Low to moderate prenatal alcohol exposure and neurodevelopment in a prospective cohort of early school aged children.

Evidence is strong for adverse fetal effects of high level or chronic prenatal alcohol exposure (PAE), but many pregnant women continue to drink at lower levels. The 'Asking Questions about Alcohol in pregnancy' prospective cohort aimed to determine the neurodevelopmental consequences at 6-8 years of age of low to moderate PAE. 1570 women from seven public antenatal clinics in Melbourne, Australia, provided information on frequency and quantity of alcohol use, and obstetric, lifestyle and socio-environmental confounders at four gestation timepoints. PAE was classified into five trajectories plus controls. At 6-8 years, 802 of 1342 eligible families took part and completed a questionnaire (60%) and 696 children completed neuropsychological assessments (52%). Multiple linear regressions examined mean outcome differences between groups using complete case and multiple imputation models. No meaningful relationships were found between any of the PAE trajectories and general cognition, academic skills, motor functioning, behaviour, social skills, social communication, and executive function. Maternal education most strongly influenced general cognition and academic skills. Parenting behaviours and financial situation were associated with academic skills, behaviour, social skills and/or executive function. The lack of association between PAE and neurodevelopment at 6-8 years may partly be explained by cumulative positive effects of socio-environmental factors.

Associations between low-moderate prenatal alcohol exposure and brain development in childhood.

BACKGROUND: The effects of low-moderate prenatal alcohol exposure (PAE) on brain development have been infrequently studied. AIM: To compare cortical and white matter structure between children aged 6 to 8 years with low-moderate PAE in trimester 1 only, low-moderate PAE throughout gestation, or no PAE. METHODS: Women reported quantity and frequency of alcohol consumption before and during pregnancy. Magnetic resonance imaging was undertaken for 143 children aged 6 to 8 years with PAE during trimester 1 only (n = 44), PAE throughout gestation (n = 58), and no PAE (n = 41). T1-weighted images were processed using FreeSurfer, obtaining brain volume, area, and thickness of 34 cortical regions per hemisphere. Fibre density (FD), fibre cross-section (FC) and fibre density and cross-section (FDC) metrics were computed for diffusion images. Brain measures were compared between PAE groups adjusted for age and sex, then additionally for intracranial volume. RESULTS: After adjustments, the right caudal anterior cingulate cortex volume (pFDR = 0.045) and area (pFDR = 0.008), and right cingulum tract cross-sectional area (pFWE < 0.05) were smaller in children exposed to alcohol throughout gestation compared with no PAE. CONCLUSION: This study reports a relationship between low-moderate PAE throughout gestation and cingulate cortex and cingulum tract alterations, suggesting a teratogenic vulnerability. Further investigation is warranted.

Early parenting behaviour is associated with complex attention outcomes in middle to late childhood in children born very preterm.

Attention deficits are common in children born very preterm (VP), especially for children with higher social risk. The aim of this study was to examine the association between parenting behavior and attention in children born VP, and whether this association is influenced by familial social risk. Two hundred and twenty-four children born <30 weeks' gestation and/or with a birth weight <1250 g were recruited at birth. At 2 years, social risk was calculated and parenting behaviors were observed during a parent-child interaction task, with children's attention skills assessed at 7 and 13 years using standardized assessments. Higher levels of sensitive parenting at 2 years were positively associated with divided attention at age 7 years, and higher levels of intrusive parenting were negatively associated with divided attention at 13 years. Children born VP with higher social risk were more positively influenced by sensitive parenting behavior for sustained attention at 7 years, selective attention at 13 years, and divided attention at 7 and 13 years than children born VP with lower social risk. Additionally, children born VP with higher social risk were more negatively influenced by intrusive parenting for sustained attention outcomes at 7 years than those with lower social risk. In summary, the evidence for a contribution of early parenting to attention outcomes in children born VP was stronger for more complex attention (divided attention) compared with basic attention domains. Our findings also suggest that early parenting behavior has a particular influence on children born VP from socially disadvantaged environments for attention outcomes.

Individual Attention Patterns in Children Born Very Preterm and Full Term at 7 and 13 Years of Age.

OBJECTIVE: To identify attention profiles at 7 and 13 years, and transitions in attention profiles over time in children born very preterm (VP; <30 weeks' gestation) and full term (FT), and examine predictors of attention profiles and transitions. METHODS: Participants were 167 VP and 60 FT children, evaluated on profiles across five attention domains (selective, shifting and divided attention, processing speed, and behavioral attention) at 7 and 13 years using latent profile analyses. Transitions in profiles were assessed with contingency tables. For VP children, biological and social risk factors were tested as predictors with a multinomial logistic regression. RESULTS: At 7 and 13 years, three distinct profiles of attentional functioning were identified. VP children were 2-3 times more likely to show poorer attention profiles compared with FT children. Transition patterns between 7 and 13 years were stable average, stable low, improving, and declining attention. VP children were two times less likely to have a stable average attention pattern and three times more likely to have stable low or improving attention patterns compared with FT children. Groups did not differ in declining attention patterns. For VP children, brain abnormalities on neonatal MRI and greater social risk at 7 years predicted stable low or changing attention patterns over time. CONCLUSIONS: VP children show greater variability in attention profiles and transition patterns than FT children, with almost half of the VP children showing adverse attention patterns over time. Early brain pathology and social environment are markers for attentional functioning.

Rates of Developmental Coordination Disorder in Children Born Very Preterm.

OBJECTIVE: To examine the stability of developmental coordination disorder (DCD) throughout childhood in children born very preterm and term. Further, in the very preterm group, to compare perinatal variables and neurobehavioral outcomes at 13 years of age for children with persisting DCD and those with typical motor development. STUDY DESIGN: Prospective study of 180 very preterm and 73 term-born children assessed at 5, 7, and/or 13 years of age using the Movement Assessment Battery for Children, with scores ≤16th percentile used to classify DCD. Children with cerebral palsy or an IQ of <80 were excluded. RESULTS: Children born very preterm had increased odds for DCD at 5 (OR, 5.53; 95% CI, 2.53-12.0; P < .001), 7 (OR, 3.63; 95% CI, 1.43-9.18; P = .06), and 13 years (OR, 4.34; 95% CI, 1.61-11.7; P = .004) compared with term-born children. The rates of DCD in very preterm children reduced from 47.9% at 5 years of age, to 28.5% at 7 years and 27.8% at 13 years of age (OR per year of age, 0.81; 95% CI, 0.75-0.87; P < .001), but less so for term-born children (15.3%, 10.0%, and 8.5% at 5, 7, and 13-years respectively [OR, 0.91; 95% CI, 0.75-1.09; P = .31]). Within the very preterm group at 13 years of age, there was evidence that children with persisting DCD performed poorer across several cognitive domains compared with children with typical motor development, with differences in the order of 0.5-1.0 SD. CONCLUSIONS: Although the rates of DCD decreased across middle childhood for both groups, the odds for DCD were consistently higher for very preterm children compared with term, with important implications for cognitive functioning in the very preterm group.

Language Skills in Children Born Preterm (<30 Wks' Gestation) Throughout Childhood: Associations With Biological and Socioenvironmental Factors.

OBJECTIVE: To examine the individual and collective contribution of biological and socioenvironmental factors associated with language function at 2, 5, 7, and 13 years in children born preterm (<30 weeks' gestation or <1250 g birth weight). METHODS: Language function was assessed as part of a prospective longitudinal study of 224 children born preterm at 2, 5, 7, and 13 years using age-appropriate tools. Language Z-scores were generated based on a contemporaneous term-born control group. A selection of biological factors (sex, small for gestational age, bronchopulmonary dysplasia, infection, and qualitatively defined brain injury) and early socioenvironmental factors at age 2 years (primary income earner employment status and type, primary caregiver education level, English as a second language, parental mental health history, parent sensitivity and facilitation, and parent-child synchrony) was chosen a priori. Associations were assessed using univariable and multivariable linear regression models applied to outcomes at each time point. RESULTS: Higher primary caregiver education level, greater parent-child synchrony, and parent sensitivity were independently associated with better language function across childhood. Socioenvironmental factors together explained an increasing percentage of the variance (9%-18%) in language function from 2 to 13 years of age. In comparison, there was little evidence for associations between biological factors and language function, even during early childhood years. CONCLUSION: This study highlights the importance of socioenvironmental factors over biological factors for language development throughout childhood. Some of these socioenvironmental factors are potentially modifiable, and parent-based interventions addressing parenting practices and education may benefit preterm children's language development.

Language Trajectories of Children Born Very Preterm and Full Term from Early to Late Childhood.

OBJECTIVE: To identify distinct language trajectories of children born very preterm and full term from 2 to 13 years of age and examine predictors for the identified trajectories. STUDY DESIGN: A cohort of 224 children born very preterm and 77 full term controls recruited at birth were followed up at ages 2, 5, 7, and 13 years. The number of distinct language trajectories was examined using latent growth mixture modeling allowing for linear and quadratic time trends. Potential predictors in the neonatal period (eg, birth group, sex, and medical risk) and at 2 years (ie, social risk and use of allied health services) for the language trajectories were tested using multinomial logistic regression. RESULTS: Five distinct language trajectories were identified across childhood: stable normal (32% of study cohort), resilient development showing catch-up (36%), precocious language skills (7%), stable low (17%), and high-risk (5%) development. The very preterm group was 8 times more likely to have a language trajectory that represented poorer language development compared with full term controls (very preterm, 40%; full term, 6%). Greater social risk and use of allied health services were associated with poorer language development. CONCLUSIONS: Variable language trajectories were observed, with a substantial proportion of children born very preterm exhibiting adverse language development. These findings highlight the need for monitoring language skills in children born very preterm before school entry and across middle childhood.

Developmental Trajectory of Language From 2 to 13 Years in Children Born Very Preterm.

OBJECTIVES: The objective of this study was to describe language functioning at 13 years of age and examine its developmental trajectory from 2 to 13 years of age in children born very preterm (VP) compared with term controls. METHODS: Two hundred and twenty-four children born VP (<30 weeks' gestation) and 77 term controls had language skills assessed by using performance-based and/or parent-report measures at 2, 5, 7, and 13 years of age. Regression models were used to compare verbal memory, grammar, semantics, and pragmatic skills between the VP and term groups at 13 years of age. Linear mixed effects regression models were used to assess language trajectories from 2 to 13 years of age. RESULTS: Compared with term controls, children born VP had poorer functioning across all components of language (mean group differences ranged from -0.5 SD to -1 SD; all P < .05) at 13 years of age. At each follow-up age, the VP group displayed poorer language functioning than the term controls, with the groups exhibiting similar developmental trajectories (slope difference = -0.01 SD per year; P = .55). CONCLUSIONS: Children born VP continue to display language difficulties compared with term controls at 13 years of age, with no evidence of developmental "catch-up." Given the functional implications associated with language deficits, early language-based interventions should be considered for children born VP.

Misoprostol as an adjunct to standard uterotonics for treatment of post-partum haemorrhage: a multicentre, double-blind randomised trial.

BACKGROUND: Post-partum haemorrhage is a leading cause of global maternal morbidity and mortality. Misoprostol, a prostaglandin analogue with uterotonic activity, is an attractive option for treatment because it is stable, active orally, and inexpensive. We aimed to assess the effectiveness of misoprostol as an adjunct to standard uterotonics compared with standard uterotonics alone for treatment of post-partum haemorrhage. METHODS: Women delivering vaginally who had clinically diagnosed post-partum haemorrhage due to uterine atony were enrolled from participating hospitals in Argentina, Egypt, South Africa, Thailand, and Vietnam between July, 2005, and August, 2008. Computer-generated randomisation was used to assign women to receive 600 microg misoprostol or matching placebo sublingually; both groups were also given routine injectable uterotonics. Allocation was concealed by distribution of sealed and sequentially numbered treatment packs in the order that women were enrolled. Providers and women were masked to treatment assignment. The primary outcome was blood loss of 500 mL or more within 60 min after randomisation. Analysis was by intention to treat. This study is registered, number ISRCTN34455240. FINDINGS: 1422 women were assigned to receive misoprostol (n=705) or placebo (n=717). The proportion of women with blood loss of 500 mL or more within 60 min was similar between the misoprostol group (100 [14%]) and the placebo group (100 [14%]; relative risk 1.02, 95% CI 0.79-1.32). In the first 60 min, an increased proportion of women on misoprostol versus placebo, had shivering (455/704 [65%] vs 230/717 [32%]; 2.01, 1.79-2.27) and body temperature of 38 degrees C or higher (303/704 [43%] vs 107/717 [15%]; 2.88, 2.37-2.50). INTERPRETATION: Findings from this study do not support clinical use of 600 microg sublingual misoprostol in addition to standard injectable uterotonics for treatment of post-partum haemorrhage. FUNDING: Bill & Melinda Gates Foundation, and UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction.

Treatment of post-partum haemorrhage with sublingual misoprostol versus oxytocin in women not exposed to oxytocin during labour: a double-blind, randomised, non-inferiority trial.

BACKGROUND: Oxytocin, the standard of care for treatment of post-partum haemorrhage, is not available in all settings because of refrigeration requirements and the need for intravenous administration. Misoprostol, an effective uterotonic agent with several advantages for resource-poor settings, has been investigated as an alternative. This trial established whether sublingual misoprostol was similarly efficacious to intravenous oxytocin for treatment of post-partum haemorrhage in women not exposed to oxytocin during labour. METHODS: In this double-blind, non-inferiority trial, 9348 women not exposed to prophylactic oxytocin had blood loss measured after vaginal delivery at four hospitals in Ecuador, Egypt, and Vietnam (one secondary-level and three tertiary-level facilities). 978 (10%) women were diagnosed with primary post-partum haemorrhage and were randomly assigned to receive 800 microg misoprostol (n=488) or 40 IU intravenous oxytocin (n=490). Providers and women were masked to treatment assignment. Primary endpoints were cessation of active bleeding within 20 min and additional blood loss of 300 mL or more after treatment. Clinical equivalence of misoprostol would be accepted if the upper bound of the 97.5% CI fell below the predefined non-inferiority margin of 6%. All outcomes were assessed from the time of initial treatment. This study is registered with ClinicalTrials.gov, number NCT00116350. FINDINGS: All randomly assigned participants were analysed. Active bleeding was controlled within 20 min with study treatment alone for 440 (90%) women given misoprostol and 468 (96%) given oxytocin (relative risk [RR] 0.94, 95% CI 0.91-0.98; crude difference 5.3%, 95% CI 2.6-8.6). Additional blood loss of 300 mL or greater after treatment occurred for 147 (30%) of women receiving misoprostol and 83 (17%) receiving oxytocin (RR 1.78, 95% CI 1.40-2.26). Shivering (229 [47%] vs 82 [17%]; RR 2.80, 95% CI 2.25-3.49) and fever (217 [44%] vs 27 [6%]; 8.07, 5.52-11.8) were significantly more common with misoprostol than with oxytocin. No women had hysterectomies or died. INTERPRETATION: In settings in which use of oxytocin is not feasible, misoprostol might be a suitable first-line treatment alternative for post-partum haemorrhage.

Blood pressure dynamics during pregnancy and spontaneous preterm birth.

OBJECTIVE: The objective of the study was to examine whether blood pressure in early pregnancy and its rise in the second half of gestation are associated with spontaneous preterm birth in healthy, normotensive, nulliparous women. STUDY DESIGN: We included 5167 women with singleton gestation who participated in the World Health Organization Calcium Supplementation for the Prevention of Preeclampsia Trial. Systolic, diastolic, and mean arterial blood pressure and pulse pressure at baseline (12-19 weeks of gestation) and at the midthird trimester (30-34 weeks) were calculated. Rise in blood pressure was the difference between the midthird trimester and baseline. Preterm birth was defined as early preterm (less than 34 completed weeks) and late preterm birth (34-36 weeks). RESULTS: Women experiencing early or late preterm birth had over 10 mm Hg and 3 mm Hg higher rise, respectively, in systolic, diastolic, and mean arterial blood pressure than women delivering at term. A rise in systolic pressure over 30 mm Hg or diastolic pressure over 15 mm Hg was associated with a statistically significant 2- to 3-fold increase in risk of spontaneous preterm birth. CONCLUSION: An excessive rise in either systolic or diastolic blood pressures from early pregnancy to the midthird trimester is associated with spontaneous preterm birth in a dose-response pattern.

World Health Organization randomized trial of calcium supplementation among low calcium intake pregnant women.

OBJECTIVE: The purpose of this trial was to determine whether calcium supplementation of pregnant women with low calcium intake reduces preeclampsia and preterm delivery. STUDY DESIGN: Randomized placebo-controlled, double-blinded trial in nulliparous normotensive women from populations with dietary calcium < 600 mg/d. Women who were recruited before gestational week 20 received supplements (1.5 g calcium/d or placebo) throughout pregnancy. Primary outcomes were preeclampsia and preterm delivery; secondary outcomes focused on severe morbidity and maternal and neonatal mortality rates. RESULTS: The groups comprised 8325 women who were assigned randomly. Both groups had similar gestational ages, demographic characteristics, and blood pressure levels at entry. Compliance were both 85% and follow-up losses (calcium, 3.4%; placebo, 3.7%). Calcium supplementation was associated with a non-statistically significant small reduction in preeclampsia (4.1% vs 4.5%) that was evident by 35 weeks of gestation (1.2% vs 2.8%; P = .04). Eclampsia (risk ratio, 0.68: 95% CI, 0.48-0.97) and severe gestational hypertension (risk ratio, 0.71; 95% CI, 0.61-0.82) were significantly lower in the calcium group. Overall, there was a reduction in the severe preeclamptic complications index (risk ratio, 0.76; 95% CI, 0.66-0.89; life-table analysis, log rank test; P = .04). The severe maternal morbidity and mortality index was also reduced in the supplementation group (risk ratio, 0.80; 95% CI, 0.70-0.91). Preterm delivery (the neonatal primary outcome) and early preterm delivery tended to be reduced among women who were < or = 20 years of age (risk ratio, 0.82; 95% CI, 0.67-1.01; risk ratio, 0.64; 95% CI, 0.42-0.98, respectively). The neonatal mortality rate was lower (risk ratio, 0.70; 95% CI, 0.56-0.88) in the calcium group. CONCLUSION: A 1.5-g calcium/day supplement did not prevent preeclampsia but did reduce its severity, maternal morbidity, and neonatal mortality, albeit these were secondary outcomes.

A randomized controlled study comparing 600 versus 1,200 microg oral misoprostol for medical management of incomplete abortion.

OBJECTIVES: Although a number of studies have shown misoprostol's promise as a nonsurgical treatment for incomplete abortion, few have systematically examined treatment protocols. This study documents the effectiveness of 600 versus 1,200 microg oral misoprostol for this indication. METHODS: From May 2002 to January 2003, 300 women with incomplete abortion were recruited at a large tertiary facility in Vietnam and randomized to either a single-dose (600 microg) or a repeated-dose (600 microg x 2) regimen of oral misoprostol for the treatment of their condition. RESULTS: Misoprostol effectively evacuated the uterus for nearly all women (94.6%; n=279), with most reporting bleeding for 4 days (+/-2.3) and pain/cramps lasting 1 day (+/-1.0). Women indicated that the side effects were tolerable (96%) and that their experience was satisfactory (95%). CONCLUSIONS: Oral misoprostol (600 or 1,200 microg) offers a safe, effective and acceptable treatment for incomplete abortion. Larger studies to assess the advantages and disadvantages of misoprostol as compared with standard surgical care are needed to assess its role in postabortion care programs worldwide.

Effectiveness of lifesaving skills training and improving institutional emergency obstetric care readiness in Lam Dong, Vietnam.

Essential obstetric care is promoted as the prime strategy to save women's lives in developing countries. We measured the effect of improving lifesaving skills (LSS) capacity in Vietnam, a country in which most women deliver in health facilities. A quasi-experimental study was implemented to assess the impact of LSS training and readiness (availability of essential obstetric equipment, supplies, and medication) on the diagnosis of life-threatening obstetric conditions and appropriate management of labor and birth. The intervention (LSS training and readiness) was provided to all clinics and hospitals from 1 of 3 demographically similar districts in southcentral Vietnam, to hospitals only in another district, with the third district serving as the comparison group. Detection of life-threatening obstetric conditions increased in both experimental clinics and hospitals, but the intervention only improved the management of these conditions in hospitals. Management of life-threatening obstetric conditions is most effective in hospitals. The intervention did not clearly benefit women delivering in clinics.