Live-born Infants Research Articles

Antibiotic use in infants in the 6 weeks after delivery in seven low- and middle-income countries: findings from the A-PLUS trial

ABSTRACT Objectives Antibiotic use is increasing in low- and middle-income countries (LMIC); however, few studies have examined the rates of use in a population. The use of antibiotics for liveborn infants in LMIC was examined. Design The study, a planned prospective, observational secondary analysis of the A-PLUS randomised controlled trial of azithromycin, was conducted in Global Network sites in seven countries: Bangladesh, Pakistan, India (two sites), Kenya, Zambia, the Democratic Republic of Congo and Guatemala. The analyses included liveborn infants of women planning a vaginal delivery who were enrolled in the A-PLUS trial. Methods Data were collected on liveborn infants related to non-study antibiotic use in two time-periods: (i) after delivery while in the facility, and (ii) after discharge until 42 days post-partum. Antibiotic use was also examined in preterm and term infants. The most commonly used antibiotics were classified into three groups: penicillins, cephalosporins and aminoglycosides. Antibiotics used in <1% of infants are not presented. Results Of the 29,354 eligible infants in the study, 2224 (7.6%, 95% CI 7.3–7.9) received non-study antibiotics in the facility after delivery, and 3847 (13.1%, 95% CI 12.7–13.5) received non-study antibiotics after facility discharge until Day 42. In the facility, antibiotics were given to newborns more frequently in sites in Asia and less frequently in sites in Africa and Guatemala. Similarly, after facility discharge, infants were more likely to receive antibiotics in the Asian sites and less so in the African sites and Guatemala. In the facilities, antibiotics were used predominately for prophylaxis (70.7%) but after facility discharge antibiotics were given more often for treatment (56.8%). Preterm infants received more non-study antibiotics than term infants. The antibiotics used varied substantially by time-period and site but, in general, penicillins, cephalosporins and aminoglycosides were the antibiotic categories used more frequently. Conclusions Across the Global Network sites, which represent a range of LMIC, nearly 8% of infants received non-study antibiotics more often for prophylaxis, with 13% of infants receiving non-study antibiotics following hospital discharge. With concerns about increasing antimicrobial resistance worldwide, further attention should be given to appropriate antibiotic use.

Validation of Fetal Medicine Foundation charts for fetal growth in twins: nationwide Danish cohort study.

To assess the validity of the Fetal Medicine Foundation (FMF) chorionicity-specific models for fetal growth in twin pregnancy. This was an external validation study of the FMF models using a nationwide Danish cohort of twin pregnancies. The cohort included all dichorionic (DC) and monochorionic diamniotic (MCDA) twin pregnancies with an estimated delivery date between 2008 and 2018, which satisfied the following inclusion criteria: two live fetuses at the first-trimester ultrasound scan (11-14 weeks' gestation); biometric measurements available for the calculation of estimated fetal weight (EFW) using the Hadlock-3 formula; and delivery of two liveborn infants. Validation involved assessing the distributional properties of the models and estimating the mean EFW Z-score deviations. Additionally, the models were applied to pregnancies that delivered preterm and attended non-scheduled visits (complicated pregnancies). Overall, 8542 DC and 1675 MCDA twin pregnancies met the inclusion criteria. In DC twins, 17 084 fetuses were evaluated at a total of 95 346 ultrasound scans, of which 44.5% were performed at scheduled visits in pregnancies carried to 37 + 0 weeks or later. The median number of growth scans per DC twin fetus from 20 + 0 weeks onwards was four. The model showed good agreement with the validation cohort for scheduled visits in DC twins delivered at 37 + 0 weeks or later (mean EFW Z-score, -0.14 ± 1.05). In MCDA twins, 3350 fetuses underwent 31 632 eligible ultrasound scans, of which 59.5% were performed at scheduled visits in pregnancies carried to 36 + 0 weeks or later. The median number of growth scans per MCDA twin fetus from 16 + 0 weeks onwards was 10. The model showed favorable agreement with the validation cohort for scheduled visits in MCDA twins delivered at 36 + 0 weeks or later (mean EFW Z-score, -0.09 ± 1.01). Non-scheduled visits and preterm delivery before 37 + 0 weeks for DC twins and before 36 + 0 weeks for MCDA twins corresponded with smaller weight estimates, which was consistent with the study's definition of complicated pregnancy. The FMF models provide a good fit for EFW measurements in our Danish national cohort of uncomplicated twin pregnancies assessed at routine scans. Therefore, the FMF models establish robust criteria for subsequent investigations and potential clinical applications. Future research should focus on exploring the consequences of clinical implementation, particularly regarding the identification of twins that are small-for-gestational age, as they are especially susceptible to adverse perinatal outcome. © 2024 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

38 Disparities in health outcomes by the age of five among preterm children in rural versus urban communities in British Columbia

Abstract Background Health disparities exist between than urban and rural communities, as rates of preterm birth, severe maternal morbidity and severe neonatal morbidity are higher in rural areas. There are limited population-based studies on early childhood health outcomes among those born preterm by geographical area. Objectives To compare health service use, morbidity, and medication use for up to five years of age between preterm children in rural versus urban residences. Design/Methods The study included liveborn infants at 22-44 weeks’ gestational age (GA) in British Columbia (BC), Canada, 2004-2014. Follow-up data to December 2019 included linked health information from four provincial databases (perinatal database, outpatient visits, hospitalizations, and outpatient prescriptions). Urban-rural status was based on maternal residence at birth. Rate ratios (RR) of health service use, childhood morbidity and medication use were compared within GA categories (22-27, 28-33, 34-36, 37-44) by rural vs. urban region using Poisson regression. Results There were 49,555 (10.9%) rural and 406,149 (89.1%) urban children included in this study. 42,789 children were born at &amp;lt;37 weeks GA, and the preterm birth rate was 9.4%. Compared to urban areas, children in rural regions had more hospitalizations (28-33 weeks: RR 1.35, 95% CI: 1.19-1.51; 34-36 weeks: RR 1.35, 95% CI 1.27-1.44; 37-44 weeks: RR 1.32, 95% CI 1.29-1.34) by five years of age; and significantly fewer outpatient visits (22-27 weeks: RR 0.90, 95% CI: 0.87-0.93; 28-33 weeks: RR 0.81, 95% CI: 0.80-0.82; 34-36 weeks: RR 0.75, 95% CI 0.74-0.75; 37-44 weeks: RR 0.71, 95% CI 0.71-0.71). Rural children born at 34-36 weeks had significantly higher rates of bronchiolitis (RR: 1.35, 95% CI: 1.16-1.56) compared to urban children. They were prescribed more antibiotics and bronchodilators (RR: 1.15, 95% CI: 1.13-1.17, and RR: 1.12, 95% CI: 1.05-1.19, respectively). Conclusion Compared with urban areas, preterm children living in rural regions of BC had higher rates of hospitalization, higher rates of bronchiolitis and more frequent prescriptions of antibiotics and bronchodilators by five years of age. These disparities in health status and service use warrant further research and public health interventions.

67 A population-based cohort study of endocrine outcomes within the first 5 years of life in children born preterm

Abstract Background Preterm birth (&amp;lt;37 weeks’ gestational age [GA]) occurs in 8% of live births in Canada. While advancements in neonatal medicine have led to increased survival in preterm births, infants born preterm continue to sustain short- and long-term health sequelae. There is paucity of large population studies evaluating childhood health care outcomes, including endocrine-related outcomes, in recent birth cohorts. Objectives To evaluate the rates of endocrine conditions during the first 5 years of life in children born preterm and term. Design/Methods The study cohort included liveborn infants at 22-44 weeks’ GA in British Columbia, Canada between 2004-2014. Follow-up data to December 2019 included linked health services use information from four BC provincial databases (perinatal database, hospitalizations, outpatient services, and outpatient prescriptions). Rates of outcomes were compared by GA at birth (37-44 weeks reference category) using robust Poisson regression. Results There were 455,960 children included in this study with 42,820 (9.4%) born at &amp;lt;37 weeks GA. Results are summarized in Table 1 and Table 2. Compared to children born at 37-44 weeks’ gestations, infants born at 36 weeks’ gestation or younger have an increased rate of thyroid disorders between 0 months and 5 years (rate ratio [RR]: 1.45, 95% confidence interval [CI]: 0.78-2.43; RR: 1.83, 95% CI 1.51-2.20; RR: 1.41 95% CI 1.26-1.57 for 22-27 weeks, 28-33 weeks and 34-36 weeks GA, respectively). Similarly, infants born at 36 weeks’ gestation or younger have a higher rate of conditions in growth and development (RR: 3.05, 95% CI: 0.76-7.96; RR: 3.20, 95% CI 2.04-4.76; RR: 1.42 95% CI 1.02-1.94 for 22-27 weeks, 28-33 weeks and 34-36 weeks gestations, respectively) and bone health conditions (RR: 1.38, 95% CI: 1.27-1.49; RR: 1.04, 95% CI 1.00-1.08; RR: 1.05 95% CI 1.03-1.07 for 22-27 weeks, 28-33 weeks and 34-36 weeks gestations, respectively). There was no difference in rates of conditions related to glucose metabolism such as diabetes mellitus or hypoglycemia. Conclusion Children born preterm have increased rates of endocrine conditions by age 5. Disorders of thyroid, growth and development are increased in infants born preterm. Children born preterm have an increase rate of bone-related disorders, including those born late-preterm. These results provide useful prognostic information for follow-up care for preterm children and for healthcare resource planning. Furthermore, these results highlight areas of future research in endocrine health among preterm infants.

Congenital Cytomegalovirus Infection: Update on Screening, Diagnosis and Treatment: Scientific Impact Paper No. 56.

Cytomegalovirus (CMV) is the most common cause of viral infection in newborn babies, and affects 1 in 200 of all live born infants in high-income countries; and 1 in 71 in low- and middle-income countries. It is a major cause of hearing loss and brain damage. Women may get CMV infection for the first time during pregnancy (primary infection) or may experience 'non-primary' infection, either by reactivation of previous CMV infection or by a new infection with a different strain of the virus. The most common source of infection to pregnant women is the saliva and urine of young children. Therefore, all pregnant women, especially those in regular contact with young children, should be informed about hygiene-based measures to reduce the risks, e.g. handwashing. The UK National Screening Committee recommends against universal antenatal or newborn screening for CMV. Testing for CMV is usually offered only to women who develop symptoms of influenza, glandular fever or hepatitis (liver inflammation) during pregnancy, or for those whom a routine ultrasound scan detects fetal anomalies that suggests possible CMV infection. The risk of harm to the fetus is greatest following primary CMV infection of the woman in early pregnancy, and appears to be very low following infection after 12 weeks of pregnancy. Babies with CMV infection at birth may have jaundice, a rash, enlarged liver or spleen, a small brain, or be small for their gestational age. Around 1 in 8 babies born with CMV infection will have clinically detectable signs at birth. The rest will not have any features detectable by clinical examination alone. Therefore, all infants with CMV infection at birth should be followed up at a minimum of up to 2 years of age or later, depending upon the disease status, to check hearing and brain development. Following primary CMV infection in the first 12 weeks of pregnancy, if the woman starts taking the antiviral medicine valaciclovir (valacyclovir) it reduces the risk of the baby becoming infected. Where CMV infection of the fetus in the womb has been confirmed (by amniocentesis, for example), regular ultrasound scans should be offered every 2-3 weeks until birth. Detailed assessment of the fetal brain is an essential part of these scans. Where maternal CMV infection occurs, but fetal infection is not confirmed, repeated ultrasound scans of the fetus should be offered every 2-3 weeks until birth. In infected fetuses, as well as ultrasound scans, an MRI scan of the brain should be offered at 28-32 weeks of gestation (and sometimes repeated 3-4 weeks later) to assess for any signs of harm to the fetal brain. All babies born to women with confirmed or suspected CMV infection should be tested for CMV with a urine or saliva sample within the first 21 days of life. In newborns with symptomatic CMV infection at birth, treatment with antiviral medicine (valganciclovir or ganciclovir) can reduce hearing loss in 5 out of 6 babies, and improve long-term brain development outcomes in some. There is no licensed vaccine for CMV.

State Social Expenditures and Preterm Birth and Low Birth Weight in the US

Adverse birth outcomes in the US, including preterm birth and low birth weight, are strongly tied to socioeconomic disadvantage and disproportionately impact infants of Black mothers. Increasing investments in social programs represents a potential policy approach to addressing disparities in birth outcomes. To examine state-level associations of government expenditures on social programs with rates of preterm birth and low birth weight both overall and by race. This cross-sectional, ecological study was conducted among liveborn infants in the 50 US states between January 1, 2011, and December 31, 2019. Data analysis was performed from May 2022 to May 2024. Yearly state and local government expenditures per low-income person on social programs in the following categories: state refundable Earned Income Tax Credit; cash assistance; childcare assistance; housing and community development; and public health. Yearly state-level rates of preterm birth (gestational age <37 weeks) and low birth weight (<2500 g). From January 1, 2011, to December 31, 2019, there were 35.1 million live births in the US, of which 3.4 million (9.8%) were preterm and 2.8 million (8.1%) were low birth weight. Median (IQR) state social expenditures per low-income person were $1546 ($1074-$2323). Greater total state social expenditures were associated with lower overall rates of preterm birth (adjusted prevalence ratio [aPR] for every increase of $1000 per low-income person, 0.99; 95% CI, 0.97-0.999) but not with overall rates of low birth weight. In secondary analyses, greater state social expenditures were associated with lower preterm birth rates for infants of Black mothers (aPR, 0.96; 95% CI, 0.92-0.999). Greater state expenditures specifically on cash assistance (aPR, 0.64; 95% CI, 0.43-0.94) and housing and community development (aPR, 0.91; 95% CI, 0.84-0.98) were associated with lower preterm birth rates for infants of Black mothers. In this cross-sectional, ecological study, greater state-level expenditures on social programs were associated with reduced rates of preterm birth, particularly for infants of Black mothers. State and local governments may consider bolstering investments in cash assistance and housing and community development to address maternal and infant health disparities.

Brief Report: Subsequent Pregnancies in the IMPAACT 2010/VESTED Trial: High Rate of Adverse Outcomes in Women Living With HIV

Introduction: Women with HIV (WHIV) have higher risks of adverse pregnancy outcomes, particularly in the absence of antiretroviral treatment (ART), and timing of ART may impact risk. Methods: In the International Maternal Pediatric Adolescent AIDS Clinical Trials 2010/VESTED study, 643 pregnant WHIV in 9 countries were randomized in a 1:1:1 ratio to initiate ART: dolutegravir (DTG)+emtricitabine (FTC)/tenofovir alafenamide (TAF), DTG+FTC/tenofovir disoproxil fumarate (TDF), or efavirenz (EFV)/FTC/TDF. We describe adverse pregnancy outcomes in women with a subsequent pregnancy during 50 weeks of postpartum follow-up: spontaneous abortion (&lt;20 weeks), stillbirth (≥20 weeks), preterm delivery (&lt;37 weeks), and small for gestational age. Results: Of 643 women, 19 (3%) had 20 subsequent pregnancies while receiving ART at conception: DTG/FTC/TAF (3), DTG/FTC/TDF (2), EFV/FTC or lamivudine (3TC)/TDF (12), EFV/abacavir/3 TC (1), and no ART (1). Four spontaneous abortions, 3 stillbirths, and 1 induced abortion occurred. Three (25%) of 12 liveborn infants were preterm (24, 26, and 36 weeks of gestation). Only 12 subsequent pregnancies (60%) resulted in live birth, and at least 1 adverse pregnancy outcome occurred in 11 of 19 (58%) (induced abortion excluded). Of 7 women who experienced spontaneous abortion/stillbirth in the subsequent pregnancy, 4 experienced a stillbirth and 1 a neonatal death as outcomes of their earlier index pregnancy. No congenital anomalies were reported. Conclusions: Adverse pregnancy outcomes were common in this cohort of WHIV who conceived on ART shortly after an index pregnancy, 35% ended in stillbirth or spontaneous abortion. The majority of fetal losses occurred in women with recent prior pregnancy loss. Data from larger cohorts of WHIV conceiving on ART and surveillance are needed to elucidate rates and predictors of adverse pregnancy outcome.

Postpartum Emergency Care Visits Among North Carolina Medicaid Beneficiaries, 2013-2019.

Objective: To describe the rate, timing, and primary diagnosis codes for emergency care visits up to 8 weeks (56 days) after live birth among Medicaid beneficiaries in North Carolina (NC). Materials and Methods: Using a linked dataset of Medicaid hospital claims and certificates of live birth, which included Medicaid beneficiaries who had a live-born infant in NC between January 1, 2013, and November 4, 2019, and met inclusion criteria (n = 321,879), we estimated week-specific visit rates for emergency care visits that did not result in hospital admission (outpatient) and those that did (inpatient). We assessed the 10 leading diagnosis code categories for emergency care visits and described the characteristics of people with 0, 1, or ≥2 outpatient emergency care visits. Results: One in eight (12.4%) Medicaid beneficiaries had an emergency care visit that did not result in inpatient hospital admission during the first 8 weeks postpartum. Visit rates peaked in postpartum week 2. Diagnosis codes for nonspecific symptoms and substance use were the two leading diagnosis code categories for outpatient emergency care visits. Respiratory concerns and gastrointestinal concerns were the two leading diagnosis code categories for inpatient emergency care visits. Compared with those with zero outpatient emergency care visits, a greater proportion of people with ≥2 visits had less than a high school education, used tobacco during pregnancy, had Medicaid insurance outside of pregnancy, had mental health as a medical comorbidity, and/or had ≥2 medical comorbidities. Conclusions: These findings support scheduling health care visits early in the postpartum period, when emergency care visits are most frequent, and point to unmet needs for substance use support.

Centralisation of extremely preterm births and decreased early postnatal mortality in Sweden, 2004-2007 versus 2014-2016.

We evaluated the increased centralisation of extremely preterm (EPT) births in Sweden in relation to the changes in mortality and morbidity. Population-based data covering Swedish live births from 22 + 0 to 26 + 6 weeks of gestation during 2004-2007 and 2014-2016 were analysed for associations between time-period, birth within (inborn) or outside (outborn) regional centres, and outcomes. Among 1626 liveborn infants, 703 were born in 2004-2007 and 923 in 2014-2016. Birth outside (vs. within) regional centres was associated with a higher infant mortality even after adjustment for birth cohort, gestational age, birthweight standard deviation score and infant sex (adjusted odds ratio 2.01, 95% confidence interval 1.31-3.07, p = 0.001). The higher 1-yearmortality in outborn infants was mainly due to more deaths within 24 h after birth. Outborn infants had a higher incidence of intraventricular haemorrhage grade 3-4 than inborn infants (22% vs. 14% in 2004-2007, and 22% vs. 13% in 2014-2016, both p < 0.05). While survival to 1 year without major morbidity increased in inborn infants (33%-40%, p = 0.008), it remained unchanged in outborn infants (29% vs. 30%, p = 0.88). Centralisation of EPT births contributed to a lower 1-year mortality in 2014-2016 than that in 2004-2007, attributed to a decrease in deaths before 24 h among inborn infants.

The association of obstetric anal sphincter injury and mediolateral episiotomy with increasing birth weight and duration of second stage of labour in spontaneous vaginal delivery

ObjectivesAnalysis of the association of mediolateral episiotomy (MLE) with obstetric anal sphincter injury (OASI) in women with spontaneous vaginal delivery.Design.Population-based cohort study with data from the Netherlands Perinatal Registry, describing 541 055 women who delivered a singleton live born infant in cephalic presentation spontaneously at term. Risk indicators for OASI were tested using univariate and multivariate analysis. Additional analysis for the interaction of MLE with other risk indicators was performed. ResultsThe rate of OASI was 4.2 % in 215 241 nulliparous and 1.4 % in 325 814 multiparous women. In nulliparous and multiparous women MLE was associated with a reduction of OASI (adjusted OR (aOR) 0.3, 95 % CI 0.30–0.34 and aOR 0.32, 95 % CI 0.30–0.34).The association of MLE with a reduced rate of OASI was stronger in high birthweight and in prolonged 2nd stage groups.In nulliparous women, the number needed to treat (NNT) for the use of MLE to prevent one OASI is 31 in general. With MLE, the OASI rate reduced from 11.5 % to 2.9 with a NNT of 12 in the group with a birth weight ≥ 4000 g and a duration of the second stage of labour of 60–120 min. The NNT is 9 In the group with a birth weight ≥ 4000 g and a duration of the second stage of labour ≥ 120 min (reduction rate of OASI from 14.2 % to 3.5 %). ConclusionsUse of MLE is associated with a reduction of OASI in spontaneous vaginal delivery.In nulliparous women, an episiotomy with an anticipated birth weight > 4000 g and a duration of the 2nd stage of more than 60 min should be considered.

TNF-α inhibitor use during pregnancy and the risk of preeclampsia: population-based cohort study.

Although the clinical importance of preeclampsia is widely recognized, few treatment options are available for prevention. TNF-α inhibitors have been hypothesized to potentially prevent the disease. We aimed to examine whether exposure to TNF-α inhibitors during pregnancy reduces the risk of preeclampsia. We conducted a population-based pregnancy cohort study using nationwide samples of publicly (Medicaid data, 2000-2018) and commercially (MarketScan Research Database, 2003-2020) insured pregnant women linked to their liveborn infants. Exposure was ascertained based on a filled prescription or administration code for TNF-α inhibitors during the first and second trimester of pregnancy. The outcomes included early-onset preeclampsia, late-onset preeclampsia, and small-for-gestational age. For baseline confounding adjustment, we leveraged propensity score overlap weights to estimate risk ratios (RR). Among 4 315 658 pregnancies in the Medicaid and the MarketScan cohort, 2736 (0.063%) were exposed to TNF-α inhibitors during the first trimester and 1712 (0.040%) during the second trimester. After adjustment, the risk of early-onset preeclampsia was not decreased among mothers exposed during the first trimester compared with unexposed women with treatment indications [RR pooled : 1.25, 95% confidence interval (CI) 0.93-1.67]. Similarly, the risk of late-onset preeclampsia was not decreased among mothers exposed during the second trimester compared with unexposed women (RR pooled : 0.99, 95% CI 0.81-1.22). Contrary to the hypothesis, exposure to TNF-α inhibitors during pregnancy did not appear to be associated with a reduced risk of early-onset or late-onset preeclampsia. These findings do not support consideration of the use of TNF-α inhibitors for the prevention of preeclampsia.

Gastroschisis Prevalence and Co-occurring Malformations Among Danish Live Births During 1994–2021: A Nationwide Register-based Study

BackgroundGastroschisis prevalence has increased for decades with corresponding increases in the need for immediate and follow-up care. Such care can be complicated by presence of co-occurring malformations. This study explores prevalence of gastroschisis and co-occurring malformations among a 28-year cohort of Danish live-born infants. MethodsThis retrospective cohort study used data from 1,695,992 infants born in Denmark during 1994–2021 and registered in the neonatal screening program. Infants were identified from the Danish Civil Registration System and Danish National Patient Register accessed through the Danish Biobank Register. Data on co-occurring malformations were ascertained to classify infants as syndromic or non-syndromic (either isolated or with co-occurring major malformations) and on selected infant and parental characteristics. Poisson regression models were used to estimate prevalence and corresponding 95% confidence intervals (CIs). ResultsPrevalence (per 10,000 live births) of gastroschisis was 1.64 (CI: 1.45–1.84). Temporal trend analyses showed a statistically significant annual increase of 2.8% (CI: 1.4–3.3). Infants with gastroschisis most often presented as isolated (77.7%; CI: 72.3–82.5), followed by those with co-occurring malformations (21.9%; CI: 17.2–27.3) or a diagnosed syndrome (0.4%, CI: <0.1–2.0). Among infants with co-occurring malformations, cardiovascular (10.9%; CI: 6.8; 12.2) and intestinal (9.0%; CI: 5.9–12.2) malformations were most frequently recorded. Prevalence was higher among infants classified as premature but not influenced by infant sex or parental nativity. ConclusionGastroschisis prevalence in Denmark increased during 1994–2021, similar to international reports, without increase in co-occurring malformations. Future work with this cohort will characterize healthcare received, comorbidities, and outcomes across the lifespan. Levels of EvidenceLevel III (High-quality prospective cohort study).

Metformin and small for gestational age babies: findings of a randomised placebo-controlled clinical trial of metformin in gestational diabetes (EMERGE).

Gestational diabetes mellitus (GDM) is associated with adverse perinatal outcomes because of suboptimal glucose management and glucose control and excessive weight gain. Metformin can offset these factors but is associated with small for gestational age (SGA) infants. We sought to identify risk factors for SGA infants, including the effect of metformin exposure on SGA status. In this prespecified secondary analysis of the EMERGE trial, which evaluated the effectiveness of metformin vs placebo in treating GDM and found reduced gestational weight gain and longer time to insulin initiation with metformin use, we included women with a live-born infant and known infant birthweight and gestational age at delivery. We compared the numbers of SGA infants in both groups and explored baseline predictive factors to help identify those at highest risk of delivering an SGA infant. Baseline maternal characteristics were similar between SGA and non-SGA pregnancies. On multivariable-adjusted regression, no baseline maternal variables were associated with SGA status. Mothers of SGA infants were more likely to develop pre-eclampsia or gestational hypertension (18.2% vs 2.0%, p=0.001; 22.7% vs 5.4%, p=0.005, respectively); after multivariable adjustment, pre-eclampsia was positively associated with SGA status). Among SGA pregnancies, important perinatal outcomes including preterm birth, Caesarean delivery and neonatal care unit admission did not differ between the metformin and placebo groups (20.0% vs 14.3%, p=1.00; 50.0% vs 28.6%, p=0.25; 13.3% vs 42.9%, p=0.27, respectively). Pre-eclampsia was strongly associated with SGA infants. Metformin-exposed SGA infants did not display a more severe SGA phenotype than infants treated with placebo. Clinical Trials.gov NCT02980276; EudraCT number: 2016-001644-19.

Fetal Intraparenchymal Hemorrhage Imaging Patterns, Etiology, and Outcomes: A Single Center Cohort Study.

This study examines associations among fetal brain magnetic resonance imaging (MRI) injury patterns, etiologies, and outcomes in fetal intraparenchymal hemorrhage (IPH). This is a retrospective, single-center cohort study of IPH diagnosed on fetal MRI (1996-2022). IPH and associated abnormalities were categorized by 2 pediatric neuroradiologists; electronic medical records were reviewed by 2 pediatric neurologists to classify etiology and outcomes including cerebral palsy, epilepsy, developmental delay, and death. Forty-four fetuses with IPH were identified (34 singleton and 10 twin gestations) with MRI at median 24 weeks gestation (interquartile range [IQR] = 22-28 weeks). IPH was commonly supratentorial (84%) and focal (50%) or focal with diffuse injury (43%) and was often associated with germinal matrix hemorrhage (GMH; 75%) and/or intraventricular hemorrhage (IVH; 52%). An etiology was identified in 75%, including twin-twin transfusion syndrome (TTTS, n = 10), COL4A1/2 variants (n = 8), or other fetal/maternal conditions (n = 15). COL4A1/2 variants were associated with focal IPH and the presence of hemorrhagic porencephaly, and intrauterine transfusion was associated with infratentorial hemorrhage. Twenty-two fetuses were liveborn, and 18 pregnancies were terminated. Among those with follow-up ≥ 12 months (median = 7 years), 12 of 13 had cerebral palsy, 6 of 13 had developmental delay, and 5 of 13 had epilepsy. An etiology for fetal IPH with or without GMH-IVH is identified in most cases in our cohort and is commonly TTTS, COL4A1/2 variants, or other maternal/fetal comorbidities. Pattern of fetal IPH on MRI is associated with etiology. Cerebral palsy and neurodevelopmental impairment were common in liveborn infants. Genetic studies should be considered in cases of fetal IPH without an otherwise apparent cause. ANN NEUROL 2024.

Evaluating the Concept of Brain Sparing in a High Income Setting, Using Historical Records of Maternal Influenza or Syphilis Infection.

In the context of adverse in utero environments, the fetal brain might be preserved at the expense of other tissues. This trade-off, brain sparing, has not been studied in the context of maternal infection. We investigated cases of maternal syphilis in the early 20th century and influenza during the 1918-1920 pandemic, in the Swiss city of Lausanne, a relatively high-income setting. We tested the brain sparing hypothesis, that head circumference is protected at the expense of birth weight. A total of 8530 individual birth records from 1911 to 1922 from the University Maternity Hospital of Lausanne were used. We fitted generalized linear and additive linear models to explain how neonatal size varies under disease exposure. Influenza reduced head circumference and birth weight among livebirths similarly, by -0.11 and -0.14 standard deviation (SD) units respectively. Conversely, for syphilis-exposed infants, head circumference was affected more than birth weight (-0.61 SD vs. -0.46 SD). Stillborn infants exposed to syphilis experienced a much greater reduction in head circumference (-1.92 SD) than liveborn infants. After adjustment for gestational age, these findings persisted in the case of influenza, but the effects of syphilis were reduced. Furthermore, half of syphilis-exposed infants were born before term, suggesting that lower infant size was partly mediated by shorter gestation. Nevertheless, head circumference among stillbirths exposed to syphilis was still substantially reduced, even after adjustment for gestational age (-1.26 SD). Our findings do not support the brain sparing hypothesis. Moreover, the substantial reduction in head circumference among syphilis-exposed fetuses might help explain why a quarter of them were stillborn.

Uterus Transplant in Women With Absolute Uterine-Factor Infertility

Uterus transplant in women with absolute uterine-factor infertility offers the possibility of carrying their own pregnancy. To determine whether uterus transplant is feasible and safe and results in births of healthy infants. A case series including 20 participants with uterine-factor infertility and at least 1 functioning ovary who underwent uterus transplant in a large US tertiary care center between September 14, 2016, and August 23, 2019. The uterus transplant (from 18 living donors and 2 deceased donors) was surgically placed in an orthotopic position with vascular anastomoses to the external iliac vessels. Participants received immunosuppression until the transplanted uterus was removed following 1 or 2 live births or after graft failure. Uterus graft survival and subsequent live births. Of 20 participants (median age, 30 years [range, 20-36]; 2 Asian, 1 Black, and 16 White), 14 (70%) had a successful uterus allograft; all 14 recipients gave birth to at least 1 live-born infant. Eleven of 20 recipients had at least 1 complication. Maternal and/or obstetrical complications occurred in 50% of the successful pregnancies, with the most common being gestational hypertension (2 [14%]), cervical insufficiency (2 [14%]), and preterm labor (2 [14%]). Among the 16 live-born infants, there were no congenital malformations. Four of 18 living donors had grade 3 complications. Uterus transplant was technically feasible and was associated with a high live birth rate following successful graft survival. Adverse events were common, with medical and surgical risks affecting recipients as well as donors. Congenital abnormalities and developmental delays have not occurred to date in the live-born children. ClinicalTrials.gov Identifier: NCT02656550.

Comparative Safety of In Utero Exposure to Buprenorphine Combined With Naloxone vs Buprenorphine Alone

Buprenorphine combined with naloxone is commonly used to treat opioid use disorders outside of pregnancy. In pregnancy, buprenorphine alone is generally recommended because of limited perinatal safety data on the combination product. To compare perinatal outcomes following prenatal exposure to buprenorphine with naloxone vs buprenorphine alone. Population-based cohort study using health care utilization data from Medicaid-insured beneficiaries in the US from 2000 to 2018. The cohort was restricted to pregnant individuals linked to their liveborn infants, with maternal Medicaid enrollment from 3 months before pregnancy to 1 month after delivery and infant enrollment for the first 3 months after birth, unless they died sooner. Use of buprenorphine with naloxone vs buprenorphine alone during the first trimester based on outpatient dispensings. Outcomes included major congenital malformations, low birth weight, neonatal abstinence syndrome, neonatal intensive care unit admission, preterm birth, respiratory symptoms, small for gestational age, cesarean delivery, and maternal morbidity. Confounder-adjusted risk ratios were calculated using propensity score overlap weights. This study identified 3369 pregnant individuals exposed to buprenorphine with naloxone during the first trimester (mean [SD] age, 28.8 [4.6] years) and 5326 exposed to buprenorphine alone or who switched from the combination to buprenorphine alone by the end of the first trimester (mean [SD] age, 28.3 [4.5] years). When comparing buprenorphine combined with naloxone with buprenorphine alone, a lower risk for neonatal abstinence syndrome (absolute risk, 37.4% vs 55.8%; weighted relative risk, 0.77 [95% CI, 0.70-0.84]) and a modestly lower risk for neonatal intensive care unit admission (absolute risk, 30.6% vs 34.9%; weighted relative risk, 0.91 [95% CI, 0.85-0.98]) and small for gestational age (absolute risk, 10.0% vs 12.4%; weighted relative risk, 0.86 [95% CI, 0.75-0.98]) was observed. For maternal morbidity, the comparative rates were 2.6% vs 2.9%, respectively, and the weighted relative risk was 0.90 (95% CI, 0.68-1.19). No differences were observed with respect to major congenital malformations overall, low birth weight, preterm birth, respiratory symptoms, or cesarean delivery. Results were consistent across sensitivity analyses. There were similar and, in some instances, more favorable neonatal and maternal outcomes for pregnancies exposed to buprenorphine combined with naloxone compared with buprenorphine alone. For the outcomes assessed, compared with buprenorphine alone, buprenorphine with naloxone during pregnancy appears to be a safe treatment option. This supports the view that both formulations are reasonable options for the treatment of opioid use disorder in pregnancy, affirming flexibility in collaborative treatment decision-making.

Nipocalimab in Early-Onset Severe Hemolytic Disease of the Fetus and Newborn

BackgroundIn early-onset severe hemolytic disease of the fetus and newborn (HDFN), transplacental transfer of maternal antierythrocyte IgG alloantibodies causes fetal anemia that leads to the use of high-risk intrauterine transfusions in order to avoid fetal hydrops and fetal death. Nipocalimab, an anti–neonatal Fc receptor blocker, inhibits transplacental IgG transfer and lowers maternal IgG levels.MethodsIn an international, open-label, single-group, phase 2 study, we assessed treatment with intravenous nipocalimab (30 or 45 mg per kilogram of body weight per week) administered from 14 to 35 weeks’ gestation in participants with pregnancies at high risk for recurrent early-onset severe HDFN. The primary end point was live birth at 32 weeks’ gestation or later without intrauterine transfusions as assessed against a historical benchmark (0%; clinically meaningful difference, 10%).ResultsLive birth at 32 weeks’ gestation or later without intrauterine transfusions occurred in 7 of 13 pregnancies (54%; 95% confidence interval, 25 to 81) in the study. No cases of fetal hydrops occurred, and 6 participants (46%) did not receive any antenatal or neonatal transfusions. Six fetuses received an intrauterine transfusion: five fetuses at 24 weeks’ gestation or later and one fetus before fetal loss at 22 weeks and 5 days’ gestation. Live birth occurred in 12 pregnancies. The median gestational age at delivery was 36 weeks and 4 days. Of the 12 live-born infants, 1 received one exchange transfusion and one simple transfusion and 5 received only simple transfusions. Treatment-related decreases in the alloantibody titer and IgG level were observed in maternal samples and cord blood. No unusual maternal or pediatric infections were observed. Serious adverse events were consistent with HDFN, pregnancy, or prematurity.ConclusionsNipocalimab treatment delayed or prevented fetal anemia or intrauterine transfusions, as compared with the historical benchmark, in pregnancies at high risk for early-onset severe HDFN. (Funded by Janssen Research and Development; UNITY ClinicalTrials.gov number, NCT03842189.)

Down syndrome and associated atrioventricular septal defects in a nationwide Norwegian cohort: Prevalence, time trends, and outcomes.

The prevalence of Down syndrome (DS) is approximately 1 per 1000 births and is influenced by increasing maternal age over the last few decades. DS is strongly associated with congenital heart defects (CHDs), especially atrioventricular septal defect (AVSD). Our objectives were to investigate the prevalence of live-born infants with DS having a severe CHD in the Norwegian population over the last 20 years and compare outcomes in infants with AVSD with and without DS. Information on all births from January 1, 2000 to December 31, 2019 was obtained from the Medical Birth Registry of Norway. We also obtained data on all infants with severe CHDs in Norway registered in Oslo University Hospital's Clinical Registry for Congenital Heart Defects during 2000-2019 and accessed individual-level patient data from the electronic hospital records of selected cases. Infants with AVSD and DS were compared to infants with AVSD without chromosomal defects. Crude and adjusted odds ratios (ORs) of infant mortality and need for surgery during the first year of life, with associated 95% confidence intervals (CIs), were estimated by logistic regression. A total of 1 177 926 infants were live-born in Norway during the study period. Among these, 1456 (0.1%) had DS. The prevalence of infants with DS having a severe CHDs was relatively stable, with a mean of 17 cases per year. The most common CHD associated with DS was AVSD (44.4%). Infants with AVSD and DS were more likely to have cardiac intervention during their first year of life compared to infants with AVSD without chromosomal defects (adjusted OR [aOR]: 2.52; 95% CI 1.27, 4.98). However, we observed no difference in infant mortality during first year of life between the two groups (aOR: 1.08; 95% CI 0.43, 2.70). The prevalence of live-born infants with severe CHDs and DS has been stable in Norway across 20 years. Infants with AVSD and DS did not have higher risk of mortality during their first year of life compared to infants with AVSD without chromosomal defects, despite a higher risk of operative intervention.

Characterizing HIV drug resistance in cases of vertical transmission in the VESTED randomized antiretroviral treatment trial.

VESTED (NCT03048422) compared the safety and efficacy of three antiretroviral treatment (ART) regimens in pregnant and postpartum women: dolutegravir+emtricitabine/tenofovir alafenamide fumarate; dolutegravir+emtricitabine/tenofovir disoproxil fumarate (TDF); efavirenz/emtricitabine/TDF. Vertical HIV transmission (VT) occurred to 4/617 (0.60%) live-born infants, who were evaluated for HIV drug resistance (HIVDR) and other risk factors. In 2018-2020, pregnant (weeks-14-28) women living with HIV and ≤14 days of ART were enrolled at 22 international sites and followed with their infants through 50 weeks postpartum. HIV sequences derived by single genome amplification (SGA) from longitudinally collected specimens were assessed from VT Cases for HIVDR in protease, reverse transcriptase, integrase, and the nef 3'polypurine tract (3'PPT). The four Case mothers were prescribed efavirenz-based-ART for 1-7 days prior to randomization to study ART. Their infants received postnatal nevirapine+/-zidovudine prophylaxis and were breastfed. A total of 833 SGA sequences were derived. The "major" (Stanford HIVDR Score ≥60) non-nucleoside reverse transcriptase inhibitor (NNRTI) mutation (K103N) was detected persistently in one viremic mother, and likely contributed to VT of HIVDR. Major NNRTI HIVDR mutations were detected in all three surviving infants. No integrase, nor high frequencies of 3'PPT mutations conferring dolutegravir HIVDR were detected. The timing of HIV infant diagnosis, plasma HIV RNA levels and HIVDR suggests one in utero, one peripartum, one early, and one late breastfeeding transmission. VT was rare. New-onset NNRTI HIVDR in Case mothers was likely from efavirenz-ART prescribed prior to study dolutegravir-ART, and in one case appeared transmitted to the infant despite nevirapine prophylaxis.