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Poor representation of pregnant and lactating women and people in clinical trials has marginalised their health concerns and denied the maternal-fetal/infant dyad benefits of innovation in therapeutic research and development. This mixed-methods systematic review synthesised factors affecting the participation of pregnant and lactating women in clinical trials, across all levels of the research ecosystem. We searched 8 databases from inception to 14 February 2024 to identify qualitative, quantitative, and mixed-methods studies that described factors affecting participation of pregnant and lactating women in vaccine and therapeutic clinical trials in any setting. We used thematic synthesis to analyse the qualitative literature and assessed confidence in each qualitative review finding using the GRADE-CERQual approach. We compared quantitative data against the thematic synthesis findings to assess areas of convergence or divergence. We mapped review findings to the Theoretical Domains Framework (TDF) and Capability, Opportunity, and Motivation Model of Behaviour (COM-B) to inform future development of behaviour change strategies. We included 60 papers from 27 countries. We grouped 24 review findings under 5 overarching themes: (a) interplay between perceived risks and benefits of participation in women's decision-making; (b) engagement between women and the medical and research ecosystems; (c) gender norms and decision-making autonomy; (d) factors affecting clinical trial recruitment; and (e) upstream factors in the research ecosystem. Women's willingness to participate in trials was affected by: perceived risk of the health condition weighed against an intervention's risks and benefits, therapeutic optimism, intervention acceptability, expectations of receiving higher quality care in a trial, altruistic motivations, intimate relationship dynamics, and power and trust in medicine and research. Health workers supported women's participation in trials when they perceived clinical equipoise, had hope for novel therapeutic applications, and were convinced an intervention was safe. For research staff, developing reciprocal relationships with health workers, having access to resources for trial implementation, ensuring the trial was visible to potential participants and health workers, implementing a woman-centred approach when communicating with potential participants, and emotional orientations towards the trial were factors perceived to affect recruitment. For study investigators and ethics committees, the complexities and subjectivities in risk assessments and trial design, and limited funding of such trials contributed to their reluctance in leading and approving such trials. All included studies focused on factors affecting participation of cisgender pregnant women in clinical trials; future research should consider other pregnancy-capable populations, including transgender and nonbinary people. This systematic review highlights diverse factors across multiple levels and stakeholders affecting the participation of pregnant and lactating women in clinical trials. By linking identified factors to frameworks of behaviour change, we have developed theoretically informed strategies that can help optimise pregnant and lactating women's engagement, participation, and trust in such trials.

Prophylactic oral azithromycin vs. placebo reduced maternal, but not neonatal, mortality/sepsis in the A-PLUS Randomized Trial. While prophylactic intrapartum azithromycin reduces maternal mortality/sepsis, it may promote antimicrobial resistance (AMR) in commensal bacteria,. Randomly selected women and their infants participating in A-PLUS were enrolled in a longitudinal cross-sectional sub-study to assess the presence of azithromycin resistance in selected bacteria in nasal cultures. Staphylococcus aureus and Streptococcus pneumoniae were cultured on selective agar, then azithromycin-containing agar to select for azithromycin resistant bacteria, identified biochemically. Azithromycin susceptibility was assessed by E-test. Nasal cultures were collected from women and infants between August 11, 2021 and September 18, 2023 during labor/day 1, day 7, 6 weeks, and 3, 6 and 12 months after delivery. The study enrolled 911 women and 915 liveborn infants at 8 sites in 7 countries. Azithromycin resistance in S aureus was higher and azithromycin susceptibility was lower in women receiving azithromycin compared with those receiving placebo on day 7 (P < 0.001), 6 weeks (P < 0.001) and 3 months (P = 0.009) after delivery. Azithromycin resistance in S aureus was also higher and azithromycin susceptibility was lower 6 weeks after delivery (P < 0.001) in infants born to women receiving azithromycin, Azithromycin resistance in S. pneumoniae was too sparse to interpret. There was an increase in prevalence of azithromycin resistance (or reduction in azithromycin susceptibility) in commensal nasal S. aureus between day 7, 6 weeks and 3 months in women exposed to azithromycin vs. placebo and only at 6 weeks in infants exposed to azithromycin vs. placebo. These differences between the azithromycin and placebo groups were no longer detected at 6 and 12 months post-partum in the women and after 6 weeks through 12 months in the infants.

IntroductionAntenatal corticosteroid (ACS) regimens have remained unchanged since the initial trials in 1972, with the optimal regimen still undetermined. The WHO ACTION (Antenatal CorticosTeroids for Improving Outcomes in preterm Newborns)-III trial is a three-arm individually randomised double-blind trial evaluating the efficacy and safety of two different ACS dosing regimens (currently used and lower-dose ACS regimens vs placebo) in women with a high probability of having a late preterm birth. This study protocol nested within this trial aims to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) effects of two different ACS dosing regimens in pregnant women in the late preterm period (34–36 weeks) to help inform an optimal dosing regimen.Methods and analysisThe study will be conducted in two of the five countries participating in the WHO ACTION-III trial—India (Delhi, Belagavi) and Nigeria (Ibadan and Ile-Ife). We will use a population PK approach using sparse sampling to study the PK effects of the two ACS regimens, that is, 6 mg dexamethasone phosphate (DEXp) or 2 mg betamethasone phosphate (BETp), administered intramuscularly every 12 hours for a maximum of four doses or till birth, whichever is earlier, compared with placebo. We will also ascertain the fetal–maternal ratio of DEXp and BETp at birth.Maternal venous blood samples will be collected at 0, 1–4 hours, 8–12 hours after the first dose, and at 24–36 hours, 48–60 hours, 72–96 hours after the last dose, and immediately after birth, along with cord blood. Concentrations of DEXp and BETp will be measured at set time points using a validated liquid chromatography mass spectroscopy assay. PD parameters measured will include total and differential white blood cell count (by automated analysers using electrical impedance), plasma glucose (hexokinase method) and serum cortisol (using a validated electrochemiluminescence immunoassay), at predefined time points. PK models will be developed for each drug using non-linear mixed effects methods. Optimal dosing will be investigated using Monte Carlo simulations.Ethics and disseminationThe study has been approved by the WHO Ethics Review Committee and the site-specific ethics committees of the participating leading institutions. Written informed consent will be obtained from all participants. The study results will be published in a peer-reviewed journal and presented at scientific conferences.Trial registration numberISRCTN11434567.

Adverse pregnancy outcomes (APOs) such as prematurity, low birth weight, stillbirth, and birth defects remain significant global health challenges. While many risk factors are known, APOs encompass a wide range of outcomes with diverse, sometimes poorly understood etiologies. Pregnancy-related acute kidney injury (PR-AKI) and liver injury are particularly associated with increased maternal and fetal mortality. This study investigated the association between hematological parameters, kidney and liver injury markers and adverse pregnancy outcomes. This cross-sectional study involved 714 pregnant women aged 18–40 years, conducted between August 2021 and August 2022. Maternal blood samples were collected before and after delivery to compare hematological parameters. Kidney and liver injury markers were measured using standard methods. The study analysed the association of these parameters with adverse pregnancy outcomes. The median age of participants was 24 years (Q1, Q3: 21, 26). Women with adverse pregnancy outcomes had statistically significant serum creatinine levels [0.52 mg/dL (0.45, 0.58)] compared to those without [0.50 mg/dL (0.44, 0.56)], although the difference was not clinically significant. Elevated Aspartate Transaminase (AST) levels (>90th percentile) were statistically associated with adverse pregnancy outcomes. Pairwise comparisons with Bonferroni corrections revealed significant differences in Hemoglobin (Hb), White Blood Cell (WBC), Red Blood Cell (RBC), platelet, and Packed Cell Volume (PCV) levels before and after delivery (p < 0.05) in both groups. Elevated AST levels, but not other hematological or biochemical parameters, were independently associated with adverse pregnancy outcomes, whereas creatinine differences lacked clinical impact.

Background Few studies have shown how the move toward institutional delivery in low and middle-income countries (LMIC) impacts stillbirth and newborn mortality. Objectives The study evaluated trends in institutional delivery in research sites in Belagavi and Nagpur India, Guatemala, Kenya, Pakistan, and Zambia from 2010 to 2018 and compared them to changes in the rates of neonatal mortality and stillbirth. Methods We analyzed data from a nine-year interval captured in the Global Network (GN) Maternal Newborn Health Registry (MNHR). Mortality rates were estimated from generalized estimating equations controlling for within-cluster correlation. Cluster-level analyses were performed to assess the association between institutional delivery and mortality rates. Results From 2010 to 2018, a total of 413,377 deliveries in 80 clusters across 6 sites in 5 countries were included in these analyses. An increase in the proportion of institutional deliveries occurred in all sites, with a range in 2018 from 57.7 to 99.8%. In 2010, the stillbirth rates ranged from 19.3 per 1000 births in the Kenyan site to 46.2 per 1000 births in the Pakistani site and by 2018, ranged from 9.7 per 1000 births in the Belagavi, India site to 40.8 per 1000 births in the Pakistani site. The 2010 neonatal mortality rates ranged from 19.0 per 1000 live births in the Kenyan site to 51.3 per 1000 live births in the Pakistani site with the 2018 neonatal mortality rates ranging from 9.2 per 1000 live births in the Zambian site to 50.2 per 1000 live births in the Pakistani site. In multivariate modeling, in some but not all sites, the reductions in stillbirth and neonatal death were significantly associated with an increase in the institutional deliveries. Conclusions There was an increase in institutional delivery rates in all sites and a reduction in stillbirth and neonatal mortality rates in some of the GN sites over the past decade. The relationship between institutional delivery and a decrease in mortality was significant in some but not all sites. However, the stillbirth and neonatal mortality rates remain at high levels. Understanding the relationship between institutional delivery and stillbirth and neonatal deaths in resource-limited environments will enable development of targeted interventions for reducing the mortality burden. Trial registration The study is registered at clinicaltrials.gov . ClinicalTrial.gov Trial Registration: NCT01073475 .

Systematic under-representation of pregnant women and gender diverse pregnant people in clinical research has prevented them from benefitting fairly from biomedical advances. The resulting lack of pharmacological safety and efficacy data leads to medicine discontinuation, sub-optimal dosing, and reliance on repurposed therapies. We identify four roadblocks to fair inclusion. First, investment and research are inhibited by protectionist attitudes among research gatekeepers who view pregnancy as a vulnerable state. Second, exclusion ignores human-specific biological variations affecting medication absorption and impacts on the pregnant body. Third, pregnant populations in low-and middle-income countries face a double disadvantage due to gender and location, despite bearing a disproportionate maternal mortality burden. Fourth, perspectives and experiences of pregnant populations are undervalued in clinical intervention design. We propose five actions to optimize fair inclusion: fostering reciprocal partnerships, prioritizing multi-disciplinary research, awareness-raising of the need for pharmaceutical innovation, conducting regulatory analyses, and promoting responsible inclusion over presumptive exclusion. Shankar et al. discuss how to better undertake research and assure health interests of pregnant women and gender diverse pregnant people. Their recommendations include growing research and regulatory partnerships and innovation, plus promoting responsible inclusion in place of presumptive exclusion.

Maternal iodine (I) status is critical in embryonic and foetal development. We examined the effect of preconception iodine supplementation on maternal iodine status and on birth outcomes. Non‐pregnant women in Guatemala, India and Pakistan (n ~ 100 per arm per site) were randomized ≥ 3 months prior to conception to one of three intervention arms: a multimicronutrient‐fortified lipid‐based nutrient supplement containing 250‐μg I per day started immediately after randomization (Arm 1), the same supplement started at ~12 weeks gestation (Arm 2) and no intervention supplement (Arm 3). Urinary I (μg/L) to creatinine (mg/dl) ratios (I/Cr) were determined at 12 weeks for Arm 1 versus Arm 2 (before supplement started) and 34 weeks for all arms. Generalized linear models were used to assess the relationship of I/Cr with arm and with newborn anthropometry. At 12 weeks gestation, adjusted mean I/Cr (μg/g) for all sites combined was significantly higher for Arm 1 versus Arm 2: (203 [95% CI: 189, 217] vs. 163 [95% CI: 152, 175], p < 0.0001). Overall adjusted prevalence of I/Cr < 150 μg/g was also lower in Arm 1 versus Arm 2: 32% (95% CI: 26%, 38%) versus 43% (95% CI: 37%, 49%) (p = 0.0052). At 34 weeks, adjusted mean I/Cr for Arm 1 (235, 95% CI: 220, 252) and Arm 2 (254, 95% CI: 238, 272) did not differ significantly but were significantly higher than Arm 3 (200, 95% CI: 184, 218) (p < 0.0001). Nominally significant positive associations were observed between I/Cr at 12 weeks and birth length and head circumference z‐scores (p = 0.028 and p = 0.005, respectively). These findings support the importance of first trimester iodine status and suggest need for preconception supplementation beyond salt iodization alone.

Background Obstetric haemorrhage continues to be a leading cause of maternal mortality, contributing to more than a quarter of the 2,443,000 maternal deaths reported between 2003 and 2009. During this period, about 70% of the haemorrhagic deaths occurred postpartum. In addition to other identifiable risk factors for greater postpartum blood loss, the duration of the third stage of labour (TSL) seems to be important, as literature shows that a longer TSL can be associated with more blood loss. To better describe the association between the duration of TSL and postpartum blood loss in women receiving active management of third stage of labour (AMTSL), this secondary analysis of the WHO CHAMPION trial data has been conducted. Methods This was a secondary analysis of the WHO CHAMPION trial conducted in twenty-three sites in ten countries. We studied the association between the TSL duration and blood loss in the sub cohort of women from the CHAMPION trial (all of whom received AMTSL), with TSL upto 60 min and no interventions for postpartum haemorrhage. We used a general linear model to fit blood loss as a function of TSL duration on the log scale, arm and center, using a normal distribution and the log link function. We showed this association separately for oxytocin and for Heat stable (HS) carbetocin. Results For the 10,040 women analysed, blood loss rose steeply with third stage duration in the first 10 min, but more slowly after 10 min. This trend was observed for both Oxytocin and HS carbetocin and the difference in the trends for both drugs was not statistically significant (p-value = 0.2070). Conclusions There was a positive association between postpartum blood loss and TSL duration with either uterotonic. Blood loss rose steeply with TSL duration until 10 min, and more slowly after 10 min. Study registration The main trial was registered with Australian New Zealand Clinical Trials Registry ACTRN12614000870651 and Clinical Trial Registry of India CTRI/2016/05/006969 Plain Language Summary The duration of the third stage of labour (TSL) seems to be an important risk factor for greater postpartum blood loss, as literature shows that a longer TSL can be associated with more blood loss. Active management of third stage of labour (AMTSL), included in the WHO guidelines for prevention of postpartum haemorrhage (PPH), is effective in reducing both the amount of postpartum blood loss and the duration of the third stage. To better describe the association between duration of TSL and postpartum blood loss in women receiving AMTSL, we conducted this secondary analysis of WHO CHAMPION trial data. To assess the association between the duration of third stage of labour and postpartum blood loss, a subcohort of the CHAMPION modified ITT population was selected by excluding women with missing blood loss or missing TSL duration or TSL duration more than 60 min and women with interventions. Thus, the subcohort consisted of 10,040 women. In women with vaginal birth and not receiving interventions for treating atonic PPH or other sources of bleeding, and with TSL duration up to 60 min, there was a positive association between duration of the TSL and postpartum blood loss. The blood loss rose steeply with duration in women with TSL of 10 min or less, while in women with longer TSL duration the slope was less steep. There was no evidence of a difference between oxytocin and HS carbetocin in the pattern of association of duration of the TSL and blood loss.

According to World Health Organization (WHO), iron deficiency anaemia (IDA) is considered the most prevalent nutritional deficiency worldwide, affecting approximately 30% of the global population. While gastrointestinal bleeding and menstruation in women are the primary causes of IDA, insufficient dietary iron intake and reduced iron absorption contribute to the condition. The aim of IDA treatment is to restore iron stores and normalise haemoglobin levels in affected patients. Iron plays a critical role in various cellular mechanisms, including oxygen delivery, electron transport, and enzymatic activity. During pregnancy, the mother’s blood volume increases, and the growing foetus requires a significant increase in iron. Iron deficiency during pregnancy is associated with adverse outcomes such as maternal illness, low birth weight, preterm birth, and intrauterine growth restriction. Iron supplementation is commonly used to treat IDA; however, not all patients benefit from this therapy due to factors such as low compliance and ineffectiveness. In the past, IV iron therapy was underutilised due to its unfavourable and occasionally unsafe side effects. Nevertheless, the development of new type II and III iron complexes has improved compliance, tolerability, efficacy, and safety profiles. This article aims to provide an updated overview of the diagnosis and management of IDA during pregnancy. It will discuss the advantages and limitations of oral versus intravenous iron and the pathophysiology, diagnosis, treatment, and overall management of IDA in pregnancy.