BMC Pregnancy and Childbirth

Background: Pregnancy is a uniquely complex ethical and clinical context in which precision medicine approaches, including genomics-driven risk prediction tools, biomarker-based stratification, and data-intensive analytics, are rapidly evolving. There is a need for community consultation on the ethical, social, and practical implications of precision medicine in pregnancy research and healthcare. Aim: The primary aim of this study was to engage healthcare consumers to build consensus on the acceptability of precision medicine approaches in pregnancy research and healthcare. We also sought to identify consumer priorities for future research. Methods: A two-round modified Delphi study was conducted to determine consumer opinions on the use of precision medicine approaches in pregnancy research and healthcare. Seven in-person workshops (round one) were held, with purposeful recruitment to ensure a representative group of healthcare consumers who engage with the healthcare system during pregnancy. These included first-time parents, culturally and linguistically diverse women, Aboriginal and Torres Strait Islander women, and women and their partners who had experienced previous pregnancy complications. Recruitment was conducted through established advocacy networks, and each workshop was facilitated by representatives from each organization. A second-round online survey, based on workshop content, was completed to assess the acceptability of precision medicine and to determine consumer priorities for future precision medicine research on pregnancy health. Results: Precision medicine research and the implementation of new technologies in clinical care were acceptable to participants; however, the need for transparency and trust between participants and researchers regarding the use and storage of genetic material was highlighted, particularly among Aboriginal and culturally and linguistically diverse participants. Outcomes related to survival and perinatal complications (stillbirth, preterm birth, and labor complications) were the highest-rated consumer research priorities, along with maternal mental health and breastfeeding. When asked whether participants would like to see PM available as part of routine pregnancy care for conditions with available treatments, complete consensus (100%) was reached. Conclusion: Healthcare consumers strongly support the use of precision medicine in pregnancy research and its translation into routine clinical care, particularly when effective interventions are available. However, implementation must be underpinned by transparency, trust, culturally appropriate governance, and clear communication about the collection, storage, and use of genetic material. These findings provide a consumer-informed framework for prioritizing future precision medicine research and guiding its responsible translation into pregnancy care.

Background Despite being originally developed to support labour monitoring in low-resource and rural settings, the partograph has remained the standard tool for labour management and continues to be used by obstetricians and midwives across diverse settings worldwide. However, inappropriate use and non-use of the partograph persist and have been associated with increased odds of adverse perinatal outcomes, including perinatal death. To address these limitations, the World Health Organization introduced the Labour Care Guide in 2020 as a comprehensive tool to standardise and improve the quality of care during childbirth. Henceforth, some countries such as Rwanda and Uganda have since implemented its use. This study aimed to assess the effect of WHO Labour Care Guide implementation, compared with the traditional partograph, on selected maternal and perinatal outcomes across participating facilities. Methods This was a quasi-experimental implementation study conducted in selected referral hospitals in Zambia, comparing maternal and perinatal outcomes before and after implementation of the WHO Labour Care Guide. Facilities were grouped into implementation and comparison sites. Routine HMIS/DHIS2 data were used to assess selected outcomes across the pre- and post-implementation periods. Descriptive statistics were used to summarise outcome trends, while a difference-in-differences analytical approach was applied using Stata version 18 to compare changes over time between implementation and comparison sites. Results The analysis included 12 hospitals, 192 facility-month observations, 89,122 total births, and 87,004 live births. Overall, the stillbirth rate was 23.8 per 1,000 total births, birth asphyxia rate was 40.1 per 1,000 live births, caesarean section rate was 34.6 per 100 live births, low-birthweight rate was 168.6 per 1,000 live births, and maternal mortality ratio was 313.8 per 100,000 live births. The implementation sites reporting higher birth asphyxia rates (42.7 versus 38.0 per 1,000 live births). Difference-in-differences analysis showed no statistically significant effect of LCG implementation on stillbirths, IRR 1.07 (95% CI: 0.69-1.67, p=0.752); fresh stillbirths, IRR 1.23 (95% CI: 0.74-2.05, p=0.431); birth asphyxia, IRR 0.65 (95% CI: 0.34-1.27, p=0.207); or caesarean section, IRR 1.02 (95% CI: 0.80-1.30, p=0.892). Conclusion Implementation of the WHO Labour Care Guide was not associated with statistically significant changes in stillbirths, fresh stillbirths, birth asphyxia, or caesarean section rates during the study period. Despite the higher birth asphyxia rates in the implementation sites the difference remained statistically not significant. Scale-up of the LCG should be accompanied by sustained training, mentorship, audit and feedback, and strengthening of emergency obstetric and newborn care systems.

Stillbirth remains a major public health concern, particularly in resource-constrained settings. Barriers to timely, high-quality antenatal care may delay the recognition and management of pregnancy complications. We explored the perspectives of women, Village Health Team (VHT) members and healthcare workers on community-delivered approaches to improve pregnancy care, in particular prevention of stillbirth in Uganda. An exploratory qualitative study was conducted at four referral hospitals in Uganda. Data were collected through focus group discussions, in-depth interviews, and key informants interviews with women, Village Health Team members and healthcare workers. Audio-recordings were transcribed verbatim and translated into English where required. Data were analysed thematically using an iteratively developed codebook and NVivo software. In total, 56 participants took part, comprising women (n=27), Village Health Team members (n=11) and frontline healthcare workers (n=18). Participants highlighted the need for the adoption of simple and user-friendly wearable pregnancy monitoring tools for self-monitoring of early warning signs. Health education sessions focused on identifying early warning signs of pregnancy complications highlighted, emphasizing the importance of empowering women with information to seek care early through digital platforms. Limited follow-up support was also a critical concern, with the majority of the women advocating for better emotional and psychological care after a stillbirth, both at a facility and at home. Participants viewed community-delivered antenatal care as an acceptable approach to reducing access barriers. Implementation would require trained personnel, quality-assured tools, clear referral pathways and integration with facility-based care. Structured communication and psychosocial support after stillbirth were also identified as priorities. These findings should inform co-design and prospective evaluation of community-delivered models.

Abstract Background: Birth preparedness and complication readiness (BPCR) knowledge is important for recognizing maternal and newborn danger signs and preparing for timely care. However, conventional translation of BPCR educational materials may not adequately address local linguistic and cultural contexts. This study evaluated whether a culturally adapted Swahili BPCR training manual improved knowledge more than a standard translated Swahili BPCR training manual among Hehe pregnant women in rural Iringa, Tanzania. Methods: A controlled pretest-posttest quasi-experimental study was conducted among 176 pregnant women attending antenatal care in Mufindi and Kilolo districts. Eighty-eight women received the Culturally Adapted Swahili BPCR Training Manual and 88 received the Standard Translated Swahili BPCR Training Manual. Both groups received comparable BPCR education with standardized session duration, delivery format, language, and follow-up procedures. BPCR knowledge was assessed using a 64-item questionnaire at baseline and four weeks after the intervention. The primary analysis used Difference-in-Differences regression to compare changes in knowledge between groups. Multiple linear regression was used to assess the association between intervention-group assignment and post-intervention knowledge after adjustment for baseline knowledge and participant characteristics. Results: All 176 participants completed both assessments. Mean knowledge scores increased from 21.01 (SD 7.42) to 38.49 (SD 7.54) in the culturally adapted group and from 22.51 (SD 5.80) to 32.81 (SD 5.55) in the standard translated group. The culturally adapted group demonstrated a 7.18-point greater increase in knowledge than the standard translated group ({beta} = 7.18, 95% CI: 4.40-9.97; p < 0.001). After adjustment for baseline knowledge, age, education, gravidity, marital status, living arrangement, reading ability, and occupation, intervention-group assignment remained significantly associated with higher post-intervention knowledge ({beta} = 5.88, 95% CI: 3.84-7.92; p < 0.001). Conclusion: Culturally adapted BPCR education was associated with greater short-term improvement in knowledge than standard translated education among Hehe pregnant women. Integrating culturally and linguistically appropriate terminology, contextual explanations, and locally meaningful communication into BPCR education may strengthen knowledge outcomes. Multisite studies with stronger allocation procedures and longer follow-up are needed to confirm these findings.

Background: Women are recommended to take folic acid supplements (FAS) periconceptionally to prevent neural tube defects, but the low levels of FAS uptake are poorly understood. This study aimed to determine how parity, pregnancy planning and other maternal factors affect the timing of FAS initiation. Method: We used data from a representative sample of 966 pregnant women from the Northern Ireland Baby Hearts study. Questionnaire responses on health behaviours, including FAS, were linked to maternity and area-based deprivation data. Logistic regression assessed determinants of FAS initiation preconception. Time-varying Cox regression assessed associations between initiation postconception and pregnancy-related milestones. Results: Forty-one per cent of women initiated FAS preconception. Lower odds of preconception initiation were associated with multiparity (adjusted OR 0.47 (0.32 to 0.68)), unplanned pregnancy (adjusted OR 0.08 (0.05 to 0.13)), deprivation and consuming a low folate diet. Higher odds were associated with fertility treatment and previous pregnancy loss. Forty-seven per cent of women initiated FAS postconception, mainly after pregnancy recognition (median 5 weeks), including 34.1% of those who planned their pregnancy. For primiparous women with unplanned pregnancies, the first health service contact (median 7 weeks) further increased FAS initiation. Conclusion: Many women, even multiparous women with previous pregnancy experience and women who planned their pregnancies, are initiating FAS after pregnancy recognition. This shows awareness of FAS benefits, but is too late to prevent neural tube defects. Public health interventions need to go beyond awareness to address motivation and opportunity for FAS, and pay more attention to multiparous women.

Objective: Maternal malnutrition, encompassing both undernutrition and overnutrition, can adversely affect maternal and foetal health and therefore requires effective nutritional assessment during antenatal care. Although body mass index (BMI) is commonly used for nutritional assessment, its application during pregnancy has limitations and may be difficult to implement in low-resource settings. Mid-upper arm circumference (MUAC) is a simple, inexpensive and easily interpretable anthropometric measure that may be suitable for community-based screening. This study aimed to evaluate the diagnostic accuracy and utility of MUAC for screening malnutrition among pregnant women in a community-based setting in eastern India. Design: This is a secondary analysis of data from a cross-sectional study. Anthropometric measurements were obtained using standardised procedures. Nutritional status assessed by MUAC was compared with body mass index (BMI). Diagnostic performance was evaluated using sensitivity, specificity, accuracy, positive predictive value (PPV), negative predictive value (NPV), Cohen Kappa, simple linear regression and receiver operating characteristic (ROC) curve analysis. Setting: Selected health sub-centres (Ayushman Arogya Mandir) under the rural field practice area of a medical college in Ranchi district of Jharkhand, a state in eastern India. Participant: A total of 337 pregnant women were randomly selected from antenatal care registers and enrolled after obtaining informed consent. Women with chronic medical conditions, such as hypertension, diabetes mellitus and hypothyroidism were excluded. Result: Based on BMI, 21.4% of participants were underweight, while MUAC classified 38.3% as having moderate malnutrition and 0.6% as having severe acute malnutrition. For detecting undernutrition, MUAC demonstrated 94.4% sensitivity, 70.3% specificity, 76.4% accuracy, 51.9% PPV and 97.4% NPV. Agreement between BMI and MUAC was moderate (Cohen Kappa=0.509, p<0.001). ROC analysis identified 22.8 cm as the optimal cut-off for undernutrition, and 24.8 cm for overnutrition. Conclusion: MUAC may be a useful and effective screening tool for maternal malnutrition, particularly in community and low-resource settings where conventional anthropometric assessment may be difficult. Further studies are required to establish robust MUAC cut-offs across different populations and gestational ages.

Preeclampsia is a multisystem hypertensive disorder of pregnancy that emerges after 20 weeks of gestation, and remains a leading cause of maternal and perinatal morbidity and mortality globally, yet evidence on its predictors and outcomes in Kenya remains limited. This prospective cohort study compared pregnant women with and without preeclampsia who attended selected hospitals in Kiambu County, to determine the predictors of preeclampsia and its associated maternal and neonatal outcomes. The results indicated a very strong statistical association between preeclampsia and the following i.e parity, time taken to reach the hospital, hypertension and diabetes mellitus (p-value <0.001) and religion (p-value <0.013). Women with preeclampsia had nearly twice the risk and six times the odds of delivering low-birth-weight infants compared with women without preeclampsia (RR = 1.97; OR = 6.25). A strong statistically significant association was observed between multiparity and prematurity (RR = 5.3, OR = 8.4, p < 0.001). Multiparous women with preeclampsia had approximately 5.3 times the risk and 8.4 times the odds of experiencing a premature birth compared with women without preeclampsia. In conclusion preeclampsia significantly increased adverse maternal and neonatal outcomes, highlighting the need for early high-risk pregnancies identification and strengthened antenatal care to improve both maternal and neonatal outcomes.

Background: The Greater Manchester Care Record (GMCR) integrates health and social care data for 2.8 million individuals. While it contains maternity information, identifying individual pregnancies, including timing and outcomes, is complex due to variations in healthcare interactions and recording practices. This study develops open-source code to create a pregnancy register within the GMCR using diagnosis- and procedure-based algorithm established in other databases. Methods: 1,448 maternity SNOMED clinical codes identified pregnancy-related primary care records among women aged 14-49 years between March 2012 and August 2023. Codes were grouped by pregnancy outcome, with a hierarchical ruling approach where multiple outcomes appeared within one episode. Pregnancy start dates were derived from hierarchical coded events or imputed using biologically plausible duration based on outcome type. Internal validation compared GMCR register episodes against Hospital Episode Statistics (HES) hospital maternity admissions; external validation compared outcome rates against published UK estimates. Results: The algorithm was developed across 379,832 women, identifying 880,926 pregnancies. Internal validation showed nearly half of register deliveries had a corresponding HES record, with a positive predictive value (PPV) of 48.1%and a median date difference of 17 days (IQR 1-30). External comparison revealed live birth (927.8 vs. 995.6 per 1,000 deliveries) and stillbirth (2.12 vs. 3.9 per 1,000 births) rates close to national estimates but a notable discrepancy for miscarriage (8.00 vs. 15.3 per 100 pregnancies) and termination of pregnancy (5.36 vs. 25.1 per 1,000 women). Demographic alignment was strong for maternal age (31 vs. 29.8 years) and deprivation (IMD10 median: 3 vs. 2.6), though ethnic minority representation was expectedly higher in the GMCR (37.0% vs. 28.7%). Conclusions: This pregnancy register enriches the GMCR for maternal health research, enabling more comprehensive and regionally tailored studies to inform healthcare delivery and policy. This work represents an important first step in developing a scalable, open-source algorithmic tool to support pregnancy research across diverse populations. By making the code openly available, it can be adapted for use in federated data environments, enhancing reproducibility and collaboration.

Abstract Background: We developed and evaluated a behaviour change intervention to improve health outcomes for pregnant women and neonates in rural Pakistan. Methods: We used a parallel, three-arm, unblinded, cluster randomised controlled trial design. Eligible clusters were upgraded health facilities plus all associated community health workers (CHWs) and catchment populations. Randomisation was by computer program (1:1:1 ratio). All pregnant women were eligible. Control CHWs provided usual care to pregnant women. Arm 1 CHWs provided structured birth planning, including birth preparedness and complication readiness planning, and a voucher allowing free travel to access emergency obstetric/neonatal care. Arm 2 CHWs provided structured planning alone. Co-primary outcomes were skilled (doctors and midwifery-trained cadres) birth attendance and neonatal mortality (NNM) at 28 days. Findings: Between November 2011 to May 2012, respectively in arms 1, 2 and the control 21,317, 19,267 and 18,867 women were recruited, and 21,214, 19,125 and 18,812 were followed-up and analysed. Vouchers were almost never used to reclaim travel costs. Skilled attendance was 64% (12,045/18,812) in the control arm, 72.3% (15,335/21,214) (adjusted odds ratio [aOR] 1.56 [95% CI: 0.93, 2.62; p = 0.21]) in arm 1 and 78.1% (14,944/19,125) (aOR 2.16 [95% CI: 1.29, 3.62; p = 0.007]) in arm 2. NNM was 13.4 (per 1,000 live births) in the control arm, 45 (aOR 2.32 [95% CI: 1.48, 3.63; p < 0.001]) in arm 1 and 16.2 (aOR 1.36 [95% CI: 0.84, 2.21; p = 0.21]) in arm 2. Conclusions: Birth planning had inconsistent effects on skilled attendance and NNM, including apparently negative effects on NNM, with concerns about the quality of midwifery care. However, the control arm and arm 2 NNM was improbably low for this setting, and bias in the outcome may explain the observed differences. The travel voucher was little used.

Background: Stillbirths are a neglected problem in India, and the data we have are often unreliable. This study aimed to assess stillbirth record quality in an urban setting and understand the experiences, health impacts, and perceived causes from both families and health workers. Methods: A mixed-methods study was conducted in Vadodara Municipal Corporation during January to December 2023. All reported stillbirths (>=28 weeks or >=1000 g) were reviewed. Families were interviewed at home using a standardized questionnaire, with in-depth interviews conducted with 9 families and 17 health workers (doctors, ANMs, ASHAs). Quantitative data were analysed using Excel and Jamovi; qualitative data were analysed thematically. Results: Of 61 stillbirths reported by VMC, quality audits revealed 7 errors (duplicates/misclassifications) and 2 data entry errors, yielding a true stillbirth rate of 1.7 per 1000 total births. The eastern zone recorded the most cases (21), while the southern zone had the highest rate (4.1 per 1000). Most deliveries occurred in government hospitals (64%). Common reported causes were intrauterine foetal death on routine ultrasound (26%) and premature delivery (19%). Families reported delayed care access, undertrained staff, poor facilities, and challenges accessing government scheme benefits. Health workers identified preventable factors (hypertension, diabetes, anaemia, meconium aspiration, growth restriction, birth defects) and non-preventable factors (extreme prematurity, multiple pregnancy). Interpretation & conclusions: Stillbirth data in Vadodara have serious quality problems which can be fixed. Many stillbirths could be avoided with better pregnancy monitoring, better communication, stronger referral systems and more awareness in the community.

Background: Access to maternal healthcare services is essential for improving maternal and neonatal health outcomes. Health insurance can reduce financial barriers to healthcare access and may facilitate utilisation of maternal health services, and contextualized evidence can further support policy development and implementation. This study assessed the association between health insurance coverage and utilisation of antenatal care (ANC), institutional delivery, skilled birth attendance and postnatal care (PNC) services among women in Nepal. Methods: This study used data from the 2022 Nepal Demographic and Health Survey (NDHS), a nationally representative cross-sectional survey. The analysis included women aged 15-49 years who had a live birth within the 24 months preceding the survey. Inverse probability of treatment weighting (IPTW) based on propensity scores was applied to balance measured socioeconomic and demographic characteristics between insured and uninsured women. Weighted marginal structural models were used to estimate the association between health insurance coverage and maternal healthcare utilisation outcomes. Robustness was assessed using alternative propensity score specifications and E-values for unmeasured confounding. Results: Among 14,845 women interviewed, 2,078 reported a recent live birth and were included in the analysis (unweighted; 1,998 when survey-weighted). Of these, 201 (9.7%) had health insurance coverage and 1,877 (90.3%) were uninsured. After adjustment using IPTW, health insurance coverage was associated with significantly higher utilisation of maternal healthcare services. Insured women had more than twice the odds of attending at least four ANC visits compared with uninsured women (AOR 2.14; 95% CI 1.15-3.98). Similarly, insured women had higher odds of receiving a PNC check-up within two days of delivery (AOR 2.05; 95% CI 1.28-3.27) and receiving PNC from a skilled provider (AOR 1.94; 95% CI 1.23-3.06). Although insurance coverage was positively associated with institutional delivery (AOR 1.55; 95% CI 0.91-2.62) and skilled birth attendance (AOR 1.57; 95% CI 0.90-2.72), these associations did not reach statistical significance. Conclusion: Health insurance coverage was associated with greater utilisation of antenatal and postnatal healthcare services among women in Nepal. However, no significant association was observed for institutional delivery or skilled birth attendance. Expanding health insurance coverage, particularly among underserved populations, may help improve maternal healthcare utilisation and support progress towards universal health coverage and maternal health-related Sustainable Development Goals.

Background: Both fetal and maternal genomes contribute to birthweight, but the timing and relative magnitude of their effects during gestation remain unclear. Polygenic risk scores (PRSs), constructed from genome-wide association studies (GWAS), capture the cumulative influence of common birthweight-associated variants to quantify genetic predisposition to fetal growth. We constructed fetal and maternal PRSs for birthweight in two UK birth cohorts, the Pregnancy Outcome Prediction Study (POPS) and Born in Bradford (BiB), to evaluate their associations with estimated fetal weight (EFW) throughout pregnancy and with birthweight at delivery. We also investigated whether PRSs could improve risk stratification of infants born below the 10th centile by distinguishing those with pathological intrauterine growth restriction (IUGR) from those who are constitutionally small-for-gestational-age (SGA). Methods: In POPS and BiB, we used LDpred2-auto to estimate PRSs based on the largest available maternal and fetal GWAS for birthweight. We longitudinally assessed EFW associations with PRSs using linear mixed effects models in POPS and BiB. We evaluated birthweight associations with PRSs using linear models, where birthweight was adjusted for gestational age and fetal sex. We estimated R2 and conducted variance decomposition analyses for all models. Genetically-predicted birthweights were estimated from joint models of fetal and maternal PRSs plus ten genetic principal components (PCs). BiB analyses were conducted separately for genetically-inferred European (EUR) and South Asian (SAS) ancestry. Results: While PRSfetus was significantly associated with EFW at baseline ([~]22 weeks gestation) across cohorts, PRSmother was not. Both the interaction of PRSfetus and PRSmother with gestational age (GA) were significantly associated with EFW. The effect of PRSmother on EFW increased more quickly across gestation than the effect of PRSfetus in POPS, but this finding was not replicated in BiB. Jointly, fetal and maternal polygenic risk explained 4% of variance in EFW in POPS and 1% in BiB-EUR. In POPS, fetal and maternal PRSs showed independent contributions to EFW variance of 3% and 0.5%, respectively. Joint and univariable linear models showed significant positive associations of PRSfetus and PRSmother with observed birthweight. In POPS, PRSfetus and PRSmother accounted for [~]10% and [~]4% of variance in birthweight over covariates alone, respectively, which was replicated in BiB-EUR. Maternal and fetal genetic effects jointly explained 11% of birthweight variance in POPS, similar to BiB-EUR, at 12%; however, the variance explained was reduced by half in BiB-SAS, at 6%. Among POPS babies born <10th birthweight centile, the magnitude of the difference between observed and genetically-predicted birthweight was greater in the group judged clinically to be IUGR vs. SGA (p=0.008; point estimate=0.29, 95%CI: 0.12, 0.47). Conclusions: Maternal and fetal PRSs jointly account for [~]11-12% of birthweight variance in European ancestry groups, but much less in a South Asian cohort. In POPS, the effect of birthweight-associated SNPs on estimated fetal weight increases more rapidly across pregnancy for maternal than for fetal genetic effects. Deviation from genetically-predicted birthweight may be a useful metric to help distinguish growth-restricted from constitutionally small babies.

Gestational diabetes mellitus (GDM) is associated with significant maternal and neonatal morbidity. Screening strategies vary internationally and the diagnostic performance of the 50g glucose challenge test (50g GCT) as a universal screening tool remains uncertain across diverse populations. This retrospective cohort study included 18,213 singleton pregnancies at a London tertiary hospital between 2010 and 2023. Women routinely underwent the universal two-step GDM screening pathway: a 50g GCT at 24 - 32 weeks' gestation, followed by a diagnostic 75-g oral glucose tolerance test if the 50g GCT result was greater than or equal to 7.8 mmol/L. We evaluated the use of universal two-step screening in detecting GDM, how its prevalence varies with maternal characteristics, including ethnicity, body mass index, age, and in those who would not have been included in risk factor-indicated screening, and the association between the 50g GCT and adverse outcomes. 2,015 women had an abnormal GCT, and 406 (20.1%) had an abnormal 75g OGTT, with GDM diagnosed at 24-28 weeks. We also found 87 women, despite a normal GCT and/or normal OGTT, developed late-onset GDM. The overall prevalence of GDM was 4.4% (810/18,213). Universal screening will therefore identify a significant number of GDM cases, notably including those in a low-risk cohort who would not have been screened using a risk factor-based approach. When we examined glucose as a continuous variable, there was an association between increasing 50g GCT values and adverse maternal and neonatal outcomes. Universal screening with a GCT is a feasible and safe approach and addresses a significant health disparity gap, in that women without risk factors are screened and may be diagnosed with GDM. Given the long-term cardiometabolic implications of GDM, pregnancy diagnosis is important to allow for longer-term targeting of cardiometabolic risk factors to improve long-term health screening for type 2 diabetes and obesity.

Abstract Background: Placental insufficiency (PI), characterized by impaired placental function, is a leading cause of stillbirth. Although rare coding variants are known to cause a subset of stillbirths, their contribution to PI is poorly understood. Methods: We conducted a secondary analysis of stillbirth cases (N=292) of the Stillbirth Collaborative Research Network study with exome sequencing available on postmortem placental or fetal samples. PI was defined by standardized placental pathological lesions (e.g., maternal vascular malperfusion) and prespecified clinical criteria for placental dysfunction. Candidate gene-based rare-variant burden analysis was performed using the Sequence Kernel Association Test-Optimal framework, focusing on evolutionarily constrained developmental and placental-function genes. Primary analysis compared stillbirths with and without placental vascular malperfusion. Similar comparisons by clinical PI and other placental pathological lesions were conducted in secondary analysis. Results: Stillbirths with PI phenotypes demonstrated different patterns of genetic variation than stillbirths without PI. Specifically, we observed nominal differential enrichment of constrained variants in biologically prioritized placental-function genes, regulating extravillous trophoblast invasion and spiral artery remodeling (CTNND2, PHACTR1, SLIT1, VEGFA), placental angiogenesis (IGF2R, TEK), mitochondrial homeostasis (OPA1), and fetal growth (DLK1, GNAS). Secondary analyses on specific placental pathological lesions suggested recurrent enrichment of genes within similar placental developmental pathways. Conclusions: We observed nominal differential enrichment of constrained developmental and placental-function genes in stillbirths with PI compared to stillbirths without PI. The observed genetic signals across PI phenotypes suggest shared biological pathways underlie placental dysfunction. Our findings advance genotype-phenotype characterization and help prioritize candidate pathways for larger collaborative genomic and functional studies to improve stillbirth risk stratification and prevention.

BACKGROUND Twin pregnancies have a two- to three-fold higher risk of preeclampsia (PE), but early prediction remains poor because current biomarkers and prediction models are largely derived from singleton pregnancies. Defining the biological changes that precede PE in twins may facilitate the development of more effective risk assessment approaches. OBJECTIVE We aimed to characterize maternal plasma protein changes preceding PE in twin pregnancies and to explore whether early circulating proteins could serve as improved risk stratification for twin PE. STUDY DESIGN We performed a nested case-control study within a prospective twin pregnancy cohort at Peking University Third Hospital. A total of 84 women with twin pregnancies were included, comprising 40 pregnancies complicated by PE and 44 normotensive controls. Longitudinal maternal plasma samples were collected in the first, second, and third trimesters. In the discovery cohort, maternal plasma proteins were profiled by mass spectrometry to identify trimester-specific protein changes associated with PE. Candidate proteins were then validated in an independent validation set. We further assessed the functional relevance of selected proteins in trophoblast and endothelial cell models and constructed prediction models integrating biomarkers with maternal clinical characteristics. RESULTS Twin pregnancies complicated by PE showed distinct trimester-dependent protein alterations, with first- and second-trimester changes mainly involving immune regulation and glycolipid metabolism, and later changes enriched in cardiovascular-related pathways. Several proteins demonstrated early discriminatory patterns, including increased annexin A3, chitotriosidase-1, and ferritin light chain (FTL), together with decreased annexin A2 in the first trimester, whereas the conventional singleton markers (sFlt-1 and PAPP-A) did not differ. ELISA validation of these candidate biomarkers yielded an AUC of 0.93 for twin preeclampsia prediction; integration with standard maternal clinical factors further improved discriminatory performance to an AUC of 0.97. Accordingly, a multivariable model combining annexin A2, annexin A3, chitotriosidase-1, FTL, and maternal clinical factors achieved strong internal performance for early discrimination of PE in twin pregnancies (AUC, 0.97; 95% CI, 0.93-1.00). Moreover, annexin A2 knockdown impaired trophoblast migration and invasion and reduced inflammatory cytokine secretion in endothelial cells, supporting a role in placental development and maternal vascular adaptation. CONCLUSION Twin pregnancies that later develop PE exhibit early and progressive maternal plasma protein alterations that can be detected before clinical disease onset. These findings identify candidate biomarkers and biologically relevant pathways that may help explain why PE in twins differs from singleton disease and may support future twin-specific risk stratification strategies. These results require external validation before clinical application.

Abstract Background: The qualitative study was conducted to understand the socio-cultural factors (challenges and enabling factors) those influence the decisions and ability of the pregnant women and their families to make better use of the available safe birthing and EmONC services in two districts (Khanewal and Jhang) of Punjab, Pakistan. Objectives: To explore the key social, personal and professional considerations (factors) that influence the women (and family) decision and ability to utilise various birthing and EMONC services and to understand care providers interest and ability to offer these safe birthing services in the districts of Jhang and Khanewal in Pakistan. Study Design: The qualitative study was conducted, during the year 2013/14, on three rural health centers and two district headquarter hospitals in Kanewal and Jhang districts in Punjab. Through purposive sampling, 42 registered clients were interviewed to explain the different birthing experience along with 15 service providers, 2 district level programme managers and 2 transport vendors. The collected qualitative data from interviews were transcribed, and key emerging concepts/ themes were identified. A range and continuum of coded responses/ comments were compiled and discussed under each theme. Results: Main themes were structured birth planning; antenatal at health centres; skilled birth attendance; emergency obstetric and neonatal care (EmONC); and EmONC travel. The study found that pregnant women consult their husbands and mother in laws for taking birthing decisions; consult the skilled birth attendant for management of complication; private clinics are preferred for various social and logistic reasons; many private clinics doing caesarean are not adequately equipped; male reluctance (for cultural reasons) to make in-advance transport arrangement for possible EmONC; travel voucher utilisation remained low because of limited coverage and less-friendly procedures. Conclusion: Safe birthing decisions could be complex; and influenced by multiple social, cultural, economic, service access and quality considerations. Safe birthing practices can be improved if interventions remain sensitive to these preferences and realities. Keywords: Skilled birth attendance, social determinants, lady health workers, birth planning

Background Oral glucose tolerance test (OGTT), the gold standard for diagnosing gestational diabetes mellitus (GDM), faces significant implementation challenges, prompting interest in alternative biomarkers, such as glycated hemoglobin (HbA1c), for early detection. This study aimed to assess the association between early pregnancy HbA1c and subsequent GDM and adverse perinatal outcomes in low- and middle-income countries. Methods We analyzed data from the Pregnancy Risk, Infant Surveillance, and Measurement Alliance - Maternal and Newborn Health (PRISMA-MNH) cohort, which followed pregnant women enrolled before 20 weeks of gestation across five study sites in Kenya, India, Pakistan, and Zambia. We excluded participants with overt diabetes, severe anemia (Hb <7.0 g/dl), multiple gestations, or pregnancies that ended before 24 weeks of gestation. HbA1c was measured at enrollment. The primary outcome was GDM, diagnosed according to the International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria based on OGTT performed after 24 weeks of gestation. Secondary outcomes included hypertensive disorder of pregnancy, emergent Cesarean section, preterm birth, large for gestational age, and stillbirth after 28 weeks. We used AUC and ROC analyses to evaluate predictive performance and single- and two-threshold approaches to identify optimal cutoffs for predicting GDM. We used modified Poisson regression with robust standard errors to assess associations between early HbA1c and outcomes, and meta-analysis to pool site-specific estimates. Results Among 10,918 pregnancies, GDM prevalence was 6.4%. Women with GDM were older (28.0 +/- 5.4 versus 26.0 +/- 5.3 years) and had higher BMI at enrollment (25.0 +/- 5.8 versus 22.9 +/- 5.0 kg/m2) than women without GDM. The AUC for HbA1c alone in predicting GDM was 0.65 (95% confidence interval 0.63-0.67). A single early HbA1c threshold of 5.4%, based on the largest Youden's index, showed limited predictive performance (sensitivity 46.7%, specificity 75.8%). A two-threshold approach identified rule-out and rule-in cutoffs of 5.0% (sensitivity 80.3%, specificity 35.6%) and 5.5% (sensitivity 34.5%, specificity 83.1%), respectively. In adjusted models, each 0.1% increase in HbA1c was associated with a 12% higher risk (RR 1.12, 95% CI 1.10-1.15) of GDM, while no significant associations were observed for any secondary outcomes. Conclusion Early pregnancy HbA1c is independently associated with an increased risk of subsequent GDM. However, it demonstrated limited discriminatory ability as a standalone alternative to OGTT for identifying women who would later develop GDM. The identified rule-out threshold may help identify women at low risk of GDM, although the majority would still require OGTT for definitive diagnosis.

Objective Although numerous clinical prediction models (CPMs) have been developed to identify pregnancies at risk of serious adverse outcomes, most lack robust external validation, which restricts their reliability in clinical practice. This study aims to systematically review and externally validate existing clinical prediction models for Gestational Diabetes Mellitus (GDM), Pre-eclampsia (PE), Stillbirth, and Small-for-Gestational-Age (SGA) focusing on models for use in pre-conception or early pregnancy. The models were evaluated using a large, representative primary care cohort to assess their performance within a UK population. Method and Analysis A two-stage systematic review identified CPMs for GDM, PE, Stillbirth, and SGA. Eligible models used routinely collected maternal characteristics, fully reported the model equation, and included predictors commonly measured during the preconception or early pregnancy period. Validation was performed using the UK Clinical Practice Research Datalink (CPRD Aurum), including over 1.58 million pregnancies for women aged 14 - 49 between 2000 to 2020. Model performance was assessed through discrimination (C-statistic), calibration-in-the-large (CITL), calibration slope and calibration plot, with pooled estimates across 20 imputations. Results Of 30 studies included, 48 models were identified, comprising 47 binary outcome models and one continuous outcome model, and 23 models used UK cohorts. Models were developed in cohorts comprising 101 to 113,415 participants (median N=5,013). Whilst 29 models have been externally validated, only three have been validated in cohorts including UK population satisfying the requisite sample size. Across all outcomes, most models demonstrated limited generalisability in the UK population. The C-statistic for GDM ranged from 0.29 to 0.77, for PE from 0.42 to 0.71, whilst models for stillbirth and SGA showed weaker discrimination from 0.54 to 0.56 and 0.58 to 0.62, respectively. Models across all outcomes exhibited substantial miscalibration, with calibration-in-the-large ranging from -5.66 to 1.35, and calibration slope from -0.65 to 17.61. Conclusion Existing CPMs for pre-conception and early prediction of adverse pregnancy outcomes showed poor discrimination and frequent miscalibration in a large UK cohort. Whilst some models for SGA had excellent performance, most existing models for GDM, PE, and stillbirth demonstrated suboptimal generalisability, likely a result of differences in population characteristics and outcome prevalence. Therefore, most CPMs evaluated are not suitable for direct implementation in UK clinical practice and require further calibration, updating, even re-development using large, representative data before achieving clinical utility.

Summary Background We used sequential target trial emulation (TTE) to examine associations between opioid analgesic initiation and adverse maternal and neonatal outcomes while accounting for gestational timing, time at risk, and potential confounding. Methods Using the Early Life Course platform, comprising linked population-based data for births in New South Wales, Australia (2013-2019), we emulated a new trial at each gestational week, comparing women who initiated a prescribed opioid analgesic with eligible non-initiators. Baseline covariates were balanced using inverse probability weighting. Weighted logistic regression estimated odds ratios (ORs) for neonatal outcomes, postpartum haemorrhage, and severe maternal morbidity. Pooled logistic regression estimated hazard ratios (HRs) for other maternal outcomes, combined across gestational weeks using fixed-effects meta-analysis. Sensitivity analyses assessed unmeasured confounding, exposure misclassification, and potential reverse causation. Findings Among 511,357 pregnancies, over 80% of opioid initiators received only one dispensing. Opioid initiation was not associated with increased risks of placental abruption (HR 0.94, 95% CI 0.75-1.16), severe maternal morbidity (OR 1.05, 0.97-1.11), postpartum haemorrhage (OR 0.98, 0.95-1.02), low Apgar score (OR 0.99, 0.87-1.08), small for gestational age (OR 0.90, 0.85-0.95), or neonatal abstinence syndrome (OR 0.98, 0.72-1.30). Risks were elevated for PPROM (HR 1.10, 0.98-1.23), preterm birth (HR 1.26, 1.19-1.33), severe neonatal morbidity (OR 1.08, 1.02-1.17), and perinatal death (OR 1.29, 1.10-1.52). Perinatal death estimates attenuated in analyses addressing potential reverse causation. Interpretation Using a TTE approach that accounted for gestational timing and time at risk, we found no appreciable increase in most maternal or neonatal outcomes following predominantly short-term opioid initiation. Elevated risks of preterm birth, perinatal death, and third-trimester PPROM may reflect causal effects or confounding by pregnancy-related indications. Studies using time-appropriate designs and detailed information on prescribing indications and their timing are needed to clarify these associations.

Background: Short birth intervals are a well-documented, modifiable risk factor for child death in low- and middle-income countries, yet nationally representative evidence from Ghana's most recent Demographic and Health Survey has not been fully examined. This study assessed the association between the preceding birth interval and under-five mortality using the 2022 Ghana Demographic and Health Survey. Methods: The analysis used the complete birth history reported by women aged 15-49 years. The cohort comprised births occurring 60-119 completed months (5-10 years) before the survey, which allowed a complete five-year observation window for under-five survival (n = 8,418; 397 deaths). Spacing models were restricted to second-or-higher-order births with a defined preceding interval (n = 6,340; 282 deaths), categorised as under 18, 18-23, 24-35 (reference), 36-47, and 48 or more months. Crude and adjusted odds ratios were estimated using survey-weighted, Taylor-linearised logistic regression, adjusting for birth order, child sex, plurality, maternal age, residence, region, maternal education, wealth quintile, and marital status. Results: Weighted under-five mortality in the cohort was 45.4 per 1,000 live births (4.54%). Among second-or-higher-order births, weighted mortality fell from 9.3% after intervals of under 18 months and 8.0% after 18-23 months to 4.2%, 3.2%, and 3.5% after 24-35, 36-47, and 48 or more months, respectively. Relative to 24-35 months, the adjusted odds of death were higher after intervals of under 18 months (adjusted odds ratio [AOR] 2.58, 95% confidence interval [CI] 1.48-4.49, p < 0.001) and 18-23 months (AOR 2.09, 95% CI 1.33-3.29, p = 0.001); longer intervals did not differ from the reference. Multiple birth (AOR 2.48, 95% CI 1.33-4.63) and having a mother who was never in union (AOR 3.25, 95% CI 1.29-8.17) were also associated with higher odds of death, and marked regional variation persisted after adjustment. Conclusion: A short preceding birth interval, particularly one of under 18 months, was independently associated with an approximately two- to two-and-a-half-fold increase in the odds of under-five death in this nationally representative sample. The findings support continued investment in postpartum family planning to help women space births at least 24 months apart, alongside closer attention to multiple births, unmarried mothers, and the regions carrying the greatest burden.