Adverse birth outcomes related to concentrations of per- and polyfluoroalkyl substances (PFAS) in maternal blood collected from pregnant women in 1960-1966.

BACKGROUND: Prior animal and epidemiological studies suggest that per- and polyfluoroalkyl substances (PFAS) exposure may be associated with reduced birth weight. However, results from prior studies evaluated a relatively small set of PFAS. OBJECTIVES: Determine associations of gestational PFAS concentrations in maternal serum samples banked for 60 years with birth outcomes. METHODS: We used data from 97 pregnant women from Boston and Providence that enrolled in the Collaborative Perinatal Project (CPP) study (1960-1966). We quantified concentrations of 27 PFAS in maternal serum in pregnancy and measured infant weight, height and ponderal index at birth. Covariate-adjusted associations between 11 PFAS concentrations (>75% detection limits) and birth outcomes were estimated using linear regression methods. RESULTS: Median concentrations of PFOA, PFNA, PFHxS, and PFOS were 6.189, 0.330, 14.432, and 38.170 ng/mL, respectively. We found that elevated PFAS concentrations during pregnancy were significantly associated with lower birth weight and ponderal index at birth, but no significant associations were found with birth length. Specifically, infants born to women with PFAS concentrations ≥ median levels had significantly lower birth weight (PFOS: ß = -0.323, P = 0.006; PFHxS: ß = -0.292, P = 0.015; PFOA: ß = -0.233, P = 0.03; PFHpS: ß = -0.239, P = 0.023; PFNA: ß = -0.239, P = 0.017). Similarly, women with PFAS concentrations ≥ median levels had significantly lower ponderal index (PFHxS: ß = -0.168, P = 0.020; PFHxA: ß = -0.148, P = 0.018). CONCLUSIONS: Using data from this US-based cohort study, we found that 1) maternal PFAS levels from the 1960s exceeded values in contemporaneous populations and 2) that gestational concentrations of certain PFAS were associated with lower birth weight and infant ponderal index. Additional studies with larger sample size are needed to further examine the associations of gestational exposure to individual PFAS and their mixtures with adverse birth outcomes.

A population-based cohort study of electronic tolling, traffic congestion, and adverse birth outcomes.

BACKGROUND: Although traffic-related air pollution is largely regulated at the federal level, congestion reduction projects may reduce local traffic and air pollution to levels that create positive co-benefits for population health. In recent years, many urban areas have implemented electronic tolling systems to improve traffic conditions. OBJECTIVE: Quantify associations between implementing electronic tolling and local changes in traffic and infant health. METHODS: Using a population-based birth cohort (Texas, 1999-2016), we calculated residential proximity to the nearest tolled road segment within 5 km (n = 625,279) and examined changes in local traffic before and after toll implementation. Using a difference-in-differences design, we compared four markers of adverse birth outcomes (term birth weight, term low birth weight, preterm birth, very preterm birth) among infants from pregnant people residing < 0.5 km from a road segment before and after the tolls were implemented and compared them to a contemporaneous population of pregnant people residing at 2-5 km. RESULTS: We observed minimal changes in local traffic after the implementation of tolling. Among births within 500 m of a tolled road, we found little evidence of an association between the implementation of tolling and adverse birth outcomes (term birth weight [ß: -4.5, 95 % CI: -11.7, 2.6], term low birth weight [OR: 1.00, 95 % CI: 0.89, 1.13], preterm birth [OR: 0.99, 95 % CI: 0.92, 1.05], very preterm birth [OR: 1.00, 95 % CI: 0.84, 1.18]), compared to the contemporaneous control group of births at 2-5 km. In sub-analyses, we found some evidence of a reduced association between toll booth removal and preterm birth (OR: 0.84, 95 % CI: 0.70, 1.01) but not for other outcomes or tolling types. DISCUSSION: In this large population-based retrospective cohort study of births in Texas, we found little evidence that the implementation of tolling was consistently associated with improvements in local infant health outcomes.

Wildfire smoke exposure during pregnancy and perinatal, obstetric, and early childhood health outcomes: A systematic review and meta-analysis.

BACKGROUND: Maternal exposure to air pollution during pregnancy is associated with adverse birth outcomes, although less is known for wildfire smoke. This systematic review evaluated the association between maternal exposure to wildfire smoke during pregnancy and the risk of perinatal, obstetric, and early childhood health outcomes. METHODS: We searched CINAHL Complete, Ovid/EMBASE, Ovid/MEDLINE, ProQuest, PubMed, Scopus, Web of Science, and Google Scholar to identify relevant epidemiological observational studies indexed through September 2023. The screening of titles, abstracts, and full-texts, data extraction, and risk of bias assessment was performed by pairs of independent reviewers. RESULTS: Our systematic search yielded 28,549 records. After duplicate removal, we screened 14,009 studies, identifying 31 for inclusion in the present review. Data extraction highlighted high methodological heterogeneity between studies, including a lack of geographic variation. Approximately 56.5% and 16% originated in the United States and Brazil, respectively, and fewer in other countries. Among the studies, wildfire smoke exposure during pregnancy was assessed using distance of residence from wildfire-affected areas (n = 15), measurement of air pollutant concentration during wildfires (n = 11), number of wildfire records (n = 3), aerosol index (n = 1), and geographic hot spots (n = 1). Pooled meta-analysis for birthweight and low birthweight were inconclusive, likely due to low number of methodologically homogenous studies. However, the reviewed studies provided suggestive evidence for an increased risk of birthweight reduction, low birthweight, preterm birth, and other adverse health outcomes. CONCLUSIONS: This review identified 31 studies evaluating the impacts of maternal wildfire smoke exposure on maternal, infant, and child health. Although we found suggestive evidence of harm from exposure to wildfire smoke during pregnancy, more methodologically homogenous studies are required to enable future meta-analysis with greater statistical power to more accurately evaluate the association between maternal wildfire smoke and adverse birth outcomes and other health outcomes.

Maternal serum levels of prokineticin-1 related to pregnancy complications and metformin use in women with polycystic ovary syndrome: a post hoc analysis of two prospective, randomised, placebo-controlled trials.

OBJECTIVE: Serum prokineticin-1 (s-PROK1) in the second and third trimester of pregnancy is positively correlated to preeclampsia, intrauterine growth restriction (IUGR) and preterm delivery. Women with polycystic ovary syndrome (PCOS) are prone to these adverse pregnancy outcomes. However, the contribution of PROK1 to the development of pregnancy complications and the effect of metformin and hyperandrogenism on s-PROK1 in PCOS have not been studied previously. DESIGN: This work is a post hoc analysis of two prospective, randomised, placebo-controlled trials. SETTING: Pregnant women with PCOS were included from 11 study centres in Norway. PARTICIPANTS: From 313 women, 264 participated in the present study after exclusions due to dropouts or insufficient serum samples. INTERVENTION: Women with PCOS were randomly administered with metformin or placebo, from first trimester to delivery. PRIMARY AND SECONDARY OUTCOME MEASURES: s-PROK1 was analysed using ELISA at gestational week 19 and related to pregnancy complications, fasting insulin levels, homoeostatic model assessment for insulin resistance (HOMA-IR), testosterone, or androstenedione levels, metformin use, PCOS phenotype and hyperandrogenism. RESULTS: Maternal s-PROK1 in the second trimester did not predict pregnancy-induced hypertension, pre-eclampsia or late miscarriage/preterm delivery in women with PCOS. However, s-PROK1 was lower in women who used metformin before inclusion, both in those randomised to metformin and to placebo, compared with those who did not. s-PROK1 was also lower in those who used metformin both at conception and during pregnancy compared with those who used metformin from inclusion or did not use metformin at all. s-PROK1 was lower in hyperandrogenic compared with normo-androgenic women with PCOS. CONCLUSIONS: Maternal s-PROK1 in the second trimester did not predict pregnancy complications in PCOS. Those who used metformin at conception and/or during pregnancy had lower s-PROK1. PCOS women with hyperandrogenism exhibited lower s-PROK1 compared with normo-adrogenic phenotypes. TRIAL REGISTRATION NUMBER: NCT03259919 and NCT00159536.

Prenatal serotonin reuptake inhibitor antidepressant exposure, SLC6A4 genetic variations, and cortisol activity in 6-year-old children of depressed mothers: A cohort study.

Prenatal exposure to maternal depression and serotonin reuptake inhibitor (SRI) antidepressants both affect the development of the hypothalamic-pituitary-adrenal (HPA) system, possibly via the neurotransmitter serotonin (5HT). In a community cohort, we investigated the impact of two factors that shape prenatal 5HT signaling (prenatal SRI [pSRI] exposure and child SLC6A4 genotype) on HPA activity at age 6 years. Generalized estimating equation (GEE) models were used to study associations between cortisol reactivity, pSRI exposure, and child SLC6A4 genotype, controlling for maternal depression, child age, and sex (48 pSRI exposed, 74 nonexposed). Salivary cortisol levels were obtained at five time points during a laboratory stress challenge: arrival at the laboratory, following two sequential developmental assessments, and then 20 and 40 min following the onset of a stress-inducing cognitive/social task. Cortisol decreased from arrival across both developmental assessments, and then increased across both time points following the stress challenge in both groups. pSRI-exposed children had lower cortisol levels across all time points. In a separate GEE model, we observed a lower cortisol stress response among children with LG /S alleles compared with children with La/La alleles, and this was particularly evident among children of mothers reporting greater third trimester depressed mood. Our findings suggest that pSRI exposure and a genetic factor associated with modulating 5HT signaling shaped HPA reactivity to a laboratory stress challenge at school age.

Does the Micronutrient Molybdenum Have a Role in Gestational Complications and Placental Health?

Molybdenum is an essential trace element for human health and survival, with molybdenum-containing enzymes catalysing multiple reactions in the metabolism of purines, aldehydes, and sulfur-containing amino acids. Recommended daily intakes vary globally, with molybdenum primarily sourced through the diet, and supplementation is not common. Although the benefits of molybdenum as an anti-diabetic and antioxidant inducer have been reported in the literature, there are conflicting data on the benefits of molybdenum for chronic diseases. Overexposure and deficiency can result in adverse health outcomes and mortality, although physiological doses remain largely unexplored in relation to human health. The lack of knowledge surrounding molybdenum intake and the role it plays in physiology is compounded during pregnancy. As pregnancy progresses, micronutrient demand increases, and diet is an established factor in programming gestational outcomes and maternal health. This review summarises the current literature concerning varied recommendations on molybdenum intake, the role of molybdenum and molybdoenzymes in physiology, and the contribution these play in gestational outcomes.

Ambient fine particulate matter and pregnancy outcomes: An umbrella review.

The available evidence on the effects of ambient fine particulate matter (PM2.5) and pregnancy outcomes (birth outcomes and pregnancy complications) has increased substantially. The purpose of this umbrella review is to refine the evidence of the association between birth outcome (birth defects) and PM2.5; and summarize the credibility of existing research on the association between pregnancy complications and PM2.5. We searched PubMed, Web of Science, Embase, and Cochrane databases for relevant systematic reviews and meta-analyses up to March 16, 2022 in accordance with PRISMA guidelines. Two independent investigators conducted data extraction. AMSTAR 2 and GRADE assessment criteria were used to evaluate the methodological and evidence quality. We performed subgroup analyses by trimesters of pregnancy. The review protocol for this study has been registered in PROSPERO (CRD42022325550). This umbrella review identified a total of 41 systematic reviews, including 28 articles evaluating the influence of PM2.5 on birth outcomes and 13 on pregnancy complications. Positive associations between perinatal PM2.5 exposure and adverse birth outcomes were found, including low birth weight, preterm birth, stillbirth, small for gestational age, and birth defects. Pregnant women exposed to PM2.5 had a significantly higher risk of developing hypertensive disorder of pregnancy, gestational diabetes mellitus, gestational hypertension, and preeclampsia. The findings of subgroup analysis demonstrated that the effects of ambient PM2.5 exposure on pregnancy outcomes varied by trimesters. The findings of this extensive umbrella review provide convincing proof that exposure to ambient PM2.5 raises the risks of unfavorable birth outcomes and pregnancy complications. Some associations show considerable disparity between trimesters. These findings have implications for strengthen perinatal health care on air pollution and improving intergenerational equity.

Behavioural outcomes of children exposed to antidepressants and unmedicated depression during pregnancy.

BACKGROUND: Antenatal exposure to both antidepressants and maternal depression has been associated with child behavioural difficulties. However, previous research has not adequately distinguished between the effects of the antidepressants and the underlying maternal depression. METHODS: Child behavioural difficulties were assessed using the Strengths and Difficulties Questionnaire at 2-, 4.5-, and 8-years of age by mothers in the Growing Up in New Zealand study (N = 6233 at 2-years; N = 6066 at 4.5-years; N = 4632 at 8-years). Mothers were classified as either on antidepressants, unmedicated depression, or neither based on self-reported antidepressant intake during pregnancy and the Edinburgh Postnatal Depression Scale. Hierarchical multiple logistic regressions were used to examine whether antenatal exposure to antidepressants and unmedicated depression had a differential association with child behavioural outcomes relative to no exposure. RESULTS: When later life depression in the mother and a range of birth and sociodemographic variables were accounted for, neither antenatal exposure to unmedicated depression or antidepressants remained associated with an increased risk of behavioural difficulties at the ages investigated. However, maternal later life depression was associated with behavioural difficulties in the fully adjusted analyses at all three ages investigated. LIMITATIONS: The current study relied on mother-report of child behaviour which may be susceptible to bias due to maternal mental health problems. CONCLUSIONS: Adjusted results did not show an adverse association between antenatal antidepressant exposure or unmedicated depression in relation to child behaviour. Findings also suggest that efforts to improve child behaviour need to include more family-based approaches that support maternal wellbeing.

Modification effects of ambient temperature on associations of ambient ozone exposure before and during pregnancy with adverse birth outcomes: A multicity study in China.

BACKGROUND: Epidemiological studies suggest that both ambient ozone (O3) and temperature were associated with increased risks of adverse birth outcomes. However, very few studies explored their interaction effects, especially for small for gestational age (SGA) and large for gestational age (LGA). OBJECTIVES: To estimate the modification effects of ambient temperature on associations of ambient O3 exposure before and during pregnancy with preterm birth (PTB), low birth weight (LBW), SGA and LGA based on multicity birth cohorts. METHODS: A total of 56,905 singleton pregnant women from three birth cohorts conducted in Tianjin, Beijing and Maoming, China, were included in the study. Maximum daily 8-h average O3 concentrations of each pregnant woman from the preconception period to delivery for every day were estimated by matching their home addresses with the Tracking Air Pollution in China (TAP) datasets. We first applied the Cox proportional-hazards regression model to evaluate the city-specific effects of O3 exposure before and during pregnancy on adverse birth outcomes at different temperature levels with adjustment for potential confounders, and then a meta-analysis across three birth cohorts was conducted to calculate the pooled associations. RESULTS: In pooled analysis, significant modification effects of ambient temperature on associations of ambient O3 with PTB, LBW and LGA were observed (Pinteraction < 0.05). For a 10 µg/m3 increase in ambient O3 exposure at high temperature level (> 75th percentile), the risk of LBW increased by 28 % (HR: 1.28, 95% CI: 1.13-1.46) during the second trimester and the risk of LGA increased by 116% (HR: 2.16, 95%CI: 1.16-4.00) during the entire pregnancy, while the null or weaker association was observed at corresponding low (≤ 25th percentile) and medium (> 25th and ≤ 75th percentile) temperature levels. CONCLUSION: This multicity study added new evidence that ambient high temperature may enhance the potential effects of ambient O3 on adverse birth outcomes.

Proposal for reference values for the developmental effects of valproate based on human data using a benchmark dose approach.

Following accidental release of valproate into ambient air during manufacture at a French production site in 2018, concerns were raised for inhabitants of the surrounding area. As no toxicological reference value (TRV) was available, the risks could not be properly assessed. The French Agency for Food, Environmental and Occupational Health and Safety (ANSES) was mandated to determine a TRV by inhalation to be used for risk assessment. Major congenital malformations (MCMs) in offsprings of mothers exposed to valproate during pregnancy have been reported in international scientific literature. As these adverse effects were the most sensitive effect identified, they were retained as the critical effect to be used for the TRV. The data from a robust registry on MCMs established by the International Registry of Antiepileptic Drugs and Pregnancy (EURAP) were modellized and support a strong DRR between the prevalence of MCMs in the fetus and in utero exposure. A benchmark dose (BMD) was then calculated as the dose that may trigger a 5% increase in this risk. A lower 95% confidence limit (BMD5%L95%) of 2.26 mg/kg/day, leading to an oral TRV of 0.08 mg/kg/day and a respiratory TRV of 0.26 mg.m-3 after applying an uncertainty factor of 30, was determined.

Aspirin Discontinuation at 24 to 28 Weeks' Gestation in Pregnancies at High Risk of Preterm Preeclampsia: A Randomized Clinical Trial.

Importance: Aspirin reduces the incidence of preterm preeclampsia by 62% in pregnant individuals at high risk of preeclampsia. However, aspirin might be associated with an increased risk of peripartum bleeding, which could be mitigated by discontinuing aspirin before term (37 weeks of gestation) and by an accurate selection of individuals at higher risk of preeclampsia in the first trimester of pregnancy. Objective: To determine whether aspirin discontinuation in pregnant individuals with normal soluble fms-like tyrosine kinase-1 to placental growth factor (sFlt-1:PlGF) ratio between 24 and 28 weeks of gestation was noninferior to aspirin continuation to prevent preterm preeclampsia. Design, Setting, and Participants: Multicenter, open-label, randomized, phase 3, noninferiority trial conducted in 9 maternity hospitals across Spain. Pregnant individuals (n = 968) at high risk of preeclampsia during the first-trimester screening and an sFlt-1:PlGF ratio of 38 or less at 24 to 28 weeks of gestation were recruited between August 20, 2019, and September 15, 2021; of those, 936 were analyzed (intervention: n = 473; control: n = 463). Follow-up was until delivery for all participants. Interventions: Enrolled patients were randomly assigned in a 1:1 ratio to aspirin discontinuation (intervention group) or aspirin continuation until 36 weeks of gestation (control group). Main Outcomes and Measures: Noninferiority was met if the higher 95% CI for the difference in preterm preeclampsia incidences between groups was less than 1.9%. Results: Among the 936 participants, the mean (SD) age was 32.4 (5.8) years; 3.4% were Black and 93% were White. The incidence of preterm preeclampsia was 1.48% (7/473) in the intervention group and 1.73% (8/463) in the control group (absolute difference, -0.25% [95% CI, -1.86% to 1.36%]), indicating noninferiority. Conclusions and Relevance: Aspirin discontinuation at 24 to 28 weeks of gestation was noninferior to aspirin continuation for preventing preterm preeclampsia in pregnant individuals at high risk of preeclampsia and a normal sFlt-1:PlGF ratio. Trial Registration: ClinicalTrials.gov Identifier: NCT03741179 and ClinicalTrialsRegister.eu Identifier: 2018-000811-26.

Continuation of psychiatric medications during pregnancy.

Background: While medications for anxiety and depression are commonly used in the United States, it is unclear to what degree they are continued during pregnancy.Methods: We used a large administrative database to determine whether psychiatric medications are continued during pregnancy and predictors of continued medication treatment.Results: Of 2,672,656 women included in our analysis, 86,454 (3.1%) filled a pre-pregnancy prescription for an anxiolytic or antidepressant medication within 3 months of estimated conception. Of women who filled a pre-pregnancy prescription, 49.4%, 26.1%, and 20.1% filled subsequent prescriptions in the 1st, 2nd, and 3rd trimesters. Discontinuation rates ranged by pharmaceutical agent, from 16% for fluoxetine to 71% for alprazolam. White women and women over 25 were more likely to continue anxiolytic and antidepressant treatment during pregnancy.Conclusion: Because untreated and under-treated mental health conditions are linked to adverse maternal outcomes, high discontinuation rates may have important implications for maternal health.

Adverse perinatal outcomes associated with prenatal exposure to protease-inhibitor-based versus non-nucleoside reverse transcriptase inhibitor-based antiretroviral combinations in pregnant women with HIV infection: a systematic review and meta-analysis.

BACKGROUND: About 1.3 million pregnant women lived with HIV and were eligible to receive antiretroviral therapy (ART) worldwide in 2021. The World Health Organization recommends protease inhibitors (PI)-based regimen as second or third-line during pregnancy. With remaining pregnant women exposed to PIs, there is still an interest to assess whether this treatment affects perinatal outcomes. Adverse perinatal outcomes after prenatal exposure to PI-based ART remain conflicting: some studies report an increased risk of preterm birth (PTB) and low-birth-weight (LBW), while others do not find these results. We assessed adverse perinatal outcomes associated with prenatal exposure to PI-based compared with non-nucleoside reverse transcriptase (NNRTI)-based ART. METHODS: We performed a systematic review searching PubMed, Reprotox, Clinical Trial Registry (clinicaltrials.gov) and abstracts of HIV conferences between 01/01/2002 and 29/10/2021. We used Oxford and Newcastle-Ottawa scales to assess the methodological quality. Studied perinatal outcomes were spontaneous abortion, stillbirth, congenital abnormalities, PTB (< 37 weeks of gestation), very preterm birth (VPTB, < 32 weeks of gestation), LBW (< 2500 grs), very low-birth-weight (VLBW, < 1500 g), small for gestational age (SGA) and very small for gestational age (VSGA). The association between prenatal exposure to PI-based compared to NNRTI-based ART was measured for each adverse perinatal outcome using random-effect meta-analysis to estimate pooled relative risks (RR) and their corresponding 95% confidence intervals (CI). Pre-specified analyses were stratified according to country income and study quality assessment, and summarized when homogeneous. RESULTS: Out of the 49,171 citations identified, our systematic review included 32 published studies, assessing 45,427 pregnant women. There was no significant association between prenatal exposure to PIs compared to NNRTIs for VPTB, LBW, SGA, stillbirth, and congenital abnormalities. However, it was inconclusive for PTB, and PI-based ART is significantly associated with an increased risk of VSGA (sRR 1.41 [1.08-1.84]; I2 = 0%) compared to NNRTIs. CONCLUSIONS: We did not report any significant association between prenatal exposure to PIs vs NNRTIs-based regimens for most of the adverse perinatal outcomes, except for VSGA significantly increased (+ 41%). The evaluation of antiretroviral exposure on pregnancy outcomes remains crucial to fully assess the benefice-risk balance, when prescribing ART in women of reproductive potential with HIV. PROSPERO NUMBER: CRD42022306896.

Should Antidepressants be Avoided in Pregnancy?

Many (> 40%) women discontinue antidepressants during pregnancy because of concerns about effects on the foetus, based on information from inadequately-controlled studies. The sibling-control study design provides the best control for confounding factors, notably maternal depression. The purpose of this review was to investigate the evidence from sibling-control analyses for adverse outcomes in offspring associated with antidepressant exposure during pregnancy. Fourteen sibling-control studies were identified through searches of PubMed and Embase. Outcomes included preterm birth, small for gestational age, neonatal size, birth defects, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), behavioural problems, neurodevelopmental deficits, and scholastic attainment. For the majority of these outcomes, no statistically significant associations were found when comparing exposed and unexposed siblings. Single studies reported associations with preterm birth, reduced gestational age, ADHD, anxiety at 36 months, and lower mathematics test scores, which persisted in the sibling-control analyses. However, differences were small and possibly not clinically significant. Moreover, effects of residual confounding could not be excluded. These findings provide evidence that many of the previously reported associations between prenatal antidepressant exposure and adverse outcomes in offspring are no longer statistically significant when exposed offspring are compared with unexposed siblings. The few statistically significant differences in sibling-control analyses were generally small with doubtful clinical significance. Decisions on antidepressant treatment during pregnancy should be made individually, based on evidence from properly controlled studies, not on misleading information based on studies that have not controlled adequately for confounding factors.

Fármacos antiepilépticos usados en el embarazo y sus consecuencias sobre los resultados fetales: una revisión de la literatura / Antiepileptic drugs used in pregnancy and their consequences on fetal outcomes: a review of the literature

Los riesgos teratogénicos ocasionados por la exposición intrauterina a fármacos antiepilépticos (FAE) son conocidos, por lo que su prescripción se mantiene bajo estricto control. Describir los efectos adversos fetales de la exposición a FAE durante la gestación, reportados en la literatura durante el período 2016-2022. Revisión sistematizada de estudios que reportaron los efectos adversos fetales inducidos por la exposición a FAE en mujeres embarazadas en tratamiento por diagnósticos neurológicos, principalmente de epilepsia. La búsqueda se realizó en PubMed, Cochrane, Web of Science, SCOPUS, Biblioteca Virtual en Salud, Lilacs y SciELO. Se identificaron 37 artículos distribuidos en 13 países de Asia, Europa, América del Norte y Oceanía. Se observaron resultados perinatales adversos, tanto físicos como cognitivos, en la mayoría de los estudios. Los fármacos identificados como los más utilizados en los últimos años fueron valproato, topiramato, carbamazepina, lamotrigina y levetiracetam. Los FAE tienen potencial teratogénico en distintos grados de riesgo, provocando anomalías congénitas o efectos adversos en múltiples sistemas del cuerpo humano, siendo los sistemas nervioso, circulatorio y osteomuscular los más afectados.

The teratogenic risks caused by intrauterine exposure to antiepileptic drugs (AED) are known, so their prescription is kept under strict control. To describe the fetal adverse effects AED exposure during gestation, reported in the literature during the period 2016-2022. Systematized review of studies that reported fetal adverse effects induced for the exposure to AED in pregnant women in treatment for neurological diagnoses, mainly epilepsy. The search was carried out in PubMed, Cochrane, Web of Science, SCOPUS, Virtual Health Library, Lilacs and SciELO. 37 articles distributed in thirteen countries in Asia, Europe, North America and Oceania were identified. Adverse perinatal outcomes, both physical and cognitive, were observed in most studies. The most common drugs identified were valproate, topiramate, carbamazepine, lamotrigine and levetiracetam. AED have teratogenic potential in different degrees of risk, causing congenital anomalies or adverse effects in multiple systems of the human body, being the nervous, circulatory and musculoskeletal systems the most affected.

Validation of MAPK signalling pathway as a key role of paeoniflorin in the treatment of intrahepatic cholestasis of pregnancy based on network pharmacology and metabolomics.

Numerous studies have clarified the effectiveness of paeoniflorin in the treatment of cholestasis. However, the therapeutic efficacy and mechanisms of action of paeoniflorin in intrahepatic cholestasis of pregnancy (ICP) were still unknown. This study aimed to investigate the molecular biological mechanisms of paeoniflorin against ICP by combining network pharmacology and metabolomics. The effects of paeoniflorin were investigated in the ICP rat model induced by 17α-ethinylestradiol, showing improvements in the liver indices, liver histopathological changes, bile flow rate, and serum levels of TBA and ALP. The underlying mechanisms and metabolic pathways of paeoniflorin were revealed by network pharmacology and untargeted metabolomics, showing that paeoniflorin exerted its curative effect against ICP-induced ferroptosis through PI3K/AKT and MAPK signalling pathways. In conclusion, paeoniflorin protected against ICP-induced liver injury through MAPK signaling pathways.

Effects of antiepileptic drugs polytherapy on pregnancy outcomes in women with epilepsy: An observation study in northwest China.

OBJECTIVE: The management of pregnant women with epilepsy (WWE) treated with antiepileptic drugs (AEDs) polytherapy poses a great challenge. The purpose of this study was to evaluate the major congenital malformations (MCMs) associated with AED polytherapy, to assess the impacts of polytherapy regimens on seizure control and breastfeeding, and to determine the potential predictors for pregnancy outcomes. METHODS: This study was based on prospectively acquired data from a registry enrolling WWE in early pregnancy from Feb 2010 to July 2019, in which 123 pregnancies in 110 WWE were exposed to 27 different AED combinations. RESULTS: There were 123 pregnancies in 110 WWE analyzed in our study. The live birth rate was 86.2 % and the risk of MCMs was 10.4 %. Multivariate analysis indicated that prenatal exposure to phenobarbital (odds ratio [OR], 17.424; 95 %CI, 1.510-201.067; P = 0.022) and topiramate (OR, 9.469; 95 %CI, 1.149-62.402; P = 0.036) was associated with increased risk of MCMs. Valproate (OR, 4.441; 95 %CI, 1.165-16.934; P = 0.029), phenobarbital (OR, 13.636; 95 %CI, 2.146-86.660; P = 0.006) and topiramate (OR, 7.527; 95 %CI, 1.764-32.118; P = 0.006) were significantly correlated with adverse pregnancy outcomes. Among 67 pregnancies in four combinations over 10 patients, 15 (22.4 %) remained seizure free through pregnancy, seizure frequency increased in 17 (25.4 %), decreased in 24 (35.8 %) women, in 26 (38.8 %) remained unchanged. Only 23.6 % of mothers undertook exclusive breastfeeding. Planned pregnancy was the only independent factor significantly associated with decreased risk of adverse pregnancy outcomes (OR, 0.139; 95 % CI, 0.051-0.382; P < 0.001). Notably, no adverse pregnancy outcome was recorded in pregnancies exposed to the combination of lamotrigine plus levetiracetam. CONCLUSION: Prenatal exposure to the combinations containing valproate, phenobarbital, or topiramate was associated with increased risk of adverse pregnant outcomes. AED-related teratogenicity may be reduced by planned pregnancy in WWE exposed to polytherapy. Our findings also suggest the combination of lamotrigine and levetiracetam seems to be most desirable to balance seizure control and fetal safety.

Interactive effects of ambient air pollution and sunshine duration on the risk of intrahepatic cholestasis of pregnancy.

INTRODUCTION: While the associations among ambient pollutants and various pregnancy complications are well documented, the effect of ambient pollutants on intrahepatic cholestasis of pregnancy (ICP) has not been examined. This study aimed to explore the effects of ambient pollutants and sunshine duration on ICP. METHODS: The study enrolled 169,971 pregnant women who delivered between 2015 and 2020 in two hospitals. The associations between ICP and exposure to ambient pollutants and sunshine duration, averaged throughout different periods (including the 3 months before conception, 1st trimester and 2nd trimester), were estimated using a generalized linear model. The interaction effects of ambient pollutants and sunshine duration on ICP were estimated. RESULTS: The fitted curves for ICP incidence were similar to the temporal trends of PM2.5, PM10, SO2, CO and NO2 but not that of O3. The risk of ICP was significantly elevated following a 10-µg/m3 increase in PM2.5 (aOR [adjusted odds ratio] = 1.057, 95% CI [confidence interval]: 1.017-1.099) and PM10 (aOR = 1.043, 95% CI: 1.013-1.074) and a 1-h decrease in sunshine duration (aOR = 1.039, 95% CI: 1.011-1.068) during the 3 months before conception. In the second trimester, a 1-µg/m3 increase in the concentration of SO2 was associated with an increased risk of ICP (aOR = 1.011, 95% CI: 1.001-1.021). Increased concentrations of PM2.5 and PM10 had interactive effects with reduced sunshine duration during the 3 months before conception on increasing the risk of ICP. CONCLUSIONS: Exposure to PM2.5 and PM10 during the 3 months before conception and exposure to SO2 in the second trimester were associated with an increased ICP risk. Reduced sunshine duration had an interactive effect with increased concentrations of PM2.5 and PM10 during the 3 months before conception on the occurrence of ICP.

Associations of pregnancy complications with ambient air pollution in China.

BACKGROUND: Gestational hypertension (GH), preeclampsia (PE), and gestational diabetes mellitus (GDM) are common pregnancy complications and can result in maternal and prenatal morbidity and mortality. Air pollution exposure could adversely impact pregnancy complications; however, evidence remains limited in China, where ambient air pollution is relatively severe. OBJECTIVE: This study aims to examine the associations of GH, PE, and GDM with exposure to six air pollutants (PM2.5, PM10, SO2, NO2, O3, and CO) during pregnancy. METHODS: Leveraging a multicenter birth cohort study among pregnant women in 24 hospitals from 15 provinces in China, we obtained data for maternal characteristics and pregnancy outcomes. We generated ambient concentrations of the six air pollutants using a combination of chemical transport model simulations with monitoring data. We used multivariable logistic regression models to estimate the effects on pregnancy complications from exposure to six air pollutants in each trimester and the entire pregnancy. RESULTS: Among the total 3754 pregnant women in this study, the prevalences of GH, GDM, and PE were 2.6 %, 11.2 %, and 0.7 %, respectively. GH risk increased 11.9 % (95 % CI, -8.5 %, 36.8 %) and 13.8 % (1.4 %, 27.8 %) per 10 µg/m3 increases in PM2.5 and PM10 in the entire pregnancy, respectively. PM2.5 and PM10 exposures in the first trimester were significantly associated with an increased risk of GDM. Exposure to O3, SO2, NO2, and CO in early pregnancy could be associated with GDM risk. Geographic region and season of conception may influence the associations of GH and PE with air pollution. CONCLUSIONS: Ambient particulate matter pollution adversely affects GH, GDM, and PE among Chinese pregnant women. Since most regions of China still suffer from hazardous levels of air pollution, our findings indicate importance of better protecting pregnant women from the risk of air pollution.