in some instances, more favorable neonatal and maternal outcomes for pregnancies exposed to buprenorphine combined with naloxone compared with buprenorphine alone. For the outcomes assessed, compared with buprenorphine alone, buprenorphine with naloxone during pregnancy appears to be a safe treatment option. This supports the view that both formulations are reasonable options for the treatment of opioid use disorder in pregnancy, affirming flexibility in collaborative treatment decision-making.

Pregnancy and Infant Outcomes After Prenatal Exposure to Golimumab in Denmark, Finland, and Sweden 2006-2019.

PURPOSE: To present the main findings of a post-authorization safety study assessing pregnancy and infant outcomes after prenatal golimumab exposure in a real-world setting. METHODS: This observational population-based cohort study included data from pregnancies ending in 2006-2018 (Finland) or 2019 (Denmark, Sweden). Infants born to women with rheumatic diseases or ulcerative colitis diagnoses were identified. Based on prescription fills from 90 days prior to pregnancy until delivery, infants were assigned to one of the four drug-exposure cohorts: golimumab, other anti-TNF biologics, other biologics, and nonbiologic systemic therapy, and the general population. Prevalence of adverse pregnancy outcomes, mortality, diagnoses of major congenital anomalies (MCA), and inpatient infections in the infants' first year of life were assessed. Odds ratios and 95% CIs were calculated for MCA and infection. RESULTS: Among 134 infants in the golimumab cohort, none were stillborn or died in the first year of life. MCA were diagnosed in 4.5% of the infants in the golimumab cohort, versus 6.8%, 10.9%, 5.5%, and 4.6% in the other anti-TNF biologics, other biologics, nonbiologic systemic therapy and general population cohorts, respectively. Inpatient infections were diagnosed in 11% of golimumab-exposed infants, compared with 9%-11% of infants in the other cohorts. Unadjusted and selected adjusted comparisons showed no association between prenatal golimumab exposure and MCA or infection compared with the other exposure cohorts or general population. CONCLUSIONS: The number of infants with prenatal golimumab exposure was low, but results are reassuringly consistent with the evidence available for other anti-TNF biologics. Continued monitoring is needed.

Validation of a new protocol for a zebrafish MEFL (malformation or embryo-fetal lethality) test method that conforms to the ICH S5 (R3) guideline.

Detecting the toxic effects of chemicals on reproduction and development without using mammalian animal models is crucial in the exploitation of pharmaceuticals for human use. Zebrafish are a promising animal model for investigating pharmacological effects and toxicity during vertebrate development. Several studies have suggested the use of zebrafish embryos for the assessment of malformations or embryo-fetal lethality (MEFL). However, a reproducible protocol as a standard for the zebrafish MEFL test method that fulfills global requests has not been established based on the International Council of Harmonisation (ICH) S5 (R3) guidelines. To establish such a toxicity test method, we developed a new and easy protocol to detect MEFL caused by chemicals, especially those with teratogenic potential, using fertilized zebrafish eggs (embryos) within 5 days of development. Our toxicity test trials using the same protocol in two to four different laboratories corroborated the high inter-laboratory reproducibility. Our test method enabled the detection of 18 out of 22 test compounds that induced rat MEFL. Thus, the prediction rate of our zebrafish test method for MEFL was almost 82% compared with that of rat MEFL. Collectively, our study proposes the establishment of an easy and reproducible protocol for the zebrafish MEFL test method for reproductive and developmental toxicity that meets ICH guideline S5 (R3), which can be further considered in combination with information from other sources for regulatory use.

Integrase inhibitor drugs during pregnancy and congenital anomalies: A case/non-case study from the global pharmacovigilance database VigiBase®.

In 2018, a significant neural tube defects (NTD) signal was reported after pre-conceptional exposure to dolutegravir, but was not confirmed in further analysis. Since 2019, dolutegravir-based regimen, an integrase inhibitor (INI), is recommended by WHO as the most-effective first-line therapy in all patients living with HIV. To explore the potential INI-related teratogenic effect, we searched disproportionate signals between exposure to INI-class drugs and congenital anomalies, compared to non-INI drugs, using the international pharmacovigilance database, VigiBase®. We selected all the reports registered in VigiBase® between 01/01/2007 and 30/03/2021 on any antiretroviral drug-related fetal or neonatal adverse drug reactions, declared either in children (<2 years) exposed in utero or in pregnant women (12-50 years). A case/non-case study was conducted to detected signals between congenital anomalies and prenatal exposure to any INI-class drug, compared to non-INI drugs, by estimating adjusted reporting odds ratios (aROR) with 95% confidence intervals (95%CI). We identified 2521 unique reports, among which 664 (26.3%) were related to INI-class use. Overall, 520 congenital anomalies were cited from 327 unique reports, of whom 31.0% were INI-related. Compared to non-INI drugs, no significant disproportionate reporting signal between prenatal exposure to INI-class drugs and congenital anomalies was found (aROR 1.13; 95% CI:0.85-1.51). However, specific significant signals were reported for raltegravir/elvitegravir/dolutegravir drug exposure and urinary malformations (aROR 2.43; 95%CI:1.08-5.43), digestive malformations (aROR 3.09; 95%CI:1.22-7.84), and NTDs (aROR 3.02; 95%CI:1.09-8.37). Although specific congenital anomalies signals associated with raltegravir/elvitegravir/dolutegravir exposure were notified, causal relationship needs to be further investigated in prospective studies.

Drug exposure characteristics and related pregnancy outcomes in pregnant women: an observational cohort study.

Aims/Background The relationship between drug exposure and pregnancy outcomes is still unclear. The study was designed to characterise the overall condition of drug exposure during pregnancy and uncover related pregnancy outcomes. Methods Pregnant women were enrolled in the study from 1 October 2019 to 31 April 2022, at a tertiary hospital in Jiangsu Province, China. Basic maternal information and data regarding drug exposure during different pregnancy trimesters were gathered using the 'Eugenic Baby' platform. Based on drug use data and the pregnancy and lactation labelling rule, pregnant women were divided into three groups to explore the relationship between drug exposure and pregnancy outcomes. Results Analysis revealed that fetal protection drugs were used in 43.99% of early pregnancy cases. Pregnant women utilised more unrecommended drugs (according to the pregnancy and lactation labelling rule) in the first trimester than in the following trimesters. Regarding pregnancy outcomes, 56 of the 837 live infants had a malformation, and congenital heart disease was the main type. Gestational age, mode of delivery, birth weight, height, and head circumference were significantly different (p < 0.05) among the three groups. According to multivariate logistic regression analysis, preterm birth (odds ratio=3.226, 95% confidence intervals: 1.447-7.194, p=0.004) and low birth weight (odds ratio=4.270, 95% confidence intervals: 1.299-14.034, p=0.017) predicted increased risk of maternal drug exposure after adjusting for covariates. Conclusion Drug exposure of various types is common during pregnancy. Compared to the second and third trimester, unrecommended drugs are used more frequently in the first trimester. Drug exposure is associated with adverse pregnancy outcomes and these associations need to be further confirmed. It is vital to fully consider treatment benefits and potential risks before medication initiation during pregnancy.

Teratogenic effects of voriconazole (anti-fungal drug) on Swiss albino mice.

Antifungals are a class of drugs that target the treatment of invasive fungal infections. This includes polyenes, triazoles, and echinocadins. Among these, azoles are being extensively used nowadays. Triazoles have become standard for the azoles and have replaced amphotericin B as the first line of defence for fungal infections. With the increased cases of fungal infection, which affect a majority of the population at different stages and situations, one such section of the population is pregnant females. The rate and susceptibility of fungal infections are particularly higher in pregnant females, as the immunity of the mother is highly compromised. Systemic fungal infections like invasive aspergillosis, esophageal candidiasis, and candidemia are being treated with new age triazole antifungals like voriconazole. Prolonged and high concentrations of this drug are associated with various developmental anomalies. With this aim, teratogenic studies were performed on pregnant female mice during gestation and the weaning/lactation period to observe the effects of voriconazole at different dosages (8 mg/kg b.w., 10 mg/kg b.w., and 20 mg/kg b.w.). Pregnant dams were subjected to 20 mg/kg b.w. Voriconazole had a small litter size and a high number of resorptions. Craniofacial defects in the form of reduced ossification and widely open sutures, the presence of the 14th rib, asymmetry in the sternebrae, and the absence of ossified distal phalanges were some of the skeletal anomalies which were significant in the foetus and pups subjected to both 10 mg/kg b.w. and 20 mg/kg b.w. doses of voriconazole.

Pregnancy Outcomes in Patients Treated with Upadacitinib: Analysis of Data from Clinical Trials and Postmarketing Reports.

BACKGROUND AND OBJECTIVE: Upadacitinib is indicated for diseases affecting persons of childbearing potential including rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, atopic dermatitis, Crohn's disease, and ulcerative colitis; however, teratogenicity was observed in animal studies. Given the potential for human fetal risk, pregnancy avoidance measures were required during clinical trials. This analysis describes pregnancy outcomes in patients exposed to upadacitinib during pregnancy. METHODS: Clinical trial and postmarketing cases of in utero exposure to upadacitinib were identified in AbbVie's safety database through 25 April, 2023. Analysis of clinical trial cases and postmarketing reports are presented separately; prospective and retrospectively reported pregnancy outcomes are integrated for each. Descriptive rates are presented to summarize outcomes. RESULTS: There were 128 maternal upadacitinib-exposed pregnancies with known outcomes identified; 80 and 48 pregnancies were reported in clinical trials and the postmarketing setting, respectively. In clinical trials (mean in utero exposure of 5 weeks, 3 days), live births (54%), spontaneous abortions (24%), elective terminations (21%), and ectopic pregnancy (1%) were reported. There was one report of a congenital malformation: a 35-week infant with an atrial septal defect. In postmarketing cases, live births (46%), spontaneous abortions (38%), elective terminations (15%), and ectopic pregnancy (2%) were reported. CONCLUSIONS: As the data are limited for in utero exposure to upadacitinib, definitive conclusions cannot be drawn regarding the effect of upadacitinib on pregnancy outcomes. Rates of adverse pregnancy outcomes with upadacitinib exposure were comparable to rates observed in the general population or patients with autoimmune inflammatory diseases. To date, no apparent evidence of teratogenicity exists in the analyses of human pregnancies exposed to upadacitinib during the first trimester.

Assessment of the Safety of Exposure to Cefcapene Pivoxil during the First Trimester of Pregnancy: A Prospective Cohort Study in Japan.

Cefcapene pivoxil hydrochloride is an antibiotic often used by women who are or may be pregnant. However, the safety of exposure to it during the first trimester of pregnancy has not been assessed. In this study, we aimed to clarify the effects of exposure during the first trimester of pregnancy on maternal and fetal outcomes. Data were obtained from pregnant women who were counseled on drug use during pregnancy at two Japanese facilities from April 1988 to December 2017. The incidence of major malformations in singleton pregnancy was compared between neonates born to women who took cefcapene pivoxil hydrochloride (n = 270) and control drugs (n = 1594) during their first trimester. The adjusted odds ratio of the incidence of major malformations was calculated using multivariate logistic regression analysis adjusted for smoking during pregnancy and maternal age. The incidence of major malformations was 2.6% in the cefcapene pivoxil hydrochloride group and 1.8% in the control group. There were no significant differences in the incidence between the cefcapene pivoxil hydrochloride and control groups (adjusted odds ratio: 1.48 [95% confidence interval: 0.64-3.42], p = 0.36). This prospective cohort study showed that exposure to cefcapene pivoxil hydrochloride during the first trimester of pregnancy was not associated with increased risk of major malformations in infants. Our findings will help healthcare providers in choosing appropriate medicines.

Epilepsy, Antiepileptic Drugs, and Adverse Pregnancy Outcomes, 2: Major Congenital Malformations With Antiepileptic Drug Monotherapy.

Women with epilepsy (WWE) are usually advised antiepileptic drug (AED) treatment even during pregnancy. It is therefore important to know what the major congenital malformation (MCM) risks might be with untreated epilepsy, and with first-trimester exposure to different AEDs in monotherapy. This article reviews recent findings from a large multinational registry, a large multinational population based study, and a large meta-analysis. In summary, data from the meta-analysis suggest that the MCM rate is 2%-3% in women without epilepsy and about 3% in WWE who were unexposed to AEDs during pregnancy. Data from the meta analysis also suggest that the MCM rate is approximately population level at 2.6%-3.5% with levetiracetam and lamotrigine and that it is about 4%-5% with carbamazepine, 2.8%-4.8% with oxcarbazepine, about 4% with topiramate, about 5%-7% with phenytoin, about 6%-9% with phenobarbital, and nearly 10% with valproate. The MCM risk with valproate is significantly higher than that with other AEDs (including topiramate and phenobarbital) that significantly increase the risk. Data from the registry suggest that risks are dose-dependent with valproate, phenobarbital, and carbamazepine and that the risk with valproate may be as high as 25% at doses >1,450 mg/d. Valproate is also associated with a wide range of MCMs. Data from the population-based study were generally confirmatory. Strengths and limitations of the studies are considered. The findings of these studies encourage the consideration of levetiracetam or lamotrigine monotherapy for WWE who are pregnant and strongly discourage the consideration of the older AEDs, especially phenytoin and phenobarbitone, and most especially valproate. These considerations also apply to all WWE of childbearing age because it may not be easy to change AEDs when pregnancy is planned and because pregnancy is often unplanned.

Exposure to golimumab during pregnancy: Results from the Company's global safety database.

Data on the use of golimumab (GLM) during pregnancy are limited. This study evaluated pregnancy outcomes in women treated with GLM during pregnancy. Cumulative data on GLM-exposed pregnancies from the Company's global safety database (GSD) are summarized. Cases were medically confirmed maternal exposures to GLM during pregnancy or within 3 months prior to conception with a reported pregnancy outcome. Pregnancy outcomes (e.g., live births) and congenital anomalies in prospectively reported cases (i.e., pregnancy outcome not known when first reported to the company) are presented in a descriptive manner. As of May 31, 2022, 261 prospectively reported pregnancies exposed to GLM were reported in the GSD: 214 (82.0%) live births (including six sets of twins), 31 (11.9%) spontaneous abortions (including one set of twins), 13 (5.0%) induced/elective abortions, 2 (0.8%) reported intrauterine death/still birth, and 1 (0.4%) fetal adverse event in an ongoing pregnancy. The majority of pregnancies had exposure to GLM at least in the first trimester of pregnancy. In total, seven congenital anomalies (7/261; 2.7%) were reported. Of these seven congenital anomalies, five were considered major according to EUROCAT classification version 1.4. Among the five prospectively reported congenital anomalies noted in live births (5/214; 2.3%), four were classified as major (4/214; 1.8%). The rates of adverse pregnancy outcomes and major congenital anomalies in prospectively reported pregnancy cases with exposure to GLM in the Company's GSD were consistent with published background rates for the general population.

Multicentre study and systematic review: Allopurinol exposure during pregnancy.

BACKGROUND: Data about the safety of allopurinol in pregnant women are sparsely reported. AIMS: To investigate the risk of adverse pregnancy outcome and congenital abnormalities after in utero exposure to allopurinol in inflammatory bowel disease (IBD) pregnancies and in general. METHODS: We collected safety data of patients with IBD who were treated with allopurinol during pregnancy between January 2013 and March 2022. Additionally, we performed a systematic review about the teratogenic potential of allopurinol. RESULTS: We collected data from 42 allopurinol-exposed pregnancies, including one twin pregnancy; in all women, allopurinol was combined with a thiopurine. Six pregnancies (14.3%) resulted in miscarriage and one in stillbirth at 32 weeks. A congenital anomaly was observed in one newborn (coarctation of the aorta discovered postpartum). Three pregnancies, including the twin pregnancy, ended in moderate preterm delivery and one in very preterm delivery. Five neonates (15.2%) were small for gestational age. From our literature search, we identified an additional 102 allopurinol-exposed pregnancies resulting in 129 live births, including 36 infants from our cohort. Ten infants (7.8%) were born with a congenital anomaly. Two (1.6%) had a comparable pattern of multiple anomalies. The systematic review sub-analysis including only infants born to mothers with IBD (n = 76) revealed that 2.6% of infants had congenital anomalies after in utero exposure to a low dose of allopurinol. CONCLUSIONS: Overall, the teratogenicity of allopurinol remains inconclusive. Children conceived by mothers treated for IBD with allopurinol/thiopurine co-therapy do not seem to have an increased risk of congenital anomalies.

Evaluation of temperature- and ethanol-related developmental degree variations by a new scoring system (FETAX-score) applicable to Frog Embryo Teratogenicity Assay: Xenopus.

The aim of the present work is to propose a new quantitative assessment method (FETAX-score) for determining the degree of Xenopus laevis embryo development intended for use in embryotoxicity studies. Inspired by a similar scoring system used to evaluate developmental delays (young-for-age phenotypes) in rat embryos cultured in vitro, the FETAX-score was established by considering seven morphological features (head, naris, mouth, lower jaw, tentacles, intestine, anus) that are easily evaluable in tadpoles during the late stages of development at the conclusion of the test. Given that X. laevis development is temperature-dependent and that temperatures below 14°C and above 26°C are teratogenic, the FETAX-score was tested in embryos maintained at 17, 20, 23 and 26°C. No abnormalities were observed in any group, while the total score was temperature-related, suggesting that the FETAX-score is sensitive to moderate distress that does not influence general morphology. Intestine and anus were the least sensitive structures to temperature variations. To assess the applicability of the FETAX-score in developmental toxicological studies, we evaluated FETAX-score in tadpoles exposed during the morphogenetic period to Ethanol (Eth) at concentrations of 0, 0.25, 0.5, 1, 1.5, and 2 % v/v. Gross malformations were observed only in tadpoles from the Eth 2 % group. By contrast, data analysis of the other Eth groups showed dose-related reductions in the FETAX-score. Tentacles were the most sensitive structures to Eth-related delays. These results support the use of the FETAX-score to quantitatively assess developmental deviations in FETAX embryotoxicity studies.

Embryo-fetal developmental toxicity of carbamazepine administered orally in wistar rat.

Carbamazepine is an anticonvulsant medication commonly used to treat epilepsy and other neurological disorders. The purpose of this study was to assess the impact of carbamazepine on prenatal development, including maternal-fetal, external, visceral, and skeletal toxicity. Additionally, the study aimed to investigate the effects of orally administered Carbamazepine at a lower dose range in Wistar rats. Pregnant female rats were randomly distributed into control (G1) group administered with distilled water orally (n=8), low dose (G2) group administered at 25 mg/kg, intermediate dose (G3) group at 50 mg/kg, and high dose (G4) group at 100 mg/kg through oral gavage from gestation day (GD) 5-19. Pregnant female rats were scheduled to necropsy on gestation day (GD) 20. During the evaluation, the uterus was observed for number of live or viable fetuses, dead fetuses, early resorptions, late resorptions, number of corpora lutea and the sex ratio (m/f) per litter. Further, fetuses were subjected to materno-fetal examination which included observation for placenta, amniotic fluid, and umbilical cord followed by external evaluation. Additionally, half of the fetuses were subjected to visceral, craniofacial evaluation and other half of the fetuses were subjected to skeletal evaluation by double staining method using Alcian Blue for cartilages and Alizarin Red S for bones. It was observed that there was a significant decrease in the rate of pregnancy in the intermediate dose (G3) group and in high dose (G4) group when compared with the control group. Moreover, treatment with the Carbamazepine caused significant increase in fetal malformations such as dilation of lateral and third ventricle in brain, in intermediate dose (G3) group and high dose (G4) group when compared with the control (G1) group, dilation of ureters in high dose (G4) group. Fetal skeletal malformations like bent and nodulated ribs were also observed in intermediate dose (G3) group. Existing research substantially supports the claim that carbamazepine can cause teratogenic effects and prenatal development toxicity even at a lower dose range.

Concomitant use of antidepressants and benzodiazepines during pregnancy and associated risk of congenital malformations: a population-based cohort study in Taiwan.

BACKGROUND: Despite the frequent co-administration of antidepressants and benzodiazepines, the association between such concomitant use during pregnancy and the risk of congenital malformations remains inadequately explored. This study aims to examine the association between concomitant use of antidepressants and benzodiazepines during the first trimester and organ-specific congenital malformations. METHODS: We conducted a population-based cohort study using Taiwan's National Birth Certificate Application database, the Maternal and Child Health database, and Taiwan's National Health Insurance database. Pregnant people aged 15-50 years with singleton births between Jan 1, 2004, and Dec 31, 2018, were included. Use of antidepressants and benzodiazepines was defined as at least one prescription during the first trimester, and concomitant use was defined as the overlapping prescription of both drugs with an overlapping prescription period. The primary outcomes were overall congenital malformations and eight organ-specific malformations, consisting of the nervous system, heart, respiratory system, oral cleft, digestive system, urinary system, genital system, and limb malformations. Logistic regression models with propensity score fine stratification weighting approach were used to control for measured confounders. Analyses controlling for confounding by indication and sibling comparison analyses were done to address unmeasured confounders. No individuals with lived experience participated in the research or writing process. FINDINGS: The cohort included 2 634 021 singleton pregnancies, and 8599 (0·3%) individuals were concomitant users of antidepressants and benzodiazepines during the first trimester (mean age at delivery was 31·8 years [SD 5·2] for pregnancies with exposure to antidepressants and benzodiazepines vs 30·7 years [SD 4·9] for pregnancies without exposure). All study participants were female, and information about ethnicity was not available. Absolute risk of overall malformations was 3·81 per 100 pregnancies with exposure, compared with 2·87 per 100 pregnancies without exposure. The propensity score-weighted odds ratios (weighted ORs) did not suggest an increased risk for overall malformations (weighted OR 1·10, 95% CI 0·94-1·28), heart defects (1·01, 0·83-1·23), or any of the other organ-specific malformations, except for digestive system malformations, for which the weighted OR remained statistically significant after adjustment (1·63, 1·06-2·51). The absence of an increased risk for overall congenital malformations associated with concomitant use of antidepressants and benzodiazepines was supported by the analyses controlling for confounding by indication and sibling-matched comparisons. INTERPRETATION: The findings of this study suggest that the concomitant use of antidepressants and benzodiazepines during the first trimester is not associated with a substantial increase in risk for most malformation subtypes. However, considering other potential adverse effects of using both medications concomitantly, a thorough assessment of the risks and benefits is crucial for clinical decision making. FUNDING: National Science and Technology Council.

Prescription Medication Use in Pregnancy in People with Disabilities: A Population-Based Cohort Study.

Background: Individuals with disabilities may require specific medications in pregnancy. The prevalence and patterns of medication use, overall and for medications with known teratogenic risks, are largely unknown. Methods: This population-based cohort study in Ontario, Canada, 2004-2021, comprised all recognized pregnancies among individuals eligible for public drug plan coverage. Included were those with a physical (n = 44,136), sensory (n = 13,633), intellectual or developmental (n = 2,446) disability, or multiple disabilities (n = 5,064), compared with those without a disability (n = 299,944). Prescription medication use in pregnancy, overall and by type, was described. Modified Poisson regression generated relative risks (aRR) for the use of medications with known teratogenic risks and use of ≥2 and ≥5 medications concurrently in pregnancy, comparing those with versus without a disability, adjusting for sociodemographic and clinical factors. Results: Medication use in pregnancy was more common in people with intellectual or developmental (82.1%), multiple (80.4%), physical (73.9%), and sensory (71.9%) disabilities, than in those with no known disability (67.4%). Compared with those without a disability (5.7%), teratogenic medication use in pregnancy was especially higher in people with multiple disabilities (14.2%; aRR 2.03, 95% confidence interval [CI]: 1.88-2.20). Furthermore, compared with people without a disability (3.2%), the use of ≥5 medications concurrently was more common in those with multiple disabilities (13.4%; aRR 2.21, 95% CI: 2.02-2.41) and an intellectual or developmental disability (9.3%; aRR 2.13, 95% CI: 1.86-2.45). Interpretation: Among people with disabilities, medication use in pregnancy is prevalent, especially for potentially teratogenic medications and polypharmacy, highlighting the need for preconception counseling/monitoring to reduce medication-related harm in pregnancy.

Risk of teratogenicity in continued pregnancy after gestational exposure to mifepristone and/or misoprostol: a systematic review and meta-analysis.

PURPOSE: This meta-analysis aimed to comprehensively assess the teratogenic risk to offspring associated with continuing pregnancy after administering mifepristone and/or misoprostol during gestation. METHODS: We conducted a systematic search of multiple databases, including PubMed, Web of Science, Embase, Cochrane, CNKI, and CBM, from their inception to February 2024, with no language restrictions. We included cohort and case-control studies that analyzed the teratogenic effects of mifepristone and/or misoprostol on fetuses and newborns. Quality assessment was performed using the Newcastle-Ottawa Scale (NOS). The odds ratios (OR) from individual studies were combined using meta-analysis. Sensitivity testing and heterogeneity analysis were conducted. RESULTS: A total of 13 studies were eligible for inclusion, comprising 5193 cases of congenital malformations and 12,232 controls. CONCLUSION: Our findings indicated that the use of misoprostol during early pregnancy increased the risk of congenital abnormalities in offspring (OR = 2.69; 95% CI: 1.57-4.62). However, the potential teratogenic effect of mifepristone during pregnancy cannot be ruled out. Additionally, the use of mifepristone and/or misoprostol has been linked to a higher risk of certain congenital anomalies, such as hydrocephalus (OR = 3.41; 95% CI: 1.17-9.97), Möbius syndrome (OR = 26.48; 95% CI: 11.30-62.01), and terminal transverse limb defects (OR = 10.75; 95% CI: 3.93-29.41). (PROSPERO, CRD42024522093, 03182024).

Valproate Use During Spermatogenesis and Risk to Offspring.

Importance: Concerns exist about teratogenic and long-term neurodevelopmental outcomes of paternal use of valproate during spermatogenesis. Objective: To evaluate the association between paternal use of valproate during spermatogenesis and offspring risk of congenital malformations and neurodevelopmental disorders. Design, Setting, and Participants: This nationwide cohort study included 1 235 353 singletons born in Denmark between January 1, 1997, and December 31, 2017, identified in the Medical Birth Register; 1336 children had fathers who had filled prescriptions for valproate during spermatogenesis. Congenital malformations were identified in the first year of life and neurodevelopmental disorders were identified from 1 year of age until December 31, 2018. Statistical analysis was performed March 2024. Exposures: Paternal valproate exposure was defined as fathers who filled 1 or more prescriptions for valproate immediately before or during the time of spermatogenesis (ie, 3 months prior to conception). Main Outcomes and Measures: Children with major congenital malformations in the first year of life and with neurodevelopmental disorders before death or end of follow-up were identified in Danish health registers. Log-binomial regression was used to estimate adjusted relative risks (ARRs) of congenital malformations, and Cox proportional hazards regression was used to estimate adjusted hazards ratios (AHRs) of neurodevelopmental disorders, adjusted for relevant confounders. Results: Among 1 235 353 live births (634 415 boys [51.4%] and 600 938 girls [48.6%]), 1336 children (0.1%) had fathers who filled prescriptions for valproate during spermatogenesis. The median follow-up was 10.1 years (IQR, 5.1-14.8 years) for valproate-exposed children and 10.3 years (IQR, 5.2-15.6 years) for valproate-unexposed children. A total of 43 903 children (3.6%) received a diagnosis of major congenital malformations in the first year of life, and 51 633 children (4.2%) received a diagnosis of neurodevelopmental disorders during follow-up. When comparing the risk among valproate-exposed children with that among unexposed children, the ARR of major congenital malformations was 0.89 (95% CI, 0.67-1.18), the AHR of neurodevelopmental disorders was 1.10 (95% CI, 0.88-1.37), and the AHR of autism spectrum disorder was 0.92 (95% CI, 0.65-1.30). In analyses addressing the robustness of the findings (ie, dose-response analyses, sibling analyses, analyses restricted to children of fathers with epilepsy, analyses that used children with paternal lamotrigine exposure as active comparator, and analyses that used children with paternal exposure to valproate only before spermatogenesis as a negative control exposure), there still was no increased risk of any of the included end points. Conclusions and Relevance: In all analyses based on this large Danish cohort study, results suggest that exposure to valproate during spermatogenesis was not associated with offspring risk of congenital malformations or neurodevelopmental disorders, including autism spectrum disorder.