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1.  Intrapartum Antibiotic Exposure and Early Neonatal Morbidity and Mortality in Africa 
Pediatrics  2009;124(1):e137-e144.
Infants born to women who receive intrapartum antibiotics may have higher rates of infectious morbidity and mortality than unexposed infants.
To determine the association of maternal intrapartum antibiotics and early neonatal morbidity and mortality.
Secondary analysis of data from a multi-site randomized placebo-controlled clinical trial of antibiotics to prevent chorioamnionitis-associated mother-to-child transmission of HIV-1 and preterm birth in sub-Saharan Africa. Early neonatal morbidity and mortality were analyzed. In an intent-to-treat (ITT) analysis, infants born to women randomized to antibiotics or placebo were compared. Additionally, non-ITT analysis was performed because some women received non-study antibiotics for various clinical indications.
Overall, 2659 pregnant women were randomized. Of these, 2466 HIV-1-infected and -uninfected women delivered 2413 live born and 84 stillborn infants. In the ITT analysis, there were no significant associations between exposure to antibiotics and early neonatal outcomes. Non-ITT analyses showed more illness at birth (11.2% vs. 8.6%, p=0.03) and more admissions to the Special Care Baby Unit (12.6% vs. 9.8%, p = 0.04) among infants exposed to maternal intrapartum antibiotics than among unexposed infants. Further analyses revealed greater early neonatal morbidity and mortality among infants of mothers who received non-study antibiotics than of mothers who received study antibiotics.
There is no association between intrapartum exposure to antibiotics and early neonatal morbidity or mortality. The associations observed in non-ITT analyses are most likely the result of women with peripartum illnesses being more likely to receive non-study antibiotics.
PMCID: PMC2764263  PMID: 19564260
Antibiotic resistance; Antibiotics; Neonatal morbidity; Neonatal mortality; Neonatal sepsis
2.  Risk Factors for Preterm Birth in Five Maternal and Child Health Hospitals in Beijing 
PLoS ONE  2012;7(12):e52780.
Preterm birth, the birth of an infant prior to 37 completed weeks of gestation, is the leading cause of perinatal morbidity and mortality. Preterm infants are at greater risk of respiratory, gastrointestinal and neurological diseases. Despite significant research in developed countries, little is known about the causes of preterm birth in many developing countries, especially China. This study investigates the association between sciodemographic data, obstetric risk factor, and preterm birth in five Maternal and Child Health hospitals in Beijing, China.
Methods and Findings
A case-control study was conducted on 1391 women with preterm birth (case group) and 1391 women with term delivery (control group), who were interviewed within 48 hours of delivery. Sixteen potential factors were investigated and statistical analysis was performed by univariate analysis and logistic regression analysis. Univariate analysis showed that 14 of the 16 factors were associated with preterm birth. Inter-pregnancy interval and inherited diseases were not risk factors. Logistic regression analysis showed that obesity (odds ratio (OR) = 3.030, 95% confidence interval (CI) 1.166–7.869), stressful life events (OR = 5.535, 95%CI 2.315–13.231), sexual activity (OR = 1.674, 95%CI 1.279–2.191), placenta previa (OR 13.577, 95%CI 2.563–71.912), gestational diabetes mellitus (OR = 3.441, 95%CI1.694–6.991), hypertensive disorder complicating pregnancy (OR = 6.034, 95%CI = 3.401–10.704), history of preterm birth (OR = 20.888, 95%CI 2.519–173.218) and reproductive abnormalities (OR = 3.049, 95%CI 1.010–9.206) were independent risk factors. Women who lived in towns and cities (OR = 0.603, 95%CI 0.430–0.846), had a balanced diet (OR = 0.533, 95%CI 0.421–0.675) and had a record of prenatal care (OR = 0.261, 95%CI 0.134–0.510) were less likely to have preterm birth.
Obesity, stressful life events, sexual activity, placenta previa, gestational diabetes mellitus, hypertensive disorder complicating pregnancy, history of preterm birth and reproductive abnormalities are independent risk factors to preterm birth. Identification of remedial factors may inform local health and education policy.
PMCID: PMC3531336  PMID: 23300774
3.  Critical appraisal and clinical utility of atosiban in the management of preterm labor 
Preterm birth is the major cause of perinatal morbidity and mortality in the developed world, and spontaneous preterm labor is the commonest cause of preterm birth. Interventions to treat women in spontaneous preterm labor have not reduced the incidence of preterm births but this may be due to increased risk factors, inclusion of births at the limits of viability, and an increase in the use of elective preterm birth. The role of antibiotics remains unproven. In the largest of the randomized controlled trials, evaluating the use of antibiotics for the prevention of preterm births in women in spontaneous preterm labor, antibiotics against anaerobes and bacterial vaginosis-related organisms were not included, and no objective evidence of abnormal genital tract flora was obtained. Atosiban and nifedipine are the main tocolytic agents used to treat women in spontaneous preterm labor, but atosiban is the tocolytic agent with the fewest maternal – fetal side effects. A well conducted randomized controlled trial comparing atosiban with nifedipine for their effectiveness and safety is needed.
PMCID: PMC2861440  PMID: 20463780
preterm labor; preterm births; management; tocolytics; atosiban
4.  Increased Risk of Preterm Delivery Among HIV-Infected Women Randomized to Protease Versus Nucleoside Reverse Transcriptase Inhibitor-Based HAART During Pregnancy 
The Journal of Infectious Diseases  2011;204(4):506-514.
(See the editorial commentary by Kourtis, on pages 493–4.)
Background. Protease inhibitor (PI)-based highly active antiretroviral therapy (HAART) use in pregnancy has been associated with preterm deliveries in some observational studies.
Methods. HIV-infected, HAART-naive pregnant women with CD4+ counts ≥200 cells/mm3 were randomized between 26 and 34 weeks gestation to lopinavir/ritonavir/zidovudine/lamivudine (PI group) or abacavir/zidovudine/lamivudine (NRTI group) in a clinical trial to prevent mother-to-child HIV transmission. Risk factors for preterm delivery (<37 weeks) and differences by randomization arm were evaluated for live infants by logistic regression.
Results. Preterm delivery rates were higher among 267 women in the PI group than 263 women in the NRTI group (21.4% vs 11.8%, P = .003). PI-based HAART was the most significant risk factor for preterm delivery [odds ratio = 2.03, 95% confidence interval 1.26–3.27, P = .004]. Mean change in maternal body mass index (BMI) 1 month after HAART initiation was lower in the PI group (P < .001); however, this was not significantly associated with preterm delivery. Neither infant hospitalizations nor mortality through 6 months of life differed by maternal regimen.
Conclusions. PI-based HAART was associated with increased preterm delivery but not increased infant hospitalizations or mortality in a clinical trial setting. The association between PI use and lower increase in BMI in late pregnancy warrants further study.
PMCID: PMC3144169  PMID: 21791651
5.  Infant feeding practice and associated factors of HIV positive mothers attending prevention of mother to child transmission and antiretroviral therapy clinics in Gondar Town health institutions, Northwest Ethiopia 
BMC Public Health  2012;12:240.
It has been estimated that 430,000 children under 15 years of age were newly infected with HIV in 2008, and more than 71% are living in sub-Saharan Africa. In the absence of intervention to prevent mother-to-child transmission, 30-45% of infants born to HIV-positive mothers in developing countries become infected during pregnancy, delivery and breastfeeding. The aim of this study was to assess infant feeding practice and associated factors of HIV positive mothers attending prevention of mother to child transmission and antiretroviral therapy clinics of Northwest Ethiopia.
Institution based cross sectional study was conducted from January to May 2011 among all HIV positive mothers with less than two years old child attending prevention of mother to child transmission and antiretroviral therapy clinics in Gondar Town health institutions. A structured pre-tested questionnaire using interview technique was used for data collection. The data was entered and analyzed using SPSS version 16 statistical package.
A total of 209 HIV positive mothers were included in the study. Of these, 187 (89.5%) had followed the recommended way of infant feeding practice while significant percentage (10.5%) had practiced mixed breast feeding. In multivariate analysis, disclosure of HIV status with their spouse, insufficient breast milk and occupational status were found to be independently associated (p-value of < 0.05) with recommended infant feeding practice. Lack of resource, stigma of HIV/AIDS, and husband opposition were also obtained as factors that influenced choice of infant feeding options by respondents.
Higher proportion of respondents used the recommended way of infant feeding practice by WHO as well as by Ethiopian Ministry of Health. However, mixed feeding in the first 6 months of age, an undesirable practice in infant feeding, were reported in this study. Infant feeding education that is aligned to national policy should be strengthened in primary health care, particularly in situations where prevention of mother to child transmission of HIV is prioritized.
PMCID: PMC3326701  PMID: 22449092
6.  Progesterone for the prevention of preterm birth in women with multiple pregnancies: the AMPHIA trial 
15% of multiple pregnancies ends in a preterm delivery, which can lead to mortality and severe long term neonatal morbidity. At present, no generally accepted strategy for the prevention of preterm birth in multiple pregnancies exists. Prophylactic administration of 17-alpha hydroxyprogesterone caproate (17OHPC) has proven to be effective in the prevention of preterm birth in women with singleton pregnancies with a previous preterm delivery. At present, there are no data on the effectiveness of progesterone in the prevention of preterm birth in multiple pregnancies.
We aim to investigate the hypothesis that 17OHPC will reduce the incidence of the composite neonatal morbidity of neonates by reducing the early preterm birth rate in multiple pregnancies. Women with a multiple pregnancy at a gestational age between 15 and 20 weeks of gestation will be entered in a placebo-controlled, double blinded randomised study comparing weekly 250 mg 17OHPC intramuscular injections from 16–20 weeks up to 36 weeks of gestation versus placebo. At study entry, cervical length will be measured. The primary outcome is composite bad neonatal condition (perinatal death or severe morbidity). Secondary outcome measures are time to delivery, preterm birth rate before 32 and 37 weeks, days of admission in neonatal intensive care unit, maternal morbidity, maternal admission days for preterm labour and costs. We need to include 660 women to indicate a reduction in bad neonatal outcome from 15% to 8%. Analysis will be by intention to treat. We will also analyse whether the treatment effect is dependent on cervical length.
This trial will provide evidence as to whether or not 17OHPC-treatment is an effective means of preventing bad neonatal outcome due to preterm birth in multiple pregnancies.
Trial registration
Current Controlled Trials ISRCTN40512715
PMCID: PMC1914085  PMID: 17578562
7.  When Women Deliver with No One Present in Nigeria: Who, What, Where and So What? 
PLoS ONE  2013;8(7):e69569.
With the current maternal mortality ratio (MMR) of 630/100,000 live births, Nigeria ranks among the nations with the highest mortality rates in the world. The use of skilled assistants during delivery has been identified a key predictor in the reduction of mortality rates in the world over. Not only are Nigerian women predominantly using unskilled attendants, one in five births are delivered with No One Present (NOP). We assessed who, what, where and the so what of this practice using 2008 Nigeria DHS (NDHS) data. The study revealed that the prevalence of NOP is highest in the northern part of Nigeria with 94% of all observed cases. Socio-demographic factors, including, women’s age at birth, birth order, being Muslim, and region of residence, were positively associated with NOP deliveries. Mother’s education, higher wealth quintiles, urban residence, decision-making autonomy, and a supportive environment for women’s social and economic security were inversely associated with NOP deliveries. Women’s autonomy and social standing were critical to choosing to deliver with skilled attendance, which were further amplified by economic prosperity. Women’s’ economic wellbeing is entwined with their feelings of independence and freedom. Programs that seek to improve the autonomy of women and their strategic participation in sound health seeking decisions will, most likely, yield better results with improvements in women’s education, income, jobs, and property ownership. As a short term measure, the use of conditional cash transfer, proven to work in several countries, including 18 in sub-Saharan Africa, is recommended. Its use has the potential to reduce household budget constraint by lowering cost-related barriers associated with women’s ability to demand and use life-saving services. Given the preponderance of NOP in the Northern region, the study suggests that interventions to eradicate NOP deliveries must initially focus this region as priority.
PMCID: PMC3723888  PMID: 23936047
8.  Maternal HIV infection associated with small-for-gestational age infants but not preterm births: evidence from rural South Africa 
Human Reproduction (Oxford, England)  2012;27(6):1846-1856.
 Human immunodeficiency virus (HIV) is prevalent in many countries where small-for-gestational age (SGA) and premature delivery are also common. However, the associations between maternal HIV, preterm delivery and SGA infants remain unclear. We estimate the prevalence of SGA and preterm (<37 weeks) births, their associations with antenatal maternal HIV infection and their contribution to infant mortality, in a high HIV prevalent, rural area in South Africa.
Data were collected, in a non-randomized intervention cohort study, on all women attending antenatal clinics (2001–2004), before the availability of antiretroviral treatment. Newborns were weighed and gestational age was determined (based on last menstrual period plus midwife assessment antenatally). Poisson regression with robust variance assessed risk factors for preterm and SGA birth, while Cox regression assessed infant mortality and associated factors.
Of 2368 live born singletons, 16.6% were SGA and 21.4% were preterm. HIV-infected women (n= 1189) more commonly had SGA infants than uninfected women (18.1 versus 15.1%; P = 0.051), but percentages preterm were similar (21.8 versus 20.9%; P = 0.621). After adjustment for water source, delivery place, parity and maternal height, the SGA risk in HIV-infected women was higher [adjusted relative risk (aRR) 1.28, 95% confidence interval (CI): 1.06–1.53], but the association between maternal HIV infection and preterm delivery remained weak and not significant (aRR: 1.07, 95% CI: 0.91–1.26). In multivariable analyses, mortality under 1 year of age was significantly higher in SGA and severely SGA than in appropriate-for-gestational-age infants [adjusted hazard ratio (aHR): 2.12, 95% CI: 1.18–3.81 and 2.77, 95% CI: 1.56–4.91], but no difference in infant mortality was observed between the preterm and term infants (aHR: 1.18 95% CI: 0.79–1.79 for 34–36 weeks and 1.31, 95% CI: 0.58–2.94 for <34 weeks).
Maternal HIV infection increases the risk of SGA, but not preterm births, in this cohort.
PMCID: PMC3357196  PMID: 22442245
HIV; SGA; preterm; Africa; low birthweight
9.  Maternal selenium status during early gestation and risk for preterm birth 
Preterm birth occurs in 5%–13% of pregnancies. It is a leading cause of perinatal mortality and morbidity and has adverse long-term consequences for the health of the child. Because of the role selenium plays in attenuating inflammation, and because low concentrations of selenium have been found in women with preeclampsia, we hypothesized that low maternal selenium status during early gestation would increase the risk of preterm birth.
White Dutch women with a singleton pregnancy (n = 1197) were followed prospectively from 12 weeks’ gestation. Women with thyroid disease or type 1 diabetes were excluded. At delivery, 1129 women had complete birth-outcome data. Serum concentrations of selenium were measured during the 12th week of pregnancy. Deliveries were classified as preterm or term, and preterm births were subcategorized as iatrogenic, spontaneous or the result of premature rupture of the membranes.
Of the 60 women (5.3%) who had a preterm birth, 21 had premature rupture of the membranes and 13 had preeclampsia. The serum selenium concentration at 12 weeks’ gestation was significantly lower among women who had a preterm birth than among those who delivered at term (mean 0.96 [standard deviation (SD) 0.14] μmol/L v. 1.02 [SD 0.13] μmol/L; t = 2.9, p = 0.001). Women were grouped by quartile of serum selenium concentration at 12 weeks’ gestation. The number of women who had a preterm birth significantly differed by quartile (χ2 = 8.01, 3 degrees of freedom], p < 0.05). Women in the lowest quartile of serum selenium had twice the risk of preterm birth as women in the upper three quartiles, even after adjustment for the occurrence of preeclampsia (adjusted odds ratio 2.18, 95% confidence interval 1.25–3.77).
Having low serum selenium at the end of the first trimester was related to preterm birth and was independent of the mother having preeclampsia. Low maternal selenium status during early gestation may increase the risk of preterm premature rupture of the membranes, which is a major cause of preterm birth.
PMCID: PMC3060183  PMID: 21324870
10.  Correlates and outcomes of preterm birth, low birth weight, and small for gestational age in HIV-exposed uninfected infants 
Preterm birth (PTB), low birth weight (LBW) and small for gestational age (SGA) contribute to neonatal mortality. Maternal HIV-1 infection has been associated with an increased risk of PTB, but mechanisms underlying this association are undefined. We describe correlates and outcomes of PTB, LBW, and SGA in HIV-exposed uninfected infants.
This was a retrospective analysis of cohort study. Between 1999–2002, pregnant, HIV-infected women were enrolled into an HIV-1 transmission study. Logistic regression was used to identify correlates of PTB, LBW and SGA in HIV-negative, spontaneous singleton deliveries. Associations between birth outcomes and mortality were measured using survival analyses.
In multivariable models, maternal plasma (OR = 2.1, 95% CI = 1.1-3.8) and cervical HIV-1 RNA levels (OR = 1.6, 95% CI = 1.1-2.4), and CD4 < 15% (OR = 2.4, 95% CI = 1.0-5.6) were associated with increased odds of PTB. Abnormal vaginal discharge and cervical polymorphonuclear leukocytes were also associated with PTB. Cervical HIV-1 RNA level (OR = 2.4, 95% CI = 1.5-6.7) was associated with an increased odds of LBW, while increasing parity (OR = 0.46, 95% CI = 0.24-0.88) was associated with reduced odds. Higher maternal body mass index (OR = 0.75, 95% CI = 0.61-0.92) was associated with a reduced odds of SGA, while bacterial vaginosis was associated with >3-fold increased odds (OR = 3.2, 95% CI = 1.4-7.4). PTB, LBW, and SGA were each associated with a >6-fold increased risk of neonatal death, and a >2-fold increased rate of infant mortality within the first year.
Maternal plasma and cervical HIV-1 RNA load, and genital infections may be important risk factors for PTB in HIV-exposed uninfected infants. PTB, LBW, and SGA are associated with increased neonatal and infant mortality in HIV-exposed uninfected infants.
PMCID: PMC3897882  PMID: 24397463
Preterm birth; Low birth weight; Small for gestational age; Pediatric HIV
11.  A Potential Novel Spontaneous Preterm Birth Gene, AR, Identified by Linkage and Association Analysis of X Chromosomal Markers 
PLoS ONE  2012;7(12):e51378.
Preterm birth is the major cause of neonatal mortality and morbidity. In many cases, it has severe life-long consequences for the health and neurological development of the newborn child. More than 50% of all preterm births are spontaneous, and currently there is no effective prevention. Several studies suggest that genetic factors play a role in spontaneous preterm birth (SPTB). However, its genetic background is insufficiently characterized. The aim of the present study was to perform a linkage analysis of X chromosomal markers in SPTB in large northern Finnish families with recurrent SPTBs. We found a significant linkage signal (HLOD  = 3.72) on chromosome locus Xq13.1 when the studied phenotype was being born preterm. There were no significant linkage signals when the studied phenotype was giving preterm deliveries. Two functional candidate genes, those encoding the androgen receptor (AR) and the interleukin-2 receptor gamma subunit (IL2RG), located near this locus were analyzed as candidates for SPTB in subsequent case-control association analyses. Nine single-nucleotide polymorphisms (SNPs) within these genes and an AR exon-1 CAG repeat, which was previously demonstrated to be functionally significant, were analyzed in mothers with preterm delivery (n = 272) and their offspring (n = 269), and in mothers with exclusively term deliveries (n = 201) and their offspring (n = 199), all originating from northern Finland. A replication study population consisting of individuals born preterm (n = 111) and term (n = 197) from southern Finland was also analyzed. Long AR CAG repeats (≥26) were overrepresented and short repeats (≤19) underrepresented in individuals born preterm compared to those born at term. Thus, our linkage and association results emphasize the role of the fetal genome in genetic predisposition to SPTB and implicate AR as a potential novel fetal susceptibility gene for SPTB.
PMCID: PMC3515491  PMID: 23227263
12.  Biochemical Markers of Spontaneous Preterm Birth in Asymptomatic Women 
BioMed Research International  2014;2014:164081.
Preterm birth is a delivery that occurs at less than 37 completed weeks of gestation and it is associated with perinatal morbidity and mortality. Spontaneous preterm birth accounts for up to 75% of all preterm births. A number of maternal or fetal characteristics have been associated with preterm birth, but the use of individual or group biochemical markers have advanced some of the understanding on the mechanisms leading to spontaneous preterm birth. This paper provides a summary on the current literature on the use of biochemical markers in predicting spontaneous preterm birth in asymptomatic women. Evidence from the literature suggests fetal fibronectin, cervical interleukin-6, and α-fetoprotein as promising biochemical markers in predicting spontaneous preterm birth in asymptomatic women. The role of gene-gene and gene-environment interactions, as well as epigenetics, has the potential to further elucidate and improve understanding of the underlying mechanisms or pathways of spontaneous preterm birth. Refinement in study design and methodology is needed in future research for the development and validation of individual or group biochemical marker(s) for use independently or in conjunction with other potential risk factors such as genetic variants and environmental and behavioral factors in predicting spontaneous preterm birth across diverse populations.
PMCID: PMC3914291  PMID: 24551837
13.  All Our Babies Cohort Study: recruitment of a cohort to predict women at risk of preterm birth through the examination of gene expression profiles and the environment 
Preterm birth is the leading cause of perinatal morbidity and mortality. Risk factors for preterm birth include a personal or familial history of preterm delivery, ethnicity and low socioeconomic status yet the ability to predict preterm delivery before the onset of preterm labour evades clinical practice. Evidence suggests that genetics may play a role in the multi-factorial pathophysiology of preterm birth. The All Our Babies Study is an on-going community based longitudinal cohort study that was designed to establish a cohort of women to investigate how a women's genetics and environment contribute to the pathophysiology of preterm birth. Specifically this study will examine the predictive potential of maternal leukocytes for predicting preterm birth in non-labouring women through the examination of gene expression profiles and gene-environment interactions.
Collaborations have been established between clinical lab services, the provincial health service provider and researchers to create an interdisciplinary study design for the All Our Babies Study. A birth cohort of 2000 women has been established to address this research question. Women provide informed consent for blood sample collection, linkage to medical records and complete questionnaires related to prenatal health, service utilization, social support, emotional and physical health, demographics, and breast and infant feeding. Maternal blood samples are collected in PAXgene™ RNA tubes between 18-22 and 28-32 weeks gestation for transcriptomic analyses.
The All Our Babies Study is an example of how investment in clinical-academic-community partnerships can improve research efficiency and accelerate the recruitment and data collection phases of a study. Establishing these partnerships during the study design phase and maintaining these relationships through the duration of the study provides the unique opportunity to investigate the multi-causal factors of preterm birth. The overall All Our Babies Study results can potentially lead to healthier pregnancies, mothers, infants and children.
PMCID: PMC3022739  PMID: 21192811
14.  Precursors for Late Preterm Birth in Singleton Gestations 
Obstetrics and gynecology  2010;116(5):1047-1055.
Previous studies have investigated the consequences of late preterm birth between 34 – 36 weeks gestation, but less is known about the “indicated” reasons and potential differences in neonatal outcomes from various delivery indications. . In singletons, we characterized precursors for late preterm birth and incidences of neonatal morbidities and perinatal mortality by gestational age and precursor.
Using retrospective observational data, we compared 15,136 gestations born late preterm to 170,593 deliveries between 37 0/7 and 41 6/7 weeks. We defined the following categories of precursors for late preterm delivery: “spontaneous labor”, “premature rupture of the membranes (preterm PROM)”, “indicated” delivery and “unknown.” Incidences of neonatal morbidities were calculated according to category of precursor stratified by gestational age at delivery. Neonatal morbidities and mortality associated with potentially avoidable deliveries (e.g. “soft” precursors or elective) were compared between late preterm births and neonates born at 37 – 40 weeks.
Late preterm birth comprised 7.8% of all births and 65.7% of preterm births. Percentages of precursors were 29.8% spontaneous labor, 32.3% preterm PROM, 31.8% indicated and 6.1% unknown. Different precursors for delivery were associated with varying incidences of neonatal morbidity. One in 15 neonates delivered late preterm for “soft” or elective precursors, and neonatal morbidity and mortality were increased compared to delivery ≥ 37 weeks for these same indications
A significant number of late preterm births were potentially avoidable Elective deliveries should be postponed until 39 weeks' gestation. More prospective data is needed to guide which indications can be managed expectantly.
PMCID: PMC3014049  PMID: 20966688
15.  Reduction in Preterm Delivery and Neonatal Mortality after the Introduction of Antenatal Cotrimoxazole Prophylaxis among HIV-Infected Women with Low CD4 Cell Counts 
The Journal of infectious diseases  2006;194(11):1510-1518.
Cotrimoxazole prophylaxis is recommended for subgroups of human immunodeficiency virus (HIV)-infected adults and children to reduce all-cause morbidity and mortality. We investigated whether antenatal cotrimoxazole prophylaxis begun during pregnancy for HIV-infected pregnant women with low CD4 cell counts would affect birth outcomes.
Cotrimoxazole prophylaxis was introduced as a routine component of antenatal care for HIV-infected women with CD4 cell counts <200 cells/μL during the course of a trial of mother-to-child HIV transmission in Lusaka, Zambia. Rates of preterm delivery, low birth weight, and neonatal mortality were compared for women with low CD4 cell counts before and after its introduction.
Among 255 women with CD4 cell counts <200 cells/μL, the percentage of preterm births (≤34 weeks of gestation) was lower (odds ratio [OR], 0.49 [95% confidence interval {CI}, 0.24-0.98]) after cotrimoxazole prophylaxis was introduced than before; there was a significant decrease in neonatal mortality (9% to 0%; P = .01) and a trend toward increased birth weight (β = 114 g [95% CI, -42 to 271 g]). In contrast, there were no significant changes in these parameters over the same time interval among women with CD4 cell counts ≥200 cells/μL.
Antenatal provision of cotrimoxazole for HIV-infected pregnant women with low CD4 cell counts may have indirect benefits for neonatal health.
PMCID: PMC1773010  PMID: 17083035
16.  Maternal caffeine intake during pregnancy is associated with birth weight but not with gestational length: results from a large prospective observational cohort study 
BMC Medicine  2013;11:42.
Pregnant women consume caffeine daily. The aim of this study was to examine the association between maternal caffeine intake from different sources and (a) gestational length, particularly the risk for spontaneous preterm delivery (PTD), and (b) birth weight (BW) and the baby being small for gestational age (SGA).
This study is based on the Norwegian Mother and Child Cohort Study conducted by the Norwegian Institute of Public Health. A total of 59,123 women with uncomplicated pregnancies giving birth to a live singleton were identified. Caffeine intake from different sources was self-reported at gestational weeks 17, 22 and 30. Spontaneous PTD was defined as spontaneous onset of delivery between 22+0 and 36+6 weeks (n = 1,451). As there is no consensus, SGA was defined according to ultrasound-based (Marsal, n = 856), population-based (Skjaerven, n = 4,503) and customized (Gardosi, n = 4,733) growth curves.
The main caffeine source was coffee, but tea and chocolate were the main sources in women with low caffeine intake. Median pre-pregnancy caffeine intake was 126 mg/day (IQR 40 to 254), 44 mg/day (13 to 104) at gestational week 17 and 62 mg/day (21 to 130) at gestational week 30. Coffee caffeine, but not caffeine from other sources, was associated with prolonged gestation (8 h/100 mg/day, P <10-7). Neither total nor coffee caffeine was associated with spontaneous PTD risk. Caffeine intake from different sources, measured repeatedly during pregnancy, was associated with lower BW (Marsal-28 g, Skjaerven-25 g, Gardosi-21 g per 100 mg/day additional total caffeine for a baby with expected BW 3,600 g, P <10-25). Caffeine intake of 200 to 300 mg/day increased the odds for SGA (OR Marsal 1.62, Skjaerven 1.44, Gardosi 1.27, P <0.05), compared to 0 to 50 mg/day.
Coffee, but not caffeine, consumption was associated with marginally increased gestational length but not with spontaneous PTD risk. Caffeine intake was consistently associated with decreased BW and increased odds of SGA. The association was strengthened by concordant results for caffeine sources, time of survey and different SGA definitions. This might have clinical implications as even caffeine consumption below the recommended maximum (200 mg/day in the Nordic countries and USA, 300 mg/day according to the World Health Organization (WHO)) was associated with increased risk for SGA.
PMCID: PMC3606471  PMID: 23421532
preterm delivery; gestational length; small for gestational age; birth weight; growth curve; intrauterine growth restriction; caffeine; coffee; tea; soft drinks
17.  Morbidity and Mortality Among a Cohort of Human Immunodeficiency Virus Type 1-Infected and Uninfected Pregnant Women and Their Infants From Malawi, Zambia, and Tanzania 
Morbidity and mortality patterns among pregnant women and their infants (before antiretroviral therapy was widely available) determines HIV-1 diagnostic, monitoring, and care interventions.
Data from mothers and their infants enrolled in a trial of antibiotics to reduce mother-to-child-transmission of HIV-1 at 4 sub-Saharan African sites were analyzed. Women were enrolled during pregnancy and follow-up continued until the infants reached 12 months of age. We describe maternal and infant morbidity and mortality in a cohort of HIV-1-infected and HIV-1-uninfected mothers. Maternal and infant factors associated with mortality risk in the infants were assessed using Cox proportional hazard modeling.
Among 2292 HIV-1-infected mothers, 166 (7.2%) had a serious adverse event (SAE) and 42 (1.8%) died, whereas no deaths occurred among the 331 HIV-1 uninfected mothers. Four hundred twenty-four (17.8%) of 2383 infants had an SAE and 349 (16.4%) died before the end of follow-up. Infants with early HIV-1 infection (birth to 4 – 6 weeks) had the highest mortality. Among infants born to HIV-1-infected women, maternal morbidity and mortality (P = 0.0001), baseline CD4 count (P = 0.0002), and baseline plasma HIV-1 RNA concentration (P < 0.0001) were significant predictors of infant mortality in multivariate analyses.
The high mortality among infants with early HIV-1 infection supports access to HIV-1 diagnostics and appropriate early treatment for all infants of HIV-1-infected mothers. The significant association between stage of maternal HIV-1 infection and infant mortality supports routine CD4 counts at the time of prenatal HIV-1 testing.
PMCID: PMC2739309  PMID: 18679152
HIV-1 infection; infant mortality; maternal morbidity and mortality; sub-Saharan Africa; pregnant women
18.  Fish Consumption, Erythrocyte Fatty Acids, and Preterm Birth 
Obstetrics and gynecology  2011;117(5):1071-1077.
To estimate the association between fish consumption and erythrocyte omega-3 long chain polyunsaturated fatty acids and preterm birth in a high-risk cohort.
This was an ancillary study to a randomized trial of omega-3 supplementation to prevent preterm birth in women with at least one prior spontaneous preterm delivery. Dietary fish intake was assessed by questionnaire and erythrocyte fatty acids were measured at enrollment (16 to 21 completed weeks of gestation). The association between fish consumption and preterm delivery was modeled with linear and quadratic terms.
The probability of preterm birth was 48.6% among women eating fish less than once a month and 35.9% among women eating fish more often (p<0.001). The adjusted odds ratio for preterm birth among women reporting moderately frequent fish consumption (three servings per week) was 0.60 (95% confidence interval 0.38 – 0.95), with no further reduction in preterm birth among women who consumed more than three servings of fish per week. Erythrocyte omega-3 levels correlated weakly but significantly with frequency of fish intake (Spearman r=0.22, p<0.001); women in the lowest quartile of erythrocyte omega-3 levels were more likely to report consuming less than one fish meal per month (40.3%) than were women in the highest three quartiles (26.3%, p<0.001).
Moderate fish intake (up to three meals per week) prior to 22 weeks of gestation was associated with a reduction in repeat preterm birth. More than moderate consumption did not confer additional benefit. These results support the recommendations of the U.S. Food and Drug Administration and the American Congress of Obstetricians and Gynecologists for fish consumption during pregnancy.
PMCID: PMC3754827  PMID: 21508745
19.  Cancer burden among HIV-positive persons in Nigeria: preliminary findings from the Nigerian AIDS-cancer match study 
Although Nigeria has a large HIV epidemic, the impact of HIV on cancer in Nigerians is unknown.
We conducted a registry linkage study using a probabilistic matching algorithm among a cohort of HIV positive persons registered at health facilities where the Institute of Human Virology Nigeria (IHVN) provides HIV prevention and treatment services. Their data was linked to data from 2009 to 2012 in the Abuja Cancer Registry. Match compatible files with first name, last name, sex, date of birth and unique HIV cohort identification numbers were provided by each registry and used for the linkage analysis. We describe demographic characteristics of the HIV clients and compute Standardized Incidence Ratios (SIRs) to evaluate the association of various cancers with HIV infection.
Between 2005 and 2012, 17,826 persons living with HIV (PLWA) were registered at IHVN. Their median age (Interquartile range (IQR)) was 33 (27–40) years; 41% (7246/17826) were men and 59% (10580/17826) were women. From 2009 to 2012, 2,029 clients with invasive cancers were registered at the Abuja Cancer Registry. The median age (IQR) of the cancer clients was 45 (35–68) years. Among PLWA, 39 cancer cases were identified, 69% (27/39) were incident cancers and 31% (12/39) were prevalent cancers. The SIR (95% CI) for the AIDS Defining Cancers were 5.7 (4.1, 7.2) and 2.0 (0.4, 3.5), for Kaposi Sarcoma and Cervical Cancer respectively.
The risk of Kaposi Sarcoma but not Cervical Cancer or Non-Hodgkin’s Lymphoma, was significantly increased among HIV positive persons, compared to the general population in Nigeria.
PMCID: PMC3942812  PMID: 24597902
HIV; Cancer; AIDS-cancer match; Registry linkage; Nigeria
20.  Factors Associated with Preterm, Early Preterm and Late Preterm Birth in Malawi 
PLoS ONE  2014;9(3):e90128.
Assessment of risk factors for preterm birth in a population with high incidence of preterm birth and HIV infection.
Secondary analysis of data for 2,149 women included in a community based randomized placebo controlled trial for the prevention of preterm birth (APPLe trial (ISRCTN84023116) with gestational age at birth determined through ultrasound measurement in early pregnancy. Multivariate Logistic Regression analyses to obtain models for three outcome variables: all preterm, early preterm, and late preterm birth.
No statistical differences were noted for the prevalence of HIV infection (p = 0.30) or syphilis (p = 0.12) between women who delivered preterm versus term. BMI (Adjusted OR 0.91 (0.85–0.97); p = 0.005) and weight gain (Adjusted OR 0.89 (0.82–0.97); p = 0.006) had an independent, protective effect. Previous preterm birth doubled the odds of preterm birth (Adjusted OR 2.13 (1.198–3.80); p = 0.01). Persistent malaria (despite malaria prophylaxis) increased the risk of late preterm birth (Adjusted OR 1.99 (1.05–3.79); p = 0.04). Age <20 (Adjusted OR 1.73 (1.03–2.90); p = 0.04) and anemia (Adjusted OR 1.95 (1.08–3.52); p = 0.03) were associated with early preterm birth (<34 weeks).
Despite claims that HIV infection is an important cause of preterm birth in Africa, we found no evidence of an association in this population (unexposed to anti-retroviral treatment). Persistent malaria was associated with late preterm birth. Maternal undernourishment and anemia were independently associated with early preterm birth. The study did not assess whether the link was direct or whether a common precursor such as chronic infection was responsible for both maternal effects and early labour.
PMCID: PMC3940843  PMID: 24595186
21.  Progestogens to prevent preterm birth in twin pregnancies: an individual participant data meta-analysis of randomized trials 
Preterm birth is the principal factor contributing to adverse outcomes in multiple pregnancies. Randomized controlled trials of progestogens to prevent preterm birth in twin pregnancies have shown no clear benefits. However, individual studies have not had sufficient power to evaluate potential benefits in women at particular high risk of early delivery (for example, women with a previous preterm birth or short cervix) or to determine adverse effects for rare outcomes such as intrauterine death.
We propose an individual participant data meta-analysis of high quality randomized, double-blind, placebo-controlled trials of progestogen treatment in women with a twin pregnancy. The primary outcome will be adverse perinatal outcome (a composite measure of perinatal mortality and significant neonatal morbidity). Missing data will be imputed within each original study, before data of the individual studies are pooled. The effects of 17-hydroxyprogesterone caproate or vaginal progesterone treatment in women with twin pregnancies will be estimated by means of a random effects log-binomial model. Analyses will be adjusted for variables used in stratified randomization as appropriate. Pre-specified subgroup analysis will be performed to explore the effect of progestogen treatment in high-risk groups.
Combining individual patient data from different randomized trials has potential to provide valuable, clinically useful information regarding the benefits and potential harms of progestogens in women with twin pregnancy overall and in relevant subgroups.
PMCID: PMC3315727  PMID: 22420582
22.  Progesterone for the prevention of preterm birth: indications, when to initiate, efficacy and safety 
Preterm birth is the leading cause of neonatal mortality and morbidity and long-term disability of non-anomalous infants. Previous studies have identified a prior early spontaneous preterm birth as the risk factor with the highest predictive value for recurrence. Two recent double blind randomized placebo controlled trials reported lower preterm birth rate with the use of either intramuscular 17 alpha-hydroxyprogesterone caproate (IM 17OHP-C) or intravaginal micronized progesterone suppositories in women at risk for preterm delivery. However, it is still unclear which high-risk women would truly benefit from this treatment in a general clinical setting and whether socio-cultural, racial and genetic differences play a role in patient’s response to supplemental progesterone. In addition the patient’s acceptance of such recommendation is also in question. More research is still required on identification of at risk group, the optimal gestational age at initiation, mode of administration, dose of progesterone and long-term safety.
PMCID: PMC2697509  PMID: 19436604
preterm birth prevention; 17-alpha-hydroxyprogesterone caproate
23.  Timing of Indicated Late Preterm and Early Term Birth In Chronic Medical Complications: Diabetes 
Seminars in perinatology  2011;35(5):297-301.
The number of pregnant women who have type 2 diabetes and the number found to have gestational diabetes are progressively increasing. In the future as many as 20% of pregnant women may have a diagnosis of diabetes. Although there is consensus regarding many issues in the treatment of pregnant women with diabetes, there are few evidenced-based studies upon which to base the timing of delivery. There must be a balance between increased neonatal morbidity of late preterm and early term delivery and fetal mortality. Potential adverse outcomes associated with late preterm and early term delivery include respiratory problems as well as other metabolic dysfunctions characteristic of the preterm infant of a mother with diabetes. Delivery at term increases the risk of fetal demise, fetal overgrowth, and birth injury. Even among diabetic women who are in good glycemic control, the risk of intrauterine fetal demise in third trimester appears greater than that of neonatal death. Additional prospective data are urgently needed to better understand the short and long-term risks and benefits of the timing of delivery in this very common obstetrical dilemma.
PMCID: PMC3185292  PMID: 21962630
24.  Brazilian multicenter study on prevalence of preterm birth and associated factors 
The occurrence of preterm birth remains a complex public health condition. It is considered the main cause of neonatal morbidity and mortality, resulting in a high likelihood of sequelae in surviving children. With variable incidence in several countries, it has grown markedly in the last decades. In Brazil, however, there are still difficulties to estimate its real occurrence. Therefore, it is essential to establish the prevalence and causes of this condition in order to propose prevention actions. This study intend to collect information from hospitals nationwide on the prevalence of preterm births, their associated socioeconomic and environmental factors, diagnostic and treatment methods resulting from causes such as spontaneous preterm labor, prelabor rupture of membranes, and therapeutic preterm birth, as well as neonatal results.
This proposal is a multicenter cross-sectional study plus a nested case-control study, to be implemented in 27 reference obstetric centers in several regions of Brazil (North: 1; Northeast: 10; Central-west: 1; Southeast: 13; South: 2). For the cross sectional component, the participating centers should perform, during a period of six months, a prospective surveillance of all patients hospitalized to give birth, in order to identify preterm birth cases and their main causes. In the first three months of the study, an analysis of the factors associated with preterm birth will also be carried out, comparing women who have preterm birth with those who deliver at term. For the prevalence study, 37,000 births will be evaluated (at term and preterm), corresponding to approximately half the deliveries of all participating centers in 12 months. For the case-control study component, the estimated sample size is 1,055 women in each group (cases and controls). The total number of preterm births estimated to be followed in both components of the study is around 3,600. Data will be collected through a questionnaire all patients will answer after delivery. The data will then be encoded in an electronic form and sent online by internet to a central database. The data analysis will be carried out by subgroups according to gestational age at preterm birth, its probable causes, therapeutic management, and neonatal outcomes. Then, the respective rates, ratios and relative risks will be estimated for the possible predictors.
These findings will provide information on preterm births in Brazil and their main social and biological risk factors, supporting health policies and the implementation of clinical trials on preterm birth prevention and treatment strategies, a condition with many physical and emotional consequences to children and their families.
PMCID: PMC2889846  PMID: 20482822
25.  Birth outcomes in South African women receiving highly active antiretroviral therapy: a retrospective observational study 
Use of highly active antiretroviral therapy (HAART), a triple-drug combination, in HIV-infected pregnant women markedly reduces mother to child transmission of HIV and decreases maternal morbidity. However, there remains uncertainty about the effects of in utero exposure to HAART on foetal development.
Our objectives were to investigate whether in utero exposure to HAART is associated with low birth weight and/or preterm birth in a population of South African women with advanced HIV disease. A retrospective observational study was performed on women with CD4 counts ≤250 cells/mm3 attending antenatal antiretroviral clinics in Johannesburg between October 2004 and March 2007. Low birth weight (<2.5 kg) and preterm birth rates (<37 weeks) were compared between those exposed and unexposed to HAART during pregnancy. Effects of different HAART regimen and duration were assessed.
Among HAART-unexposed infants, 27% (60/224) were low birth weight compared with 23% (90/388) of early HAART-exposed (exposed <28 weeks gestation) and 19% (76/407) of late HAART-exposed (exposed ≥28 weeks) infants (p = 0.05). In the early HAART group, a higher CD4 cell count was protective against low birth weight (AOR 0.57 per 50 cells/mm3 increase, 95% CI 0.45-0.71, p < 0.001) and preterm birth (AOR 0.68 per 50 cells/mm3 increase, 95% CI 0.55-0.85, p = 0.001). HAART exposure was associated with an increased preterm birth rate (15%, or 138 of 946, versus 5%, or seven of 147, in unexposed infants, p = 0.001), with early nevirapine and efavirenz-based regimens having the strongest associations with preterm birth (AOR 5.4, 95% CI 2.1-13.7, p < 0.001, and AOR 5.6, 95% CI 2.1-15.2, p = 0.001, respectively).
In this immunocompromised cohort, in utero HAART exposure was not associated with low birth weight. An association between NNRTI-based HAART and preterm birth was detected, but residual confounding is plausible. More advanced immunosuppression was a risk factor for low birth weight and preterm birth, highlighting the importance of earlier HAART initiation in women to optimize maternal health and improve infant outcomes.
PMCID: PMC3163172  PMID: 21843356

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