Risk Of Congenital Malformations Research Articles

The safety of benzodiazepines and related drugs during pregnancy: an updated meta-analysis of cohort studies.

The prevalence of benzodiazepines and related drugs (BZRDs) use during pregnancy increased sharply in recent years. Thus, there are concerns regarding the pregnancy outcomes following exposure to BZRDs. Two electronic databases were thoroughly searched to identify related clinical studies published from inception until June 2023. English-language cohort studies with high-quality comparing antenatal BZRDs exposure to an unexposed group on any delivery outcome were included. Ten cohort studies that estimated adverse neonatal outcomes associated with exposure to BZRDs during pregnancy were included. Exposure to BZRDs during pregnancy was associated with an increased risk of congenital malformation [odds ratio (OR) 1.09, 95% confidence interval (CI) 1.05-1.13, p < 0.001], heart malformation (OR 1.13, 95% CI 1.04-1.22, p = 0.003), preterm birth (OR 1.45, 95% CI 1.23-1.7, p < 0.001), SGA (OR 1.18, 95% CI 1.08-1.29, P < 0.001), LBW (OR 1.42, 95% CI 1.25-1.6, p = 0.001) or low Apgar score (OR 1.42, 95% CI 1.08-1.87, p = 0.011),compared with no exposure. Further analyses limited to the first trimester exposure yielded consistent results. Exposure to BZRDs during pregnancy may be associated with several adverse neonatal outcomes. However, we could not rule out the potential indication confounding factor, further studies with high-quality that control for important confounders are still needed to verify our findings.

Risk of congenital malformations associated with first-trimester exposure to antipsychotics: a propensity score-weighted population-based cohort study.

Risk of congenital malformations associated with first-trimester exposure to antipsychotics: a propensity score-weighted population-based cohort study.

Risks of congenital malformations and neonatal intensive care unit admissions with gabapentin use in pregnancy: A cohort study and scoping review with meta-analysis.

The increasing and prevalent use of gabapentin among pregnant people highlights the necessity to assess its neonatal safety. This study aimed to investigate the foetal safety of gabapentin during pregnancy using a cohort study and scoping review with a meta-analysis of published evidence. We conducted a population-based cohort study using the Manitoba health databases between 1995 and 2019. We examined the association between gabapentin use during pregnancy and the prevalence of major congenital malformations, cardiac and orofacial malformations, and neonatal intensive care unit (NICU) admissions using multivariate regression models. We searched the literature in MEDLINE and EMBASE databases from inception to October 2022 to identify relevant observational studies and conducted a meta-analysis using random-effects models, including our cohort study results. Of the 289,227 included pregnancies, 870 pregnant people were exposed to gabapentin. Gabapentin exposure during the First trimester was not associated with an increased risk of any malformations (adjusted relative risk [aRR]) 1.16 (95%confidence interval [CI] 0.92, 1.46), cardiac malformations (aRR 1.29, 95% CI 0.72, 2.29), orofacial malformations (aRR 1.37, 95% CI 0.50, 3.75), and major congenital malformations (aRR 1.00, 95% CI 0.73, 1.36). whereas exposure during any trimester was associated with an increased NICU admission risk (aRR, 1.99 [95% CI 1.70, 2.32]). The meta-analysis of unadjusted results revealed an increased risk of major congenital malformations (RR 1.44, 95% CI 1.28, 1.61, I2 = 0%), cardiac malformations (RR1.66, 95% CI 1.11, 2.47, I2 = 68%), and NICU admissions (RR 3.15, 95% CI 2.90, 3.41, I2 = 10%), and increased trend of orofacial malformations (RR 1.98, 95%CI 0.79, 5.00, I2 = 0%). Gabapentin use was associated with an increased risk of NICU admissions in the cohort study and pooled meta-analysis. Clinicians should prescribe gabapentin with caution during pregnancy and further studies are warranted.

Post-Conceptional Exposure to Clomiphene Citrate and Congenital Malformations: A Cohort Study.

Clomiphene citrate is an ovulation inductor for which inadvertent post-conceptional exposures may occur in early pregnancy. In preclinical studies, post-conceptional exposures showed a teratogenic effect in different species. In humans, to date, little is known about the outcomes of inadvertently post-conceptionally exposed pregnancies. The objectives of our study were to assess the association between post-conceptional exposures to clomiphene citrate and major and minor congenital malformations in the offspring. A retrospective cohort study of prospectively ascertained cases was undertaken, based on clinical data from the Centre de Référence sur les Agents Tératogènes (CRAT), Paris, France. Women with post-conceptional exposure to clomiphene citrate (n = 309), and unexposed pregnant women (n = 1236, 1:4 ratio) with prospectively collected data, known pregnancy outcome and delivery date prior to 01/02/2022, were matched by calendar year. An adjudication committee classified major and minor congenital malformations according to the EUROCAT (European Registration of Congenital Anomalies and Twins) classification. Among post-conceptional exposed women, no increased risk of major malformation was found (crude relative risk = 0.64, 95% confidence interval 0.19-2.15) as compared to unexposed women. Three major and ten minor congenital malformations were reported in the exposed group. An increased risk of minor malformations was found (crude relative risk = 4.05, 95% confidence interval 1.70-9.64) although there was no specific clinical pattern. Post-conceptional exposure to clomiphene citrate was not associated with an increased risk of major congenital malformations. Given potential confounding and information biases, the results about minor malformations should be interpreted with caution as no specific clinical pattern was identified.

Opioid analgesic exposure during the first trimester of pregnancy and the risk of major congenital malformations in infants: a systematic review and meta-analysis†.

Prescribed opioid analgesics are frequently used to manage pain in pregnancy. However, the available literature regarding the teratogenic potential of opioid use during pregnancy has not been systematically summarised. This systematic review and meta-analysis aimed to assess the quality of the evidence on these potential risks and calculate a pooled estimate of risk for any opioid analgesic and individual opioids. We searched PubMed, Embase and CINAHL for published studies assessing the risk of major congenital malformations in infants following first-trimester exposure to opioid analgesics compared with a reference group, excluding studies examining opioid agonist therapy or illicit opioid use. We assessed the risk of bias using the Risk of Bias in Non-Randomised Studies of Intervention tool. We pooled adjusted risk estimates from studies rated at serious risk of bias or better in a random-effects meta-analysis. Of 12 identified studies, 11 were at high risk of bias (eight serious; three critical). Relative to unexposed infants, those exposed to any opioid use during the first trimester of pregnancy were not at an increased risk of major congenital malformations overall (relative risk 1.04, 95%CI 0.98-1.11); cardiovascular malformations (relative risk 1.07, 95%CI 0.96-1.20); or central nervous system malformations (relative risk 1.06, 95%CI 0.92-1.21). Raised risk estimates were observed for gastrointestinal malformations (relative risk 1.40, 95%CI 0.38-5.16) and cleft palate (relative risk 1.57, 95%CI 0.48-5.13) following any opioid exposure and atrial septal defects (relative risk 1.20, 95%CI 1.05-1.36) following codeine exposure. Although the meta-analysis did not indicate substantial increased risk for most malformations examined, this risk remains uncertain due to the methodological limitations of the included studies. Healthcare professionals and pharmaceutical regulators should be aware of the issues related to the quality of research in this field.

The causal relationship between COVID-19 and ten esophageal diseases: a study utilizing Mendelian randomization.

Clinical signs of dysphagia, pancreatic achalasia, and esophagitis have been reported in patients with COVID-19. However, the causal relationship between COVID-19 and esophageal diseases is not clear. Therefore, we utilized Mendelian randomization to explore the potential association between COVID-19 and esophageal diseases. The summary statistics for a Genome-wide association study (GWAS) were obtained from The COVID-19 Host Genetics Initiative, encompassing four types of COVID-19 as exposure: severe COVID-19, hospitalized COVID-19 versus ambulatory COVID-19, hospitalized COVID-19 versus uninfected, and confirmed COVID-19. Additionally, summary statistics for ten esophageal diseases as outcomes were sourced from the GWAS Catalog and FinnGen databases. Univariate Mendelian randomization (MR) analysis was utilized to thoroughly investigate and validate the potential causal association between COVID-19 and various esophageal conditions, including esophageal varices, Barrett's esophagus, esophagitis, esophageal obstruction, esophageal ulcer, esophageal perforation, gastroesophageal reflux, congenital esophageal malformations, benign esophageal tumors, and esophageal adenocarcinoma. An inverse variance-weighted (IVW) model was utilized for univariate Mendelian randomization (MR) analysis, which revealed that genetic liability in patients with confirmed COVID-19 was associated with esophageal obstruction (OR [95% CI]: 0.5275458 [0.2822400-0.9860563]; p-value = 0.0450699). Furthermore, a suggestive causal association was found between genetic liability and a reduced risk of benign esophageal tumors (OR [95% CI]: 0.2715453 [0.09368493-0.7870724]; p-value = 0.0163510), but with a suggestively increased risk of congenital esophageal malformations (OR [95% CI]: 6.959561 [1.1955828-40.51204]; p-value = 0.03086835). Additionally, genetic liability in hospitalized COVID-19 patients, compared to non-hospitalized COVID-19 patients, was suggestively associated with an increased risk of esophagitis (OR [95% CI]: 1.443859 [1.0890568-1.914252]; p-value = 0.01068201). The reliability of these causal findings is supported by Cochran's Q statistic and the MR-Egger intercept test. The results of this study suggest the existence of a causal relationship between COVID-19 and esophageal diseases, highlighting differing risk effects of COVID-19 on distinct esophageal conditions.

Maternal human papillomavirus infection and the risk of congenital malformations: A nationwide population-based cohort study.

Previous research has explored theories regarding the vertical transmission of human papillomavirus (HPV) infection and its association with adverse pregnancy and perinatal outcomes. However, the impact of maternal HPV infection on congenital anomalies (CAs) in offspring remains relatively understudied. We conducted a population-based cohort study linking the Taiwan Birth Registry, Taiwan Death Registry, and National Health Insurance Research Database, in which newborns born in Taiwan between 2009 and 2015 were included. We established a maternal HPV infection cohort comprising 37 807 newborns and matched them with a comparison group of 151 228 newborns at a 1:4 ratio based on index year, age, and sex. The study examined a composite outcome and subgroups of different types of congenital malformations. Differences in cumulative incidence of CAs were assessed using Kaplan-Meier curves and log-rank tests. Adjusted hazard ratios (aHRs) were estimated using Cox proportional hazard regressions. No significant association was found between HPV infection and the broad spectrum of CAs (aHR: 1.04, 95% confidence interval [CI]: 0.98-1.10; log-rank test p = 0.14). However, we observed a 19% increased risk of musculoskeletal CAs in the maternal HPV infection group (aHR: 1.19; 95% CI: 1.05-1.34) compared to those without maternal HPV exposure. Other factors, including the type of HPV (aHR: 0.65; 95% CI: 0.16-2.63), the timing of exposure (during or before pregnancy), and maternal age (aHR for <30 years: 1.02, 95% CI: 0.94-1.1; aHR for 30-39 years: 1.05, 95% CI: 0.99-1.11; aHR for ≥40 years: 0.88, 95% CI: 0.67-1.17), did not significantly affect the risk for any CA. In conclusion, gestation detection of HPV infection was associated with musculoskeletal CAs but not other major CAs. Prospective studies are warranted to elucidate the necessity of prenatal screening in populations at risk.

Fibrates and risk of congenital malformations: a nationwide cohort study in South Korea.

To examine the association between maternal prescriptions for fibrates and congenital malformations in live births. Nationwide retrospective cohort study was conducted using the data sourced from the Korean National Health Insurance database. A cohort of 756,877 completed pregnancies linked to live-born infants in 215,600 women with dyslipidemia between 2012 and 2021. The study compared data on congenital anomalies between pregnancies who were exposed to fibrates and those who were not exposed to fibrates in the first trimester. Odds ratios (OR) were calculated by a multivariable analyses using logistic regression models to adjust for potential confounders. 260 pregnancies (0.12%) were exposed to fibrates during the first trimester. The prevalence of malformations in exposed offspirng was 10.77%, not significantly different compared with 9.68% in offspring of women who were not prescribed fibrates during pregnancy in patients with dyslipidemia (OR 1.13; 95% CI 0.75-1.70). This study implies that the use of fibrates during pregnancy may be safe, as it did not show any association with congenital anomalies. However, caution is warranted due to an elevated risk associated with prolonged exposure.

Viral infections in pregnancy and impact on offspring neurodevelopment: mechanisms and lessons learned.

Pregnant individuals with viral illness may experience significant morbidity and have higher rates of pregnancy and neonatal complications. With the growing number of viral infections and new viral pandemics, it is important to examine the effects of infection during pregnancy on both the gestational parent and the offspring. Febrile illness and inflammation during pregnancy are correlated with risk for autism, attention deficit/hyperactivity disorder, and developmental delay in the offspring in human and animal models. Historical viral epidemics had limited follow-up of the offspring of affected pregnancies. Infants exposed to seasonal influenza and the 2009 H1N1 influenza virus experienced increased risks of congenital malformations and neuropsychiatric conditions. Zika virus exposure in utero can lead to a spectrum of abnormalities, ranging from severe microcephaly to neurodevelopmental delays which may appear later in childhood and in the absence of Zika-related birth defects. Vertical infection with severe acute respiratory syndrome coronavirus-2 has occurred rarely, but there appears to be a risk for developmental delays in the infants with antenatal exposure. Determining how illness from infection during pregnancy and specific viral pathogens can affect pregnancy and neurodevelopmental outcomes of offspring can better prepare the community to care for these children as they grow. IMPACT: Viral infections have impacted pregnant people and their offspring throughout history. Antenatal exposure to maternal fever and inflammation may increase risk of developmental and neurobehavioral disorders in infants and children. The recent SARS-CoV-2 pandemic stresses the importance of longitudinal studies to follow pregnancies and offspring neurodevelopment.

Risk of Major Congenital Malformations and Exposure to Antiseizure Medication Monotherapy

Women with epilepsy (WWE) require treatment with antiseizure medications (ASMs) during pregnancy, which may be associated with an increased risk of major congenital malformations (MCMs) in their offspring. To investigate the prevalence of MCMs after prenatal exposure to 8 commonly used ASM monotherapies and changes in MCM prevalence over time. This was a prospective, observational, longitudinal cohort study conducted from June 1999 to October 2022. Since 1999, physicians from more than 40 countries enrolled ASM-treated WWE before pregnancy outcome was known and followed up their offspring until 1 year after birth. Participants aged 14 to 55 years who were exposed to 8 of the most frequently used ASMs during pregnancy were included in this study. Data were analyzed from April to September 2023. Maternal use of ASMs at conception. MCMs were assessed 1 year after birth by a committee blinded to type of exposure. Teratogenic outcomes across exposures were compared by random-effects logistic regression adjusting for potential confounders and prognostic factors. A total of 10 121 prospective pregnancies exposed to ASM monotherapy met eligibility criteria. Of those, 9840 were exposed to the 8 most frequently used ASMs. The 9840 pregnancies occurred in 8483 women (mean [range] age, 30.1 [14.1-55.2] years). MCMs occurred in 153 of 1549 pregnancies for valproate (9.9%; 95% CI, 8.5%-11.5%), 9 of 142 for phenytoin (6.3%; 95% CI, 3.4%-11.6%), 21 of 338 for phenobarbital (6.2%; 95% CI, 4.1%-9.3%), 121 of 2255 for carbamazepine (5.4%; 95% CI, 4.5%-6.4%), 10 of 204 for topiramate (4.9%; 95% CI, 2.7%-8.8%), 110 of 3584 for lamotrigine (3.1%; 95% CI, 2.5%-3.7%), 13 of 443 for oxcarbazepine (2.9%; 95% CI, 1.7%-5.0%), and 33 of 1325 for levetiracetam (2.5%; 95% CI, 1.8%-3.5%). For valproate, phenobarbital, and carbamazepine, there was a significant increase in the prevalence of MCMs associated with increasing dose of the ASM. Overall prevalence of MCMs decreased from 6.1% (153 of 2505) during the period 1998 to 2004 to 3.7% (76 of 2054) during the period 2015 to 2022. This decrease over time was significant in univariable logistic analysis but not after adjustment for changes in ASM exposure pattern. Of all ASMs with meaningful data, the lowest prevalence of MCMs was observed in offspring exposed to levetiracetam, oxcarbazepine, and lamotrigine. Prevalence of MCMs was higher with phenytoin, valproate, carbamazepine, and phenobarbital, and dose dependent for the latter 3 ASMs. The shift in exposure pattern over time with a declining exposure to valproate and carbamazepine and greater use of lamotrigine and levetiracetam was associated with a 39% decline in prevalence of MCMs, a finding that has major public health implications.

Hydroxychloroquine in lupus or rheumatoid arthritis pregnancy and risk of major congenital malformations: a population-based cohort study.

To assess the infant risk of major congenital malformations (MCM) associated with first-trimester exposure to hydroxychloroquine (HCQ) among mothers with systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA). This population-based cohort study utilised Swedish nationwide registers and included all singleton births (2006-2021) among individuals with prevalent SLE or RA in Sweden. The exposure was filling ≥1 HCQ prescription during the first trimester. The outcome was infant MCM within one year of birth. Inverse probability of treatment weighting was applied to adjust for potential confounders (e.g. maternal smoking, body mass index, pregestational diabetes, and corticosteroids). Modified Poisson regression models with robust variance estimated risk ratios and 95% confidence intervals (RR 95%CI). We included 1,007 births (453 exposed) and 2,500 births (144 exposed) in the SLE and RA cohorts, respectively. The MCM risks in the SLE overall cohort, exposed, and unexposed groups were 3.6%, 3.7%, and 3.4%, respectively. The corresponding figures in the RA cohort were 4.4%, 5.6%, and 4.3%, respectively. The adjusted RRs (95%CI) were 1.29 (0.65-2.56) in the SLE cohort, 1.32 (0.56-3.13) in the RA cohort, and 1.30 (0.76-2.23) in the pooled analysis. The adjusted risk difference (exposed vs unexposed) was small (0.9% in SLE and 1.3% in RA). Sensitivity analyses examining different exposure and outcome windows yielded similar findings. First-trimester exposure to HCQ was not associated with a significantly increased risk of MCM. HCQ's benefits may outweigh the risks in managing SLE or RA during pregnancy.

Diagnosis of single umbilical artery and risk of foetal congenital malformations by prenatal ultrasound: a retrospective study

BackgroundSingle umbilical artery (SUA) is strongly associated with foetal structural abnormalities; however, the exact pattern of this association has not been described. We aimed to investigate the occurrence of malformations in singleton pregnancies with SUA in China and to study the association between the absent side of the umbilical artery and foetal malformations.MethodsThis was a retrospective study of singleton pregnancies for which routine first-trimester anatomical screening was performed at 11+ 0-13+ 6 gestational weeks and, if the pregnancy continued, a second-trimester scan was performed at 20+ 0-24+ 0 weeks. Data were extracted from records at the referral centre, the Obstetrics and Gynecology Hospital of Fudan University, between January 2011 and April 2019 (n = 47,894). Using logistic regression, the odds ratios (OR) with 95% confidence intervals (CIs) were calculated for malformations associated with SUA.ResultsThe incidence of SUA in our study was 2.0% (970/47,894). Of all foetuses with SUA, 387 (39.9%) had structural malformations. The malformation type varied, with cardiovascular complications being the most common. A robust association was observed between SUA and oesophageal stenosis or atresia (OR: 25.33), followed by cardiovascular (OR: 9.98–24.02), scoliosis (OR: 18.62), genitourinary (OR: 2.45–15.66), and brain malformations (OR: 4.73–9.12). The absence of the left umbilical artery (n = 445, 45.9%) was consistent with that of the right umbilical artery (n = 431, 44.4%). Furthermore, a significantly higher rate of an absent right than the left umbilical artery (p<0.01) was observed in SUA with foetal abnormalities than in SUA with no malformations.ConclusionsOverall, we observed a higher risk of various specific malformations in foetuses with SUA, and a strong association between SUA and oesophageal stenosis or atresia. The absence of the right umbilical artery was most common in foetuses with SUA and structural malformations. This study provides a reference for ultrasonographers in conducting foetal structural screening for pregnant women with SUA.

Epilepsy and pregnancy

Regarding treatment of women of childbearing potential with epilepsy, several aspects of family planning and desire to have children have to be taken into account. Overview of current data on mutual implications of epileptic seizures, antiseizure medication (ASM), pregnancy and child development. Review of the current literature, discussion and presentation of resulting treatment recommendations. Many ASMs bear the potential for clinically relevant interactions with both contraceptives and altered concentrations of sexual hormones and modified pharmacokinetics during pregnancy. All ASMs show an increased risk for congenital malformations; however, due to seizure-related risks for the mother and child effective ASM treatment during pregnancy is crucial. When considering the special aspects of consultation and treatment of women of childbearing potential with epilepsy most pregnancies are uncomplicated.

Maternal and neonatal outcomes of dichorionic twin pregnancies achieved with assisted reproductive technology: meta-analysis of contemporary data.

Assisted reproductive technology (ART) is commonly used to achieve pregnancy and often results in dichorionic diamniotic (DCDA) twin pregnancies. However, the potential risks of ART on maternal and neonatal outcomes in these pregnancies are not well understood. The objective is to compare the maternal and neonatal outcomes in DCDA twin pregnancies between those achieved through ART and those spontaneously conceived (SC). We carried out a systematic comprehensive search of electronic databases; namely, PubMed, Embase, Scopus, and the Cochrane Library, from inception to March 2023 with a study period of recruitment between 2003 and 2023. We included all studies comparing the maternal and neonatal outcomes of DCDA twin pregnancies between those achieved by ART and those SC. We analyzed data from 18 cohort studies involving 10,485 women with DCDA twin pregnancies. The meta-analysis showed that ART-conceived pregnancies had a significantly higher risk of preeclampsia or gestational hypertension (GH), gestational diabetes mellitus (GDM), placenta previa (PP), placental abruption (PA), postpartum hemorrhage (PPH), and elective and emergency cesarean sections than SC twin pregnancies. The absolute risks of these complications remained relatively low. We also found a slightly higher risk of respiratory distress syndrome (RDS) and congenital malformations in ART-conceived infants compared to the risks in SC infants. Finally, the risk of neonatal intensive care unit (NICU) admissions was significantly higher in ART-conceived infants than in SC infants, but with high heterogeneity. We found associations between DCDA twin pregnancies conceived through ART and increased frequencies of adverse maternal outcomes. However, the absolute risks of these complications remained low, and the benefits of ART for achieving successful pregnancies may well outweigh the potential risks. Additionally, ART-conceived DCDA twin pregnancies may pose higher risks of RDS, congenital malformations and NICU, admissions than SC DCDA twin pregnancies.

An open-source implementation of tree-based scan statistics.

We develop an open-source R package to implement tree-based scan statistics (TBSS) analyses. TBSS are data mining methods used by the United States Food and Drug Administration and the Centers for Disease Control. They simultaneously screen thousands of hierarchically aggregated outcomes to identify unsuspected adverse effects of drugs or vaccines, accounting for multiple comparisons. The general structure of TBSS is highly adaptable, with four essential components: (1) a hierarchical outcome structure, (2) a test statistic to be computed for each element of the hierarchy, (3) an algorithm to generate data replicates under a null distribution, and (4) observed outcomes at the lower level of the hierarchy. We encode the general TBSS framework in a convenient R package that offers user-friendly functions for the most used TBSS methods. To illustrate the performance of our software, we evaluated two examples of archetypical TBSS analyses previously analyzed using proprietary, closed-source TreeScan™ software. The first considers the risk of congenital malformations associated with first-trimester exposure to valproate, and the second compares exposure to newly prescribed canagliflozin with a dipeptidyl peptidase 4 inhibitor in adults affected by type 2 diabetes. The results of the original studies are replicated. The diffusion of an open-source implementation of TBSS can enhance innovation of TBSS methods and foster collaborations. We offer an intuitive R package implementing standard TBSS methods with accompanying tutorials. Our unified object-oriented implementation allows expert users to extend the framework, introduce new features, or enhance existing ones.

Maternal and perinatal outcomes in twin pregnancies following assisted reproduction: a systematic review and meta-analysis involving 802462 pregnancies.

ART is associated with higher rates of twin pregnancies than singleton pregnancies. Whether twin pregnancies conceived following ART have additional maternal and neonatal complications compared with non-ART twin pregnancies is not known. The objective was to quantify the risk of adverse maternal and perinatal outcomes among twin pregnancies conceived following ART compared with non-ART and natural conception. Existing reviews vary in the reported outcomes, with many studies including triplet pregnancies in the study population. Therefore, we aimed to perform an up-to-date review with an in-depth analysis of maternal and perinatal outcomes limited to twin pregnancies. We searched electronic databases MEDLINE and EMBASE from January 1990 to May 2023 without language restrictions. All cohort studies reporting maternal and perinatal outcomes following ART compared with non-ART twin pregnancies and natural conception were included. Case-control studies, case reports, case series, animal studies, and in vitro studies were excluded. The Newcastle-Ottawa Scale was used to assess the methodological quality of the studies. Using random-effects meta-analysis, the estimates were pooled and the findings were reported as odds ratios (OR) with 95% CI. We included 111 studies (802462 pregnancies). Twin pregnancies conceived following ART were at higher risk of preterm birth at <34 weeks (OR 1.33, 95% CI 1.14-1.56, 29 studies, I2 = 73%), <37 weeks (OR 1.26, 95% CI 1.19-1.33, 70 studies, I2 = 76%), hypertensive disorders in pregnancy (OR 1.29, 95% CI 1.14-1.46, 59 studies, I2 = 87%), gestational diabetes mellitus (OR 1.61, 95% CI 1.48-1.75, 51 studies, I2 = 65%), and caesarean delivery (OR 1.80, 95% CI 1.65-1.97, 70 studies, I2 = 89%) compared with non-ART twins. The risks for the above maternal outcomes were also increased in the ART group compared with natural conception. Of the perinatal outcomes, ART twins were at significantly increased risk of congenital malformations (OR 1.17, 95% CI 1.05-1.30, 39 studies, I2 = 59%), birthweight discordance (>25% (OR 1.31, 95% CI 1.05-1.63, 7 studies, I2 = 0%)), respiratory distress syndrome (OR 1.32, 95% CI 1.09-1.60, 16 studies, I2 = 61%), and neonatal intensive care unit admission (OR 1.24, 95% CI 1.14-1.35, 32 studies, I2 = 87%) compared with non-ART twins. When comparing ART with natural conception, the risk of respiratory distress syndrome, intensive care admissions, and birthweight discordance >25% was higher among the ART group. Perinatal complications, such as stillbirth (OR 0.83, 95% CI 0.70-0.99, 33 studies, I2 = 49%), small for gestational age <10th centile (OR 0.90, 95% CI 0.85-0.95, 26 studies, I2 = 36%), and twin-twin transfusion syndrome (OR 0.45, 95% CI 0.25-0.82, 9 studies, I2 = 25%), were reduced in twin pregnancies conceived with ART versus those without ART. The above perinatal complications were also fewer amongst the ART group than natural conception. ART twin pregnancies are associated with higher maternal complications than non-ART pregnancies and natural conception, with varied perinatal outcomes. Women seeking ART should be counselled about the increased risks of ART twin pregnancies and should be closely monitored in pregnancy for complications. We recommend exercising caution when interpreting the study findings owing to the study's limitations.

Adverse neonatal outcomes in pregnant women with asthma: An updated systematic review and meta-analysis.

A systematic review and meta-analysis from 2013 reported increased risks of congenital malformations, neonatal death and neonatal hospitalization amongst infants born to women with asthma compared to infants born to mothers without asthma. Our objective was to update the evidence on the associations between maternal asthma and adverse neonatal outcomes. We performed an English-language MEDLINE, Embase, CINAHL, and COCHRANE search with the terms (asthma or wheeze) and (pregnan* or perinat* or obstet*). Studies published from March 2012 until September 2023 reporting at least one outcome of interest (congenital malformations, stillbirth, neonatal death, perinatal mortality, neonatal hospitalization, transient tachypnea of the newborn, respiratory distress syndrome and neonatal sepsis) in a population of women with and without asthma. The study was reported following the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) and the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines. Quality of individual studies was assessed by two reviewers independently using the Newcastle-Ottawa Scale. Random effects models (≥3 studies) or fixed effect models (≤2 studies) were used with restricted maximum likelihood to calculate relative risk (RR) from prevalence data and the inverse generic variance method where adjusted odds ratios (aORs) from individual studies were combined. A total of 18 new studies were included, along with the 22 studies from the 2013 review. Previously observed increased risks remained for perinatal mortality (relative risk [RR] 1.14, 95% confidence interval [CI]: 1.05, 1.23 n = 16 studies; aOR 1.07, 95% CI: 0.98-1.17 n = 6), congenital malformations (RR 1.36, 95% CI: 1.32-1.40 n = 17; aOR 1.42, 95% CI: 1.38-1.47 n = 6), and neonatal hospitalization (RR 1.27, 95% CI: 1.25-1.30 n = 12; aOR 1.1, 95% CI: 1.07-1.16 n = 3) amongst infants born to mothers with asthma, while the risk for neonatal death was no longer significant (RR 1.33, 95% CI: 0.95-1.84 n = 8). Previously reported non-significant risks for major congenital malformations (RR1.18, 95% CI: 1.15-1.21; aOR 1.20, 95% CI: 1.15-1.26 n = 3) and respiratory distress syndrome (RR 1.25, 95% CI: 1.17-1.34 n = 4; aOR 1.09, 95% CI: 1.01-1.18 n = 2) reached statistical significance. Healthcare professionals should remain aware of the increased risks to neonates being born to mothers with asthma.

Genetically proxied low-density lipoprotein cholesterol lowering via PCSK9-inhibitor drug targets and risk of congenital malformations.

Current guidelines advise against the use of lipid-lowering drugs during pregnancy. This is based only on previous observational evidence demonstrating an association between statin use and congenital malformations, which is increasingly controversial. In the absence of clinical trial data, we aimed to use drug-target Mendelian randomization to model the potential impact of fetal LDL-lowering, overall and through PCSK9 drug targets, on congenital malformations. Instrumental variants influencing LDL levels overall and through PCSK9-inhibitor drug targets were extracted from genome-wide association study (GWAS) summary data for LDL on 1 320 016 individuals. Instrumental variants influencing circulating PCSK9 levels (pQTLs) and liver PCSK9 gene expression levels (eQTLs) were extracted, respectively, from a GWAS on 10 186 individuals and from the genotype-tissue expression project. Gene-outcome association data was extracted from the 7th release of GWAS summary data on the FinnGen cohort (n = 342 499) for eight categories of congenital malformations affecting multiple systems. Genetically proxied LDL-lowering through PCSK9 was associated with higher odds of malformations affecting multiple systems [OR 2.70, 95% confidence interval (CI) 1.30-5.63, P = 0.018], the skin (OR 2.23, 95% CI 1.33-3.75, P = 0.007), and the vertebral, anorectal, cardiovascular, tracheo-esophageal, renal, and limb association (VACTERL) (OR 1.51, 95% CI 1.16-1.96, P = 0.007). An association was also found with obstructive defects of the renal pelvis and ureter, but this association was suggestive of horizontal pleiotropy. Lower PCSK9 pQTLs were associated with the same congenital malformations. These data provide genetic evidence supporting current manufacturer advice to avoid the use of PCSK9 inhibitors during pregnancy.

Maternal pre-pregnancy overweight or obesity and risk of birth defects in offspring: Population-based cohort study.

Maternal obesity, a health condition increasingly prevalent worldwide, has been suggested to be associated with a higher risk of birth defects in offspring, whereas evidence from population-based data from China was largely lacking. Additionally, the role of gestational diabetes in the association between maternal obesity and birth defects remains unclear. We aimed to investigate the association of maternal pre-pregnancy overweight or obesity with any and different types of birth defects in offspring and the interaction between pre-pregnancy overweight or obesity and gestational diabetes. We conducted a population-based cohort study including 257 107 singletons born between 2015 and 2021 in Longgang District, Shenzhen, China, using data from the Shenzhen Maternal and Child Health Management System. Poisson regression was conducted to estimate the associations of maternal pre-pregnancy overweight or obesity, as well as the interaction between pre-pregnancy overweight or obesity and gestational diabetes, with the risk of birth defects. Models were adjusted for maternal age at delivery, educational level, type of household registration, and gravidity. Maternal pre-pregnancy overweight was associated with a higher risk of any birth defect (risk ratio [RR] 1.21, 95% confidence interval [CI] 1.12 to 1.31) as well as of congenital malformations of the circulatory system (RR 1.26, 95% CI 1.12 to 1.41), eye/ear/face/neck (RR 1.42, 95% CI 1.04 to 1.94), and musculoskeletal system (RR 1.21, 95% CI 1.01 to 1.44). Maternal pre-pregnancy obesity was associated with a higher risk of any birth defect (RR 1.38, 95% CI 1.18 to 1.63) and congenital malformations of the circulatory system (RR 1.61, 95% CI 1.30 to 1.98). Infants born to overweight or obese mothers with gestational diabetes had a higher risk of congenital malformations of the circulatory system than infants born to overweight or obese mothers without gestational diabetes. Maternal pre-pregnancy overweight or obesity was associated with a higher risk of birth defects, particularly congenital malformations of the circulatory system, in offspring. Gestational diabetes interacts additively with pre-pregnancy overweight or obesity on modifying the risk of congenital malformations of the circulatory system. The importance of improving weight management and assessment of glucose and metabolic functions was emphasized among women planning for pregnancy who are overweight or obese.

Comparative Risk of Major Congenital Malformations With Antiseizure Medication Combinations vs Valproate Monotherapy in Pregnancy.

Valproate should be avoided in pregnancy, but it is the most effective drug for generalized epilepsies. Alternative treatment may require combinations of other drugs. Our objectives were to describe first trimester use of antiseizure medication (ASM) combinations that are relevant alternatives to valproate and determine whether specific combinations were associated with a lower risk of major congenital malformations (MCM) compared with valproate monotherapy. We conducted a population-based cohort study using linked national registers from Denmark, Finland, Iceland, Norway, and Sweden and administrative health care data from the United States and New South Wales, Australia. We described first trimester use of ASM combinations among pregnant people with epilepsy from 2000 to 2020. We compared the risk of MCM after first trimester exposure to ASM combinations vs valproate monotherapy and low-dose valproate plus lamotrigine or levetiracetam vs high-dose valproate (≥1,000 mg/d). We used log-binomial regression with propensity score weights to calculate adjusted risk ratios (aRRs) and 95% CIs for each dataset. Results were pooled using fixed-effects meta-analysis. Among 50,905 pregnancies in people with epilepsy identified from 7.8 million total pregnancies, 788 used lamotrigine and levetiracetam, 291 used lamotrigine and topiramate, 208 used levetiracetam and topiramate, 80 used lamotrigine and zonisamide, and 91 used levetiracetam and zonisamide. After excluding pregnancies with use of other ASMs, known teratogens, or a child diagnosed with MCM of infectious or genetic cause, we compared 587 exposed to lamotrigine-levetiracetam duotherapy and 186 exposed to lamotrigine-topiramate duotherapy with 1959 exposed to valproate monotherapy. Pooled aRRs were 0.41 (95% CI 0.24-0.69) and 1.26 (0.71-2.23), respectively. Duotherapy combinations containing low-dose valproate were infrequent, and comparisons with high-dose valproate monotherapy were inconclusive but suggested a lower risk for combination therapy. Other combinations were too rare for comparative safety analyses. Lamotrigine-levetiracetam duotherapy in first trimester was associated with a 60% lower risk of MCM than valproate monotherapy, while lamotrigine-topiramate was not associated with a reduced risk. Duotherapy with lamotrigine and levetiracetam may be favored to treat epilepsy in people with childbearing potential compared with valproate regarding MCM, but whether this combination is as effective as valproate remains to be determined. This study provides Class II evidence that in people with epilepsy treated in the first trimester of pregnancy, the risk of major congenital malformations is lower with lamotrigine-levetiracetam duotherapy than with valproate alone, but similar with lamotrigine-topiramate.