Neurodevelopmental outcomes after prenatal exposure to lamotrigine monotherapy in women with epilepsy: a systematic review and meta-analysis.

BACKGROUND: Lamotrigine has become one of the most commonly prescribed antiseizure medications (ASM) in epileptic women during pregnancy and therefore requires regular updates regarding its safety. The aim of this study was to estimate the association between in utero exposure to lamotrigine monotherapy and the occurrence of neurodevelopmental outcomes. METHODS: All comparative studies assessing the occurrence of neurodevelopmental outcomes after epilepsy-indicated lamotrigine monotherapy exposure during pregnancy were searched. First, references were identified through a snowballing approach, then, through electronic databases (Medline and Embase) from 2015 to June 2022. One investigator evaluated study eligibility and extracted data and a second independent investigator reviewed the meta-analysis (MA). A systematic review and random-effects model approach were performed using a collaborative WEB-based meta-analysis platform (metaPreg.org) with a registered protocol (osf.io/u4gva). RESULTS: Overall, 18 studies were included. For outcomes reported by at least 4 studies, the pooled odds ratios and 95% confidence interval obtained with the number of exposed (N1) and unexposed children (N0) included were: neurodevelopmental disorders as a whole 0.84 [0.66;1.06] (N1 = 5,271; N0 = 22,230); language disorders or delay 1.16 [0.67;2.00] (N1 = 313; N0 = 506); diagnosis or risk of ASD 0.97 [0.61;1.53] (N1 = at least 5,262; N0 = 33,313); diagnosis or risk of ADHD 1.14 [0.75;1.72] (N1 = at least 113; N0 = 11,530) and psychomotor developmental disorders or delay 2.68 [1.29-5.56] (N1 = 163; N0 = 220). The MA of cognitive outcomes included less than 4 studies and retrieved a significant association for infants exposed to lamotrigine younger than 3 years old but not in the older age groups. CONCLUSION: Prenatal exposure to lamotrigine monotherapy is not found to be statistically associated with neurodevelopmental disorders as a whole, language disorders or delay, diagnosis or risk of ASD and diagnosis or risk of ADHD. However, the MA found an increased risk of psychomotor developmental disorders or delay and cognitive developmental delay in less than 3 years old children. Nevertheless, these findings were based exclusively on observational studies presenting biases and on a limited number of included children. More studies should assess neurodevelopmental outcomes in children prenatally exposed to lamotrigine.

Use of proton pump inhibitors during pregnancy: A systematic review and meta-analysis of congenital malformations.

Use of proton pump inhibitors (PPI) are common among pregnant women to relieve gastrointestinal symptoms. The number of exposed pregnancies is therefore considerable, and a recent meta-analysis (MA) from 2020 raised concern about their teratogenicity. The aim of the study was to provide a MA of the risk of major congenital malformations (MCM) after PPI exposure during the first trimester of pregnancy. A systematic review and random-effects model approach were performed using a collaborative WEB-based meta-analysis platform (metaPreg.org) with a registered protocol (osf.io/u4gva). The primary outcome was the incidence of overall MCM. The secondary outcomes of interest were specific MCM reported by at least three studies. All comparative studies assessing these outcomes in PPI exposed pregnancies were searched from inception to April 2022. From the 211 initially identified studies, 11 were included in the MA. The pooled odds ratio (OR) for the primary outcome showed no significant results based on 5 618 exposed pregnancies (OR 1.10, 95% CI [0.95;1.26]; I²=0%). Similarly, no result was significant for the secondary outcomes. The total exposed sample size ranged from 3 161-5 085; OR ranged between 0.60 and 1.92; heterogeneity was between 0% and 23%. Based on the results of the present MA, first trimester PPI exposure was not associated with a significantly increased risk of overall or specific MCM. However, this MA included only observational studies which are prone to bias and there were insufficient data to evaluate PPI at a substance level. Future studies are needed to address this concern.

Risk of drug use during pregnancy: master protocol for living systematic reviews and meta-analyses performed in the metaPreg project.

BACKGROUND: Knowledge about the risks of drugs during pregnancy is continuously evolving due to the frequent publication of a large number of epidemiological studies. Systematic reviews and meta-analyses therefore need to be regularly updated to reflect these advances. To improve dissemination of this updated information, we developed an initiative of real-time full-scale living meta-analyses relying on an open online dissemination platform ( www.metapreg.org ). METHOD: All living meta-analyses performed in this project will be conducted in accordance with this master protocol after adaptation of the search strategy. A systematic literature search of PubMed and Embase will be performed. All analytical studies (e.g., cohort, case-control, randomized studies) reporting original empirical findings on the association between in utero exposure to drugs and adverse pregnancy outcomes will be included. Study screening and data extraction will be performed in a semi-automation way supervised by a biocurator. A risk of bias will be assessed using the ROBINS-I tools. All clinically relevant pregnancy adverse outcomes (malformations, stillbirths, neuro-developmental disorders, pre-eclampsia, etc.) available in the included studies will be pooled through random-effects meta-analysis. Heterogeneity will be evaluated by I2 statistics. DISCUSSION: Our living systematic reviews and subsequent updates will inform the medical, regulatory, and health policy communities as the news results evolve to guide decisions on the proper use of drugs during the pregnancy. SYSTEMATIC REVIEW REGISTRATION: Open Science Framework (OSF) registries.