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.

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 .

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.

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.

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.

Maternal paracetamol intake and fetal ductus arteriosus constriction or closure: a case series analysis.

Recent case reports describe an association between maternal paracetamol intake and fetal ductus arteriosus constriction or closure. To put these cases into perspective and explore causality, a structured literature search was conducted. The World Health Organization Uppsala Monitoring Centre (WHO-UMC) causality tool was applied to the cases retrieved. The search resulted in 12 papers with 25 case descriptions, of which one case was classified as unlikely, nine as possible, 11 as probable and four as certain. Consequently, we concluded that a causal relationship between maternal paracetamol intake and fetal ductus arteriosus constriction or closure is likely. These findings suggest that pharmacovigilance studies on paracetamol safety during pregnancy are warranted to quantify the event and put the current findings into clinical perspective. Although analgesia during pregnancy and during the peripartum period is of obvious relevance, alternative analgesics such as opioids or other nonsteroidal anti-inflammatory drugs also have side effects.

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.

Caffeine exposure during pregnancy, small for gestational age birth and neonatal outcome - results from the Norwegian Mother and Child Cohort Study.

BACKGROUND: Maternal caffeine intake has repeatedly been linked to babies being born small for gestational age (SGA). SGA babies are known to be at increased risk for adverse neonatal outcomes. The aim of this study was to explore the associations between prenatal caffeine exposure and neonatal health. METHODS: The study is based on 67,569 full-term singleton mother-infant pairs from the Norwegian Mother and Child Cohort Study. Caffeine consumption from different sources was self-reported in gestational week 22. Neonatal compound outcomes, namely (1) morbidity/mortality and (2) neonatal intervention, were created based on the Medical Birth Registry of Norway. Adjusted logistic regression was performed. RESULTS: Caffeine exposure was associated to SGA (OR = 1.16, 95%CI: 1.10; 1.23) and being born SGA was significantly associated with neonatal health (OR = 3.09, 95%CI: 2.54; 3.78 for morbidity/mortality; OR = 3.94, 95%CI: 3.50; 4.45 for intervention). However, prenatal caffeine exposure was neither associated with neonatal morbidity/mortality (OR = 1.01, 95%CI: 0.96; 1.07) nor neonatal intervention (OR = 1.02, 95%CI: 1.00; 1.05 for a 100 mg caffeine intake increase). Results did not change after additional adjustment for SGA status. CONCLUSIONS: Moderate prenatal caffeine exposure (< 200 mg/day) does not seem to impair neonatal health, although prenatal caffeine exposure is associated with the child being born SGA and SGA with neonatal health. We suggest diversity in neonatal outcomes of SGA infants according to the underlying cause of low birth weight.

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.

Ritodrine-induced rhabdomyolysis, infantile myotonic dystrophy, and maternal myotonic dystrophy unveiled.

A primiparous pregnant woman in remission of myositis suffered very acute-onset ritodrine-induced rhabdomyolysis. At 29 gestational weeks, ritodrine was administered for threatened preterm labor. Just 3 h later, she complained of severe limb muscle pain, with serum creatinine phosphokinase elevated to 32 019 U/L and myoglobinuria. The muscle pain disappeared immediately after ceasing administration of ritodrine. At 31 weeks, premature rupture of the membranes occurred, necessitating cesarean section, yielding a baby with weak tonus, and the presence of infantile muscle diseases was suspected. Genetic analysis of the infant confirmed myotonic dystrophy (dystrophia myotonica, DM), which prompted us to perform maternal genetic analysis, confirming maternal DM. Ritodrine can induce rhabdomyolysis even in the prodromal phase with a mild phenotype of DM. A literature review suggested that ritodrine-induced rhabdomyolysis may be likely to occur more acutely after ritodrine administration in DM compared with non-DM mothers.

Insulin pump use compared with intravenous insulin during labour and delivery: the INSPIRED observational cohort study.

AIMS: To assess the safety and efficacy of pump therapy (continuous subcutaneous insulin infusion; CSII) during labour and delivery in women with Type 1 diabetes. METHODS: A retrospective cohort study of 161 consecutive Type 1 diabetic pregnancies delivered during 2000-2010 at Mount Sinai Hospital, Toronto, Canada. Capillary blood glucose levels during labour and delivery and time in/out of target (target: 4-6 mmol/l) were compared along with neonatal outcomes for three groups: (1) women on pumps who stayed on pumps during labour (pump/pump n = 31), (2) women on pumps who switched to intravenous (IV) insulin infusion during labour (pump/IVn = 25), and (3) women on multiple daily injections who switched to IV insulin infusion during labour (MDIn = 105). RESULTS: There were no significant differences between the mean or median glucose values during labour and delivery across all three groups, and no significant difference in time spent hypoglycaemic. However, women in the pump/pump group had significantly better glycaemic control as defined by mean glucose (5.5 vs. 6.4 mmol/l; P = 0.01), median glucose (5.4 vs. 6.3 mmol/l; P = 0.02), and more time spent in target (60.9% vs. 39.2%; P = 0.06) compared with women in the pump/IV group (after removing one outlier). CONCLUSIONS: This study demonstrates that the continuation of CSII therapy during labour and delivery appears safe and efficacious. Moreover, women who choose to continue CSII have better glucose control during delivery than those who switch to IV insulin, suggesting that it should be standard practice to allow women the option of continuing CSII during labour and delivery.

Metformin in women with type 2 diabetes in pregnancy (MiTy): a multi-center randomized controlled trial.

BACKGROUND: The incidence of type 2 diabetes in pregnancy is rising and rates of serious adverse maternal and fetal outcomes remain high. Metformin is a biguanide that is used as first-line treatment for non-pregnant patients with type 2 diabetes. We hypothesize that metformin use in pregnancy, as an adjunct to insulin, will decrease adverse outcomes by reducing maternal hyperglycemia, maternal insulin doses, maternal weight gain and gestational hypertension/pre-eclampsia. In addition, since metformin crosses the placenta, metformin treatment of the fetus may have a direct beneficial effect on neonatal outcomes. Our aim is to compare the effectiveness of the addition of metformin to insulin, to standard care (insulin plus placebo) in women with type 2 diabetes in pregnancy. METHODS: The MiTy trial is a multi-centre randomized trial currently enrolling pregnant women with type 2 diabetes, who are on insulin, between the ages of 18-45, with a gestational age of 6 weeks 0 days to 22 weeks 6 days. In this randomized, double-masked, parallel placebo-controlled trial, after giving informed consent, women are randomized to receive either metformin 1,000 mg twice daily or placebo twice daily. A web-based block randomization system is used to assign women to metformin or placebo in a 1:1 ratio, stratified for site and body mass index. The primary outcome is a composite neonatal outcome of pregnancy loss, preterm birth, birth injury, moderate/severe respiratory distress, neonatal hypoglycemia, or neonatal intensive care unit admission longer than 24 h. Secondary outcomes are large for gestational age, cord blood gas pH < 7.0, congenital anomalies, hyperbilirubinemia, sepsis, hyperinsulinemia, shoulder dystocia, fetal fat mass, as well as maternal outcomes: maternal weight gain, maternal insulin doses, maternal glycemic control, maternal hypoglycemia, gestational hypertension, preeclampsia, cesarean section, number of hospitalizations during pregnancy, and duration of hospital stays. The trial aims to enroll 500 participants. DISCUSSION: The results of this trial will inform endocrinologists, obstetricians, family doctors, and other healthcare professionals caring for women with type 2 diabetes in pregnancy, as to the benefits of adding metformin to insulin in this high risk population. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: no. NCT01353391 . Registered February 6, 2009.

Perinatal Outcomes after Short versus Prolonged Indomethacin for Tocolysis in Women with Preterm Labor.

Objective Indomethacin tocolysis is generally limited to 48 hours. Indomethacin has been administered for longer durations to prolong gestation in extreme prematurity. Our aim is to compare perinatal outcomes after a prolonged course, > 48 hours versus ≤ 48 hours in preterm labor. Methods A retrospective chart review of women admitted with preterm labor < 32 weeks gestation who received indomethacin for tocolysis. The primary maternal outcome was latency from admission until delivery. The primary neonatal outcome was a composite of severe neonatal morbidities. Results A total of 73 women were included: 32 (43.8%) received indomethacin for > 48 hours (prolonged) and 41 (56.2%) for ≤ 48 hours (standard). Prolonged group started on indomethacin at an earlier gestational age compared with standard group (23.9 [23.1-27.3] vs. 25.7 [23.8-28.5] weeks, p = 0.03). Latency from admission until delivery was longer in the prolonged group versus the standard group (1.8 [1.1-3] vs. 0.4 [0.1-0.8] weeks, p < 0.001). Prolonged use was not associated with increased risk of the composite neonatal outcome; however, there was a trend for more necrotizing enterocolitis. Conclusion A prolonged course of indomethacin may be an option for women with preterm labor at risk of extreme prematurity; it may also be associated with higher risks of some adverse neonatal outcomes.

Maternal Lopinavir/Ritonavir Is Associated with Fewer Adverse Events in Infants than Nelfinavir or Atazanavir.

Combination antiretroviral therapy (cART) is successfully used for prevention of perinatal HIV transmission. To investigate safety, we compared adverse events (AE) among infants exposed to different maternal cART regimens. We reviewed 158 HIV-uninfected infants born between 1997 and 2009, using logistic regression to model grade ≥1 AE and grade ≥3 AE as a function of maternal cART and confounding variables (preterm, C-section, illicit drug use, race, ethnicity, infant antiretrovirals, and maternal viremia). Frequently used cART regimens included zidovudine (63%), lamivudine (80%), ritonavir-boosted lopinavir (37%), nelfinavir (26%), and atazanavir (10%). At birth, anemia occurred in 13/140 infants (9%), neutropenia in 27/107 (25%), thrombocytopenia in 5/133 (4%), and liver enzyme elevation in 21/130 (16%). Corresponding rates of AE at 4 weeks were 59/141 (42%), 54/130 (42%), 3/137 (2%), and 3/104 (3%), respectively. Serious AE (grade ≥ 3) exceeded 2% only for neutropenia (13% at birth; 9% at 4 weeks). Compared with infants exposed to maternal lopinavir/ritonavir, infants exposed to nelfinavir and atazanavir had a 5-fold and 4-fold higher incidence of AE at birth, respectively. In conclusion, hematologic and hepatic AE were frequent, but rarely serious. In this predominantly protease inhibitor-treated population, lopinavir/ritonavir was associated with the lowest rate of infant AE.

The impact of air pollution in the Southern Bohemia Region on fetuses and newborns.

Air pollution with increased concentrations of carcinogenic polycyclic aromatic hydrocarbons (c-PAHs, represented by benzo[a]pyrene, B[a]P) affect fetal development, reduce birth weights (LBW) of newborns, and increases intrauterine growth retardation (IUGR). The Southern Bohemia Region is believed to be one of the least air polluted regions in the Czech Republic. Monitoring air pollution in the city of Ceské Budejovice from 2011-2015, PM2.5 (particulate matter <2.5 µm) decreased from 20.3 ± 14.5 µg/m3 to 14.3 ± 8.6 µg/m3, but concentrations of B[a]P did not change between the years 2007-2015: 1.5 ± 0.6 ng/m3 vs. 1.4 ± 1.4 ng/m3. Higher B[a]P concentrations the winter induce genetic damage in newborns, increase frequency of micronuclei (chromosomal aberrations), deregulate genes for immunity in umbilical cord blood, and increase incidence of IUGR and LBW in newborns.

[Congenital Intermittent Third-degree Atrioventricular Block Associated with Retinoid Exposure in Pregnancy]. / Konnataler intermittierender AV-Block III° nach Retinoideinnahme in der Schwangerschaft.

BACKGROUND: The retinoid acitretin, which has been approved as an effective therapy for severe keratinization disorders, is highly teratogenic, and exposure in the first trimester of pregnancy is associated with the risk of miscarriage and various malformations, including congenital heart defects. Cardiac conduction system disorders have not been described so far. CASE REPORT: A 24-year-old woman was treated with acitretin for dyskeratosis follicularis until pregnancy was diagnosed at 12 weeks of gestation. The female infant was born after 35 weeks gestation by cesarean section because of intermittent fetal bradycardia. The baby was vigorous at birth (Apgar 9, 10, 10 at 1, 5 and 10 min) but displayed intermittent third-degree atrioventricular block. A search for maternal autoantibodies and viral infections gave negative findings. CONCLUSION: The spectrum of disorders caused by intrauterine retinoid exposure appears to include atrioventricular conduction failure.

Increased risk of serious bacterial infections due to maternal immunosuppression in HIV-exposed uninfected infants in a European country.

BACKGROUND: Morbidity and mortality are higher among human immunodeficiency virus (HIV) exposed but uninfected (HEU) infants than unexposed infants, particularly if the mother had a low CD4 count. We investigated the possible association between maternal immune depression during pregnancy and the risk of infection in HEU infants in the national French Perinatal Cohort (EPF). METHODS: All neonates, born alive, to HIV-1-infected women enrolled in the EPF between 2002 and 2010 were included. The primary outcome was the first serious (hospitalization or death) infection during the first year of life. The main exposure variable was maternal CD4 cell count near delivery. The Kaplan-Meier method and multivariate Cox models were applied, with the different types of infections managed as competing events. RESULTS: Among 7638 HEU neonates, 699 had at least 1 serious infection (of which 159 were bacterial) with a Kaplan-Meier probability of 9.3% (95% confidence interval, 8.7-10.0) at 1 year. The risk of serious bacterial infection during the first year of life significantly increased with lower maternal CD4 cell count, before and after adjustment for maternal CD4 cell count <350 and 350-499 CD4/mm(3) (adjusted hazard ratio = 1.7 [1.2-2.6] and 1.2 [0.8-1.9], respectively; P = .03). This association mainly concerned infections involving encapsulated bacteria (P = .03). The risk of serious viral infection was, by contrast, independent of the mother's CD4 cell count. CONCLUSIONS: Maternal CD4 count is significantly and specifically associated with the risk of serious infections with encapsulated bacteria in HEU infants.

Living with uncertainty: antidepressants and pregnancy.

There have been a large number of studies in recent years reporting on the reproductive safety of antidepressant medication. Some studies, but not all, have reported an association of antidepressant exposure in pregnancy and the subsequent development of autism spectrum disorders. It remains difficult to know whether the modest increase in risk is due to the medication, to the mood disorder itself, or to other confounding factors. For any individual woman the decision to commence or continue antidepressant medication in pregnancy must be made after a full consideration of the potential risks and benefits of all options, including non-pharmacological treatments. In making these difficult decisions it is important to recognise that episodes of severe psychiatric illness may have very serious negative consequences for the woman, her baby and her family, and these must be weighed against what is known about the risks of taking medication.

Neonatal therapy after maternal central neurotropic drug exposure-a retrospective cohort study.

OBJECTIVE: Evaluation of neonatal morbidity after maternal central neurotropic drug exposure. METHODS: Retrospective single-center level-III neonatology cohort analysis of neonates after CND from 2018 to 2021. Control group of neonates born to mothers without CND cared for at the maternity ward. RESULTS: Significantly more frequent therapy need of neonates with CND [OR 23 (95% CI: 7.8-62); RR 14 (95% CI: 5.4-37); p < 0.01]. Neonates after CND had lower Apgar-scores LM 1 [CND 8.1; CG 8.6; p < 0.05]; LM 5 [CND 9; CG 9.7; p < 0.01]; LM 10 [CND 9.6; CG 9.9; p < 0.05]. The first symptom occurred in 95.35% within 24 h (mean: 3.3 h). CND group showed significantly more often preterm delivery [OR 3.5; RR 3.2; p < 0.05], and especially cumulative multiple symptoms [OR 9.4; RR 6.6; p < 0.01] but no correlation to multiple maternal medication use (p = 0.3). CONCLUSIONS: Neonates exposed to CND are at increased risk for postnatal therapy, often due to multiple symptoms. Neonates should be continuously monitored for at least 24 h.