Anthropometric and sociodemographic variables, but not preconception or prenatal maternal nutrition supplementation, predict neurodevelopment in offspring of the 'Women First' trial.

Multiple factors influence infant and child neurodevelopment in low resource settings. In offspring of participants in the preconception maternal nutrition trial, Women First (WF), we examined the impact of providing a preconception (Arm 1) or prenatal (Arm 2) nutrient supplement (compared to controls, Arm 3) on neurodevelopmental outcomes at 24 months; predictors of neurodevelopment scores; and associations of infant anthropometrics with neurodevelopmental scores. Follow-up visits for anthropometry were conducted at 6-, 12-, 18- and 24-month of age. At 24-months, in a randomized subset, the Bayley Scales of Infant Development, 3rd edition (BSID-III), including cognitive, motor and social-emotional subscales, and the Family Care Indicators (FCI) questionnaire, assessing family and home environment, were completed. Multiple covariates (intervention arm, site, maternal sociodemographic characteristics, FCI subscales, birthweight and 6-24 months' change in anthropometry z-scores, (e.g., ΔLAZ6-2 4) were evaluated by linear regression to predict BSID-III outcomes and to assess associations of anthropometric changes with BSID-III scores. The analysis consisted of 1386 infants (n = 441, 486, 459 for Arms 1, 2 and 3, respectively). None of the domain-specific BSID-III subscale scores differed by maternal intervention arm. Four covariates significantly predicted (p ≤ 0.01) all 3 BSID-III subscales: secondary maternal education, ΔLAZ6 - 24, birthweight >2500 g, and FCI play materials. Linear growth was associated with all domains of neurodevelopment. The results underscore the multi-dimensional aspects of child development represented by the nurturing care framework, including prenatal maternal nutrition, post-natal growth, maternal education for responsive caregiving and opportunities for early learning.

The Association Between Breastfeeding and Growth Among Infants with Moderately Low Birth Weight: A Prospective Cohort Study.

OBJECTIVE: To assess the association between breastfeeding competency, as determined by Latch, Audible swallowing, Type of nipple, Comfort, and Hold (LATCH) and Preterm Infant Breastfeeding Behavior Scale (PIBBS) scores, and exclusive breastfeeding and growth among infants with low birth weight (LBW) in India, Malawi, and Tanzania. STUDY DESIGN: We conducted LATCH and PIBBS assessments among mother-infant dyads enrolled in the Low Birthweight Infant Feeding Exploration (LIFE) observational study of infants with moderately LBW (1500g-2499 g) in India, Malawi, and Tanzania. We analyzed feeding and growth patterns among this cohort. RESULTS: We observed 988 infants. We found no association between LATCH or PIBBS scores and rates of exclusive breastfeeding at 4 or 6 months. Higher week 1 LATCH and PIBBS scores were associated with increased likelihood of regaining birth weight by 2 weeks of age [LATCH: aRR 1.42 (95% CI 1.15, 1.76); PIBBS: aRR 1.15 (95% CI 1.07, 1.23); adjusted for maternal age, parity, education, residence, delivery mode, LBW type, number of offspring, and site]. Higher PIBBS scores at 1 week were associated with improved weight gain velocity (weight-for-age z-score change) at 1, 4, and 6 months [adjusted beta coefficient: 1 month 0.04 (95% CI 0.01, 0.06); 4 month 0.04 (95% CI 0.01, 0.06); and 6 month 0.04 (95% CI 0.00, 0.08)]. CONCLUSION: Although week 1 LATCH and PIBBS scores were not associated with rates of exclusive breastfeeding, higher scores were positively associated with growth metrics among infants with LBW, suggesting that these tools may be useful to identify dyads who would benefit from early lactation support.

Predictors of Preterm Neonatal Mortality in India and Pakistan: A Secondary Analysis of Data from PURPOSe Study.

Objective. To create a prediction model for preterm neonatal mortality. Methods. A secondary analysis was conducted using data from a prospective cohort study, the Project to Understand and Research Preterm Pregnancy Outcome South Asia. The Cox proportional hazard model was used and adjusted hazard ratios (AHR) with 95% confidence intervals (95% CI) were reported. Results. Overall, 3446 preterm neonates were included. The mean age of preterm neonates was 0.65 (1.25) hours and 52% were female. The preterm neonatal mortality rate was 23.3%. The maternal factors predicting preterm neonatal death was any antepartum hemorrhage, AHR 1.99 (1.60-2.47), while neonatal predictors were preterm who received positive pressure ventilation AHR 1.30 (1.08-1.57), temperature <35.5°C AHR 1.18 (1.00-1.39), and congenital malformations AHR 3.31 (2.64-4.16). Conclusion. This study identified key maternal and neonatal predictors of preterm neonatal mortality, emphasizing the need for targeted interventions and collaborative public health efforts to address disparities and regional variations.

Neurodevelopment of Children Whose Mothers Were Randomized to Low-Dose Aspirin During Pregnancy.

OBJECTIVE: Because low-dose aspirin is now commonly prescribed in pregnancy, we sought to assess the association between early antenatal exposure and child neurodevelopment. METHODS: We performed a noninferiority, masked, neurodevelopmental follow-up study of children between age 33 and 39 months whose mothers had been randomized to daily low-dose aspirin (81 mg) or placebo between 6 0/7 and 13 6/7 weeks of gestation through 37 weeks. Neurodevelopment was assessed with the Bayley-III (Bayley Scales of Infant and Toddler Development, 3rd Edition) and the ASQ-3 (Ages and Stages Questionnaire, 3rd Edition). The primary outcome was the Bayley-III cognitive composite score with a difference within 4 points demonstrating noninferiority. RESULTS: A total of 640 children (329 in the low-dose aspirin group, 311 in the placebo group) were evaluated between September 2021 and June 2022. The Bayley-III cognitive composite score was noninferior between the two groups (-1, adjusted mean -0.8, 95% CI, -2.2 to 0.60). Significant differences were not seen in the language composite score (difference 0.7, 95% CI, -0.8 to 2.1) or the motor composite score (difference -0.6, 95% CI, -2.5 to 1.2). The proportion of children who had any component of the Bayley-III score lower than 70 did not differ between the two groups. Similarly, the communication, gross motor, fine motor, problem-solving, and personal-social components of the ASQ-3 did not differ between groups. Maternal characteristics, delivery outcomes, breastfeeding rates, breastfeeding duration, and home environment as measured by the Family Care Indicators were similar. CONCLUSION: Antenatal low-dose aspirin exposure was not associated with altered neurodevelopmental outcomes at age 3 years. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT04888377.

Facilitators, barriers, and key influencers of breastfeeding among low birthweight infants: a qualitative study in India, Malawi, and Tanzania.

BACKGROUND: Low birthweight (LBW) infants are at increased risk of morbidity and mortality. Exclusive breastfeeding up to six months is recommended to help them thrive through infection prevention, growth improvements, and enhancements in neurodevelopment. However, limited data exist on the feeding experiences of LBW infants, their caregivers and key community influencers. The qualitative component of the Low Birthweight Infant Feeding Exploration (LIFE) study aimed to understand practices, facilitators, and barriers to optimal feeding options in the first six months for LBW infants in low-resource settings. METHODS: This study was conducted in four sites in India, Malawi, and Tanzania from July 2019 to August 2020. We conducted 37 focus group discussions with mothers and family members of LBW infants and community leaders and 142 in-depth interviews with healthcare providers, government officials, and supply chain and donor human milk (DHM) experts. Data were analyzed using a framework approach. RESULTS: All participants believed that mother's own milk was best for LBW infants. Direct breastfeeding was predominant and feeding expressed breast milk and infant formula were rare. DHM was a new concept for most. Adequate maternal nutrition, lactation support, and privacy in the facility aided breastfeeding and expression, but perceived insufficient milk, limited feeding counseling, and infant immaturity were common barriers. Most believed that DHM uptake could be enabled through community awareness by overcoming misconceptions, safety concerns, and perceived family resistance. CONCLUSION: This study fills an evidence gap in LBW infant feeding practices and their facilitators and barriers in resource-limited settings. LBW infants face unique feeding challenges such as poor latching and tiring at the breast. Similarly, their mothers are faced with numerous difficulties, including attainment of adequate milk supply, breast pain and emotional stress. Lactation support and feeding counseling could address obstacles faced by mothers and infants by providing psychosocial, verbal and physical support to empower mothers with skills, knowledge and confidence and facilitate earlier, more and better breast milk feeding. Findings on DHM are critical to the future development of human milk banks and highlight the need to solicit partnership from stakeholders in the community and health system.

Safety and immunogenicity of a new formulation of a pentavalent DTwP-HepB-Hib vaccine in healthy Indian infants-A randomized study.

BACKGROUND: Pentavalent vaccines (DTP-HepB-Hib) have been introduced in many countries in their routine public immunization programmes to protect against diphtheria (D), tetanus (T), pertussis (P), hepatitis B (Hep B) and Hemophilus influenzae type b (Hib) diseases. This study compared the safety and immunogenicity of a new formulation of a whole-cell Bordetella pertussis (wP) based pentavalent vaccine (DTwP-HepB-Hib). The new formulation was developed using well-characterized hepatitis B and pertussis whole cell vaccine components. METHODS: This was a phase III, observer-blind, randomized, non-inferiority, multi-center study conducted in India among 460 infants who were followed up for safety and immunogenicity for 28 days after administration of three doses of either investigational or licensed comparator formulations at 6-8, 10-12 and 14-16 weeks of age. RESULTS: The investigational formulation of DTwP-HepB-Hib vaccine was non-inferior to the licensed formulation in terms of hepatitis B seroprotection rate (% of subjects with HepB antibodies ≥10mIU/mL were 99.1% versus 99.0%, respectively, corresponding to a difference of 0.1% (95% CI, -2.47 to 2.68)) and pertussis immune responses (adjusted geometric mean concentrations of antibodies for anti-PT were 76.7 EU/mL versus 63.3 EU/mL, with a ratio of aGMTs of 1.21 (95% CI, 0.89-1.64), and for anti-FIM were 1079 EU/mL versus 1129 EU/mL, with a ratio of aGMTs of 0.95 (95% CI, 0.73-1.24), respectively). The immune responses to other valences (D, T, and Hib) in the two formulations were also similar. The safety profile of both formulations was found to be similar and were well tolerated. CONCLUSIONS: The investigational DTwP-HepB-Hib vaccine formulation was immunogenic and well-tolerated when administered as three dose primary series in infants. CLINICAL TRIAL REGISTRATION: Clinical Trials Registry India number: CTRI/2018/12/016692.

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.

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.

Data usefulness in determining cause of stillbirth in South Asia.

OBJECTIVE: To evaluate the usefulness of data to determine cause of stillbirth in India and Pakistan. DESIGN: Prospective, observational study. SETTINGS: Study hospitals in India and Pakistan. POPULATION: 200 fetal deaths with placental evaluation and minimally invasive tissue sampling (MITS) of internal organs and polymerase chain reaction (PCR) test for 75 pathogens. MAIN OUTCOME MEASURES: Data defined as useful to determine stillbirth causes. RESULTS: Placental pathology was the most useful to determine cause of stillbirth. Comparing placental and fetal weight with standard weights was useful in 44.5% and 48.5%, respectively. Lung histology was useful in 42.5%. Most of the other findings of internal organ histology were only occasionally useful. Signs of abruption, by maternal history or placental evaluation, were always deemed useful. Placenta, brain and cord blood PCR were also useful, but less often than histology. CONCLUSION: Based on this analysis, maternal clinical history, placental histology and fetal examination were most informative. Comparing the placental and fetal weights with recognised standards was useful in nearly half the cases. Fetal tissue histology and PCR were also informative. Of all the potential tests of MITS-obtained specimens, we would first recommend histological evaluation of the lungs, and using a multiplex PCR platform would determine pathogens in blood and brain/CSF. We recognise that this approach will not identify some causes, including some genetic and internal organ anomalies, but will confirm most common causes of stillbirth and most of the preventable causes of stillbirth in low- and middle-income countries.

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.

Lessons learned in implementing the Low Birthweight Infant Feeding Exploration study: A large, multi-site observational study.

OBJECTIVE: Globally, early and optimal feeding practices and strategies for small and vulnerable infants are limited. We aim to share the challenges faced and implementation lessons learned from a complex, mixed methods research study on infant feeding. DESIGN: A formative, multi-site, observational cohort study using convergent parallel, mixed-methods design. SETTING: Twelve tertiary/secondary, public/private hospitals in India, Malawi and Tanzania. POPULATION OR SAMPLE: Moderately low birthweight infants (MLBW; 1.50-2.49 kg). METHODS: We assessed infant feeding and care practices through: (1) assessment of in-facility documentation of 603 MLBW patient charts; (2) intensive observation of 148 MLBW infants during facility admission; and (3) prospective 1-year follow-up of 1114 MLBW infants. Focus group discussions and in-depth interviews gathered perspectives on infant feeding among clinicians, families, and key stakeholders. MAIN OUTCOME MEASURES: The outcomes of the primary study were: (1) To understand the current practices and standard of care for feeding LBW infants; (2) To define and document the key outcomes (including growth, morbidity, and lack of success on mother's own milk) for LBW infants under current practices; (3) To assess the acceptability and feasibility of a system-level Infant and Young Child Feeding (IYCF) intervention and the proposed infant feeding options for LBW infants. RESULTS: Hospital-level guidelines and provision of care for MLBW infants varied across and within countries. In all, 89% of charts had missing data on time to first feed and 56% lacked discharge weights. Among 148 infants observed in-facility, 18.5% were discharged prior to meeting stated weight goals. Despite challenges during COVID, 90% of the prospective cohort was followed until 12 months of age. CONCLUSIONS: Enrolment and follow-up of this vulnerable population required additional effort from researchers and the community. Using a mixed-methods exploratory study allowed for a comprehensive understanding of MLBW health and evidence-based planning of targeted large-scale interventions. Multi-site partnerships in global health research, which require active and equal engagement, are instrumental in avoiding duplication and building a stronger, generalisable evidence base.

Safe infant feeding in healthcare facilities: Assessment of infection prevention and control conditions and behaviors in India, Malawi, and Tanzania.

Infants need to receive care in environments that limit their exposure to pathogens. Inadequate water, sanitation, and hygiene (WASH) environments and suboptimal infection prevention and control practices in healthcare settings contribute to the burden of healthcare-associated infections, which are particularly high in low-income settings. Specific research is needed to understand infant feeding preparation in healthcare settings, a task involving multiple behaviors that can introduce pathogens and negatively impact health. To understand feeding preparation practices and potential risks, and to inform strategies for improvement, we assessed facility WASH environments and observed infant feeding preparation practices across 12 facilities in India, Malawi, and Tanzania serving newborn infants. Research was embedded within the Low Birthweight Infant Feeding Exploration (LIFE) observational cohort study, which documented feeding practices and growth patterns to inform feeding interventions. We assessed WASH-related environments and feeding policies of all 12 facilities involved in the LIFE study. Additionally, we used a guidance-informed tool to carry out 27 feeding preparation observations across 9 facilities, enabling assessment of 270 total behaviors. All facilities had 'improved' water and sanitation services. Only 50% had written procedures for preparing expressed breastmilk; 50% had written procedures for cleaning, drying, and storage of infant feeding implements; and 33% had written procedures for preparing infant formula. Among 270 behaviors assessed across the 27 feeding preparation observations, 46 (17.0%) practices were carried out sub-optimally, including preparers not handwashing prior to preparation, and cleaning, drying, and storing of feeding implements in ways that do not effectively prevent contamination. While further research is needed to improve assessment tools and to identify specific microbial risks of the suboptimal behaviors identified, the evidence generated is sufficient to justify investment in developing guidance and programing to strengthen infant feeding preparation practices to ensure optimal newborn health.

Neurodevelopment, vision and auditory outcomes at age 2 years in offspring of participants in the 'Women First' maternal preconception nutrition randomised controlled trial.

BACKGROUND: Maternal nutrition in preconception and early pregnancy influences fetal growth. Evidence for effects of prenatal maternal nutrition on early child development (ECD) in low-income and middle-income countries is limited. OBJECTIVES: To examine impact of maternal nutrition supplementation initiated prior to or during pregnancy on ECD, and to examine potential association of postnatal growth with ECD domains. DESIGN: Secondary analysis regarding the offspring of participants of a maternal multicountry, individually randomised trial. SETTING: Rural Democratic Republic of the Congo, Guatemala, India and Pakistan. PARTICIPANTS: 667 offspring of Women First trial participants, aged 24 months. INTERVENTION: Maternal lipid-based nutrient supplement initiated preconceptionally (arm 1, n=217), 12 weeks gestation (arm 2, n=230) or not (arm 3, n=220); intervention stopped at delivery. MAIN OUTCOME MEASURES: The INTERGROWTH-21st Neurodevelopment Assessment (INTER-NDA) cognitive, language, gross motor, fine motor, positive and negative behaviour scores; visual acuity and contrast sensitivity scores and auditory evoked response potentials (ERP). Anthropometric z-scores, family care indicators (FCI) and sociodemographic variables were examined as covariates. RESULTS: No significant differences were detected among the intervention arms for any INTER-NDA scores across domains, vision scores or ERP potentials. After adjusting for covariates, length-for-age z-score at 24 months (LAZ24), socio-economic status, maternal education and FCI significantly predicted vision and INTER-NDA scores (R2=0.11-0.38, p<0.01). CONCLUSIONS: Prenatal maternal nutrition supplementation was not associated with any neurodevelopmental outcomes at age 2 years. Maternal education, family environment and LAZ24 predicted ECD. Interventions addressing multiple components of the nurturing care model may offer greatest impact on children's developmental potential. TRIAL REGISTRATION NUMBER: NCT01883193.

Pathogens identified in the internal tissues and placentas of stillbirths: results from the prospective, observational PURPOSe study.

OBJECTIVE: To examine internal organ tissues and placentas of stillbirths for various pathogens. DESIGN: Prospective, observational study. SETTINGS: Three study hospitals in India and a large maternity hospital in Pakistan. POPULATION: Stillborn infants delivered in a study hospital. METHODS: A prospective observational study. MAIN OUTCOME MEASURES: Organisms identified by pathogen polymerase chain reaction (PCR) in internal organs and placental tissues of stillbirths. RESULTS: Of 2437 stillbirth internal tissues, 8.3% (95% CI 7.2-9.4) were positive. Organisms were most commonly detected in brain (12.3%), cerebrospinal fluid (CSF) (9.5%) and whole blood (8.4%). Ureaplasma urealyticum/parvum was the organism most frequently detected in at least one internal organ (6.4% of stillbirths and 2% of all tissues). Escherichia coli/Shigella was the next most common (4.1% one or more internal organ tissue sample and 1.3% of tissue samples), followed by Staphylococcus aureus in at least one internal organ tissue (1.9% and 0.9% of all tissues). None of the other organisms was found in more than 1.4% of the tissue samples in stillbirths or more than 0.6% of the internal tissues examined. In the placenta tissue, membrane or cord blood combined, 42.8% (95% CI 40.2-45.3) had at least one organism identified, with U. urealyticum/parvum representing the most commonly identified (27.8%). CONCLUSIONS: In about 8% of stillbirths, there was evidence of a pathogen in an internal organ. Ureaplasma urealyticum/parvum was the most common organism found in the placenta and in the internal tissues, especially in the fetal brain.

Facility-based care for moderately low birthweight infants in India, Malawi, and Tanzania.

Globally, increasing rates of facility-based childbirth enable early intervention for small vulnerable newborns. We describe health system-level inputs, current feeding, and discharge practices for moderately low birthweight (MLBW) infants (1500-<2500g) in resource-constrained settings. The Low Birthweight Infant Feeding Exploration study is a mixed methods observational study in 12 secondary- and tertiary-level facilities in India, Malawi, and Tanzania. We analyzed data from baseline facility assessments and a prospective cohort of 148 MLBW infants from birth to discharge. Anthropometric measuring equipment (e.g., head circumference tapes, length boards), key medications (e.g., surfactant, parenteral nutrition), milk expression tools, and human milk alternatives (e.g., donor milk, formula) were not universally available. MLBW infants were preterm appropriate-for-gestational age (38.5%), preterm large-for-gestational age (3.4%), preterm small-for-gestational age (SGA) (11.5%), and term SGA (46.6%). The median length of stay was 3.1 days (IQR: 1.5, 5.7); 32.4% of infants were NICU-admitted and 67.6% were separated from mothers at least once. Exclusive breastfeeding was high (93.2%). Generalized group lactation support was provided; 81.8% of mother-infant dyads received at least one session and 56.1% had 2+ sessions. At the time of discharge, 5.1% of infants weighed >10% less than their birthweight; 18.8% of infants were discharged with weights below facility-specific policy [1800g in India, 1500g in Malawi, and 2000g in Tanzania]. Based on descriptive analysis, we found constraints in health system inputs which have the potential to hinder high quality care for MLBW infants. Targeted LBW-specific lactation support, discharge at appropriate weight, and access to feeding alternatives would position MLBW for successful feeding and growth post-discharge.

Feeding practices and growth patterns of moderately low birthweight infants in resource-limited settings: results from a multisite, longitudinal observational study.

OBJECTIVES: To describe the feeding profile of low birthweight (LBW) infants in the first half of infancy; and to examine growth patterns and early risk factors of poor 6-month growth outcomes. DESIGN: Prospective observational cohort study. SETTING AND PARTICIPANTS: Stable, moderately LBW (1.50 to <2.50 kg) infants were enrolled at birth from 12 secondary/tertiary facilities in India, Malawi and Tanzania and visited nine times over 6 months. VARIABLES OF INTEREST: Key variables of interest included birth weight, LBW type (combination of preterm/term status and size-for-gestational age at birth), lactation practices and support, feeding profile, birthweight regain by 2 weeks of age and poor 6-month growth outcomes. RESULTS: Between 13 September 2019 and 27 January 2021, 1114 infants were enrolled, comprising 4 LBW types. 363 (37.3%) infants initiated early breast feeding and 425 (43.8%) were exclusively breastfed to 6 months. 231 (22.3%) did not regain birthweight by 2 weeks; at 6 months, 280 (32.6%) were stunted, 222 (25.8%) underweight and 88 (10.2%) wasted. Preterm-small-for-gestational age (SGA) infants had 1.89 (95% CI 1.37 to 2.62) and 2.32 (95% CI 1.48 to 3.62) times greater risks of being stunted and underweight at 6 months compared with preterm-appropriate-for-gestational age (AGA) infants. Term-SGA infants had 2.33 (95% CI 1.77 to 3.08), 2.89 (95% CI 1.97 to 4.24) and 1.99 (95% CI 1.13 to 3.51) times higher risks of being stunted, underweight and wasted compared with preterm-AGA infants. Those not regaining their birthweight by 2 weeks had 1.51 (95% CI 1.23 to 1.85) and 1.55 (95% CI 1.21 to 1.99) times greater risks of being stunted and underweight compared with infants regaining. CONCLUSION: LBW type, particularly SGA regardless of preterm or term status, and lack of birthweight regain by 2 weeks are important risk identification parameters. Early interventions are needed that include optimal feeding support, action-oriented growth monitoring and understanding of the needs and growth patterns of SGA infants to enable appropriate weight gain and proactive management of vulnerable infants. TRIAL REGISTRATION NUMBER: NCT04002908.

Pathogens Identified by Minimally Invasive Tissue Sampling in India and Pakistan From Preterm Neonatal Deaths: The PURPOSE Study.

BACKGROUND: We identified pathogens found in internal organs and placentas of deceased preterm infants cared for in hospitals in India and Pakistan. METHODS: Prospective, observational study conducted in delivery units and neonatal intensive care units. Tissue samples from deceased neonates obtained by minimally invasive tissue sampling and placentas were examined for 73 different pathogens using multiplex polymerase chain reaction (PCR). RESULTS: Tissue for pathogen PCR was obtained from liver, lung, brain, blood, cerebrospinal fluid, and placentas from 377 deceased preterm infants. Between 17.6% and 34.1% of each type of tissue had at least 1 organism identified. Organism detection was highest in blood (34.1%), followed by lung (31.1%), liver (23.3%), cerebrospinal fluid (22.3%), and brain (17.6%). A total of 49.7% of the deceased infants had at least 1 organism. Acinetobacter baumannii was in 28.4% of the neonates compared with 14.6% for Klebsiella pneumoniae, 11.9% for Escherichia coli/Shigella, and 11.1% for Haemophilus influenzae. Group B streptococcus was identified in only 1.3% of the neonatal deaths. A. baumannii was rarely found in the placenta and was found more commonly in the internal organs of neonates who died later in the neonatal period. The most common organism found in placentas was Ureaplasma urealyticum in 34% of the samples, with no other organism found in >4% of samples. CONCLUSIONS: In organ samples from deceased infants in India and Pakistan, evaluated with multiplex pathogen PCR, A. baumannii was the most commonly identified organism. Group B streptococcus was rarely found. A. baumannii was rarely found in the placentas of these deceased neonates.

The causes of preterm neonatal deaths in India and Pakistan (PURPOSe): a prospective cohort study.

BACKGROUND: Preterm birth remains the major cause of neonatal death worldwide. South Asia contributes disproportionately to deaths among preterm births worldwide, yet few population-based studies have assessed the underlying causes of deaths. Novel evaluations, including histological and bacteriological assessments of placental and fetal tissues, facilitate more precise determination of the underlying causes of preterm deaths. We sought to assess underlying and contributing causes of preterm neonatal deaths in India and Pakistan. METHODS: The project to understand and research preterm pregnancy outcomes and stillbirths in South Asia (PURPOSe) was a prospective cohort study done in three hospitals in Davangere, India, and two hospitals in Karachi, Pakistan. All pregnant females older than 14 years were screened at the time of presentation for delivery, and those with an expected or known preterm birth, defined as less than 37 weeks of gestation, were enrolled. Liveborn neonates with a weight of 1000 g or more who died by 28 days after birth were included in analyses. Placentas were collected and histologically evaluated. In addition, among all neonatal deaths, with consent, minimally invasive tissue sampling was performed for histological analyses. PCR testing was performed to assess microbial pathogens in the placental, blood, and fetal tissues collected. An independent panel reviewed available data, including clinical description of the case and all clinical maternal, fetal, and placental findings, and results of PCR bacteriological investigation and minimally invasive tissue sampling histology, from all eligible preterm neonates to determine the primary and contributing maternal, placental, and neonatal causes of death. FINDINGS: Between July 1, 2018, and March 26, 2020, of the 3470 preterm neonates enrolled, 804 (23%) died by 28 days after birth, and, of those, 615 were eligible and had their cases reviewed by the panel. Primary maternal causes of neonatal death were hypertensive disease (204 [33%] of 615 cases), followed by maternal complication of pregnancy (76 [12%]) and preterm labour (76 [11%]), whereas the primary placental causes were maternal and fetal vascular malperfusion (172 [28%] of 615) and chorioamnionitis, funisitis, or both (149 [26%]). The primary neonatal cause of death was intrauterine hypoxia (212 [34%] of 615) followed by congenital infections (126 [20%]), neonatal infections (122 [20%]), and respiratory distress syndrome (126 [20%]). INTERPRETATION: In south Asia, intrauterine hypoxia and congenital infections were the major causes of neonatal death among preterm babies. Maternal hypertensive disorders and placental disorders, especially maternal and fetal vascular malperfusion and placental abruption, substantially contributed to these deaths. FUNDING: Bill & Melinda Gates Foundation.