Inflammatory markers and their association with preeclampsia among pregnant women: A systematic review and meta-analysis.

The goal of this review was to investigate the levels of pro-inflammatory markers such as Tumour necrosis factor-α (TNF-α) Interlukin-6 (IL-6), C-reactive protein (CRP), Transforming growth factor-ß1 (TGF-ß1) and ferritin in pre-eclamptic and normotensive pregnant women. Using PubMed, ProQuest and Google Scholar databases, a literature search was carried out and case-control studies showing associations between inflammatory markers and preeclampsia in pregnancy published between 2010 and 2023 were included. The risk of bias was assessed by using the Newcastle Ottawa quality assessment scale. A random effect meta-analysis was performed and pooled difference in means with 95 % CI were reported. All statistical analyses were performed using R software. Out of 660 articles, 25 articles were included in the systematic review. The differences in means for TGF-ß1, CRP, ferritin and TNF-α levels between the preeclamptic women and normotensive women were 2.37 pg/mL [95 % CI: -1.66,6.39], 5.62 mg/L [95 % CI: -4.11,15.36], 32.93 ng/mL [95 % CI: -7.66,58.19] and 13.67 pg/mL [95 % CI: 4.20,23.14] respectively which showed moderate increase. The pooled differences in means for hs-CRP and IL-6 levels between the preeclamptic and normotensive women were 3.20 mg/L [95 % CI: 0.27,6.12] and 17.64 pg/mL [95 % CI: -8.36,43.64] respectively which showed significant increase. Sub-group analysis showed significant differences for CRP, ferritin and TNF-α levels across ethnicities. Meta-analysis demonstrates an increase in the maternal circulating levels of inflammatory markers such as hs-CRP, IL-6 and showed moderate increase in TGF-ß1, CRP, ferritin, TNF-α markers among women affected by preeclampsia compared to those with normotensive pregnancies.

Factors influencing the participation of pregnant and lactating women in clinical trials: A mixed-methods systematic review.

BACKGROUND: 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. METHODS AND FINDINGS: 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. CONCLUSIONS: 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.

Zinc Supplementation Initiated Prior to or During Pregnancy Modestly Impacted Maternal Status and High Prevalence of Hypozincemia in Pregnancy and Lactation: The Women First Preconception Maternal Nutrition Trial.

BACKGROUND: Data regarding effects of small-quantity-lipid-based nutrient supplements (SQ-LNS) on maternal serum zinc concentrations (SZC) in pregnancy and lactation are limited. OBJECTIVES: The objectives of this study were to evaluate the effect of preconception compared with prenatal zinc supplementation (compared with control) on maternal SZC and hypozincemia during pregnancy and early lactation in women in low-resource settings, and assess associations with birth anthropometry. METHODS: From ∼100 women/arm at each of 3 sites (Guatemala, India, and Pakistan) of the Women First Preconception Maternal Nutrition trial, we compared SZC at 12- and 34-wk gestation (n = 651 and 838, respectively) and 3-mo postpartum (n = 742) in women randomly assigned to daily SQ-LNS containing 15 mg zinc from ≥3 mo before conception (preconception, arm 1), from ∼12 wk gestation through delivery (early pregnancy, arm 2) or not at all (control, arm 3). Birth anthropometry was examined for newborns with ultrasound-determined gestational age. Statistical analyses were performed separately for each time point. RESULTS: At 12-wk gestation and 3-mo postpartum, no statistical differences in mean SZC were observed among arms. At 34-wk, mean SZC for arms 1 and 2 were significantly higher than for arm 3 (50.3, 50.8, 47.8 µg/dL, respectively; P = 0.005). Results were not impacted by correction for inflammation or albumin concentrations. Prevalence of hypozincemia at 12-wk (<56 µg/dL) was 23% in Guatemala, 26% in India, and 65% in Pakistan; at 34 wk (<50 µg/dL), 36% in Guatemala, 48% in India, and 74% in Pakistan; and at 3-mo postpartum (<66 µg/dL) 79% in Guatemala, 91% in India, and 92% in Pakistan. Maternal hypozincemia at 34-wk was associated with lower birth length-for-age Z-scores (all sites P = 0.013, Pakistan P = 0.008) and weight-for-age Z-scores (all sites P = 0.017, Pakistan P = 0.022). CONCLUSIONS: Despite daily zinc supplementation for ≥7 mo, high rates of maternal hypozincemia were observed. The association of hypozincemia with impaired fetal growth suggests widespread zinc deficiency in these settings. This trial is registered at clinicaltrials.gov as #NCT01883193.

Pd-catalysed synthesis of oxomalonamides through adjacent triple carbonylation of tertiary amines.

The monocarbonylation and dicarbonylation reactions are well-established reactions in carbonylation chemistry. This work reports unusual oxidative adjacent triple carbonylation of the tertiary amine towards oxomalonamide synthesis using a Pd catalyst. The protocol involves the use of inert tertiary amines as an active reservoir of secondary amines through sp3 C-N bond activation using O2 as an ideal oxidant.

Safety, Tolerability, and Pharmacokinetics of Single- and Multiple-Ascending Doses of Sunobinop in Healthy Participants.

Sunobinop is an investigational, potent, selective partial agonist at the nociceptin/orphanin FQ peptide receptor in vitro. Three phase 1 studies were conducted to evaluate the safety, tolerability, and pharmacokinetics (PK) of escalating single- and multiple-dose administration of sunobinop in healthy participants. Study 1 was a randomized, double-blind, placebo-controlled, single-ascending dose study. Study 2 was a randomized, double-blind, placebo-controlled, multiple-ascending dose study. Study 3 was a randomized, open-label, single-dose, 4-way crossover study of oral and sublingual sunobinop comparing morning (AM) and bedtime (PM) administration. Seventy participants were included. Systemic exposure (peak plasma concentration [Cmax], area under the plasma concentration-time curve from time 0 to the time of last quantifiable concentration [AUC0-t], and area under the plasma concentration-time curve from time 0 extrapolated to infinity [AUCinf]) of sunobinop was characterized by dose proportionality from 0.6 to 2 mg and increased less than proportionally from 3 to 30 mg. The PKs of sunobinop were similar, regardless of AM or PM administration, for both the oral and sublingual formulations. The majority of absorbed sunobinop was excreted unchanged in the urine within 8 hours of dosing, thereby showing rapid elimination with no appreciable accumulation following 14 consecutive days of once-daily dosing and suggesting exclusive renal elimination. Most treatment-emergent adverse events (TEAEs) were mild in severity; 1 severe TEAE occurred and all TEAEs resolved by the end of the studies. Sunobinop was generally well-tolerated and safe across the range of doses evaluated and presents a clinical profile suitable for continued development.

Evaluation of dermal toxicity and toxicokinetics of povidone­iodine in Göttingen minipigs.

BACKGROUND: Povidone­iodine (PVP-I) is an effective and commonly used broad-spectrum antiseptic; limited information exists around its long-term safety and impact on endocrine disruption. We assessed the dermal toxicity and toxicokinetics following a once-daily application of 7.5% (w/v) and 10% (w/v) PVP-I in Göttingen Minipigs® for up to 39 weeks. METHODS: An in vivo study was conducted in male (n = 27) and female (n = 27) minipigs. Animals were randomized into untreated control, 7.5% and 10% PVP-I, and matching vehicle treatment groups. Animals were assessed for general in-life measurements, including skin irritation and organ weights. Serum samples were analyzed for PVP, total iodine, triiodothyronine [T3], thyroxine [T4], thyroid stimulating hormone [TSH], and toxicokinetic parameters. RESULTS: Neither 7.5% nor 10% PVP-I affected general in-life measurements. Increased mean thyroid gland absolute weights were noted with 7.5% and 10% PVP-I. Serum levels of PVP, T3, T4, and TSH in the 7.5% and 10% PVP-I treatment group animals were similar to those in vehicle treatment group animals. Mean total serum iodine concentration was 52- and 13-fold higher with 7.5% and 10% PVP-I, respectively, vs respective vehicle treatments. There was no dose-dependent increase in mean maximum serum concentration and area under the curve from 0 to 24 h for PVP, T3, T4, and TSH, nor accumulation of PVP, T3, T4, or TSH in the study. CONCLUSION: Once-daily dermal application of 7.5% and 10% PVP-I for up to 39 weeks was safe and well tolerated in Göttingen Minipigs® and was not associated with skin irritation, thyroid dysfunction, or endocrine disruption. As the anatomy and physiology of the minipig skin closely resembles that of human skin, the findings of this study suggest that 7.5% and 10% PVP-I may be translated into antimicrobial benefits for humans without the risk of endocrine disruption.

The nociceptin/orphanin FQ receptor partial agonist sunobinop promotes non-REM sleep in rodents and patients with insomnia.

The potent and partial agonist sunobinop activates the nociceptin/orphanin-FQ peptide receptor and promotes non-REM sleep in rodents and patients with insomnia.

RAPIDIRON Trial follow-up study - the RAPIDIRON-KIDS Study: protocol of a prospective observational follow-up study.

BACKGROUND: Anemia is a worldwide problem with iron deficiency being the most common cause. When anemia occurs in pregnancy, it increases the risk of adverse maternal, fetal, and postnatal outcomes. It induces preterm births and low birth weight (LBW) deliveries, long-term neurodevelopmental sequelae, and an increased risk of earlier onset of postnatal iron deficiency. Anemia rates are among the highest in South Asia, and India's National Family Health Survey (NFHS-5) for 2019-2021 indicated that over half of pregnant women, and more than 65% of children, in the country are classified as anemic (Sciences IIfP, National Family Health Survey-5, 2019-21, India Fact Sheet). In 2021, the parent RAPIDIRON Trial (Derman et al., Trials 22:649, 2021) was initiated in two states in India, with the goal of assessing whether a dose of intravenous (IV) iron given to anemic women during early pregnancy results in a greater proportion of participants with normal hemoglobin concentrations in the third trimester and a lower proportion of participants with LBW deliveries compared to oral iron. As a follow-up to the RAPIDIRON Trial, the RAPIDIRON-KIDS Study will follow the offspring of previously randomized mothers to assess, neurobehavioral, hematological, and health outcomes. METHODS: This prospective observational cohort study will follow a subset of participants previously randomized as part of the RAPIDIRON Trial and their newborns. Study visits occur at birth, 6 weeks, 4 months, 12 months, 24 months, and 36 months and include blood sample collection with both maternal and infant participants and specific neurobehavioral assessments conducted with the infants (depending on the study visit). The primary outcomes of interest are (1) infant iron status as indicated by both hemoglobin and ferritin (a) at birth and (b) at 4 months of age and (2) the developmental quotient (DQ) for the cognitive domain of the Bayley Scales of Infant Development Version IV (BSID-IV) at 24 months of age. DISCUSSION: This RAPIDIRON-KIDS Study builds upon its parent RAPIDIRON Trial by following a subset of the previously randomized participants and their offspring through the first 3 years of life to assess neurodevelopmental and neurobehavioral (infants, children), hematological, and health outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT05504863 , Registered on 17 August 2022. Clinical Trials Registry - India CTRI/2022/05/042933 . Registered on 31 May 2022.

Pathophysiology and management of iron deficiency anaemia in pregnancy: a review.

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.

Placental inflammation and pregnancy outcomes: A prospective, observational study in South Asia: The PURPOSe study.

OBJECTIVE: To examine inflammatory lesions in placentas of stillbirths, preterm neonatal deaths and term controls in India and Pakistan. DESIGN: Prospective, observational study. SETTING: Three hospitals in India and a large maternity hospital in Pakistan. POPULATION: The enrolled participants with placentas available for histology evaluation included stillbirths (n = 814), preterm live births who died within 28 days of birth (n = 618) and term live birth controls (n = 201). From this same population, polymerase chain reaction (PCR) analysis for pathogens was performed on 809 stillbirth placentas, 614 neonatal death placentas and the placentas of 201 term controls. Placentas from preterm infants who lived beyond day 28 (n = 1432) were only available from India. METHODS: A prospective observational study of placental inflammatory lesions defined by the Amsterdam criteria and on the same placentas, multiplex PCR evaluation for 75 pathogens using TaqMan Array Cards. MAIN OUTCOME MEASURES: Any placental inflammatory lesions, including chorioamnionitis, funisitis, villitis and intervillitis and their association with various pathogens. RESULTS: In the Indian liveborn preterm infants, placental inflammation of any kind was present in 26.2% of those who died versus 16.6% of those who lived (p = 0.0002). Chorioamnionitis was present in 25.8% of those who died versus 16.3% of those who lived (p = 0.0002) and funisitis was present in 4.1% of those who died versus 1.5% of those who lived, (p = 0.005). Across all three sites, in the placentas of the 201 term controls, 18.9% had any inflammation, 16.9% had chorioamnionitis, 5.5% had funisitis, 0.5% had intervillitis and none had villitis. Overall, for stillbirths, any inflammation was observed in 30.2%, chorioamnionitis in 26.9%, funisitis in 5.7%, intervillitis in 6.0% and villitis in 2.2%. For the neonatal deaths, any inflammation was present in 24.9%, chorioamnionitis in 23.3%, funisitis in 8.1%, intervillitis in 1.9% and villitis in 0.5%. Compared with the placentas of term controls, in neonatal deaths, only chorioamnionitis was significantly increased (23.3% versus 16.9%, p = 0.05). Among stillbirths, the rates of any inflammation, chorioamnionitis, intervillitis and villitis were similar across the birthweight groups. However, funisitis was more common in the placentas of stillborn fetuses weighing 2500 g or more (13.8%) compared with 1.0% for those weighing less than 1000 g and 4.8% for stillborn fetuses weighing 1000-2499 g. In the PCR studies, Ureaplasma spp. were by far the most common pathogens found and generally were more commonly found in association with inflammatory lesions. CONCLUSIONS: Chorioamnionitis was the most common type of placental inflammatory lesion regardless of whether the placentas evaluated were from term controls, stillbirths or neonatal deaths. For stillbirths, inflammation in each inflammation category was more common than in the term controls and significantly more so for any inflammation, chorioamnionitis, intervillitis and villitis. For neonatal deaths, compared with the placentas of term controls, all inflammation categories were more common, but only significantly so for chorioamnionitis. Ureaplasma spp. were the most common organisms found in the placentas and were significantly associated with inflammation.

Group B streptococcal prevalence in internal organs and placentas of deceased neonates and stillbirths in South Asia.

OBJECTIVE: Group B streptococcus (GBS) has been associated with adverse pregnancy outcomes, but few prospective studies have assessed its prevalence in low- and middle-income country settings. We sought to evaluate the prevalence of GBS by polymerase chain reaction (PCR) in internal organ tissues and placentas of deceased neonates and stillbirths. DESIGN: This was a prospective, observational study. SETTING: The study was conducted in hospitals in India and Pakistan. POPULATION: Pregnant women with stillbirths or preterm births were recruited at delivery, as was a group of women with term, live births, to serve as a control group. METHODS: A rectovaginal culture was collected from the women in Pakistan to assess GBS carriage. Using PCR, we evaluated GBS in various tissues of stillbirths and deceased neonates and their placentas, as well as the placentas of live-born preterm and term control infants. MAIN OUTCOME MEASURES: GBS identified by PCR in various tissues and the placentas; rate of stillbirths and 28-day neonatal deaths. RESULTS: The most obvious finding from this series of analyses from India and Pakistan was that no matter the country, the condition of the subject, the tissue studied or the methodology used, the prevalence of GBS was low, generally ranging between 3% and 6%. Among the risk factors evaluated, only GBS positivity in primigravidae was increased. CONCLUSIONS: GBS diagnosed by PCR was identified in <6% of internal organs of stillbirths and neonatal deaths, and their placentas, and control groups in South Asian sites. This is consistent with other reports from South Asia and is lower than the reported GBS rates from the USA, Europe and Africa.

Morphological study of the placenta in deliveries with pre-eclampsia: Results from a prospective, observational study in India and Pakistan (PURPOSe).

OBJECTIVE: To compare placental findings in women with and without pre-eclampsia. DESIGN: The PURPOSe study included women with stillbirths, women with preterm births and women at term as controls. The placenta of each case was evaluated using the Amsterdam criteria. SETTING: Two sites and five tertiary care hospitals of south Asia (Three in India and two in Pakistan). POPULATION: Pregnancies in India and Pakistan with placental histology including women with documented hypertension and documented proteinuria and women with neither hypertension nor proteinuria. METHODS: We compared the placental findings of the two groups using the Amsterdam criteria and further evaluated the placental findings in women with and without pre-eclampsia who had a stillbirth, preterm live birth, or term live birth (control). MAIN OUTCOME MEASURES: The main outcome measures were the frequency of maternal and fetal vascular malperfusion and the frequency of placental inflammation and its components, chorioamnionitis, funisitis, villitis and intervillitis in women with and without pre-eclampsia. RESULTS: A total of 733 women had pre-eclampsia and 2334 women had neither hypertension nor proteinuria. In the placentas of women with pre-eclampsia, 57.3% had maternal vascular malperfusion compared with 37.1% in women without pre-eclampsia (p < 0.0001). There was not a significant difference in the prevalence of fetal vascular hypertension between mothers with (17.1%) and without (14.8%, p = 0.6118) pre-eclampsia. When placentas were classified as 'histologically normal' or not, 61.3% of those from pre-eclamptic pregnancies were classified as abnormal, whereas if there was no pre-eclampsia, only 45.0% were classified as histologically abnormal (p < 0.0001). We also considered rates of placental maternal vascular malperfusion in women with and without pre-eclampsia with stillbirth, preterm neonatal death, and term live birth. In women at term with no pre-eclampsia, 16.7% of the placentas had features of maternal vascular malperfusion. This occurred in 79.9% of women with stillbirths with pre-eclampsia compared with 51.8% of those without pre-eclampsia. Maternal vascular malperfusion was present in 49.7% of preterm live births with pre-eclampsia compared with 33.8% without pre-eclampsia. We also evaluated the inflammatory lesions by whether the mother had or did not have pre-eclampsia. When all inflammatory lesions were considered, women with pre-eclampsia had significantly fewer inflammatory lesions than those women without pre-eclampsia (17.1% versus 23.6% p = 0.001). Each of the specific inflammatory lesions was less common in placentas of women with pre-eclampsia than those with chorioamnionitis (16.1% versus 21.9%, p = 0.004) and funisitis (1.5% versus. 5.1%, p = 0.0004). CONCLUSIONS: Of placental lesions in women with pre-eclampsia, maternal vascular malperfusion was the most common. Inflammatory lesions were less common in women with pre-eclampsia.

Associations between ambient temperature and pregnancy outcomes from three south Asian sites of the Global Network Maternal Newborn Health Registry: A retrospective cohort study.

OBJECTIVE: Growing evidence suggests that environmental heat stress negatively influences fetal growth and pregnancy outcomes. However, few studies have examined the impact of heat stress on pregnancy outcomes in low-resource settings. We combined data from a large multi-country maternal-child health registry and meteorological data to assess the impacts of heat stress. DESIGN: Retrospective cohort study. SETTING: Three sites based in south Asia as part of the Global Network for Women's and Children's Health research in India (Belagavi and Nagpur) and Pakistan (Thatta). POPULATION OR SAMPLE: Data from women enrolled between 2014 and 2020 in the Global Network's Maternal Newborn Health Registry (MNHR), a prospective, population-based registry of pregnancies, were used. METHODS: A total of 126 273 pregnant women were included in this analysis. Daily maximal air temperatures (Tmax ) were acquired from local meteorological records. Associations between averages of daily maximal temperatures for each trimester and main outcomes were analysed using a modified Poisson regression approach. MAIN OUTCOMES MEASURES: Incidence of stillbirth, preterm birth, low birthweight (<2500 g) or evidence of pregnancy hypertension or pre-eclampsia. RESULTS: In the overall cohort, risk of preterm birth was positively associated with greater temperature in the second trimester (relative risk [RR] 1.05, 95% CI 1.02-1.07, p = 0.0002). Among individual sites, the risk of preterm birth was greatest in Nagpur (RR 1.07, 95% CI 1.03-1.11, p = 0.0005) and associated with second-trimester temperature. The overall risk of low birthweight was associated with ambient temperature in second trimester (RR 1.02, 95% CI 1.01-1.04, p = 0.01). The risk for LBW was associated with first-trimester heat in Thatta and with second-trimester heat in Nagpur. Finally, the overall risk of gestational hypertensive disease was associated with greater temperature in the third trimester among all sites (RR 1.07, 95% CI 1.02-1.12, p = 0.005) and was particularly significant for Nagpur (RR 1.13, 95% CI 1.05-1.23, p = 0.002). These findings highlight the increased risk of detrimental obstetric and neonatal outcomes with greater temperature. CONCLUSION: In a multi-country, community-based study, greater risk of adverse outcomes was observed with increasing temperature. The study highlights the need for deeper understanding of covarying factors and intervention strategies, especially in regions where high temperatures are common.

The PURPOSe cause of death study in stillbirths and neonatal deaths in India and Pakistan: A review.

The PURPOSe study was a prospective, observational study conducted in India and Pakistan to determine the cause of death for stillbirths and preterm neonatal deaths, using clinical data together with minimally invasive tissue sampling (MITS) and the histologic and polymerase chain reaction (PCR) evaluation of fetal/neonatal tissues and the placenta. After evaluating all available data, an independent panel chose a maternal, a placental and a fetal/neonatal cause of death. Here, we summarise the major results. Among the most important findings were that most stillbirths were caused by fetal asphyxia, often preceded by placental malperfusion, and clinically associated with pre-eclampsia, placental abruption and a small-for-gestational-age fetus. The preterm neonatal deaths were primarily caused by birth asphyxia, followed by various infections. An important finding was that many of the preterm neonatal deaths were caused by a nosocomial infection acquired after neonatal intensive care (NICU) admission; the most common organisms were Acinetobacter baumannii, followed by Klebsiella pneumoniae, Escherichia coli/Shigella and Haemophilus influenzae. Group B streptococcus was less commonly present in the placentas or internal organs of the neonatal deaths.

Neonatal mortality among preterm infants admitted to neonatal intensive care units in India and Pakistan: A prospective study.

OBJECTIVE: To explore potential reasons for differences in preterm neonatal mortality in neonatal intensive care units (NICUs) in India and Pakistan. DESIGN: A prospective observational study, the Project to Understand and Research Stillbirth and Preterms in Southeast Asia (PURPOSe) was conducted July 2018 to February 2020. SETTING: Three hospitals in Davangere, India, and a large public hospital in Karachi, Pakistan. POPULATION: Of a total of 3,202 preterm infants enrolled, 1,512 were admitted to a study NICU. METHODS: We collected data for neonates, including length of stay, diagnoses, and diagnostic tests. MAIN OUTCOME MEASURES: Neonatal mortality, tests performed, diagnoses ascertained. RESULTS: For infants of equivalent weights and gestational ages, neonatal mortality in Pakistan was twice that in the Indian NICU. The mean newborn length of stay in Pakistan was 2 days compared with 10 days for India. Fewer diagnostics and other investigations were used to determine neonatal condition or guide treatment in the Pakistani NICU. Because of limited information from testing in Pakistan concerning clinical respiratory distress, respiratory distress syndrome appeared to be over-diagnosed, whereas other conditions including pneumonia, sepsis, necrotising entercolitis and intraventricular haemorrhage were rarely diagnosed. CONCLUSION: In the Pakistani site, the limited resources available to the NICU appeared related to a shorter length of stay and decreased diagnostic testing, likely explaining the higher mortality. With improved care, reduction in mortality among preterm neonates should be achievable.

Pregnancy outcomes in preterm multiple gestations: Results from a prospective study in India and Pakistan (PURPOSe).

OBJECTIVE: To evaluate perinatal outcomes in preterm multiple compared with singleton pregnancies in India and Pakistan. DESIGN: Prospective, observational study. SETTINGS: Study hospitals in India and Pakistan. POPULATION: We evaluated 3897 preterm pregnancies. These mothers gave birth to 3615 (92.8%) singleton infants, 267 (6.8%) sets of twins, 14 (0.4%) sets of triplets and one set of quadruplets. MAIN OUTCOME MEASURES: Neonatal mortality, stillbirth, cause of death. RESULTS: Of the singleton infants, 691 (19.1%) were stillborn and 2924 (80.9%) live born. Of the 534 infants from twin pregnancies, 41 (7.7%) were stillborn and 493 (92.3%) were live born. Of the 267 sets of twins, in 14 cases (5.2%) both were stillborn, in 13 cases (4.8%) one was stillborn and one live born, and in 240 cases (90.0%) both were live born. In both preterm twins and preterm singletons, the three most common causes of death were intrauterine hypoxia, infections acquired prior to birth and infections acquired at or after birth. The preterm twins appeared less likely to have died from intrauterine hypoxia but more likely to have died from infections acquired at or after birth. Respiratory distress syndrome (RDS) was less likely considered by the panel to be the primary cause of death in either the twins (9.6%) or singletons (9.7%). Congenital anomalies were also not often judged to be the cause of death in either the preterm twins 2 (2.4%) or singletons 27 (5.3%). CONCLUSION: In the PURPOSe study, neonatal mortality rates in preterm twins compared with singletons when evaluated by sex, GA, birthweight and SGA, were generally similar to rates of preterm singleton neonatal mortality in those groups. Thus, the higher rate of mortality in live-born twin infants is related to the fact that these infants were more likely to be born earlier rather than to any inherent characteristics of the babies themselves.

COVID-19 symptoms and antibody positivity among unvaccinated pregnant women: An observational study in seven countries from the Global Network.

OBJECTIVE: To determine the relation of COVID-19 symptoms to COVID-19 antibody positivity among unvaccinated pregnant women in low- and middle-income countries (LMIC). DESIGN: COVID-19 infection status measured by antibody positivity at delivery was compared with the symptoms of COVID-19 in the current pregnancy in a prospective, observational cohort study in seven LMICs. SETTING: The study was conducted among women in the Global Network for Women's and Children's Health's Maternal and Newborn Health Registry (MNHR), a prospective, population-based study in Kenya, Zambia, the Democratic Republic of the Congo (DRC), Bangladesh, Pakistan, India (Belagavi and Nagpur sites) and Guatemala. POPULATION: Pregnant women enrolled in the ongoing pregnancy registry at study sites. METHODS: Data on COVID-19 symptoms during the current pregnancy were collected by trained staff between October 2020 and June 2022. COVID-19 antibody testing was performed on samples collected at delivery. The relation between COVID-19 antibody positivity and symptoms was assessed using generalised linear models with a binomial distribution adjusting for site and symptoms. MAIN OUTCOME MEASURES: COVID-19 antibody status and symptoms of COVID-19 among pregnant women. RESULTS: Among 19 218 non-vaccinated pregnant women who were evaluated, 14.1% of antibody-positive women had one or more symptoms compared with 13.4% in antibody-negative women. Overall, 85.3% of antibody-positive women reported no COVID-19 symptoms during the present pregnancy. Reported fever was significantly associated with antibody status (relative risk [RR] 1.10, 95% CI 1.03-11.18; P = 0.008). A multiple variable model adjusting for site and all eight symptoms during pregnancy showed similar results (RR 1.13, 95% CI 1.04-1.23; P = 0.012). None of the other symptoms was significantly related to antibody positivity. CONCLUSIONS: In a population-based cohort in LMICs, unvaccinated pregnant women who were antibody-positive had slightly more symptoms during their pregnancy and a small but significantly greater increase in fever. However, for prevalence studies, evaluating COVID-19-related symptoms does not appear to be useful in differentiating pregnant women who have had a COVID-19 infection.

Aspirin delays the onset of hypertensive disorders of pregnancy among nulliparous pregnant women: A secondary analysis of the ASPIRIN trial.

OBJECTIVE: To assess the impact of low-dose aspirin (LDA) starting in early pregnancy on delaying preterm hypertensive disorders of pregnancy. DESIGN: Non-prespecified secondary analysis of a randomised masked trial of LDA. SETTING: The study was conducted among women in the Global Network for Women's and Children's Health's Maternal and Newborn Health Registry (MNHR) clusters, a prospective, population-based study in Kenya, Zambia, the Democratic Republic of the Congo (DRC), Pakistan, India (two sites-Belagavi and Nagpur) and Guatemala. POPULATION: Nulliparous singleton pregnancies between 6+0 weeks and 13+6 weeks in six low-middle income countries (Democratic Republic of Congo, Guatemala, India, Kenya, Pakistan, Zambia) enrolled in the ASPIRIN Trial. METHODS: We compared the incidence of HDP at delivery at three gestational age periods (<28, <34 and <37 weeks) between women who were randomised to aspirin or placebo. Women were included if they were randomised and had an outcome at or beyond 20 weeks (Modified Intent to Treat). MAIN OUTCOME MEASURES: Our primary outcome was pregnancies with HDP associated with preterm delivery (HDP@delivery) before <28, <34 and <37 weeks. Secondary outcomes included small for gestational age (SGA) <10th percentile, <5th percentile, and perinatal mortality. RESULTS: Among the 11 976 pregnancies, LDA did not significantly lower HDP@delivery <28 weeks (relative risk [RR] 0.18, 95% confidence interval [CI] 0.02-1.52); however, it did lower HDP@delivery <34 weeks (RR 0.37, 95% CI 0.17-0.81) and HDP@delivery <37 weeks (RR 0.66, 95% CI 0.49-0.90). The overall rate of HDP did not differ between the two groups (RR 1.08, 95% CI 0.94-1.25). Among those pregnancies who had HDP, SGA <10th percentile was reduced (RR 0.81, 95% CI 0.67-0.99), though SGA <5th percentile was not (RR 0.84, 95% CI 0.64-1.09). Similarly, perinatal mortality among pregnancies with HDP occurred less frequently (RR 0.55, 95% CI 0.33-0.92) in those receiving LDA. Pregnancies randomised to LDA delivered later with HDP compared with those receiving placebo (median gestational age 38.5 weeks vs. 37.9 weeks; p = 0.022). CONCLUSIONS: In this secondary analysis of a study of low-risk nulliparous singleton pregnancies, early administration of LDA resulted in lower rates of preterm HDP and delivery before 34 and 37 weeks but not in the overall rate of HDP. These results suggest that LDA works in part by delaying HDP.

Cu-Mediated Tandem 2,3-Disubstituted Indole Synthesis from Simple Anilines and Internal Alkynes via C-H Annulation.

A simple, cost-effective, and straightforward method for the synthesis of 2,3-disubstituted indole scaffolds has been developed. The present protocol involves copper-mediated tandem hydroamination followed by C-H annulation of unprotected anilines with a wide range of internal alkynes. In the presence of Cu(OAc)2·H2O and trifluoroacetic acid (TFA), the reaction proceeds well to afford a variety of substituted indole derivatives in moderate to good yields. This process was found to be compatible with both primary and secondary anilines coupled with aromatic/aliphatic alkynes. High-purity copper nanoparticles can be recovered after the reaction, revealing the cost-effectiveness and environmentally benign feature of the current protocol.