Neonatal Outcomes After COVID-19 Vaccination in Pregnancy.

Importance: Better knowledge about neonatal adverse events after COVID-19 vaccination during pregnancy could help address concerns about vaccine safety. Objective: To evaluate the risks of neonatal adverse events after exposure to COVID-19 vaccination during pregnancy. Design, Setting, and Participants: Population-based cohort study including all infants in Sweden and Norway born from June 2021 to January 2023. Unique personal identity numbers were used to link individual information from different national registers. Exposure: Administration of any mRNA vaccine against COVID-19 during pregnancy, irrespective of previous vaccination, number of doses during pregnancy, or vaccine manufacturer. Main Outcomes and Measures: Outcomes were neonatal conditions with bleeding/thrombosis or inflammation/infection; disorders of the central nervous system; circulatory, respiratory, or gastrointestinal problems; and neonatal mortality. Statistical methods included logistic regression adjusted for characteristics of the pregnant individuals, with additional restricted and stratified analyses. Results: Of 196 470 newborn infants included (51.3% male, 93.8% born at term, 62.5% born in Sweden), 94 303 (48.0%) were exposed to COVID-19 vaccination during pregnancy. Exposed infants exhibited no increased odds of adverse neonatal outcomes, and they exhibited lower odds for neonatal nontraumatic intracranial hemorrhage (event rate, 1.7 vs 3.2/1000; adjusted odds ratio [aOR], 0.78 [95% CI, 0.61-0.99]), hypoxic-ischemic encephalopathy (1.8 vs 2.7/1000; aOR, 0.73 [95% CI, 0.55-0.96]), and neonatal mortality (0.9 vs 1.8/1000; aOR, 0.68 [95% CI, 0.50-0.91]). Subgroup analyses found a similar association between vaccination during pregnancy and lower neonatal mortality; subgroups were restricted to infants delivered by individuals unvaccinated before pregnancy, individuals vaccinated before pregnancy, individuals vaccinated after a general recommendation of vaccination during pregnancy was issued, and individuals without COVID-19 infection during pregnancy. Analyses restricted to term infants, singleton births, or infants without birth defects yielded similar results. Stratifying the analysis by vaccine manufacturer did not attenuate the association between vaccination and low neonatal mortality. Conclusions and Relevance: In this large population-based study, vaccination of pregnant individuals with mRNA COVID-19 vaccines was not associated with increased risks of neonatal adverse events in their infants.

Metformin Plus Insulin for Preexisting Diabetes or Gestational Diabetes in Early Pregnancy: The MOMPOD Randomized Clinical Trial.

Importance: Insulin is recommended for pregnant persons with preexisting type 2 diabetes or diabetes diagnosed early in pregnancy. The addition of metformin to insulin may improve neonatal outcomes. Objective: To estimate the effect of metformin added to insulin for preexisting type 2 or diabetes diagnosed early in pregnancy on a composite adverse neonatal outcome. Design, Setting, and Participants: This randomized clinical trial in 17 US centers enrolled pregnant adults aged 18 to 45 years with preexisting type 2 diabetes or diabetes diagnosed prior to 23 weeks' gestation between April 2019 and November 2021. Each participant was treated with insulin and was assigned to add either metformin or placebo. Follow-up was completed in May 2022. Intervention: Metformin 1000 mg or placebo orally twice per day from enrollment (11 weeks -<23 weeks) through delivery. Main Outcome and Measures: The primary outcome was a composite of neonatal complications including perinatal death, preterm birth, large or small for gestational age, and hyperbilirubinemia requiring phototherapy. Prespecified secondary outcomes included maternal hypoglycemia and neonatal fat mass at birth, and prespecified subgroup analyses by maternal body mass index less than 30 vs 30 or greater and those with preexisting vs diabetes early in pregnancy. Results: Of the 831 participants randomized, 794 took at least 1 dose of the study agent and were included in the primary analysis (397 in the placebo group and 397 in the metformin group). Participants' mean (SD) age was 32.9 (5.6) years; 234 (29%) were Black, and 412 (52%) were Hispanic. The composite adverse neonatal outcome occurred in 280 (71%) of the metformin group and in 292 (74%) of the placebo group (adjusted odds ratio, 0.86 [95% CI 0.63-1.19]). The most commonly occurring events in the primary outcome in both groups were preterm birth, neonatal hypoglycemia, and delivery of a large-for-gestational-age infant. The study was halted at 75% accrual for futility in detecting a significant difference in the primary outcome. Prespecified secondary outcomes and subgroup analyses were similar between groups. Of individual components of the composite adverse neonatal outcome, metformin-exposed neonates had lower odds to be large for gestational age (adjusted odds ratio, 0.63 [95% CI, 0.46-0.86]) when compared with the placebo group. Conclusions and Relevance: Using metformin plus insulin to treat preexisting type 2 or gestational diabetes diagnosed early in pregnancy did not reduce a composite neonatal adverse outcome. The effect of reduction in odds of a large-for-gestational-age infant observed after adding metformin to insulin warrants further investigation. Trial Registration: ClinicalTrials.gov Identifier: NCT02932475.

Women with preeclampsia exposed to air pollution during pregnancy: Relationship between oxidative stress and neonatal disease - Pilot study.

Oxidative imbalance as a pathophysiological mechanism has been reported as an adverse outcome in pregnant women who develop preeclampsia and in their newborns. Furthermore, emerging evidence suggests the same mechanism by which air pollutants may exert their toxic effects. Therefore, the objective of the study was to evaluate the biomarkers of oxidative stress and their relationship with neonatal disease in premature newborns from mothers with preeclampsia exposed to air pollution during pregnancy. The data of air pollutants (PM2.5, PM10 and ozone) were collected at fixed monitoring stations. Oxidative and antioxidant status markers were obtained through special techniques in women with preeclampsia and in umbilical cord blood of their premature newborns. The oxidative stress markers were significantly higher in women with preeclampsia and their newborns who were exposed to higher levels of ambient air pollutants in the first and second trimester of pregnancy. Neonatal diseases are associated with preeclampsia in pregnancies, specifically intrauterine growth restriction (IUGR) and necrotizing enterocolitis (NEC). A significant correlation was identified in the levels of prooxidant agents and antioxidant enzyme activity in the presence of neonatal diseases associated with preeclampsia. There is increased oxidative damage in both the maternal and fetal circulation in women who develop preeclampsia exposed to air pollution during pregnancy. Therefore, these pregnancies complicated by preeclampsia have a greater adverse outcome as neonatal disease in the preterm infant.

Characteristics of Prescription Opioid Analgesics in Pregnancy and Risk of Neonatal Opioid Withdrawal Syndrome in Newborns.

Importance: Prescription opioids are often used during pregnancy even though they are associated with neonatal opioid withdrawal syndrome (NOWS). Most studies of adverse outcomes of opioid use for pain have assessed only the class-wide outcome despite the pharmacodynamic and pharmacokinetic heterogeneity across opioid medications. Objective: To compare the risk of NOWS across common types of opioids when prescribed as monotherapy during the last 3 months of pregnancy. Design, Setting, and Participants: This cohort study analyzed administrative claims data of Medicaid-insured mothers and newborns in 46 states and Washington DC from January 1, 2000, through December 31, 2014. Participants were mothers with 2 or more dispensed opioid prescriptions within 90 days before delivery and their eligible live-born neonates. Data were analyzed from February 2020 to March 2021. Exposure: Different types of opioid medications were compared by agonist strength (strong vs weak) and half-life (medium vs short and long vs short) of the opioid active ingredient. Main Outcomes and Measures: The primary outcome was NOWS, which was identified using an International Classification of Diseases, Ninth Revision, Clinical Modification diagnostic code in the 30 days after delivery. Relative risks (RRs) were adjusted for an exposure propensity score, including demographic characteristics, comorbidities, other medication use, and opioid treatment characteristics (including morphine milligram equivalents), using fine stratification. Results: The cohort comprised 48 202 opioid-exposed pregnancies with live newborns. A total of 1069 neonates (2.2%) had NOWS and 559 (1.2%) had severe NOWS. Opioid exposure during pregnancy included 16 202 pregnancies exposed to codeine, 4540 to oxycodone, 1244 to tramadol, 260 to methadone (dispensed for pain), 90 to hydromorphone, and 63 to morphine compared with 25 710 exposed to hydrocodone. Demographic characteristics varied across opioids, with tramadol, oxycodone, methadone, hydromorphone, and morphine being more commonly dispensed at older maternal age (≥35 years). Compared with hydrocodone, codeine had a lower adjusted RR of NOWS (0.57; 95% CI, 0.46-0.70), with a similar adjusted RR for tramadol (RR, 1.06; 95% CI, 0.73-1.56), and 2- to 3-fold higher adjusted RRs for oxycodone (1.87; 95% CI, 1.66-2.11), morphine (2.84; 95% CI, 1.30-6.22), methadone (3.02; 95% CI, 2.45-3.73), and hydromorphone (2.03; 95% CI, 1.09-3.78). Strong agonists were associated with a higher risk of NOWS than weak agonists (RR, 1.97; 95% CI, 1.78-2.17), and long half-life opioids were associated with an increased risk compared with short half-life products (RR, 1.33; 95% CI, 1.12-1.56). Findings were consistent across sensitivity and subgroup analyses. Conclusions and Relevance: Results of this study show higher risk of NOWS and severe NOWS among neonates with in utero exposure to strong agonists and long half-life prescription opioids. Information on the opioid-specific risk of NOWS may help prescribers select opioids for pain management in late stages of pregnancy.

Association of MTHFD1 gene polymorphisms and maternal smoking with risk of congenital heart disease: a hospital-based case-control study.

BACKGROUND: MTHFD1 gene may affect the embryonic development by elevated homocysteine levels, DNA synthesis and DNA methylation, but limited number of genetic variants of MTHFD1 gene was focused on the association with congenital heart disease (CHD). This study examined the role of MTHFD1 gene and maternal smoking on infant CHD risk, and investigated their interaction effects in Chinese populations. METHODS: A case-control study of 464 mothers of CHD infants and 504 mothers of health controls was performed. The exposures of interest were maternal tobacco exposure, single nucleotide polymorphisms (SNPs) of maternal MTHFD1 gene. The logistic regression model was used for accessing the strength of association. RESULTS: Mothers exposed to secondhand smoke during 3 months before pregnancy (adjusted odds ratio [aOR] = 1.56; 95% confidence interval [CI]: 1.13-2.15) and in the first trimester of pregnancy (aOR = 2.24; 95%CI: 1.57-3.20) were observed an increased risk of CHD. Our study also found that polymorphisms of maternal MTHFD1 gene at rs1950902 (AA vs. GG: aOR = 1.73, 95% CI: 1.01-2.97), rs2236222 (GG vs. AA: aOR = 2.38, 95% CI: 1.38-4.12), rs1256142 (GA vs.GG: aOR = 1.57, 95% CI: 1.01-2.45) and rs11849530 (GG vs. AA: aOR = 1.68, 95% CI: 1.02-2.77) were significantly associated with higher risk of CHD. However, we did not observe a significant association between maternal MTHFD1 rs2236225 and offspring CHD risk. Furthermore, we found the different degrees of interaction effects between polymorphisms of the MTHFD1 gene including rs1950902, rs2236222, rs1256142, rs11849530 and rs2236225, and maternal tobacco exposure. CONCLUSIONS: Maternal polymorphisms of MTHFD1 gene, maternal tobacco exposure and their interactions are significantly associated with the risk of CHD in offspring in Han Chinese populations. However, more studies in different ethnic populations with a larger sample and prospective designs are required to confirm our findings. TRIAL REGISTRATION: Registration number: ChiCTR1800016635 .

SGLT2 inhibitors therapy protects glucotoxicity-induced ß-cell failure in a mouse model of human KATP-induced diabetes through mitigation of oxidative and ER stress.

Progressive loss of pancreatic ß-cell functional mass and anti-diabetic drug responsivity are classic findings in diabetes, frequently attributed to compensatory insulin hypersecretion and ß-cell exhaustion. However, loss of ß-cell mass and identity still occurs in mouse models of human KATP-gain-of-function induced Neonatal Diabetes Mellitus (NDM), in the absence of insulin secretion. Here we studied the temporal progression and mechanisms underlying glucotoxicity-induced loss of functional ß-cell mass in NDM mice, and the effects of sodium-glucose transporter 2 inhibitors (SGLT2i) therapy. Upon tamoxifen induction of transgene expression, NDM mice rapidly developed severe diabetes followed by an unexpected loss of insulin content, decreased proinsulin processing and increased proinsulin at 2-weeks of diabetes. These early events were accompanied by a marked increase in ß-cell oxidative and ER stress, without changes in islet cell identity. Strikingly, treatment with the SGLT2 inhibitor dapagliflozin restored insulin content, decreased proinsulin:insulin ratio and reduced oxidative and ER stress. However, despite reduction of blood glucose, dapagliflozin therapy was ineffective in restoring ß-cell function in NDM mice when it was initiated at >40 days of diabetes, when loss of ß-cell mass and identity had already occurred. Our data from mouse models demonstrate that: i) hyperglycemia per se, and not insulin hypersecretion, drives ß-cell failure in diabetes, ii) recovery of ß-cell function by SGLT2 inhibitors is potentially through reduction of oxidative and ER stress, iii) SGLT2 inhibitors revert/prevent ß-cell failure when used in early stages of diabetes, but not when loss of ß-cell mass/identity already occurred, iv) common execution pathways may underlie loss and recovery of ß-cell function in different forms of diabetes. These results may have important clinical implications for optimal therapeutic interventions in individuals with diabetes, particularly for those with long-standing diabetes.

Effect of intra-partum Oxytocin on neonatal encephalopathy: a systematic review and meta-analysis.

BACKGROUND: Oxytocin is widely used for induction and augmentation of labour, particularly in low- and middle-income countries (LMICs). In this systematic review and meta-analysis, we examined the effect of intra-partum Oxytocin use on neonatal encephalopathy. METHODS: The protocol for this study was registered with PROSPERO (ID: CRD42020165049). We searched Medline, Embase and Web of Science Core Collection databases for papers published between January 1970 and May 2021. We considered all studies involving term and near-term (≥36 weeks' gestation) primigravidae and multiparous women. We included all randomised, quasi-randomised clinical trials, retrospective studies and non-randomised prospective studies reporting intra-partum Oxytocin administration for induction and/or augmentation of labour. Our primary outcome was neonatal encephalopathy. Risk of bias was assessed in non-randomised studies using the Risk Of Bias In Non-randomised Studies of Interventions (ROBINS-I) tool. The RoB 2.0 tool was used for randomised studies. A Mantel-Haenszel statistical method and random effects analysis model were used for meta-analysis. Odds ratios were used to determine effect measure and reported with 95% confidence intervals. RESULTS: We included data from seven studies (6 Case-control studies, 1 cluster-randomised trial) of which 3 took place in high-income countries (HICs) and 4 in LMICs. The pooled data included a total of 24,208 women giving birth at or after 36 weeks; 7642 had intra-partum Oxytocin for induction and/or augmentation of labour, and 16,566 did not receive intra-partum Oxytocin. Oxytocin use was associated with an increased prevalence of neonatal encephalopathy (Odds Ratio 2.19, 95% CI 1.58 to 3.04; p < 0.00001). CONCLUSIONS: Intra-partum Oxytocin may increase the risk of neonatal encephalopathy. Future clinical trials of uterotonics should include neonatal encephalopathy as a key outcome.

Iodine contrast prior to or during pregnancy and neonatal thyroid function: a systematic review.

OBJECTIVE: Thyroid dysfunction is a known side effect of iodinated contrast media. There is some evidence to suggest that iodinated contrast media administered to pregnant women may cause thyroid dysfunction not only in themselves but also in their offspring. Here, we systematically evaluated literature on the use of iodinated contrast media prior to or during pregnancy on the offspring's thyroid function. DESIGN: Systematic review of published literature. MATERIALS AND METHODS: Relevant studies were identified by PubMed, EMBASE and The Cochrane Library up to June 5, 2020. All study designs, reporting on the foetal or neonatal thyroid function after exposure to iodinated contrast media prior to or during pregnancy, were included. We undertook random effects meta-analysis and pooled the estimates as proportions with 95% CIs. RESULTS: We identified 402 articles, of which 26 were included. Six studies reported (n = 369) on exposure to iodinated contrast media prior to pregnancy by hysterosalpingography and 20 studies (n = 670) on exposure to these media during pregnancy by amniofetography, urography or CT. There was low to high risk of bias. The proportion of (transient) neonatal thyroid dysfunction was 0.0% (95% CI: 0.0-2.9% based on 3 studies) for hysterosalpingography, 2.25% (95% CI: 0.03-6.55% based on 2 studies) for amniofetography and 0.0% (95% CI: 0.0-0.02% based on 5 studies) for CT. There was a tendency towards an increased risk of thyroid dysfunction with higher amounts of contrast used. CONCLUSIONS: Exposure to iodinated contrast media prior to or during pregnancy may increase the risk of thyroid dysfunction in offspring. We recommend keeping the amount of contrast used as low as possible.

Epidural analgesia, intrapartum hyperthermia, and neonatal brain injury: a systematic review and meta-analysis.

BACKGROUND: Epidural analgesia is associated with intrapartum hyperthermia, and chorioamnionitis is associated with neonatal brain injury. However, it is not known if epidural hyperthermia is associated with neonatal brain injury. This systematic review and meta-analysis investigated three questions: (1) does epidural analgesia cause intrapartum hyperthermia, (2) is intrapartum hyperthermia associated with neonatal brain injury, and (3) is epidural-induced hyperthermia associated with neonatal brain injury? METHODS: PubMed, ISI Web of Knowledge, The Cochrane Library, and Embase were searched from inception to January 2020 using Medical Subject Headings (MeSH) terms relating to epidural analgesia, hyperthermia, labour, and neonatal brain injury. Studies were reviewed independently for inclusion and quality by two authors (Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach). Two meta-analyses were performed using the Mantel-Haenszel fixed effect method to generate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Forty-one studies were included for Question 1 (646 296 participants), 36 for Question 2 (11 866 021 participants), and two studies for Question 3 (297 113 participants). When the mode of analgesia was randomised, epidural analgesia was associated with intrapartum hyperthermia (OR: 4.21; 95% CI: 3.48-5.09). There was an association between intrapartum hyperthermia and neonatal brain injury (OR: 2.79; 95% CI: 2.54-2.3.06). It was not possible to quantify the association between epidural-induced hyperthermia and neonatal brain injury. CONCLUSIONS: Epidural analgesia is a cause of intrapartum hyperthermia, and intrapartum hyperthermia of any cause is associated with neonatal brain injury. Further work is required to establish if epidural-induced hyperthermia is a cause of neonatal brain injury.

Maternal Sildenafil vs Placebo in Pregnant Women With Severe Early-Onset Fetal Growth Restriction: A Randomized Clinical Trial.

Importance: Severe early onset fetal growth restriction caused by placental dysfunction leads to high rates of perinatal mortality and neonatal morbidity. The phosphodiesterase 5 inhibitor, sildenafil, inhibits cyclic guanosine monophosphate hydrolysis, thereby activating the effects of nitric oxide, and might improve uteroplacental function and subsequent perinatal outcomes. Objective: To determine whether sildenafil reduces perinatal mortality or major morbidity. Design, Setting, and Participants: This placebo-controlled randomized clinical trial was conducted at 10 tertiary referral centers and 1 general hospital in the Netherlands from January 20, 2015, to July 16, 2018. Participants included pregnant women between 20 and 30 weeks of gestation with severe fetal growth restriction, defined as fetal abdominal circumference below the third percentile or estimated fetal weight below the fifth percentile combined with Dopplers measurements outside reference ranges or a maternal hypertensive disorder. The trial was stopped early owing to safety concerns on July 19, 2018, whereas benefit on the primary outcome was unlikely. Data were analyzed from January 20, 2015, to January 18, 2019. The prespecified primary analysis was an intention-to-treat analysis including all randomized participants. Interventions: Participants were randomized to sildenafil, 25 mg, 3 times a day vs placebo. Main Outcomes and Measures: The primary outcome was a composite of perinatal mortality or major neonatal morbidity until hospital discharge. Results: Out of 360 planned participants, a total of 216 pregnant women were included, with 108 women randomized to sildenafil (median gestational age at randomization, 24 weeks 5 days [interquartile range, 23 weeks 3 days to 25 weeks 5 days]; mean [SD] estimated fetal weight, 458 [160] g) and 108 women randomized to placebo (median gestational age, 25 weeks 0 days [interquartile range, 22 weeks 5 days to 26 weeks 3 days]; mean [SD] estimated fetal weight, 464 [186] g). In July 2018, the trial was halted owing to concerns that sildenafil may cause neonatal pulmonary hypertension, whereas benefit on the primary outcome was unlikely. The primary outcome, perinatal mortality or major neonatal morbidity, occurred in the offspring of 65 participants (60.2%) allocated to sildenafil vs 58 participants (54.2%) allocated to placebo (relative risk, 1.11; 95% CI, 0.88-1.40; P = .38). Pulmonary hypertension, a predefined outcome important for monitoring safety, occurred in 16 neonates (18.8%) in the sildenafil group vs 4 neonates (5.1%) in the placebo group (relative risk, 3.67; 95% CI, 1.28-10.51; P = .008). Conclusions and Relevance: These findings suggest that antenatal maternal sildenafil administration for severe early onset fetal growth restriction did not reduce the risk of perinatal mortality or major neonatal morbidity. The results suggest that sildenafil may increase the risk of neonatal pulmonary hypertension. Trial Registration: ClinicalTrials.gov Identifier: NCT02277132.

Prenatal Antidepressant Use and Risk of Adverse Neonatal Outcomes.

OBJECTIVES: To estimate the risk of neonatal outcomes from patterns of prenatal antidepressant use. METHODS: From the OptumLabs Data Warehouse, 226 932 singleton deliveries were identified. Antidepressant claims with coverage between the last menstrual period and 35 weeks' gestation were converted to fluoxetine equivalents, and a longitudinal cluster analysis was performed. Outcomes included major cardiac malformations (11.7 of 1000 births), preterm birth (75.7 of 1000 births), and newborn respiratory distress (54.2 of 1000 births). The lowest trajectory was the primary reference group, and depression and anxiety with no antidepressant claims served as secondary reference groups. RESULTS: From 15 041 (6.6%) pregnancies exposed to an antidepressant, use patterns were best described as (1) low use (∼10 mg/day) with first-trimester reduction, (2) low sustained use (∼20 mg/day), (3) moderate use (∼40 mg/day) with first-trimester reduction, (4) moderate sustained use (∼40 mg/day), and (5) high sustained use (∼75 mg/day). Moderate sustained use increased the risk of major cardiac malformations, although results included the null when compared with depression or anxiety reference groups. Moderate sustained (adjusted risk ratio [RR] 1.31; 95% confidence interval [CI] 1.16-1.49) and high sustained (adjusted RR 1.78; 95% CI 1.48-2.14) trajectories were associated with an increased risk of preterm birth. All 4 trajectories increased the risk of neonatal respiratory distress in a dose-response fashion (adjusted RRs 1.36 [95% CI 1.20-1.50] to 2.23 [95% CI 1.83-2.77]). CONCLUSIONS: Although findings support continuation of the lowest effective dose to treat depression or anxiety, which benefits the mother, they also highlight an increased risk for newborn respiratory distress in all groups and preterm birth at moderate to high sustained doses.

Rituximab, MS, and pregnancy.

OBJECTIVE: To describe the safety and efficacy of rituximab (RTX) in MS and pregnancy, we conducted a retrospective cohort study of 74 pregnancies among 55 women treated with RTX for MS and their offspring. METHODS: We used prospectively collected information from the electronic health record at Kaiser Permanente Southern California between 2012 and 2019 of mother and baby to identify treatment history, pregnancy outcomes, and relapses. RESULTS: Last RTX exposure before conception occurred between 1.8 and 5.2 months in 32 (49%) of 65 pregnancies and accidentally during the first trimester in 9 (12%). Among 38 live births, adverse pregnancy outcomes were as follows: 3 preterm deliveries (including 1 set of twins), 1 neonatal death (preterm twin), and 1 perinatal stroke (full-term). No stillbirths, chorioamnionitis, or major malformations were found. Fifteen (27%) women had at least one first-trimester miscarriage, of whom 8 (53%) had a history of infertility. Cumulative dose or timing of last RTX infusion was not associated with an increased risk of miscarriage. Only 2 (5.4%) women experienced relapses, one during pregnancy and the other postpartum. CONCLUSION: We observed no increase in adverse pregnancy outcomes compared with expected national incidence rates and remarkably little disease activity in RTX-treated women with MS, particularly when compared with periconceptional natalizumab-treated cohorts. However, larger studies are needed to fully assess the safety of RTX use before pregnancy, especially risks associated with prolonged B-cell depletion and hypogammaglobulinemia. Until these data are available, we recommend restricting RTX use before pregnancy to women who require highly effective MS treatments. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for pregnant women with MS, RTX controls disease activity and does not increase adverse pregnancy outcomes.

Management of thyrotoxicosis during pregnancy.

Thyrotoxicosis during pregnancy should be adequately managed and controlled to prevent maternal and fetal complications. The evaluation of thyroid function in pregnant women is challenged by the physiological adaptations associated with pregnancy, and the treatment with antithyroid drugs (ATD) raises concerns for the pregnant woman and the fetus. Thyrotoxicosis in pregnant women is mainly of autoimmune origin, and the measurement of thyroid stimulating hormone-receptor antibodies (TRAb) plays a key role. TRAb helps to distinguish the hyperthyroidism of Graves' disease from gestational hyperthyroidism in early pregnancy, and to evaluate the risk of fetal and neonatal hyperthyroidism in late pregnancy. Furthermore, the measurement of TRAb in early pregnancy is recommended to evaluate the need for ATD during the teratogenic period of pregnancy. Observational studies have raised concern about the risk of birth defects associated with the use of ATD in early pregnancy and challenged the clinical management and choice of treatment.

Complications of Antenatal Corticosteroids in Infants Born by Early Term Scheduled Cesarean Section.

OBJECTIVE: To compare neonatal hypoglycemia and respiratory morbidity rates in pregnancies complicated by diabetes following early term scheduled cesarean section (ETSCS) with and without maternal corticosteroid administration. RESEARCH DESIGN AND METHODS: In a retrospective cohort study, women with any form of diabetes in pregnancy undergoing ETSCS were included. Primary outcomes were admission rates to the neonatal intensive care unit (NICU) for respiratory distress syndrome (RDS)/transient tachypnea of the newborn (TTN) and/or neonatal hypoglycemia. RESULTS: NICU admission rates for neonatal hypoglycemia were significantly higher (24.2% vs. 4.4%, P = 0.003) and RDS/TTN rates were nonsignificantly higher (15.2% vs. 7.2%, P = 0.209) following corticosteroid administration. CONCLUSIONS: Corticosteroids were not beneficial among women with any form of diabetes in pregnancy undergoing ETSCS and, indeed, may be harmful. In our hospital, we have ceased the use of corticosteroids for women under these circumstances.

Maternal and Neonatal Health Outcomes Associated with the Use of Gliclazide and Metformin for the Treatment of Diabetes in Pregnancy: A Record Linkage Study.

Background: Gliclazide is commonly used in the treatment of diabetes mellitus; however, very little is known regarding the safety of its use in pregnancy. The aims of this study was to examine the rate of maternal hospitalizations, congenital anomalies, and adverse neonatal outcomes in pregnant women treated with gliclazide compared with pregnant women treated with metformin. Methods: Women who used gliclazide during pregnancy (n = 108) between 2003 and 2012 were identified by linking national medication dispensing data with the New South Wales perinatal data collection. A comparison group of women treated with only metformin during pregnancy (n = 108) were selected using propensity score matching. Data on hospital admissions, mortality, and congenital anomalies were extracted to examine the health of mothers and their children across groups. Results: Rates of maternal hospitalizations during pregnancy were not significantly different between women in the two groups (incident rate ratio: 1.10, 95% CI: 0.90-1.34, P = 0.339). There was no significant difference in average birth weight (3402 g compared with 3572 g, P = 0.072), incidence of neonatal hypoglycemia (<4.6% compared with <4.6%, P = 0.684), or congenital anomalies (7.4% compared with 5.6%, P = 0.582) in neonates exposed to gliclazide compared with metformin. Conclusions: The use of gliclazide during pregnancy was not associated with increased maternal hospitalization or neonatal adverse outcomes in comparison with the use of metformin in pregnancy; however, the limited number of exposed pregnancies is a key limitation.

Impact of low-dose aspirin on adverse perinatal outcome: meta-analysis and meta-regression.

OBJECTIVE: To perform a meta-analysis and meta-regression of randomized controlled trials (RCTs) to evaluate the impact of low-dose aspirin (LDA) on perinatal outcome, independent of its effect on pre-eclampsia (PE), preterm birth and low birth weight. METHODS: An electronic search of EMBASE, PubMed, CENTRAL, PROSPERO and Google Scholar databases was performed to identify RCTs assessing the impact of LDA in pregnancy, published in English prior to May 2019, which reported perinatal outcomes of interest (placental abruption, delivery mode, low 5-min Apgar score, neonatal acidosis, neonatal intensive care unit admission, periventricular hemorrhage and perinatal death). Risk ratios (RR) and 95% CI were calculated and pooled for analysis. Analysis was stratified according to gestational age at commencement of treatment (≤ 16 weeks vs > 16 weeks) and subgroup analysis was performed to assess the impact of aspirin dose (< 100 mg vs ≥ 100 mg). Meta-regression was used to assess the impact of LDA on perinatal outcome, independent of the reduction in PE, preterm birth and low birth weight. RESULTS: Forty studies involving 34 807 participants were included. When LDA was commenced ≤ 16 weeks' gestation, it was associated with a significant reduction in the risk of perinatal death (RR, 0.47; 95% CI, 0.25-0.88; P = 0.02; number needed to treat, 92); however, this risk reduction was only seen when a daily dose of ≥ 100 mg was administered. If commenced > 16 weeks' gestation, LDA was associated with a significant reduction in 5-min Apgar score < 7 (RR, 0.75; 95% CI, 0.58-0.96; P = 0.02) and periventricular hemorrhage (RR, 0.68; 95% CI, 0.47-0.99; P = 0.04), but a trend towards an increase in the risk of placental abruption (RR, 1.20; 95% CI, 1.00-1.46; P = 0.06) was also noted. LDA was not associated with any significant increase in adverse events if commenced ≤ 16 weeks gestation. LDA had no effect on delivery mode, irrespective of the gestational age at which it was started. Meta-regression confirmed that the effect of LDA on perinatal death, when treatment was started ≤ 16 weeks' gestation, was independent of any reduction in the rate of PE and preterm birth. CONCLUSION: LDA improves some important perinatal outcomes, without increasing adverse events such as placental abruption or periventricular hemorrhage, and its utility, if commenced prior to 16 weeks' gestation, may be considered in a wider context beyond the prevention of PE or fetal growth restriction. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Impacto de la aspirina en dosis bajas en los resultados perinatales adversos: metaanálisis y metaregresión OBJETIVO: Realizar un metaanálisis y una metaregresión de ensayos controlados aleatorizados (ECA) para evaluar el impacto de la aspirina en dosis bajas (LDA, por sus siglas en inglés) en el resultado perinatal, independientemente de su efecto en la preeclampsia (PE), el parto pretérmino y el peso bajo al nacer. MÉTODOS: Se realizó una búsqueda electrónica en las bases de datos EMBASE, PubMed, CENTRAL, PROSPERO y Google Scholar para identificar ECA que hubieran evaluado el impacto de la LDA en el embarazo, publicados en inglés antes de mayo de 2019, que informaran sobre resultados perinatales de interés (desprendimiento de la placenta, modo de parto, baja puntuación de Apgar a los 5 minutos, acidosis neonatal, ingreso en la unidad de cuidados intensivos neonatales, hemorragia periventricular y muerte perinatal). Se calcularon los cocientes de riesgo (CR) y el IC del 95% y se combinaron para el análisis. El análisis se estratificó según la edad gestacional al comienzo del tratamiento (≤16 semanas vs. >16 semanas) y se realizaron análisis de subgrupos para evaluar el impacto de la dosis de aspirina (<100 mg vs ≥100 mg). Se utilizó la metarregresión para evaluar el impacto de LDA en el resultado perinatal, independientemente de la reducción de la PE, el parto pretérmino y el bajo peso al nacer. RESULTADOS: Se incluyeron 40 estudios con 34 807 participantes. Cuando se inició el tratamiento con LDA a ≤ 16 semanas de gestación, se asoció con una reducción significativa del riesgo de muerte perinatal (CR, 0,47; IC 95%, 0,25-0,88; P=0,02; número necesario a tratar, 92); sin embargo, esta reducción del riesgo sólo se observó cuando se administró una dosis diaria de ≥ 100 mg. Si se inició con una gestación de > 16 semanas, el tratamiento con LDA se asoció con una reducción significativa en la puntuación de Apgar a los 5 minutos < 7 (CR, 0,75; 95% CI, 0,58-0,96; P = 0,02) y la hemorragia periventricular (CR, 0,68; 95% CI, 0,47-0,99; P = 0,04), pero también se notó una tendencia al aumento en el riesgo de desprendimiento prematuro de la placenta (CR, 1,20; 95% CI, 1,00-1,46; P = 0.06). El tratamiento con LDA no se asoció con ningún aumento significativo de los eventos adversos si se inició a ≤ 16 semanas de gestación. El tratamiento con LDA no tuvo ningún efecto sobre el modo de parto, independientemente de la edad gestacional en la que se inició. La metaregresión confirmó que el efecto de la LDA en la muerte perinatal, cuando se inició el tratamiento a ≤ 16 semanas de gestación, fue independiente de cualquier reducción en la tasa de PE y de nacimientos prematuros. CONCLUSIÓN: El tratamiento con LDA mejora algunos resultados perinatales importantes, sin aumentar los eventos adversos como el desprendimiento de la placenta o la hemorragia periventricular, y su utilidad, si se inicia antes de las 16 semanas de gestación, puede considerarse en un contexto más amplio, más allá de la prevención de la PE o la restricción del crecimiento fetal. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Brief report: Metabolic acidosis in newborn infants following maternal use of acetazolamide during pregnancy.

 The information regarding fetal effects of acetazolamide use during pregnancy and lactation is sparse. We report the clinical and pharmacodynamic characteristics of maternal acetazolamide use and the timing of its effects on acid-base balance in three cases who presented with metabolic acidosis in the newborn period. We found that the infants' clinical status soon after birth was inconsistently correlated with maternal drug dose and concentrations of medication in maternal serum. However, there was low transfer of the drug in breast milk and its use did not affect clinical symptomatology. We also present a review of literature on this subject to help consolidate our current knowledge on this topic.

Comparative effectiveness of metformin versus insulin for gestational diabetes in New Zealand.

PURPOSE: To measure the comparative effectiveness of metformin versus insulin for initial pharmacological management of gestational diabetes mellitus (GDM). METHODS: We conducted a population-based retrospective cohort study using administrative claims, maternity care, and laboratory result data from New Zealand. We followed pregnant women aged 15 to 45 from GDM diagnosis through delivery and assessed outcomes using maternity care and hospitalization data. We adjusted for covariates using inverse probability of treatment weights and multiple imputation for missing covariate information. We estimated unadjusted and adjusted risk ratios (RRs), risk differences (RDs) per 100, and 95% confidence intervals (CIs). Linear regression was used to estimate the association of treatment with birthweight. We stratified analyses by ethnicity and infant sex in prespecified sensitivity analyses. RESULTS: We compared 3818 metformin-treated pregnancies with 3450 insulin-treated pregnancies. We observed differences in treatment initiation by ethnicity, socioeconomic status, region, and calendar year. Treatment groups were similar in age, body mass index (BMI), and timing of diagnosis/treatment initiation. After adjustment, metformin was associated with reduced absolute risk of planned elective c-section (RD = -2.3, 95% CI, -4.3 to -0.3), large for gestational age (RD = -3.7, 95% CI, -5.5 to -1.8), and neonatal hypoglycemia (RD = -5.0, 95% CI, -6.9 to -3.2) compared with insulin. There were no clinically meaningful differences in average birthweight between metformin- and insulin-treated pregnancies. We observed variation in estimates by ethnicity and infant sex for some neonatal outcomes. CONCLUSION: Metformin appears to be an effective treatment for women with GDM and may reduce risk of some adverse neonatal outcomes when compared with insulin.

Short-Term Neonatal Outcome among Term Infants after In-Utero Exposure to Beta Blockers.

BACKGROUND: The need for postnatal monitoring of infants exposed to intrauterine beta blockers (BBs) has not been clearly defined. OBJECTIVES: To evaluate infants exposed to intrauterine BBs in order to estimate the need for postnatal monitoring. METHODS: This retrospective case-control study comprised 153 term infants born to mothers who had been treated with BBs during pregnancy. Treatment indications included hypertension 76 mothers (49.7%), cardiac arrhythmias 48 (31.4%), rheumatic heart disease 14 (9.1%), cardiomyopathy 11 (7.2%) and migraine 4 (2.6%). The controls were infants of mothers with hypertension not exposed to BBs who were born at the same gestational age and born closest (before or after) to the matched infant in the study group. RESULTS: Compared to the control group, the infants in the study group had a higher prevalence of early asymptomatic hypoglycemia (study 30.7% vs. control 18.3%, P = 0.016), short symptomatic bradycardia events, other cardiac manifestations (P = 0.016), and longer hospitalization (P < 0.001). No life-threatening medical conditions were documented. The birth weight was significantly lower for the high-dose subgroup compared to the low-dose subgroup (P = 0.03), and the high-dose subgroup had a higher incidence of small-for-gestational-age (P = 0.02). CONCLUSIONS: No alarming or life-threatening medical conditions were observed among term infants born to BB treated mothers. These infants can be safely observed for 48 hours after birth close to their mothers in the maternity ward. Glucose follow-up is needed, especially in the first hours of life.