Sarah Hanieh

Maternal Vitamin D Status and Infant Outcomes in Rural Vietnam: A Prospective Cohort Study

Objective Vitamin D deficiency affects 1 billion people globally. It has an important role in bone homeostasis, brain development and modulation of the immune system and yet the impact of antenatal vitamin D deficiency on infant outcomes is poorly understood. We assessed the association of 25- hydroxyvitamin D levels (25-OHD) in late pregnancy and early infant growth and developmental outcomes in rural Vietnam. Design and Methods A prospective cohort study of 960 women who had previously participated in a double-blind cluster randomized controlled trial of antenatal micronutrient supplementation in rural Vietnam was undertaken. Maternal 25-OHD concentration was measured at 32 weeks gestation, and infants were followed until 6 months of age. Main outcome measures were cognitive, motor, socio-emotional and language scores using the Bayley Scales of Infant Development, 3rd edition, and infant length-for-age z scores at 6 months of age. Results 60% (582/960) of women had 25-OHD levels <75 nmol/L at 32 weeks gestation. Infants born to women with 25-OHD deficiency (<37.5 nmol/L) had reduced developmental language scores compared to those born to women who were vitamin D replete (≥75 nmol/L) (Mean Difference (MD) −3.48, 95% Confidence Interval (CI) −5.67 to −1.28). For every 25 nmol increase in 25-OHD concentration in late pregnancy, infant length-for-age z scores at 6 months of age decreased by 0.08 (95% CI −0.15 to −0.02). Conclusions Low maternal 25- hydroxyvitamin D levels during late pregnancy are of concern in rural Vietnam, and are associated with reduced language developmental outcomes at 6 months of age. Our findings strengthen the evidence for giving vitamin D supplementation during pregnancy.

Prevalence and risk factors for symptoms of common mental disorders in early and late pregnancy in Vietnamese women: A prospective population-based study.

BACKGROUND Little is known about the prevalence of and risk factors for common mental disorders (CMD) in pregnant women in low-income countries. The aim of this study was to establish the prevalence of and psychosocial risk factors for clinically significant symptoms of CMD in early and late pregnancy in women in rural Viet Nam. METHODS A population-based sample of women was surveyed in early and late pregnancy. CMD were assessed by the Edinburgh Postnatal Depression Scale-Viet Nam Validation and psychosocial risks by study-specific structured interviews. RESULTS In total 497/523 (97%) eligible women were recruited and 419 (84%) provided complete data. Prevalence of CMD only in early pregnancy was 22.4% (95% CI 18.4-26.4); only in late pregnancy was 10.7% (95% CI 7.8-13.7) and at both assessment waves was 17.4% (95% CI 13.8-21.1). Non-economic and economic coincidental life adversity, intimate partner violence, past pregnancy loss, and childhood abuse were positively associated with persistent antenatal CMD. Older age, having a preference for the babys sex, and nulli- or primiparity were risk factors for CMD in early pregnancy. CONCLUSIONS Persistent antenatal CMD are prevalent in rural areas of Viet Nam. Psychosocial risk factors play a major role in this significant public health problem.

Impact on infants' cognitive development of antenatal exposure to iron deficiency disorder and common mental disorders.

Objectives The aim of this study was to examine the effects of antenatal exposure to iron deficiency anemia (IDA) and common mental disorders (CMD) on cognitive development of 6 months old infants in a developing country. Methods A prospective population-based study in a rural province in Vietnam, which enrolled pregnant women at 12–20 weeks gestation and followed them up with their infants until six months postpartum. Criteria for IDA were Hb <11 g/dL and serum ferritin <15 ng/mL. CMD symptoms were assessed by the Edinburgh Postnatal Depression Scale-Vietnam validation. Infant cognitive development was assessed by Bayley Scales of Infant and Toddler Development, 3rd Ed. Path analyses were performed to determine the direct and indirect, partly or fully mediated, causal effects of the antenatal exposures. Results A total of 497 pregnant women were recruited, of those 378 women provided complete data which were included in the analyses. Statistically significant direct adverse effects of persistent antenatal IDA (estimated difference of −11.62 points; 95% CI −23.01 to −0.22) and antenatal CMD (−4.80 points; 95% CI: −9.40 to −0.20) on infant Bayley cognitive scores at six months were found. Higher birthweight, household wealth, and self-rated sufficient supply of breastmilk were associated with higher cognitive scores. Maternal age >30 years and primiparity had an indirect adverse effect on infants’ Bayley cognitive scores. Conclusions These findings suggest that antenatal IDA and CMD both have adverse effects on child cognitive development, which if unrecognized and unaddressed are likely to be lasting. It is crucial that both these risks are considered by policy makers, clinicians, and researchers seeking to improve child cognitive function in developing countries.

Psychological and Social Factors Associated with Late Pregnancy Iron Deficiency Anaemia in Rural Viet Nam: A Population-Based Prospective Study

Objectives The aim of this study was to examine the relationships between psychological and social factors and late pregnancy IDA among pregnant women in rural Viet Nam. Methods Pregnant women from 50 randomly-selected communes within Ha Nam province were recruited and assessed at 12 - 20 weeks gestation (Wave 1, W1). They were followed up in the last trimester (Wave 2, W2). IDA was defined as Haemoglobin < 11 g/dL and serum ferritin < 15 ng/mL. Symptoms of Common Mental Disorders (CMD) were assessed by the Edinburgh Postnatal Depression Scale-Vietnam (EPDS-V). Persistent antenatal CMD was defined as having an EPDS-V score ≥ 4 in both W1 and W2. Hypothesis models were tested by Structural Equation Modeling analyses. Results A total of 378 women provided complete data at both W1 and W2. The incidence risk of IDA in the third trimester was 13.2% (95% confidence interval (CI): 9.8-16.7). Persistent CMD was found in 16.9% (95% CI: 13.1-20.7) pregnant women and predicted by intimate partner violence, fear of other family members, experience of childhood abuse, coincidental life adversity, and having a preference for the sex of the baby. There was a significant pathway from persistent CMD to IDA in late pregnancy via the length of time that iron supplements had been taken. Receiving advice to take iron supplements and higher household wealth index were indirectly related to lower risk of late pregnancy IDA. Early pregnancy IDA and being multi-parous also contributed to late pregnancy IDA. Conclusions Antenatal IDA and CMD are prevalent public health problems among women in Viet Nam. The link between them suggests that while direct recommendations to use iron supplements are important, the social factors associated with common mental disorders should be addressed in antenatal care in order to improve the health of pregnant women and their infants.

Infant motor development in rural Vietnam and intrauterine exposures to anaemia, iron deficiency and common mental disorders: a prospective community-based study

BackgroundAntenatal anaemia, iron deficiency and common mental disorders (CMD) are prevalent in low- and middle-income countries. The aim of this study was to examine the direct and indirect effects of antenatal exposures to these risks and infant motor development.MethodsA cohort of women who were pregnant with a single foetus and between 12 and 20 weeks pregnant in 50 randomly-selected rural communes in Ha Nam province was recruited. Participants provided data twice during pregnancy (early and late gestation) and twice after giving birth (8 weeks and 6 months postpartum). The Edinburgh Postnatal Depression Scale was used at all four data collection waves to detect CMD (score ≥ 4). Maternal anaemia (Hb < 11 g/dL) and iron deficiency (ferritin < 15 ng/mL) were evaluated at early and late gestation. Infants’ motor development was assessed by the Bayley of Infant and Toddler Development Motor Scales (BSID-M) at the age of six months. Direct and indirect effects of the exposures on the outcome were examined with Path analysis.ResultsIn total, 497 of 523 (97%) eligible pregnant women were recruited and 418 mother-infant pairs provided complete data and were included in the analyses. The prevalence of anaemia was 21.5% in early pregnancy and 24.4% in late pregnancy. There was 4.1% iron deficiency at early pregnancy and 48.2% at late pregnancy. Clinically significant symptoms of CMD were apparent among 40% women in early pregnancy and 28% in late pregnancy. There were direct adverse effects on infant BSID-M scores at 6 months of age due to antenatal anaemia in late pregnancy (an estimated mean reduction of 2.61 points, 95% Confidence Interval, CI, 0.57 to 4.65) and CMD in early pregnancy (7.13 points, 95% CI 3.13 to 11.13). Iron deficiency and anaemia in early pregnancy were indirectly related to the outcome via anaemia during late pregnancy.ConclusionsAntenatal anaemia, iron deficiency, and CMD have a negative impact on subsequent infant motor development. These findings highlight the need to improve the quality of antenatal care when developing interventions for pregnant women that aim to optimise early childhood development in low- and middle-income countries.

Does Malaria Affect Placental Development? Evidence from In Vitro Models

Background Malaria in early pregnancy is difficult to study but has recently been associated with fetal growth restriction (FGR). The pathogenic mechanisms underlying malarial FGR are poorly characterized, but may include impaired placental development. We used in vitro methods that model migration and invasion of placental trophoblast into the uterine wall to investigate whether soluble factors released into maternal blood in malaria infection might impair placental development. Because trophoblast invasion is enhanced by a number of hormones and chemokines, and is inhibited by pro-inflammatory cytokines, many of which are dysregulated in malaria in pregnancy, we further compared concentrations of these factors in blood between malaria-infected and uninfected pregnancies. Methodology/Principal Findings We measured trophoblast invasion, migration and viability in response to treatment with serum or plasma from two independent cohorts of Papua New Guinean women infected with Plasmodium falciparum or Plasmodium vivax in early pregnancy. Compared to uninfected women, serum and plasma from women with P. falciparum reduced trophoblast invasion (P = .06) and migration (P = .004). P. vivax infection did not alter trophoblast migration (P = .64). The P. falciparum-specific negative effect on placental development was independent of trophoblast viability, but associated with high-density infections. Serum from P. falciparum infected women tended to have lower levels of trophoblast invasion promoting hormones and factors and higher levels of invasion-inhibitory inflammatory factors. Conclusion/Significance We demonstrate that in vitro models of placental development can be adapted to indirectly study the impact of malaria in early pregnancy. These infections could result in impaired trophoblast invasion with reduced transformation of maternal spiral arteries due to maternal hormonal and inflammatory disturbances, which may contribute to FGR by limiting the delivery of maternal blood to the placenta. Future prevention strategies for malaria in pregnancy should include protection in the first half of pregnancy.

Chronic Exposure to Malaria Is Associated with Inhibitory and Activation Markers on Atypical Memory B Cells and Marginal Zone-Like B Cells

In persistent infections that are accompanied by chronic immune activation, such as human immunodeficiency virus, hepatitis C virus, and malaria, there is an increased frequency of a phenotypically distinct subset of memory B cells lacking the classic memory marker CD27 and showing a reduced capacity to produce antibodies. However, critical knowledge gaps remain on specific B cell changes and immune adaptation in chronic infections. We hypothesized that expansion of atypical memory B cells (aMBCs) and reduction of activated peripheral marginal zone (MZ)-like B cells in constantly exposed individuals might be accompanied by phenotypic changes that would confer a tolerogenic profile, helping to establish tolerance to infections. To better understand malaria-associated phenotypic abnormalities on B cells, we analyzed peripheral blood mononuclear cells from 55 pregnant women living in a malaria-endemic area of Papua Nueva Guinea and 9 Spanish malaria-naïve individuals using four 11-color flow cytometry panels. We assessed the expression of markers of B cell specificity (IgG and IgM), activation (CD40, CD80, CD86, b220, TACI, and CD150), inhibition (PD1, CD95, and CD71), and migration (CCR3, CXCR3, and CD62l). We found higher frequencies of active and resting aMBC and marked reduction of MZ-like B cells, although changes in absolute cell counts could not be assessed. Highly exposed women had higher PD1+-, CD95+-, CD40+-, CD71+-, and CD80+-activated aMBC frequencies than non-exposed subjects. Malaria exposure increased frequencies of b220 and proapoptotic markers PD1 and CD95, and decreased expression of the activation marker TACI on MZ-like B cells. The increased frequencies of inhibitory and apoptotic markers on activated aMBCs and MZ-like B cells in malaria-exposed adults suggest an immune-homeostatic mechanism for maintaining B cell development and function while simultaneously downregulating hyperreactive B cells. This mechanism would keep the B cell activation threshold high enough to control infection but impaired enough to tolerate it, preventing systemic inflammation.

Streptococcus pneumoniae carriage prevalence in Nepal: evaluation of a method for delayed transport of samples from remote regions and implications for vaccine implementation.

Background Pneumococcal disease is a significant cause of morbidity and mortality in young children in Nepal, and currently available pneumococcal conjugate vaccines offer moderate coverage of invasive disease isolates. Methods A prevalence study of children aged 1.5 to 24 months in urban and rural Nepal was conducted. In the urban group, nasopharyngeal swabs (NPS) were transported using silica desiccant packages (SDP) with delayed processing (2 weeks), or skim-milk-tryptone-glucose-glycerin (STGG) with immediate processing (within 8 hours). Pneumococcal nasopharyngeal carriage prevalence, serogroup/type distribution and isolate genotypes (as defined by multilocus sequence typing) were determined. Results 1101 children were enrolled into the study: 574 in the urban group and 527 in the rural group. Overall carriage prevalence based on culture from specimens transported and stored in STGG was 58.7% (337/574), compared to 40.9% (235/574) in SDP. There was concordance of detection of pneumococcus in 67% of samples. Using the SDP method, pneumococcal carriage prevalence was higher in the rural population (69.2%; 364/526) compared to the urban population (40.9%; 235/574). Serogroup/type distribution varied with geographical location. Over half of the genotypes identified in both the urban and rural pneumococcal populations were novel. Conclusion The combination of delayed culture and transport using SDP underestimates the prevalence of pneumococcal carriage; however, in remote areas, this method could still provide a useful estimate of carriage prevalence and serogroup/type distribution. Vaccine impact is unpredictable in a setting with novel genotypes and limited serotype coverage as described here. Consequently, continued surveillance of pneumococcal isolates from carriage and disease in Nepali children following the planned introduction of pneumococcal conjugate vaccines introduction will be essential.

Evaluation of haemophilus influenzae type b vaccine for routine immunization in Nepali infants.

Background: Haemophilus influenzae type b (Hib) carriage and disease studies in Nepali children suggest a significant burden of infection. Hib conjugate vaccines (HibCV) do not have uniform immunogenicity between populations. We determined the immunogenicity of HibCV in Nepali infants, before its introduction into the routine immunization schedule. Methods: Ninety infants recruited at Patan Hospital, Kathmandu, received 3 doses of the HibCV with routine immunizations (diphtheria, tetanus, whole cell pertussis–hepatitis B vaccine + oral polio vaccine) at 6, 10 and 14 weeks of age, and a HibCV booster at 52 weeks. Anti-polyribosylribitol phosphate (PRP) concentrations were measured at 18, 52 and 56 weeks, and the antibody persistence at 52 weeks was compared with antibody values in unimmunized controls (n = 30). Results: After 3 doses of primary immunizations, at 18 weeks of age (n = 74), all infants had anti-PRP concentrations above the accepted thresholds for short- and long-term protection (0.15 and 1.0 µg/mL, respectively). At 1 year of age, before administration of the booster of HibCV, the anti-PRP geometric mean antibody concentration was 2.76 µg/mL (confidence interval: 1.88–4.07) in sera from the immunized children compared with 0.11 µg/mL (95% confidence interval: 0.08–0.17) in the nonimmunized control group (n = 30). Twenty-seven percent (20/74) of participants, however, had anti-PRP concentrations <1.0 µg/mL. Four weeks after the booster dose of HibCV, 98.5% of infants had anti-PRP concentrations above 1.0 µg/mL. Conclusion: Immunization with HibCV given as part of the Expanded Program on Immunization schedule in Nepal elicits robust antibody responses. Though the antibody wanes during the first year of life, most 1-year-old infants remain protected and respond robustly to a booster dose of the vaccine.

Antenatal Iron Supplementation Regimens for Pregnant Women in Rural Vietnam and Subsequent Haemoglobin Concentration and Anaemia among Their Infants.

Background Little evidence about the effects of antenatal iron supplementation on infant anaemia is available. The aim was to compare effects on six-month-old infants’ Haemoglobin (Hb) concentration and anaemia of daily iron–folic acid (IFA), twice-weekly IFA with or without other micronutrients (MMN) and usual antenatal care in rural Vietnam. Methods and Findings Secondary data analysis from: a prospective population-based observational study (OS) which examined effects of antenatal psychosocial factors, anaemia and iron deficiency on infant development and health; and a three-arm cluster randomised trial (CRT) of different antenatal iron supplementation regimens. In the OS 497 women (<20 weeks gestation) from 50 randomly-selected communes participated, and in the CRT 1,258 pregnant women (<16 weeks gestation) in 104 communes were allocated randomly to trial arms. The main outcome was six-month-old infant Hb concentration. Baseline data included women’s socio-demographic characteristics, reproductive health, Hb and serum ferritin. Mean differences in infant Hb and odds ratios of infant anaemia between CRT arms and OS were calculated by multivariable regression models, controlling for baseline differences and clustering, using robust standard errors. Infant anaemia prevalence was 68.6% in the OS, 47.2% daily IFA, 53.5% weekly IFA, and 50.3% MMN conditions. After adjustment, mean infant haemoglobin levels in daily IFA (mean difference = 0.95 g/dL; 95%CI 0.7-11.18); weekly IFA (0.91; 95%CI 0.69-1.12) and MMN (1.04; 95%CI 0.8-1.27) were higher than in the OS. After adjustment there were lower odds ratios of anaemia among infants in the daily IFA (OR = 0.31; 95% CI 0.22-0.43), weekly IFA (0.38; 95%CI 0.26-0.54) and MMN (0.33; 95%CI 0.23-0.48) groups than in the OS. Conclusions Infant anaemia is a public health problem in Vietnam and other resource-constrained countries. All supplementation regimens could have clinically significant benefits for Hb and reduce anaemia risk among six-month-old infants. Universal provision of free intermittent iron supplements is warranted.