Antenatal Endotoxin Induces Dysanapsis in Experimental Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, is characterized by impaired lung development with sustained functional abnormalities due to alterations of airways and the distal lung. Although clinical studies have shown striking associations between antenatal stress and BPD, little is known about the underlying pathogenetic mechanisms. Whether dysanapsis, the concept of discordant growth of the airways and parenchyma, contributes to late respiratory disease as a result of antenatal stress is unknown. We hypothesized that antenatal endotoxin (ETX) impairs juvenile lung function as a result of altered central airway and distal lung structure, suggesting the presence of dysanapsis in this preclinical BPD model. Fetal rats were exposed to intraamniotic ETX (10 µg) or saline solution (control) 2 days before term. We performed extensive structural and functional evaluation of the proximal airways and distal lung in 2-week-old rats. Distal lung structure was quantified by stereology. Conducting airway diameters were measured using micro-computed tomography. Lung function was assessed during invasive ventilation to quantify baseline mechanics, response to methacholine challenge, and spirometry. ETX-exposed pups exhibited distal lung simplification, decreased alveolar surface area, and decreased parenchyma-airway attachments. ETX-exposed pups exhibited decreased tracheal and second- and third-generation airway diameters. ETX increased respiratory system resistance and decreased lung compliance at baseline. Only Newtonian resistance, specific to large airways, exhibited increased methacholine reactivity in ETX-exposed pups compared with controls. ETX-exposed pups had a decreased ratio of FEV in 0.1 second to FVC and a normal FEV in 0.1 second, paralleling the clinical definition of dysanapsis. Antenatal ETX causes abnormalities of the central airways and distal lung growth, suggesting that dysanapsis contributes to abnormal lung function in juvenile rats.

Perceived barriers and facilitators for model-informed dosing in pregnancy: a qualitative study across healthcare practitioners and pregnant women.

BACKGROUND: Most women use medication during pregnancy. Pregnancy-induced changes in physiology may require antenatal dose alterations. Yet, evidence-based doses in pregnancy are missing. Given historically limited data, pharmacokinetic models may inform pregnancy-adjusted doses. However, implementing model-informed doses in clinical practice requires support from relevant stakeholders. PURPOSE: To explore the perceived barriers and facilitators for model-informed antenatal doses among healthcare practitioners (HCPs) and pregnant women. METHODS: Online focus groups and interviews were held among healthcare practitioners (HCPs) and pregnant women from eight countries across Europe, Africa and Asia. Purposive sampling was used to identify pregnant women plus HCPs across various specialties prescribing or providing advice on medication to pregnant women. Perceived barriers and facilitators for implementing model-informed doses in pregnancy were identified and categorised using a hybrid thematic analysis. RESULTS: Fifty HCPs and 11 pregnant women participated in 12 focus groups and 16 interviews between January 2022 and March 2023. HCPs worked in the Netherlands (n = 32), the UK (n = 7), South Africa (n = 5), Uganda (n = 4), Kenya, Cameroon, India and Vietnam (n = 1 each). All pregnant women resided in the Netherlands. Barriers and facilitators identified by HCPs spanned 14 categories across four domains whereas pregnant women described barriers and facilitators spanning nine categories within the same domains. Most participants found current antenatal dosing information inadequate and regarded model-informed doses in pregnancy as a valuable and for some, much-needed addition to antenatal care. Although willingness-to-follow model-informed antenatal doses was high across both groups, several barriers for implementation were identified. HCPs underlined the need for transparent model validation and endorsement of the methodology by recognised institutions. Foetal safety was deemed a critical knowledge gap by both groups. HCPs' information needs and preferred features for model-informed doses in pregnancy varied. Several pregnant women expressed a desire to access information and partake in decisions on antenatal dosing. CONCLUSIONS: Given the perceived limitations of current pharmacotherapy for pregnant women and foetuses, model-informed dosing in pregnancy was seen as a promising means to enhance antenatal care by pregnant women and healthcare practitioners.

General health and social outcomes 50 years after exposure to antenatal betamethasone: follow-up of a randomised controlled trial.

BACKGROUND: Antenatal corticosteroids are recommended for women at risk of preterm birth from 24 to 34 weeks' gestation as they reduce neonatal morbidity and mortality, but evidence regarding their long-term effects on offspring is limited. This study assessed general health and social outcomes 50 years after antenatal exposure to corticosteroids. METHODS: We assessed 424 adult offspring of women who participated in the first randomised, double-blind, placebo-controlled trial of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome. The first 717 mothers received two intramuscular injections of betamethasone (6 mg betamethasone sodium phosphate and 6 mg betamethasone acetate) or placebo given 24 h apart and the subsequent 398 received two injections of double dose betamethasone (12 mg betamethasone sodium phosphate and 12 mg betamethasone acetate) or equivalent volume of placebo. Follow-up included a health questionnaire and consent for access to administrative data sources. Outcome categories included mental health (depression, anxiety, bipolar affective disorder, schizophrenia and treatment or hospital admission for any mental health disorder), general health (chronic kidney disease, cancer diagnosis, bone fracture, oral health, allergies, functional difficulties and physical activity) and social outcomes (educational attainment, employment and criminal convictions). Investigators remained blinded to treatment allocation. Analyses were adjusted for gestational age at entry, sex and clustering. RESULTS: We assessed 424 adult offspring (46% of survivors; mean [SD] age 49.3 [1.0] years; 212 [50%] female). There was no difference in mental health, general health and social outcomes between those exposed to betamethasone and those exposed to placebo, with the exception that osteoporotic site fracture in adulthood was more likely to have occurred in the betamethasone group compared with placebo (adjusted relative risk 1.57, 95% CI 1.00, 2.48, p = 0.05). No dose-effect relationship was evident and there was no difference in the proportion with at least one fracture. Follow-up rate and lack of in-person assessments were the main limitations. CONCLUSIONS: There is no evidence that antenatal corticosteroids have clinically important effects on general health and social outcomes up to 50 years of age.

X-linked transient antenatal Bartter syndrome related to MAGED2 gene: enriching the phenotypic description and pathophysiologic investigation.

PURPOSE: Transient Bartter syndrome related to pathogenic variants of MAGED2 is the most recently described antenatal Bartter syndrome. Despite its transient nature, it is the most severe form of Bartter syndrome in the perinatal period. Our aim was to describe 14 new cases and to try to explain the incomplete penetrance in women. METHODS: We report on 14 new cases, including 3 females, and review the 40 cases described to date. We tested the hypothesis that MAGED2 is transcriptionally regulated by differential methylation of its CpG-rich promotor by pyrosequencing of DNA samples extracted from fetal and adult leukocytes and kidney samples. RESULTS: Analysis of the data from 54 symptomatic patients showed spontaneous resolution of symptoms in 27% of cases, persistent complications in 41% of cases and fatality in 32% of cases. Clinical anomalies were reported in 76% of patients, mostly renal anomalies (52%), cardiovascular anomalies (29%) and dysmorphic features (13%). A developmental delay was reported in 24% of patients. Variants were found in all regions of the gene. Methylation analysis of the MAGED2 CpG-rich promotor showed a correlation with gender, independent of age, tissue or presence of symptoms, excluding a role for this mechanism in the incomplete penetrance in women. CONCLUSION: This work enriches the phenotypic and genetic description of this recently described disease, and deepens our understanding of the pathophysiological role and regulation of MAGED2. Finally, by describing the wide range of outcomes in patients, this work opens the discussion on genetic counseling offered to families.

Gestational Exposure to Maternal Systemic Glucocorticoids and Childhood Risk of CKD.

RATIONALE & OBJECTIVE: The potential effects of antenatal glucocorticoid exposure on the health of children are unclear. We examined the association of gestational exposure to maternal systemic glucocorticoids and the risk of developing chronic kidney disease (CKD) in childhood. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Newborns cared for at the largest health care delivery system in Taiwan between 2004 and 2018. EXPOSURE: Maternal prescriptions for systemic glucocorticoids between the last menstrual period and birth as a proxy for gestational exposure. OUTCOME: Incidence of childhood CKD, including congenital anomalies of the kidney and urinary tract (CAKUT) and other kidney diseases (non-CAKUT), over 10 years. ANALYTICAL APPROACH: Cox proportional hazards models with stabilized inverse probability of treatment weighting and robust sandwich estimator were used to estimate the average association between systemic glucocorticoids and incident CKD after adjustment for offspring characteristics (adjusted HR: AHR). RESULTS: Among 23,363 singleton-born children, gestational systemic glucocorticoid exposure was significantly associated with a higher risk of childhood CKD (AHR, 1.69 [95% CI, 1.01-2.84]). Stratified analyses showed stronger associations between systemic glucocorticoids and childhood CKD within the strata of birth<37 weeks' gestational age (AHR, 2.38 [95% CI, 1.19-4.78]), male sex (AHR, 1.89 [95% CI, 1.00-3.55]), gestational exposure in the second trimester (AHR, 6.70 [95% CI, 2.17-20.64]), and total dose of>24mg hydrocortisone equivalent (AHR, 1.91 [95% CI, 1.05-3.47]). LIMITATIONS: Study was limited to the Taiwan health care delivery system and childhood CKD events through the age of 10 years. CONCLUSIONS: The findings of this study suggest that gestational exposure to systemic glucocorticoids is associated with the occurrence of kidney disease in childhood. If these findings are confirmed, they may inform clinicians who are considering prescribing systemic glucocorticoids during pregnancy. PLAIN-LANGUAGE SUMMARY: In a singleton-born cohort of neonates, maternal exposure to antenatal systemic glucocorticoids was significantly associated with a 1.7-fold increased risk of the children developing chronic kidney disease over the first 10 years of life. Children of mothers who received>24mg of hydrocortisone equivalent, systemic glucocorticoid treatment in second trimester of gestation, and children born at<37 weeks of gestational age had a higher risk of childhood kidney disease after gestational systemic glucocorticoid exposure. If these findings are confirmed, they may inform clinicians who are considering prescribing systemic glucocorticoids during pregnancy.

Identifying missed opportunities for hepatitis C virus antenatal testing and diagnosis in England.

New case-finding opportunities are needed to achieve hepatitis C virus (HCV) elimination in England by the year 2030. HCV antenatal testing is not offered universally in England but is recommended for women with risk factors for HCV (e.g. injecting drug use, being born in a high-prevalence country). The aim of this analysis was to investigate the missed opportunities for HCV antenatal testing among women who had given birth and were subsequently diagnosed with HCV at some time after childbirth. By linking data on live births (2010-2020) to laboratory reports of HCV diagnoses (1995-2021), we identified all women who were diagnosed with HCV after the date of their first childbirth. This group was considered to potentially have experienced a missed opportunity for HCV antenatal testing; HCV-RNA testing and treatment outcomes were also obtained for these women. Of the 32,295 women who gave birth between 2010 and 2020 with a linked diagnosis of HCV (median age: 34 years, 72.1% UK-born), over half (n = 17,123) were diagnosed after childbirth. In multivariable analyses, the odds of being diagnosed with HCV after childbirth were higher in those of Asian Bangladeshi, Black African or Chinese ethnicity and among those born in Africa. Over four-fifths (3510/4260) of those eligible for treatment were linked to treatment, 30.7% (747/2435) of whom had a liver scarring level of at least moderate and 9.4% (228/2435) had cirrhosis. Given the potential opportunity to identify cases of HCV with targeted case-finding through antenatal services, universal opt-out testing should be considered in these settings.

Effect of antenatal Chlamydia trachomatis and Neisseria gonorrhoeae screening on postdelivery prevalence and vertical transmission in Gaborone, Botswana: findings from an exploratory study.

OBJECTIVES: Chlamydia trachomatis and Neisseria gonorrhoeae are common sexually transmitted infections (STIs). Untreated infection in pregnancy can result in adverse neonatal outcomes, including vertical transmission. Screening for these infections is not routine in low- and middle-income countries (LMICs). METHODS: The Maduo Study was a non-randomised cluster crossover trial in Botswana to provide preliminary data on the effect of antenatal C. trachomatis and N. gonorrhoeae screening and treatment on postdelivery prevalence and vertical transmission to infants. Pregnant women asymptomatic for STIs were enrolled at four clinics (seven clusters). The intervention arm received C. trachomatis and N. gonorrhoeae screening at first antenatal care, third trimester and postdelivery. The standard-of-care arm received postdelivery screening only. Infants of women with a positive test postdelivery in both arms were screened. A cluster-level analysis was performed to compare the risk of postdelivery infection between intervention and standard-of-care arms. RESULTS: The study enrolled 500 women; 206 (82.1%) and 187 (75.1%) were retained in the intervention and standard-of-care arms, respectively and screened ≤12 weeks postdelivery. C. trachomatis prevalence in the intervention arm reduced from 22.7% at first antenatal care to 1.0% postdelivery. N. gonorrhoeae prevalence reduced from 1.2% at first antenatal care to 0% postdelivery. The risk of C. trachomatis and/or N. gonorrhoeae was lower in the intervention arm postdelivery (0.6%) compared with the standard-of-care arm (15.7%); adjusted risk difference: -14.7% (95% CI -23.0%, -6.4%). Among 26 infants born to women with either infection postdelivery, 10 (38.5%) tested positive (C. trachomatis: 9; N. gonorrhoeae: 1). CONCLUSIONS: Postdelivery prevalence of C. trachomatis was significantly lower among pregnant women in Botswana who received diagnostic antenatal screening. Among women with C. trachomatis and/or N. gonorrhoeae postdelivery, more than one-third transmitted the infection to their infants. This exploratory study suggests antenatal STI screening has the potential to reduce infection in newborns in similar LMIC settings. TRIAL REGISTRATION NUMBER: NCT04955717.

Betamethasone treatment-to-delivery interval, retreatment, and severe intraventricular hemorrhage in infants <28 weeks' gestation.

BACKGROUND: Antenatal corticosteroids decrease the incidence of severe intraventricular hemorrhage (grades 3, 4) in preterm infants. It is unclear whether their beneficial effects on intraventricular hemorrhage wane with time (as occurs in neonatal respiratory distress) and if repeat courses can restore this effect. Previous randomized controlled trials of betamethasone retreatment found no benefit on severe intraventricular hemorrhage rates. However, the trials may have included an insufficient number of infants at risk for intraventricular hemorrhage to be able to adequately address this question. Severe intraventricular hemorrhages occur almost exclusively in infants born at <28 weeks' gestation, whereas only 7% (0%-16%) of the retreatment trials' populations were <28 weeks' gestation. OBJECTIVE: This study aimed to determine if the risk for severe intraventricular hemorrhage in infants delivered at <28 weeks' gestation increases when the betamethasone treatment-to-delivery interval increases beyond 9 days and to determine if betamethasone retreatment before delivery decreases the rate of hemorrhage. STUDY DESIGN: This was an observational study that examined the incidence of intraventricular hemorrhage before (epoch 1) and after (epoch 2) a practice change that encouraged obstetricians to retreat pregnant women still at high risk for delivery before 28 weeks' gestation when >9 days elapsed from the first dose of betamethasone. Multivariable analyses with logistic regression using generalized estimating equation techniques were conducted to examine the rates of intraventricular hemorrhage among 410 infants <28 weeks' gestation who were either delivered between 1 to 9 days (n=290) after the first 2-dose betamethasone course or ≥10 days (and eligible for retreatment) after the first course (n=120). RESULTS: After adjusting for potential confounding variables, infants who were delivered ≥10 days after a single betamethasone course had an increased risk for either severe intraventricular hemorrhage alone or the combined outcome severe intraventricular hemorrhage or death before 4 days (odds ratio, 2.8; 95% confidence interval, 1.2-6.6) when compared with infants who were delivered between 1 and 9 days after betamethasone. Among the 120 infants who were delivered ≥10 days after the first dose of betamethasone, 64 (53%) received a second or retreatment course of antenatal betamethasone. The severe intraventricular hemorrhage rate in infants whose mothers received a second or retreatment course of betamethasone was similar to the rate among infants who delivered within 1 to 9 days and significantly lower than among those who delivered ≥10 days without retreatment (odds ratio, 0.10; 95% confidence interval, 0.02-0.65). Following the change in guidelines, the rate of retreatment in infants who were delivered ≥10 days after the first betamethasone course (and before 28 weeks) increased from epoch 1 to epoch 2 (25% to 87%; P<.001) and the rate of severe intraventricular hemorrhage decreased from 22% to 0% (P<.001). In contrast, the rate of severe intraventricular hemorrhage among infants who were delivered 1 to 9 days after the initial betamethasone dose (who were not eligible for retreatment) did not change between epochs 1 and 2 (12% and 11%, respectively). CONCLUSION: Although betamethasone's benefits on severe intraventricular hemorrhage appear to wane after the first dose, retreatment with a second course seems to restore its beneficial effects. Encouraging earlier retreatment of women at high risk for delivery before 28 weeks was associated with a lower rate of severe intraventricular hemorrhages among infants delivered at <28 weeks' gestation.

Equivalence of single and standard doses of antenatal corticosteroids for late preterm neonatal outcomes: insights from a secondary analysis.

BACKGROUND: The recent paradigm shift of treating individuals at risk of late preterm birth with antenatal corticosteroids warrants an assessment of the effect of single dosage. OBJECTIVE: To compare outcomes of neonates born in the late preterm period (34.0-36.6 weeks) after a single dose of antenatal corticosteroids vs placebo. STUDY DESIGN: We performed a secondary analysis of the Antenatal Late Preterm Steroids trial. All individuals enrolled in the parent trial who received only a single dose of either antenatal corticosteroids or placebo and delivered within 24 hours were included. Primary outcome was a composite of respiratory support at 72 hours, including continuous positive airway pressure or high-flow nasal cannula ≥2 hours, oxygen with an inspired fraction of ≥30% for ≥4 hours, or mechanical ventilation. RESULTS: Of the 2831 individuals in the parent trial, 1083 (38.3%) met inclusion criteria; of them, 539 (49.8%) received a single dose of antenatal corticosteroids and 544 (50.2%) a single placebo dose. The placebo and antenatal corticosteroids groups had similar demographic and clinical characteristics. There was no difference in the rate of the primary respiratory outcome (adjusted risk ratio, 1.12; 95% confidence interval, 0.85-1.47) or in the rate of respiratory distress syndrome (adjusted risk ratio, 1.47; 95% confidence interval, 0.95-2.26) between those who received a single antenatal corticosteroids dose and placebo. An exploratory stratification by randomization-to-delivery intervals of 12-hour increments also showed no association with lower primary respiratory outcome rates. CONCLUSION: In individuals with late preterm birth pregnancies who received antenatal corticosteroids and delivered before a second dose, there were no differences in neonatal respiratory morbidities compared with placebo. However, this study is not powered to detect treatment efficacy.

Survival without severe neonatal morbidity after antenatal betamethasone dose reduction: a post hoc analysis of a randomized non-inferiority trial.

BACKGROUND: Antenatal betamethasone is recommended before preterm delivery to accelerate fetal lung maturation. However, its optimal dose remains unknown. A 50% dose reduction was proposed to decrease the potential dose-related long-term neurodevelopmental side effects, including psychological development, sleep, and emotional disorders. Because noninferiority of the half dose in terms of the need for exogenous surfactant was not shown in the primary analysis, its impact on survival without major neonatal morbidity needs to be investigated. OBJECTIVE: This study aimed to investigate the impact of antenatal betamethasone dose reduction on survival of very preterm infants without severe neonatal morbidity, a factor known to have a strong correlation with long-term outcomes. STUDY DESIGN: We performed a post hoc secondary analysis of a randomized, multicenter, double-blind, placebo-controlled, noninferiority trial, testing half (11.4 mg once; n=1620) vs full (11.4 mg twice, 24 hours apart; n=1624) antenatal betamethasone doses in women at risk of preterm delivery. To measure survival without severe neonatal morbidity at hospital discharge among neonates born before 32 weeks of gestation, we used the definition of the French national prospective study on preterm children, EPIPAGE 2, comprising 1 of the following morbidities: grade 3 to 4 intraventricular hemorrhage, cystic periventricular leukomalacia, necrotizing enterocolitis stage ≥2, retinopathy of prematurity requiring anti-vascular endothelial growth factor therapy or laser, and moderate-to-severe bronchopulmonary dysplasia. RESULTS: After exclusion of women who withdrew consent or had pregnancy termination and of participants lost to follow-up (8 in the half-dose and 10 in the full-dose group), the rate of survival without severe neonatal morbidity among neonates born before 32 weeks of gestation was 300 of 451 (66.5%) and 304 of 462 (65.8%) in the half-dose and full-dose group, respectively (risk difference, +0.7%; 95% confidence interval, -5.6 to +7.1). There were no significant between-group differences in the cumulative number of neonatal morbidities. Results were similar when using 2 other internationally recognized definitions of severe neonatal morbidity and when considering the overall population recruited in the trial. CONCLUSION: In the BETADOSE trial, severe morbidity at discharge of newborns delivered before 32 weeks of gestation was found to be similar among those exposed to 11.4-mg and 22.8-mg antenatal betamethasone. Additional studies are needed to confirm these findings.

Optimization of the betamethasone and dexamethasone dosing regimen during pregnancy: a combined placenta perfusion and pregnancy physiologically based pharmacokinetic modeling approach.

BACKGROUND: Antenatal betamethasone and dexamethasone are prescribed to women who are at high risk of premature birth to prevent neonatal respiratory distress syndrome (RDS). The current treatment regimens, effective to prevent neonatal RDS, may be suboptimal. Recently, concerns have been raised regarding possible adverse long-term neurological outcomes due to high fetal drug exposures. Data from nonhuman primates and sheep suggest maintaining a fetal plasma concentration above 1 ng/mL for 48 hours to retain efficacy, while avoiding undesirable high fetal plasma levels. OBJECTIVE: We aimed to re-evaluate the current betamethasone and dexamethasone dosing strategies to assess estimated fetal exposure and provide new dosing proposals that meet the efficacy target but avoid excessive peak exposures. STUDY DESIGN: A pregnancy physiologically based pharmacokinetic (PBPK) model was used to predict fetal drug exposures. To allow prediction of the extent of betamethasone and dexamethasone exposure in the fetus, placenta perfusion experiments were conducted to determine placental transfer. Placental transfer rates were integrated in the PBPK model to predict fetal exposure and model performance was verified using published maternal and fetal pharmacokinetic data. The verified pregnancy PBPK models were then used to simulate alternative dosing regimens to establish a model-informed dose. RESULTS: Ex vivo data showed that both drugs extensively cross the placenta. For betamethasone 15.7±1.7% and for dexamethasone 14.4±1.5%, the initial maternal perfusate concentration reached the fetal circulations at the end of the 3-hour perfusion period. Pregnancy PBPK models that include these ex vivo-derived placental transfer rates accurately predicted maternal and fetal exposures resulting from current dosing regimens. The dose simulations suggest that for betamethasone intramuscular, a dose reduction from 2 dosages 11.4 mg, 24 hours apart, to 4 dosages 1.425 mg, 12 hours apart would avoid excessive peak exposures and still meet the fetal response threshold. For dexamethasone, the dose may be reduced from 4 times 6 mg every 12 hours to 8 times 1.5 mg every 6 hours. CONCLUSION: A combined placenta perfusion and pregnancy PBPK modeling approach adequately predicted both maternal and fetal drug exposures of 2 antenatal corticosteroids (ACSs). Strikingly, our PBPK simulations suggest that drug doses might be reduced drastically to still meet earlier proposed efficacy targets and minimize peak exposures. We propose the provided model-informed dosing regimens are used to support further discussion on an updated ACS scheme and design of clinical trials to confirm the effectiveness and safety of lower doses.

A comparison of 2 doses of antenatal dexamethasone for the prevention of respiratory distress syndrome: an open-label, noninferiority, pragmatic randomized trial.

BACKGROUND: Antenatal corticosteroids have been used for the prevention of respiratory complications, intraventricular hemorrhage, necrotizing enterocolitis, and other adverse neonatal outcomes for over 50 years, with limited evidence about their optimal doses. Higher steroid doses or frequencies of antenatal corticosteroids in preterm newborns pose adverse effects such as prolonged adrenal suppression, negative effects on fetal programming and metabolism, and increased risks of neurodevelopmental and neuropsychological impairments. Conversely, lower doses of antenatal corticosteroids may be an effective alternative to induce fetal lung maturation with less risk to the fetus. Late preterm births represent the largest population of all preterm neonates, with a respiratory distress syndrome risk of 8.83%. Therefore, determining the optimal antenatal corticosteroid dosage is of particular importance for this population. OBJECTIVE: This study aimed to compare the efficacy of 5-mg and 6-mg dexamethasone in preventing neonatal respiratory distress syndrome in women with preterm births at 320 to 366 weeks of gestation. STUDY DESIGN: This was an open-label, randomized, controlled, noninferiority trial. Singleton pregnant women (n=370) at 320 to 366 weeks of gestation with spontaneous preterm labor or preterm premature rupture of membranes were enrolled. They were randomly assigned (1:1) to a 5-mg or 6-mg dexamethasone group. Dexamethasone was administered intramuscularly every 12 hours for 4 doses or until delivery. The primary outcome was the reduction in neonatal respiratory distress syndrome cases, whereas the secondary outcomes were any adverse maternal or neonatal events. RESULTS: Between December 2020 and April 2022, 370 eligible women, anticipating deliveries within the gestational range of 32 0/7 to 36 6/7 weeks, willingly participated in the study. They were evenly split, with 185 women assigned to the 5-mg group and 185 to the 6-mg group. The study revealed that the demographic profiles of the participants in the 2 groups were remarkably similar, with no statistically significant disparities (P>.05). It is noteworthy that most of these women gave birth after 34 weeks of gestation. Despite a substantial proportion not completing the full course of steroid treatment, the 5-mg dose exhibited noninferiority compared with the 6-mg dose of dexamethasone, as indicated by a modest proportional difference of 0.5% (95% confidence interval, -2.8 to 43.9). Neonatal respiratory distress syndrome occurred in a relatively low percentage of newborns in both groups, affecting 2.2% in the 5-mg group and 1.6% in the 6-mg group. Notably, the risk difference of 0.6% fell comfortably within the predefined noninferiority threshold of 10%. CONCLUSION: Our study suggests that a 5-mg dexamethasone dose is noninferior to a standard 6-mg dose in preventing neonatal respiratory distress syndrome in preterm births.

Society for Maternal-Fetal Medicine Consult Series #68: Sickle cell disease in pregnancy.

Pregnant individuals with sickle cell disease have an increased risk of maternal and perinatal morbidity and mortality. However, prepregnancy counseling and multidisciplinary care can lead to favorable maternal and neonatal outcomes. In this consult series, we summarize what is known about sickle cell disease and provide guidance for sickle cell disease management during pregnancy. The following are Society for Maternal-Fetal Medicine recommendations.

Fetal size vs growth: comparative analysis of 3 models of growth velocity based on third trimester estimated fetal weights for identifying stillbirth risk.

BACKGROUND: Fetal growth velocity is being recognized as an important parameter by which to monitor fetal wellbeing, in addition to assessment of fetal size. However, there are different models and standards in use by which velocity is being assessed. OBJECTIVE: We wanted to investigate 3 clinically applied methods of assessing growth velocity and their ability to identify stillbirth risk, in addition to that associated with small for gestational age. STUDY DESIGN: Retrospective analysis of prospectively recorded routine-care data of pregnancies with 2 or more third trimester scans in New Zealand. Results of the last 2 scans were used for the analysis. The models investigated to define slow growth were (1) 50+ centile drop between measurements, (2) 30+ centile drop, and (3) estimated fetal weight below a projected optimal weight range, based on predefined, scan interval specific cut-offs to define normal growth. Each method's ability to identify stillbirth risk was assessed against that associated with small-for-gestational age at last scan. RESULTS: The study cohort consisted of 71,576 pregnancies. The last 2 scans in each pregnancy were performed at an average of 32+1 and 35+6 weeks of gestation. The 3 models defined "slow growth" at the following differing rates: (1) 50-centile drop 0.9%, (2) 30-centile drop 5.1%, and (3) below projected optimal weight range 10.8%. Neither of the centile-based models identified at-risk cases that were not also small for gestational age at last scan. The projected weight range method identified an additional 79% of non-small-for-gestational-age cases as slow growth, and these were associated with a significantly increased stillbirth risk (relative risk, 2.0; 95% CI, 1.2-3.4). CONCLUSION: Centile-based methods fail to reflect adequacy of fetal weight gain at the extremes of the distribution. Guidelines endorsing such models might hinder the potential benefits of antenatal assessment of fetal growth velocity. A new, measurement-interval-specific projection model of expected fetal weight gain can identify fetuses that are not small for gestational age, yet at risk of stillbirth because of slow growth. The velocity between scans can be calculated using a freely available growth rate calculator (www.perinatal.org.uk/growthrate).

Physical job demands in pregnancy and associated musculoskeletal health and employment outcomes: a systematic review.

OBJECTIVE: A decline in musculoskeletal health during pregnancy is an underappreciated adverse outcome of pregnancy that can have immediate and long-term health consequences. High physical job demands are known risk factors for nontraumatic musculoskeletal disorders in the general working population. Evidence from meta-analyses suggest that occupational lifting and prolonged standing during pregnancy may increase risk of adverse pregnancy outcomes. This systematic review examined associations between occupational lifting or postural load in pregnancy and associated musculoskeletal disorders and related sequalae. DATA SOURCES: Five electronic databases (Medline, Embase, CINAHL, NIOSHTIC-2, and Ergonomic Abstracts) were searched from 1990 to July 2022 for studies in any language. A Web of Science snowball search was performed in December 2022. Reference lists were manually reviewed. STUDY ELIGIBILITY CRITERIA: Eligible studies reported associations between occupational lifting or postural load and musculoskeletal health or sequelae (eg, employment outcomes) among pregnant and postpartum workers. METHODS: Data were extracted using a customized form to document study and sample characteristics; and details of exposures, outcomes, covariates, and analyses. Investigators independently assessed study quality for 7 risk-of-bias domains and overall utility, with discrepant ratings resolved through discussion. A narrative synthesis was conducted due to heterogeneity. RESULTS: Sixteen studies (11 cohort studies, 2 nested case-control studies, and 3 cross-sectional studies) from 8 countries were included (N=142,320 pregnant and N=1744 postpartum workers). Limited but consistent evidence with variable quality ratings, ranging from critical concern to high, suggests that pregnant workers exposed to heavy lifting (usually defined as ≥22 lbs or ≥10 kg) may be at increased risk of functionally limiting pelvic girdle pain and antenatal leave. Moreover, reports of dose-response relationships suggest graded risk levels according to lifting frequency, ranging from 21% to 45% for pelvic girdle pain and 58% to 202% for antenatal leave. Limited but consistent evidence also suggests that postural load increases the risk of employment cessation. CONCLUSION: Limited but consistent evidence suggests that pregnant workers exposed to heavy lifting and postural load are at increased risk of pelvic girdle pain and employment cessation. Job accommodations to reduce exposure levels may promote safe sustainable employment for pregnant workers.

Improved prenatal assessment of kidney disease using multiple ultrasound features.

BACKGROUND AND HYPOTHESIS: Congenital anomalies of the kidney and the urinary tract (CAKUT), often discovered in utero, cover a wide spectrum of outcomes ranging from normal postnatal kidney function to fetal death. The current ultrasound workup does not allow for an accurate assessment of the outcome. The present study aimed to significantly improve the ultrasound-based prediction of postnatal kidney survival in CAKUT. METHODS: Histological analysis of kidneys of 15 CAKUT fetuses was performed to better standardize the ultrasound interpretation of dysplasia and cysts. Ultrasound images of 140 CAKUT fetuses with 2-year postnatal follow-up were annotated for amniotic fluid volume and kidney number, size, dysplasia and/or cysts using standardized ultrasound readout. Association of ultrasound features and clinical data (sex and age at diagnosis) with postnatal kidney function was studied using logistic regression. Amniotic fluid proteome associated to kidney dysplasia or cysts was characterized by mass spectrometry. RESULTS: Histologically, poor ultrasound corticomedullary differentiation was associated to dysplastic lesions and ultrasound hyperechogenicity was associated to the presence of microcysts. Of all ultrasound and clinical parameters, reduced amniotic volume, dysplasia and cysts were the best predictors of poor outcome (Odd ratio = 57 [95%CI: 11-481], 20 [3-225] and 7 [1-100], respectively). Their combination into an algorithm improved prediction of postnatal kidney function compared to amniotic volume alone (area under the ROC curve = 0.92 [0.86-0.98] in a 10-fold cross validation). Dysplasia and cysts were correlated (Cramer's V coefficient = 0.44, p<0.0001), but amniotic fluid proteome analysis revealed that they had distinct molecular origin (extracellular matrix and cell contacts versus cellular death, respectively), probably explaining the additivity of their predictive performances. CONCLUSION: Antenatal clinical advice for CAKUT pregnancies can be improved by a more standardized and combined interpretation of ultrasound data.

WHO antenatal care policy and prevention of malaria in pregnancy in sub-Saharan Africa.

BACKGROUND: The WHO 2016 antenatal care (ANC) policy recommends at least eight antenatal contacts during pregnancy. This study assessed ANC8 uptake following policy implementation and explored the relationship between ANC attendance and intermittent preventive treatment in pregnancy (IPTp) coverage in sub-Saharan Africa following the rollout of the World Health Organization (WHO) 2016 ANC policy, specifically, to assess differences in IPTp uptake between women attending eight versus four ANC contacts. METHODS: A secondary analysis of data from 20 sub-Saharan African countries with available Demographic Health and Malaria Indicator surveys from 2018 to 2023 was performed. The key variables were the number of ANC contacts and IPTp doses received during a participant's last completed pregnancy in the past two years. Pooled crude and multivariable logistic regression models were used to explore factors associated with attendance of at least four or eight ANC contacts as well as receipt of at least three doses of IPTp during pregnancy. RESULTS: Overall, only a small proportion of women (median = 3.9%) completed eight or more ANC contacts (ANC8 +). Factors significantly associated with increased odds of ANC8 + included early ANC attendance (AOR: 4.61: 95% CI 4.30-4.95), literacy (AOR: 1.20; 95% CI 1.11-1.29), and higher wealth quintile (AOR: 3.03; 95% CI 2.67-3.44). The pooled estimate across all countries showed a very slight increase in the odds of IPTp3 + among women with eight (AOR: 1.06; 95% CI 1.00-1.12) compared to those with four contacts. In all but two countries, having eight instead of four ANC contacts did not confer significantly greater odds of receiving three or more doses of IPTp (IPTp3 +), except in Ghana (AOR: 1.67; 95% CI 1.38-2.04) and Liberia (AOR: 1.43; 95% CI 1.18-1.72). CONCLUSION: Eight years after the WHO ANC policy recommendation, all countries still had sub-optimal ANC8 + coverage rates. This paper is a call to action to actualize the vision of the WHO and the global malaria community of a malaria free world. Policies to improve ANC and IPTp coverage should be operationalized with clear actionable guidance and local ownership. Study findings can be used to inform multi-level policy, programmatic, and research recommendations to optimize ANC attendance and malaria in pregnancy prevention, thus improving maternal and child health outcomes, including the reduction of malaria in pregnancy.

Assessing the prevalence, risk factors, and socio-demographic predictors of malaria among pregnant women in the Bono East Region of Ghana: a multicentre hospital-based mixed-method cross-sectional study.

BACKGROUND: Malaria is one of the world's most lethal vector-borne diseases, causing significant health burdens in endemic countries. Several studies on the prevalence of malaria among pregnant women in Ghana have been conducted in various parts of the country, yielding evidence pointing to intra- and inter-regional variations. The current study assessed the prevalence, risk factors, and sociodemographic predictors of malaria among pregnant women in the Bono East Region of Ghana. METHODS: This multicentre hospital-based study employed a mixed-method cross-sectional design. A multistage sampling technique was used to select seven health facilities and recruited 1452 pregnant women who attended ANC at seven selected health facilities. Haematological examination, a structured closed-ended questionnaire, in-depth interviews (IDIs), and focus group discussions (FGDs) were used to obtain relevant data. Quantitative data were analysed with STATA 14 (StataCorp, College Station, USA). Likewise, the four-step thematic analysis was used to analyse qualitative data. A significant level was set at (p < 0.05) at a 95% confidence interval (CI). RESULTS: The ages of the pregnant women at enrolment ranged between 17 and 40 years, with a mean (SD) of 28.8 ± 3.73 (95% C.I: 28.63-29.02). The overall prevalence of malaria infection among pregnant women was 10.8% (95% CI: 9.32-12.56). Presence of farm or domestic animals, living close to drainage tunnels, living near overgrown vegetation, not married, not having formal education, living in extended-type households, living in compound-type households, mud and thatch households, mud and iron sheet households, primigravidae, multiparity, first-time pregnant women, second-time, third-time, fourth-time, and fifth-time ANC visits, blood groups A, B, and AB were independent factors or predictors significantly associated with increased risk of malaria. CONCLUSION: The current study revealed an approximately 10.8% prevalence of malaria among pregnant women. The prevalence revealed, was, however, higher than the national prevalence of 8.6%. The high prevalence of malaria, associated risk factors, and sociodemographic and maternal predictors highlight the need to strengthen screening for malaria, administer treatments, monitor maternal and foetal health, and provide education and counselling.

An exploration of prenatal breastfeeding self-efficacy: a scoping review.

BACKGROUND: Breastfeeding self-efficacy is a woman's self-belief and confidence in her perceived ability to breastfeed. This modifiable determinant is strongly associated with breastfeeding initiation, exclusivity, and duration. It is unclear how important the timing of breastfeeding self-efficacy measurement and interventions are. The prenatal period appears underexplored in the literature and yet a prenatal focus provides increased opportunity for breastfeeding self-efficacy enhancement and further potential improvement in breastfeeding outcomes. This scoping review aims to synthesise the evidence on prenatal breastfeeding self-efficacy, describing for the first time the theoretical frameworks, measurement tools, and interventions used in the prenatal period. METHODS: 8 databases were searched using the PCC framework (Problem: breastfeeding, Concept: self-efficacy, Context: prenatal period). From 4,667 citations and 156 additional sources identified through grey literature and snowballing, data were extracted from 184 studies and 2 guidance documents. All were summarised descriptively and narratively. RESULTS: Just over half (57%) of included studies stated their theoretical underpinning, with Bandura's Self-Efficacy Theory / Dennis' Breastfeeding Self-Efficacy Framework predominant. Only half of intervention studies incorporated theory in their design. More intervention studies were undertaken in the past decade than previously, but the level of theoretical underpinning has not improved. Prenatal interventions incorporating theory-led design and using components addressing the breadth of theory, more frequently reported improving breastfeeding self-efficacy and breastfeeding outcomes than those not theory-led. Intervention components used less frequently were vicarious or kinaesthetic learning (52.5%) and involvement of social circle support (26%). The Breastfeeding Self-Efficacy Scales were the most common measurement tool, despite being designed for postpartum use. Overall, issues were identified with the late prenatal timing of breastfeeding self-efficacy investigation and the design, content and phraseology of measurements and interventions used in the prenatal period. CONCLUSION: This review provides novel insights for consideration in the design and conduct of breastfeeding self-efficacy studies in the prenatal period. Future research should aim to be theory-led, commence earlier in pregnancy, and embed the breadth of self-efficacy theory into the design of interventions and measurement tools. This would provide more robust data on prenatal breastfeeding self-efficacy's role in impacting breastfeeding outcomes.

Clinic-based evaluation of point-of-care dual HIV/syphilis rapid diagnostic tests at primary healthcare antenatal facilities in South Africa and Zambia.

BACKGROUND: Southern African countries have the largest global burden of HIV and syphilis, with a high prevalence among women of reproductive age. Although antenatal screening is standard of care, syphilis screening has generally lagged behind HIV screening. We aimed to evaluate the performance and operational characteristics of two commercial dual HIV/syphilis point-of-care tests (POCTs) for simultaneous maternal HIV/syphilis screening. METHODS: A clinic-based evaluation of dual HIV/syphilis POCTs (SD Bioline and Chembio) was conducted at five primary healthcare centres (PHCs) in South Africa and Zambia. POCT results using capillary fingerprick blood were compared to reference laboratory syphilis and HIV serological assays. RESULTS: Three thousand four hundred twelve consenting pregnant women aged ≥ 18 years were enrolled. The prevalence of treponemal antibody seropositivity and HIV infection ranged from 3.7 to 9.9% (n = 253) and 17.8 to 21.3% (n = 643), respectively. Pooled sensitivity for syphilis compared to the reference assay was 66.0% (95%CI 57.7-73.4) with SD Bioline and 67.9% (95%CI 58.2-76.3) with Chembio. Pooled specificity for syphilis was above 98% with both POCTs. The sensitivities of SD Bioline and Chembio assays were 78.0% (95%CI 68.6-85.7) and 81.0% (95%CI 71.9-88.2), respectively compared to an active syphilis case definition of treponemal test positive with a rapid plasma reagin titre of ≥ 8. The negative predictive values (NPVs) based on various prevalence estimates for syphilis with both assays ranged from 97 to 99%. The pooled sensitivity for HIV was 92.1% (95%CI 89.4-94.2) with SD Bioline; and 91.5% (95%CI 88.2-93.9) with Chembio. The pooled specificities for HIV were 97.2% (95%CI 94.8-98.5) with SD Bioline and 96.7% (95%CI 95.1-97.8) with Chembio. The NPV based on various prevalence estimates for HIV with both assays was approximately 98%. Most participating women (91%) preferred dual POCTs over two single POCTs for HIV and syphilis, and healthcare providers gave favourable feedback on the utility of both assays at PHC level. CONCLUSIONS: Based on the need to improve antenatal screening coverage for syphilis, dual HIV/syphilis POCTs could be effectively incorporated into antenatal testing algorithms to enhance efforts towards elimination of mother-to-child transmission of these infections.