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1.  Mothers of Very Low Birth Weight Children at School Age: Quality of Life Outcomes from the Newborn Lung Project Statewide Cohort Study 
Purpose
This study aimed to: (1) determine the health-related quality of life (HRQoL) in mothers of five year old very low birth weight (VLBW) and normal birth weight (NBW) children; (2) determine what extent stress mediates the relationship between case status and maternal HRQoL; and (3) examine the pre-pregnancy, pregnancy, birth, and child health-related factors in predicting maternal HRQoL among mothers of five year old VLBW children.
Methods
A telephone interview was administered to 297 mothers of VLBW children and 290 mothers of NBW children who were enrolled in the Newborn Lung Project Statewide Cohort Study.
Results
Mothers of VLBW children experienced worse physical and mental HRQoL than mothers of NBW children (52.8 versus 55.3 points, p<0.0001, and 48.9 versus 50.5 points, p=0.02, respectively). Adjusted analyses showed that maternal mental HRQoL was similar between cases and controls while physical HRQoL when children were age five was significantly different between cases and controls (Beta:−2.02, p=0.0006); this relationship was mediated by maternal stress. Among mothers of VLBW children, stress significantly contributed to adverse HRQoL outcomes when children were age five. Child behavior problems at age two were also associated with worse subsequent maternal mental HRQoL (Beta: −1.8 per SD, p=0.004), while each week of neonatal intensive care unit stay was associated with worse physical HRQoL (Beta: −0.26, p=0.02).
Conclusions
While caring for a VLBW child negatively impacts the HRQoL of mothers, this relationship was partially explained by maternal stress. Addressing maternal stress may be an important way to improve long-term HRQoL.
doi:10.1007/s11136-011-0069-3
PMCID: PMC3390448  PMID: 22161725
Very low birth weight; maternal stress; maternal health-related quality of life; life course
2.  The Contribution of Infant, Maternal, and Family Conditions to Maternal Feeding Competencies 
SYNOPSIS
Objective
Because little is known about the role of family problem-solving processes in the development of mothers’ competencies in feeding a very low birth-weight (VLBW) infant, we explored the contribution made by the competence in negotiating displayed by a mother and family member as they jointly problem solve infant-care issues. The infant’s neonatal biomedical condition, maternal depressive symptoms, and family poverty status may also contribute to feeding competencies.
Design
A sample of 41 mothers of VLBW infants from 2 longitudinal studies who were observed during feeding at 1 and 8 months infant postterm age, with a family member of their choosing, participated in a dyadic problem-solving exercise. We assessed maternal feeding competencies with the Parent–Child Early Relational Assessment (Clark, 1997) and dyadic negotiating competence using an observational scale from the Iowa Family Interaction Rating Scales (Melby & Conger, 2001). We classified infant condition through medical record audit. Maternal depressive symptoms were assessed with the Center for Epidemiologic Studies-Depression (CES-D) Scale (L. S. Radloff, 1977), and family poverty status was determined through the mother’s report of family income.
Results
Mothers’ feeding competencies, structured into 2 factors, Parental Positive Affective Involvement, Sensitivity, and Responsiveness (PPAISR) and Parental Negative Affect and Behavior (PNAB, scored in the direction of low negativity) were stable from 1 to 8 months, accounting for the entire set of predictor variables. Neonatal biomedical condition had no effect on either PPAISR or PNAB; depressive symptoms were negatively associated with PNAB at 8 months; poverty status negatively predicted both PPAISR and PNAB at 1 and 8 months; and negotiating competence of the mother–family member dyad was positively associated with PNAB at 1 month.
Conclusions
Evidence that family poverty status and dyadic negotiating competence were both associated with maternal feeding competencies supports inclusion of these family-level variables in a model of feeding competencies. A mother’s negotiating competence with another family member who takes a responsible role in infant care may support maternal feeding competencies during a VLBW infant’s early weeks when parenting patterns are forming.
doi:10.1080/15295190903014596
PMCID: PMC3227219  PMID: 22140356
3.  Maternal Depressive Symptoms and Participation in Early Intervention Services for Young Children 
Maternal and Child Health Journal  2012;16(2):336-345.
Many young children with developmental delay who are eligible for early intervention (EI) services fail to receive them. We assessed the relationship between depressive symptoms in mothers, a potentially modifiable risk, and receipt of EI services by their eligible children. We conducted multivariable analyses of a nationally representative sample of children eligible for EI services at 24 months using data from the Early Childhood Longitudinal Study-Birth Cohort. Maternal depressive symptoms were assessed at 9 and 24 months. Birthweight <1,000 g, genetic and medical conditions associated with developmental delay, or low scores on measures of developmental performance defined EI eligibility. Service receipt was ascertained from parental self-report. Models were adjusted for sociodemographic and child risk. Among the 650 children who were eligible to receive EI services as infants, 33.2% of children whose mothers were depressed received services compared to 27.0% whose mothers were not depressed (aOR 1.8; 95% CI 0.8, 4.0). Among the 650 children who became eligible to receive services as toddlers, 13.0% of children whose mothers were depressed received services compared to 2.6% whose mothers were not depressed (aOR 4.6, 95% CI 1.5, 14.6). Among children receiving EI services, prevalence of depressive symptoms was 23.0% for mothers whose children became eligible as infants and 57.5% for mothers whose children became eligible as toddlers. Depressive symptoms in mothers of children eligible to receive EI services did not appear to limit participation. EI programs may be an appropriate setting in which to address maternal depressive symptoms.
doi:10.1007/s10995-010-0715-3
PMCID: PMC3108048  PMID: 21140201
Early intervention; Maternal depression; Developmental delay; Part C services; Early Child Longitudinal Study
4.  Feeding Interactions in Infants with Very Low Birth Weight and Bronchopulmonary Dysplasia 
Infants with very low birth weight (VLBW) are at increased risk for feeding disorders that can affect growth and development. One hundred and forty one mother-infant pairs were compared [55 with infants with high medical risk due to infant VLBW and bronchopulmonary dysplasia (BPD), 34 VLBW without BPD, and 52 term infants] on operationally defined measures of feeding behaviors and maternal self-report of depression and anxiety. Mothers of VLBW infants with and without BPD spent more time prompting their infants to feed when their infants engaged in nonfeeding behavior. Despite increased maternal efforts, infants with BPD took in less formula, spent less time sucking, and spent a greater proportion of time nonfeeding. VLBW infants without BPD were equivalent to term infants in percentage of time sucking and in volume of formula ingested and were more likely to take in higher calories than infants with BPD. Mothers of VLBW infants with and without BPD were also more likely to report clinically significant symptoms of depression and anxiety than mothers of term infants. Because mothers of VLBW infants who were more depressed or anxious were less likely to verbally prompt their infants to eat, maternal psychological symptoms should be considered in assessing interactions of VLBW mother-infant dyads.
PMCID: PMC4192536  PMID: 8727839
bronchopulmonary dysplasia; very low birth weight infant; feeding; maternal depression; prematurity
5.  DoMINO: Donor milk for improved neurodevelopmental outcomes 
BMC Pediatrics  2014;14:123.
Background
Provision of mother’s own milk is the optimal way to feed infants, including very low birth weight infants (VLBW, <1500 g). Importantly for VLBW infants, who are at elevated risk of neurologic sequelae, mother’s own milk has been shown to enhance neurocognitive development. Unfortunately, the majority of mothers of VLBW infants are unable to provide an adequate supply of milk and thus supplementation with formula or donor milk is necessary. Given the association between mother’s own milk and neurodevelopment, it is important to ascertain whether provision of human donor milk as a supplement may yield superior neurodevelopmental outcomes compared to formula.
Our primary hypothesis is that VLBW infants fed pasteurized donor milk compared to preterm formula as a supplement to mother’s own milk for 90 days or until hospital discharge, whichever comes first, will have an improved cognitive outcome as measured at 18 months corrected age on the Bayley Scales of Infant Development, 3rd ed. Secondary hypotheses are that the use of pasteurized donor milk will: (1) reduce a composite of death and serious morbidity; (2) support growth; and (3) improve language and motor development. Exploratory research questions include: Will use of pasteurized donor milk: (1) influence feeding tolerance and nutrient intake (2) have an acceptable cost effectiveness from a comprehensive societal perspective?
Methods/Design
DoMINO is a multi-centre, intent-to-treat, double blinded, randomized control trial. VLBW infants (n = 363) were randomized within four days of birth to either (1) pasteurized donor milk or (2) preterm formula whenever mother’s own milk was unavailable. Study recruitment began in October 2010 and was completed in December 2012. The 90 day feeding intervention is complete and long-term follow-up is underway.
Discussion
Preterm birth and its complications are a leading cause long-term morbidity among Canadian children. Strategies to mitigate this risk are urgently required. As mother’s own milk has been shown to improve neurodevelopment, it is essential to ascertain whether pasteurized donor milk will confer the same advantage over formula without undue risks and at acceptable costs. Knowledge translation from this trial will be pivotal in setting donor milk policy in Canada and beyond.
Trial registration
ISRCTN35317141; Registered 10 August 2010.
doi:10.1186/1471-2431-14-123
PMCID: PMC4032387  PMID: 24884424
Human milk; Donor milk; Neurodevelopment; Very low birth weight infants
6.  Association between Prenatal Exposure to Antiretroviral Therapy and Birth Defects: An Analysis of the French Perinatal Cohort Study (ANRS CO1/CO11) 
PLoS Medicine  2014;11(4):e1001635.
Jeanne Sibiude and colleagues use the French Perinatal Cohort to estimate the prevalence of birth defects in children born to HIV-infected women receiving antiretroviral therapy during pregnancy.
Please see later in the article for the Editors' Summary
Background
Antiretroviral therapy (ART) has major benefits during pregnancy, both for maternal health and to prevent mother-to-child transmission of HIV. Safety issues, including teratogenic risk, need to be evaluated. We estimated the prevalence of birth defects in children born to HIV-infected women receiving ART during pregnancy, and assessed the independent association of birth defects with each antiretroviral (ARV) drug used.
Methods and Findings
The French Perinatal Cohort prospectively enrolls HIV-infected women delivering in 90 centers throughout France. Children are followed by pediatricians until 2 y of age according to national guidelines.
We included 13,124 live births between 1994 and 2010, among which, 42% (n = 5,388) were exposed to ART in the first trimester of pregnancy. Birth defects were studied using both European Surveillance of Congenital Anomalies (EUROCAT) and Metropolitan Atlanta Congenital Defects Program (MACDP) classifications; associations with ART were evaluated using univariate and multivariate logistic regressions. Correction for multiple comparisons was not performed because the analyses were based on hypotheses emanating from previous findings in the literature and the robustness of the findings of the current study. The prevalence of birth defects was 4.4% (95% CI 4.0%–4.7%), according to the EUROCAT classification. In multivariate analysis adjusting for other ARV drugs, maternal age, geographical origin, intravenous drug use, and type of maternity center, a significant association was found between exposure to zidovudine in the first trimester and congenital heart defects: 2.3% (74/3,267), adjusted odds ratio (AOR) = 2.2 (95% CI 1.3–3.7), p = 0.003, absolute risk difference attributed to zidovudine +1.2% (95% CI +0.5; +1.9%). Didanosine and indinavir were associated with head and neck defects, respectively: 0.5%, AOR = 3.4 (95% CI 1.1–10.4), p = 0.04; 0.9%, AOR = 3.8 (95% CI 1.1–13.8), p = 0.04. We found a significant association between efavirenz and neurological defects (n = 4) using the MACDP classification: AOR = 3.0 (95% CI 1.1–8.5), p = 0.04, absolute risk +0.7% (95% CI +0.07%; +1.3%). But the association was not significant using the less inclusive EUROCAT classification: AOR = 2.1 (95% CI 0.7–5.9), p = 0.16. No association was found between birth defects and lopinavir or ritonavir with a power >85% for an odds ratio of 1.5, nor for nevirapine, tenofovir, stavudine, or abacavir with a power >70%. Limitations of the present study were the absence of data on termination of pregnancy, stillbirths, tobacco and alcohol intake, and concomitant medication.
Conclusions
We found a specific association between in utero exposure to zidovudine and heart defects; the mechanisms need to be elucidated. The association between efavirenz and neurological defects must be interpreted with caution. For the other drugs not associated with birth defects, the results were reassuring. Finally, whatever the impact that some ARV drugs may have on birth defects, it is surpassed by the major role of ART in the successful prevention of mother-to-child transmission of HIV.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
AIDS and HIV infection are commonly treated with antiretroviral therapy (ART), a combination of individual drugs that work together to prevent the replication of the virus and further spread of the infection. Starting in the 1990s, studies have shown that ART of HIV-infected women can substantially reduce transmission of the virus to the child during pregnancy and birth. Based on these results, ART was subsequently recommended for pregnant women. Since 2004, ART has been standard therapy for pregnant women with HIV/AIDS in high-income countries, and it is now recommended for all HIV-infected women worldwide. Several different antiviral drug combinations have been shown to be effective and are used to prevent mother-to-infant transmission. However, as with any other drugs taken during pregnancy, there is concern that ART can harm the developing fetus.
Why Was This Study Done?
Several previous studies have assessed the risk that ART taken by a pregnant woman might pose to her developing fetus, but the results have been inconsistent. Animal studies suggested an elevated risk for some drugs but not others. While some clinical studies have reported increases in birth defects in children born to mothers on ART, others have shown no such increase.
The discrepancy may be due to differences between the populations included in the studies and the different methods used to diagnose birth defects. Additional large studies are therefore necessary to obtain more and better evidence on the potential harm of individual anti-HIV drugs to children exposed during pregnancy. So in this study, the authors conducted a large cohort study in France to assess the relationship between different antiretroviral drugs and specific birth defects.
What Did the Researchers Do and Find?
The researchers used a large national health database known as the French Perinatal Cohort that contains information on HIV-infected mothers who delivered infants in 90 centers throughout France. Pediatricians follow all children, whatever their HIV status, to two years of age, and health statistics are collected according to national health-care guidelines. Analyzing the records, the researchers estimated the rate at which birth defects occurred in children exposed to antiretroviral drugs during pregnancy.
The researchers included 13,124 children who were born alive between 1994 and 2010 and had been exposed to ART during pregnancy. Children exposed in the first trimester of pregnancy, and those exposed during the second or third trimester, were compared to a control group (children not exposed to the drug during the whole pregnancy). Using two birth defect classification systems (EUROCAT and MACDP—MACDP collects more details on disease classification than EUROCAT), the researchers sought to detect a link between the occurrence of birth defects and exposure to individual antiretroviral drugs.
They found a small increase in the risk for heart defects in children with exposure to zidovudine. They also found an association between efavirenz exposure and a small increase in neurological defects, but only when using the MACDP classification system. The authors found no association between other antiretroviral drugs, including nevirapine (acting similar to efavirenz); tenofovir, stavudine, and abacavir (all three acting similar to zidovudine); and lopinavir and ritonavir (proteinase inhibitors) and any type of birth defect.
What Do These Findings Mean?
These findings show that, overall, the risks of birth defects in children exposed to antiretroviral drugs in utero are small when considering the clear benefit of preventing mother-to-child transmission of HIV. However, where there are safe and effective alternatives, it might be appropriate to avoid use by pregnant women of those drugs that are associated with elevated risks of birth defects.
Worldwide, a large number of children are exposed to zidovudine in utero, and these results suggest (though cannot prove) that these children may be at a slightly higher risk of heart defects. Current World Health Organization (WHO) guidelines for the prevention of mother-to-child transmission no longer recommend zidovudine for first-line therapy.
The implications of the higher rate of neurological birth defects observed in infants exposed to efavirenz in the first trimester are less clear. The EUROCAT classification excludes minor neurological abnormalities without serious medical consequences, and so the WHO guidelines that stress the importance of careful clinical follow-up of children with exposure to efavirenz seem adequate, based on the findings of this study. The study is limited by the lack of data on the use of additional medication and alcohol and tobacco use, which could have a direct impact on fetal development, and by the absence of data on birth defects and antiretroviral drug exposure from low-income countries. However, the findings of this study overall are reassuring and suggest that apart from zidovudine and possibly efavirenz, other antiretroviral drugs are not associated with birth defects, and their use during pregnancy does not pose a risk to the infant.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001635.
This study is further discussed in a PLOS Medicine Perspective by Mofenson and Watts
The World Health Organization has a webpage on mother-to-child transmission of HIV
The US National Institutes of Health provides links to additional information on mother-to-child transmission of HIV
The Elizabeth Glaser Pediatric AIDS Foundation also has a webpage on mother-to-child transmission
The French Perinatal Cohort has a webpage describing the cohort and its main publications (in French, with a summary in English)
doi:10.1371/journal.pmed.1001635
PMCID: PMC4004551  PMID: 24781315
7.  Maternal depression and perceived social support as predictors of cognitive function trajectories during the first 3 years of life for preterm infants in Wisconsin 
Child  2011;38(3):425-434.
Background
Among families of infants born preterm, the association between postnatal depression and children’s cognitive function is not well understood, but thought to be compromised. The purpose of this study is to investigate maternal depressive symptoms and perceived social support as predictors of children’s cognitive function trajectories.
Methods
This is a longitudinal study of a sample of infants born preterm (less than 37 weeks) in Wisconsin. This study includes 130 infants who were hospitalized in one of three Wisconsin neonatal intensive care units in 2002–2005 and followed until 36 months of age. Maternal depressive symptoms were measured using the Center for Epidemiologic Studies Depression Scale. Social support was measured using the Maternal Support scale. Children’s cognitive function was measured using the Bayley Scales of Infant Development, 2nd edition, and the Stanford-Binet Intelligence scale, 5th edition.
Results
Children’s cognitive function trajectories declined initially and then increased. Being female [coefficient=5.14, s.e.=1.89] and non-poor [coefficient =11.26 s.e=5.78], and having a mother who has a graduate degree [coefficient =7.67, s.e.=3.37)] was associated with higher levels of cognition initially. Being white was associated with a more optimal cognitive trajectory. Although depression did not predict children’s cognitive trajectories, the presence of clinically-elevated depressive symptoms at 9 months postterm was associated with lower cognitive functioning at 16 months when mothers reported low social support.
Conclusion
Postnatal depressive symptoms appear to have a meaningful, dynamic influence on the cognitive outcomes of children born preterm, above and beyond family socio-demographic risk when the presence and timing of perceived social support is considered. Interventions to ameliorate developmental risk associated with preterm birth should include repeated assessments of maternal social support and postnatal depression and be targeted toward socially disadvantaged families.
doi:10.1111/j.1365-2214.2011.01253.x
PMCID: PMC3191240  PMID: 21651608
preterm birth; cognitive function; maternal depression; social support
8.  Cord Blood Glutathione Depletion in Preterm Infants: Correlation with Maternal Cysteine Depletion 
PLoS ONE  2011;6(11):e27626.
Background
Depletion of blood glutathione (GSH), a key antioxidant, is known to occur in preterm infants.
Objective
Our aim was to determine: 1) whether GSH depletion is present at the time of birth; and 2) whether it is associated with insufficient availability of cysteine (cys), the limiting GSH precursor, or a decreased capacity to synthesize GSH.
Methodology
Sixteen mothers delivering very low birth weight infants (VLBW), and 16 mothers delivering healthy, full term neonates were enrolled. Immediately after birth, erythrocytes from umbilical vein, umbilical artery, and maternal blood were obtained to assess GSH [GSH] and cysteine [cys] concentrations, and the GSH synthesis rate was determined from the incorporation of labeled cysteine into GSH in isolated erythrocytes ex vivo, measured using gas chromatography mass spectrometry.
Principal Findings
Compared with mothers delivering at full term, mothers delivering prematurely had markedly lower erythrocyte [GSH] and [cys] and these were significantly depressed in VLBW infants, compared with term neonates. A strong correlation was found between maternal and fetal GSH and cysteine levels. The capacity to synthesize GSH was as high in VLBW as in term infants.
Conclusion
The current data demonstrate that: 1) GSH depletion is present at the time of birth in VLBW infants; 2) As VLBW neonates possess a fully active capacity to synthesize glutathione, the depletion may arise from inadequate cysteine availability, potentially due to maternal depletion. Further studies would be needed to determine whether maternal-fetal cysteine transfer is decreased in preterm infants, and, if so, whether cysteine supplementation of mothers at risk of delivering prematurely would strengthen antioxidant defense in preterm neonates.
doi:10.1371/journal.pone.0027626
PMCID: PMC3217996  PMID: 22110699
9.  Hurricane Katrina-related maternal stress, maternal mental health, and early infant temperament 
Maternal and child health journal  2009;14(4):511-518.
To investigate temperament in infants whose mothers were exposed to Hurricane Katrina and its aftermath, and to determine if high hurricane exposure is associated with difficult infant temperament. A prospective cohort study of women giving birth in New Orleans and Baton Rouge, LA (n=288) in 2006–2007 was conducted. Questionnaires and interviews assessed the mother’s experiences during the hurricane, living conditions, and psychological symptoms, two months and 12 months postpartum. Infant temperament characteristics were reported by the mother using the activity, adaptability, approach, intensity, and mood scales of the Early Infant and Toddler Temperament Questionnaires, and “difficult temperament” was defined as scoring in the top quartile for three or more of the scales. Logistic regression was used to examine the association between hurricane experience, mental health, and infant temperament. Serious experiences of the hurricane did not strongly increase the risk of difficult infant temperament (association with 3 or more serious experiences of the hurricane: adjusted odds ratio (aOR) 1.50, 95% confidence interval (CI) 0.63–3.58 at 2 months; 0.58, 0.15–2.28 at 12 months). Maternal mental health was associated with report of difficult infant temperament, with women more likely to report having a difficult infant temperament at one year if they had screened positive for PTSD (aOR 1.82, 95% confidence interval (CI) 0.61–5.41), depression, (aOR 3.16, 95% CI 1.22–8.20) or hostility (aOR 2.17, 95% CI 0.81–5.82) at 2 months. Large associations between maternal stress due to a natural disaster and infant temperament were not seen, but maternal mental health was associated with reporting difficult temperament. Further research is needed to determine the effects of maternal exposure to disasters on child temperament, but in order to help babies born in the aftermath of disaster, the focus may need to be on the mother’s mental health.
doi:10.1007/s10995-009-0486-x
PMCID: PMC3472436  PMID: 19554438
infant temperament; natural disaster; postpartum depression; post-traumatic stress disorder
10.  Parent-child interaction, maternal depressive symptoms and preterm infant cognitive function 
Infant behavior & development  2012;35(3):489-498.
Preterm infants are at risk for cognitive difficulties due to infant neurological immaturity and family social disadvantage, and this may be exacerbated by maternal depressive symptoms. This longitudinal study of infants born preterm (<35 weeks) or low birth weight (<2500 grams) (n=137) tests if maternal depressive symptoms at 4 months is associated with preterm children’s cognitive function at 16 months. Additionally, we test if this association is mediated by the quality of parent-child interaction at 9 months, and if these associations differ by levels of maternal social support. Children’s cognitive function was measured using the Bayley Scales of Infant Development, 2nd edition. Maternal depressive symptoms were measured using the Center for Epidemiologic Studies Depression Scale. Perceived social support was measured using the Maternal Support scale. The quality of parent-child interaction was measured using the Parent-Child Early Relational Assessment. Linear regression and structural equation modeling were used to test the research questions. Postnatal depression at 4 months is associated with lower cognitive function (mean difference=−5.22, 95% CI:[−10.19, −0.25]) at 16 months controlling for a host of socioeconomic characteristics. For mothers with fewer depressive symptoms, bolstering effects of maternal supports on children’s cognitive function were evident. We find no evidence for effect mediation by quality of parent-child interaction. Early exposure to maternal depressive symptoms appears to have a negative influence on preterm children’s later cognitive function. These findings suggest important policy and programmatic implications for early detection and intervention for families of preterm infants.
doi:10.1016/j.infbeh.2012.04.005
PMCID: PMC3409313  PMID: 22721747
postnatal depression; parent-child interaction; preterm birth; cognitive function
11.  Decreased Bone Mineral Density in Adults Born with Very Low Birth Weight: A Cohort Study 
PLoS Medicine  2009;6(8):e1000135.
Petteri Hovi and colleagues evaluate skeletal health in 144 adults born preterm with very low birth weight and show that as adults these individuals have significantly lower bone mineral density than do their term-born peers.
Background
Very-low-birth-weight (VLBW, <1,500 g) infants have compromised bone mass accrual during childhood, but it is unclear whether this results in subnormal peak bone mass and increased risk of impaired skeletal health in adulthood. We hypothesized that VLBW is associated with reduced bone mineral density (BMD) in adulthood.
Methods and Findings
The Helsinki Study of Very Low Birth Weight Adults is a multidisciplinary cohort study representative of all VLBW births within the larger Helsinki area from 1978 to 1985. This study evaluated skeletal health in 144 such participants (all born preterm, mean gestational age 29.3 wk, birth weight 1,127 g, birth weight Z score 1.3), and in 139 comparison participants born at term, matched for sex, age, and birth hospital. BMD was measured by dual energy X-ray absorptiometry at age 18.5 to 27.1 y. Adults born with VLBW had, in comparison to participants born at term, a 0.51-unit (95% confidence interval [CI] 0.28–0.75) lower lumbar spine Z score and a 0.56-unit (95% CI 0.34–0.78) lower femoral neck Z score for areal BMD. These differences remained statistically significant after adjustment for the VLBW adults' shorter height and lower self-reported exercise intensity.
Conclusions
Young adults born with VLBW, when studied close to the age of peak bone mass, have significantly lower BMD than do their term-born peers. This suggests that compromised childhood bone mass accrual in preterm VLBW children translates into increased risk for osteoporosis in adulthood, warranting vigilance in osteoporosis prevention.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Most pregnancies last 40 weeks but some babies arrive earlier than expected. Sadly, babies born before 37 weeks of pregnancy—premature babies—are more likely to die than full-term babies, although recent improvements in neonatal care have increased their chances of survival. Premature babies also often have serious long-term health problems, particularly those born before 32 weeks of pregnancy. Such extremely premature babies have poorly developed internal organs and are usually very small—babies whose birth weight is less than 1,500 g are called very-low-birth-weight (VLBW) babies; the average full-term birth weight is about 3,500 g. Furthermore, their bones are not as well developed as those of full-term babies. The human skeleton initially consists of a soft fibrous material called cartilage. This is gradually transformed into bone by a process called bone mineralization. The last third of pregnancy is a crucial period for bone mineralization although the process continues throughout infancy and childhood. Thus, VLBW babies often have subnormal skeletal mineralization and their accrual of bone mass during childhood is frequently compromised.
Why Was This Study Done?
It is not known whether the childhood bone deficits of VLBW babies persist into adulthood because the first generation of these infants not to die soon after birth is only just reaching adulthood. Peak bone mass is reached in early adulthood (bone mass begins to decrease from the age of 35 years onward) and is an important indicator of whether an individual will develop osteoporosis (thinning of the bones) and be susceptible to bone fractures later in life. If adults with VLBW (about 1% of live births in high-income countries are now VLBW births) do have a subnormal peak bone mass and reduced bone mineral density (BMD), they may be able reduce their risk of developing osteoporosis by eating a healthy diet and exercising regularly. In this study (part of the Helsinki Study of Very Low Birth Weight Adults), the researchers investigate the skeletal health of people who were born with VLBW in the Helsinki area between 1978 and 1985.
What Did the Researchers Do and Find?
The researchers compared the skeletal health of 144 young adults who were born prematurely with VLBW and subnormal BMD with that of 139 age- and sex-matched individuals who were born at term. They measured the BMD of the participants (average age 22.6 years) using “dual energy X-ray absorptiometry” and determined a “Z score” for the spine in the lower back (the lower lumbar spine) and the hip (two sites that are routinely examined in assessments of skeletal health). Z scores indicate whether an individual's BMD is significantly different from the average BMD of healthy age- and sex-matched people; in this study, reduced BMD was defined as a Z score of −1.0 or less. The researchers found that adults born with VLBW had an average Z score of −0.51 at the lower lumbar spine and −0.56 at the hip when compared with the adults born at term. Furthermore, 44% of the VLBW participants but only 26% of the term-born participants had a lumbar spine Z score of −1.0 or less. Adjustment for the shorter height of the VLBW participants slightly reduced these differences in BMD but the differences remained statistically significant.
What Do These Findings Mean?
These findings show that, when studied close to the age of peak bone mass, young adults born with VLBW have a significantly lower BMD than their term-born peers and a 2-fold greater risk of having a lumbar spine Z score of below −1.0; a unit decrease in Z score approximately doubles the risk of bone fractures. Because BMD measurements were only taken at one age, it remains possible, however, that the BMD of the VLBW adults might eventually match that of their full-term peers. Recently born VLBW babies still have a lower than average BMD during their childhood, note the researchers, even though their care has changed since the people included in this study were born. Thus, these findings suggest that people who were VLBW infants should be encouraged to eat food rich in vitamin D and calcium and to do regular weight-bearing exercise throughout their lives to improve their bone health and reduce their risk of developing osteoporosis.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000135.
The March of Dimes, a nonprofit organization for pregnancy and baby health, provides information on preterm birth (in English and Spanish)
The Nemours Foundation, another nonprofit organization for child health, also provides information on premature babies (in English and Spanish)
MedlinePlus provides links to other information on premature babies and to information on osteoporosis (in English and Spanish)
The US National Institute of Arthritis and Musculoskeletal and Skin Diseases and the UK National Health Service also provide detailed information on all aspects of osteoporosis
Further details about the Helsinki Study of Very Low Birth Weight Adults are available
doi:10.1371/journal.pmed.1000135
PMCID: PMC2722726  PMID: 19707270
12.  Effectiveness of female community health volunteers in the detection and management of low-birth-weight in Nepal 
Rural and remote health  2014;14(1):2508.
Introduction
Low birth weight (LBW) is a major risk factor for neonatal death. However, most neonates in low-income countries are not weighed at birth. This results in many LBW infants being overlooked. Female community health volunteers (FCHVs) in Nepal are non-health professionals who are living in local communities and have already worked in a field of reproductive and child health under the government of Nepal for more than 20 years. The effectiveness of involving FCHVs to detect LBW infants and to initiate prompt action for their care was studied in rural areas of Nepal.
Methods
FCHVs were tasked with weighing all neonates born in selected areas using color-coded spring scales. Supervisors repeated each weighing using electronic scales as the gold standard comparator. Data on the relative birth sizes of the infants, as assessed by their mothers, were also collected and compared with the measured weights. Each of the 205 FCHVs involved in the study was asked about the steps that she would take when she came across a LBW infant, and knowledge of zeroing a spring scale was also assessed through individual interviews. The effect of the background social characteristics of the FCHVs on their performance was examined by logistic regression. This study was nested within a community-based neonatal sepsis-management intervention surveillance system, which facilitated an assessment of the performance of the FCHVs in weighing neonates, coverage of FCHVs’ visits, and weighing of babies through maternal interviews.
Results
A total of 462 babies were weighed, using both spring scales and electronic scales, within 72 hours of birth. The prevalence of LBW, as assessed by the gold standard method, was 28%. The sensitivity of detection of LBW by FCHVs was 89%, whereas the sensitivity of the mothers’ perception of size at birth was only 40%. Of the 205 FCHVs participating in the study, 70% of FCHVs understood what they should do when they identified LBW and very low birth weight (VLBW) infants. Ninety-six per cent could describe how to zero a scale and approximately 50% could do it correctly. Seventy-seven per cent of FCHVs weighed infants at least once during the study period, and 19 of them (12%) miscategorized infant weights. Differences were not detected between the background social characteristics of FCHVs who miscategorized infants and those who did not. On the basis of maternal reporting, 67% of FCHVs who visited infants had weighed them.
Conclusions
FCHVs are able to correctly identify LBW and VLBW infants using spring scales and describe the correct steps to take after identification of these infants. Use of FCHVs as newborn care providers allows for utilization of their logistical, geographical, and cultural strengths, particularly a high level of access to neonates, that can complement the Nepalese healthcare system. Providing additional training to and increasing supervision of local FCHVs regarding birth weight measurement will increase the identification of high-risk neonates in resource-limited settings.
PMCID: PMC4017643  PMID: 24724713
female community health volunteer; low birth weight; Nepal; spring scale; weighing
13.  Level of Prenatal Cocaine Exposure and Scores on the Bayley Scales of Infant Development: Modifying Effects of Caregiver, Early Intervention, and Birth Weight 
Pediatrics  2002;110(6):1143-1152.
Objectives
The objectives of this study were 1) to assess whether there is an independent association between the level of prenatal cocaine exposure and infants’ developmental test scores after control of potential confounding variables; and 2) if such an association exists, to determine which biological and social variables, individually and in interaction with each other, may modify it.
Methods
In a prospective, longitudinal study of 203 urban term infants, 3 cocaine exposure groups were defined by maternal report and infant meconium assay: unexposed, heavier cocaine exposure (> 75th percentile self-reported days of use or meconium benzoylecognine concentration), or lighter cocaine exposure (all others). Examiners, masked to exposure history, tested infants at 6, 12, and 24 months of age with the Bayley Scales of Infant Development.
Results
The final mixed linear regression model included as fixed covariates level of prenatal exposure to cocaine, alcohol, and cigarettes; prenatal marijuana exposure; gestational age and birth weight z score for gestational age; and gender. Age at test, caregiver at time of each test (biological mother, kinship caregiver, unrelated foster caregiver), and any previous child-focused early intervention were included as time-dependent covariates. There were no significant adverse main effects of level of cocaine exposure on Mental Development Index (MDI), Psychomotor Development Index (PDI), or Infant Behavior Record. Child-focused early intervention interacted with level of cocaine exposure such that heavily exposed children who received such intervention showed higher adjusted mean MDI scores than all other groups. Although the sample was born at or near term, there was also a significant interaction of cocaine exposure and gestational age on MDI scores, with those in the heavier exposure group born at slightly lower gestational age having higher mean MDI scores compared with other children born at that gestational age.
There was also a significant interaction on MDI between child’s age and caregiver. At 6 months, the adjusted MDI of children living with a kinship caregiver was 15.5 points lower than that of children living with their biological mother, but this effect was diminished and was no longer significant at 24 months (difference in means: 4.3 points). The adjusted mean MDI of children in unrelated foster care at 6 months was 8.2 points lower than children of biological mothers, whereas it was 7.3 points higher at 24 months.
Early intervention attenuated the age-related decline in PDI scores for all groups. Birth weight < 10th percentile was associated with lower PDI scores for children with heavier cocaine exposure and with lower MDI scores for all groups.
Conclusions
Heavier prenatal cocaine exposure is not an independent risk factor for depressed scores on the Bayley Scales of Infant Development up to 24 months of age when term infants are compared with lighter exposed or unexposed infants of the same demographic background. Cocaine-exposed infants with birth weight below the 10th percentile for gestational age and gender and those placed with kinship caregivers are at increased risk for less optimal developmental outcomes. Pediatric clinicians should refer cocaine-exposed children to the child-focused developmental interventions available for all children at developmental risk.
PMCID: PMC2366173  PMID: 12456912
cocaine; pregnancy; meconium; child development; early intervention; kinship care; foster care
14.  Birth Weight Effects on Children’s Mental, Motor, and Physical Development: Evidence from Twins Data 
Maternal and child health journal  2009;13(6):780-794.
Objective
To determine the effect of very low birth weight (VLBW; <1500g) and moderately low birth weight (MLBW; 1500–2499g) on children’s mental and motor development and physical growth during the first two years of life and whether VLBW and MLBW babies catch up to normal birth weight (NBW; >=2500g) children by age 2.
Methods
We use data on dizygotic (DZ) and monozygotic (MZ) twins and singleton births from the first two waves of the Early Childhood Longitudinal Study – Birth Cohort (ECLS-B), a nationally representative dataset of children born in the U.S. in 2001. We estimate the effects of VLBW and MLBW on children’s mental and motor development scores, weight-for-age, weight-for-length, weight-for-height, and length-for-age z-scores at 9 months and 2 years. We examine whether differences in outcomes within twin pairs are related to differences in their birth weights. The within-twins analysis is conducted on samples of DZ and MZ twins. For comparison, we also estimate birth weight effects on child outcomes from multivariate linear regression models using the full singleton and twins sample. We also estimate the effect of being small-for-gestational age (SGA; birth weight<10th percentile for gestation) using the same set of models in order to separate out the effects of fetal growth restriction from prematurity.
Results
Evaluation of all births showed that VLBW and MLBW have large negative effects on mental development, motor development, and growth at 9 months and 2 years of age. However, results from within-twin models with DZ twins that control for shared maternal and environmental factors showed much less effect of birth weight on mental or motor development, but continued large effects on growth for the VLBW group. Within-twin models with MZ twins that control for shared maternal, environmental, and genetic factors showed statistically insignificant effects of birth weight on mental and motor development, but continued effects on growth. Similar patterns were found when examining the effects of SGA.
Conclusions
After controlling for the influence of maternal, environmental, and genetic factors, low birth weight has at most a small negative effect on children’s mental and motor development in their first two years of life. However, low birth weight is a major risk factor for children’s physical growth in the early years and there is no evidence of catch-up by age 2.
doi:10.1007/s10995-009-0461-6
PMCID: PMC2855622  PMID: 19308711
Birth weight; Twins; Mental development; Motor development; Growth
15.  A Longitudinal Study of Developmental Outcome of Infants With Bronchopulmonary Dysplasia and Very Low Birth Weight 
Pediatrics  1997;100(6):987-993.
Objective
Bronchopulmonary dysplasia (BPD) is now the leading cause of lung disease in US infants. In a large regional cohort, we tested the hypothesis that despite innovations in neonatal care, very low birth weight (VLBW) infants (<1500 g) with BPD had poorer developmental outcomes than nonaffected infants during the first 3 years of life, and that BPD predicted poorer outcome beyond the effects of other risk factors.
Methods
Three groups of infants (122 with BPD, 84 VLBW without BPD, and 123 full-term) were followed longitudinally to 3 years of age with the Bayley Scales of Mental and Motor Development. Comparison groups of VLBW infants without BPD and full-term infants did not differ in sex, race, or socioeconomic status. Statistical analyses included hierarchical and stepwise multiple regression.
Results
Infants with BPD performed more poorly at all ages. By 3 years, cognitive and/or motor development was in the range of retardation (<70 standard score) for 21% to 22% of infants with BPD. In multiple regression analyses controlling for socioeconomic and neonatal risk conditions, BPD had an independent negative effect on motor outcome at 3 years. Neurologic risk, a summary measure of neurologic problems other than intraventricular hemorrhage, and the presence of BPD independently predicted motor delay. By 3 years, social class, race, and neurologic risk predicted mental outcome, suggesting that the specific effects of BPD are primarily on the motor domain.
Conclusions
In VLBW infants, BPD predicts poorer motor outcome at 3 years, after control for other risks. Cohorts of infants with BPD also had higher rates of mental retardation, associated with greater neurologic and social risk. These findings underscore the need for intensive prevention and habilitation efforts for this growing group of VLBW survivors, as well as investigation into the potential role of BPD in the higher rates of learning disabilities in VLBW cohorts at school age.
PMCID: PMC4196670  PMID: 9374570
16.  Predictors of receiving therapy among very low birth weight 2-year olds eligible for Part C early intervention in Wisconsin 
BMC Pediatrics  2013;13:106.
Background
The Individuals with Disabilities Education Act (Part C) authorizes states to establish systems to provide early intervention services (e.g., therapy) for children at risk, with the incentive of federal financial support. This study examines family and neighborhood characteristics associated with currently utilizing physical, occupational, or speech therapy among very low birthweight (VLBW) 2-year-old children who meet Wisconsin eligibility requirements for early intervention services (EI) due to developmental delay.
Methods
This cross-sectional analysis used data from the Newborn Lung Project, a regional cohort study of VLBW infants hospitalized in Wisconsin’s newborn intensive care units during 2003–2004. We included the 176 children who were age two at follow-up, and met Wisconsin state eligibility requirements for EI based on developmental delay. Exact logistic regression was used to describe child and neighborhood socio-demographic correlates of parent-reported receipt of therapy.
Results
Among VLBW children with developmental delay, currently utilizing therapy was higher among children with Medicaid (aOR = 5.3, 95% CI: 1.3, 28.3) and concomitant developmental disability (aOR = 5.2, 95% CI: 2.1, 13.3) and lower for those living in a socially more disadvantaged neighborhood (aOR=0.48, 95% CI: 0.21, 0.98, per tertile).
Conclusions
Among a sample of VLBW 2-year olds with developmental delays who are EI-eligible in WI, 4 out of 5 were currently receiving therapy, per parent report. Participation in Medicaid positively influences therapy utilization. Children with developmental difficulties who live in socially disadvantaged neighborhoods are at highest risk for not receiving therapy.
doi:10.1186/1471-2431-13-106
PMCID: PMC3718652  PMID: 23845161
Very low birth weight; Early intervention; Physical therapy; Neighborhood disadvantage
17.  Weight-Based Policy of Hepatitis B Vaccination in Very Low Birth Weight Infants in Taiwan: A Retrospective Cross-Sectional Study 
PLoS ONE  2014;9(3):e92271.
Background
The current recommendation of giving the first dose of hepatitis B vaccine to very low birth weight (VLBW) infants at 30 days of chronologic age usually is not practical, because most VLBW infants are not medically stable at that age. We use an alternative body-weight-based protocol, and evaluate its efficacy in an endemic area under a universal immunization program.
Methods
The immunogenicity of the current hepatitis B vaccination strategy in 155 VLBW preterm infants was evaluated at age 2 to 13 years, with parental consent. All of the infants were born between 1995 and 2006, and received their first dose of hepatitis B vaccine when they reached 2,000–2,200 g, irrespective of chronological age. Hepatitis B immunoglobulin (HBIG) was given at birth to infants born to HBsAg(+)/HBeAg(+) mothers.
Results
All 155 of the recruited children were HBsAg and anti-HBc negative. The anti-HBs seropositivity rate (geometric mean titer) was 84.1% (146.5 mIU/mL) for children under 3 years, 73.5% (68.8 mIU/mL) for 4- to 7-year-olds, 27.7% (55.4 mIU/mL) for 8- to 11-year-olds and 20% (6.0 mIU/mL) for children ≥12 years of age. More than 90% of these children received the first vaccination after 30 days of age, half (51%) at 60 to 90 days, and 29 children (18.6%) after 90 days of age. Of the 26 infants born to HBsAg(+) mothers, 6/6 infants of HBeAg(+) mothers received HBIG at birth, and 12/20 infants of HBeAg(−) mothers received HBIG. None of the 26 infants became infected.
Conclusions
Delaying hepatitis B vaccinations in VLBW preterm infants until they reach a weight of 2,000 g, with the administration of HBIG at birth for infants of HBsAg(+) mothers provided adequate immunogenicity and protection in a highly endemic area. Weight-based policy of hepatitis B vaccination is an effective and practical alternative strategy for VLBW infants.
doi:10.1371/journal.pone.0092271
PMCID: PMC3956928  PMID: 24638122
18.  Maternal Posttraumatic Stress Symptoms and Infant Emotional Reactivity and Emotion Regulation 
Infant behavior & development  2011;34(4):487-503.
The current study examined associations between maternal posttraumatic stress disorder (PTSD) symptoms and infant emotional reactivity and emotion regulation during the first year of life in a primarily low-income, urban, ethnic/racial minority sample of 52 mother-infant dyads. Mothers completed questionnaires assessing their own trauma exposure history and current PTSD and depressive symptoms and their infants’ temperament when the infants were 6 months old. Dyads participated in the repeated Still-Face Paradigm (SFP-R) when the infants were 6 months old, and infant affective states were coded for each SFP-R episode. Mothers completed questionnaires assessing infant trauma exposure history and infant current emotional and behavioral symptoms when the infants were 13 months old. Maternal PTSD symptoms predicted infants’ emotion regulation at 6 months as assessed by (a) infant ability to recover from distress during the SFP-R and (b) maternal report of infant rate of recovery from distress/arousal in daily life. Maternal PTSD symptoms also predicted maternal report of infant externalizing, internalizing, and dysregulation symptoms at 13 months. Maternal PTSD was not associated with measures of infant emotional reactivity. Neither maternal depressive symptoms nor infant direct exposure to trauma accounted for the associations between maternal PTSD symptoms and infant outcomes. These findings suggest that maternal PTSD is associated with offspring emotion regulation difficulties as early as infancy. Such difficulties may contribute to increased risk of mental health problems among children of mothers with PTSD.
doi:10.1016/j.infbeh.2011.07.007
PMCID: PMC3180882  PMID: 21862136
infant; emotion regulation; reactivity; maternal PTSD
19.  Differential ethnic associations between maternal flexibility and play sophistication in toddlers born very low birth weight 
Infant behavior & development  2012;35(4):860-869.
Children born very low birth weight (<1500 grams, VLBW) are at increased risk for developmental delays. Play is an important developmental outcome to the extent that child’s play and social communication are related to later development of self-regulation and effective functional skills, and play serves as an important avenue of early intervention. The current study investigated associations between maternal flexibility and toddler play sophistication in Caucasian, Spanish speaking Hispanic, English speaking Hispanic, and Native American toddlers (18-22 months adjusted age) in a cross-sectional cohort of 73 toddlers born VLBW and their mothers. We found that the association between maternal flexibility and toddler play sophistication differed by ethnicity (F(3,65) = 3.34, p = .02). In particular, Spanish speaking Hispanic dyads evidenced a significant positive association between maternal flexibility and play sophistication of medium effect size. Results for Native Americans were parallel to those of Spanish speaking Hispanic dyads: the relationship between flexibility and play sophistication was positive and of small-medium effect size. Findings indicate that for Caucasians and English speaking Hispanics, flexibility evidenced a non-significant (negative and small effect size) association with toddler play sophistication. Significant follow-up contrasts revealed that the associations for Caucasian and English speaking Hispanic dyads were significantly different from those of the other two ethnic groups. Results remained unchanged after adjusting for the amount of maternal language, an index of maternal engagement and stimulation; and after adjusting for birth weight, gestational age, gender, test age, cognitive ability, as well maternal age, education, and income. Our results provide preliminary evidence that ethnicity and acculturation may mediate the association between maternal interactive behavior such as flexibility and toddler developmental outcomes, as indexed by play sophistication. Addressing these association differences is particularly important in children born VLBW because interventions targeting parent interaction strategies such as maternal flexibility must account for ethnic-cultural differences in order to promote toddler developmental outcomes through play paradigms.
doi:10.1016/j.infbeh.2012.07.008
PMCID: PMC3589984  PMID: 22982287
Very Low Birth Weight; Toddlers; Maternal Intrusiveness; Developmental Outcome; Ethnicity
20.  Pregnancy and Infant Outcomes among HIV-Infected Women Taking Long-Term ART with and without Tenofovir in the DART Trial 
PLoS Medicine  2012;9(5):e1001217.
Diana Gibb and colleagues investigate the effect of in utero tenofovir exposure by analyzing the pregnancy and infant outcomes of HIV-infected women enrolled in the DART trial.
Background
Few data have described long-term outcomes for infants born to HIV-infected African women taking antiretroviral therapy (ART) in pregnancy. This is particularly true for World Health Organization (WHO)–recommended tenofovir-containing first-line regimens, which are increasingly used and known to cause renal and bone toxicities; concerns have been raised about potential toxicity in babies due to in utero tenofovir exposure.
Methods and Findings
Pregnancy outcome and maternal/infant ART were collected in Ugandan/Zimbabwean HIV-infected women initiating ART during The Development of AntiRetroviral Therapy in Africa (DART) trial, which compared routine laboratory monitoring (CD4; toxicity) versus clinically driven monitoring. Women were followed 15 January 2003 to 28 September 2009. Infant feeding, clinical status, and biochemistry/haematology results were collected in a separate infant study. Effect of in utero ART exposure on infant growth was analysed using random effects models.
382 pregnancies occurred in 302/1,867 (16%) women (4.4/100 woman-years [95% CI 4.0–4.9]). 226/390 (58%) outcomes were live-births, 27 (7%) stillbirths (≥22 wk), and 137 (35%) terminations/miscarriages (<22 wk). Of 226 live-births, seven (3%) infants died <2 wk from perinatal causes and there were seven (3%) congenital abnormalities, with no effect of in utero tenofovir exposure (p>0.4). Of 219 surviving infants, 182 (83%) enrolled in the follow-up study; median (interquartile range [IQR]) age at last visit was 25 (12–38) months. From mothers' ART, 62/9/111 infants had no/20%–89%/≥90% in utero tenofovir exposure; most were also zidovudine/lamivudine exposed. All 172 infants tested were HIV-negative (ten untested). Only 73/182(40%) infants were breast-fed for median 94 (IQR 75–212) days. Overall, 14 infants died at median (IQR) age 9 (3–23) months, giving 5% 12-month mortality; six of 14 were HIV-uninfected; eight untested infants died of respiratory infection (three), sepsis (two), burns (one), measles (one), unknown (one). During follow-up, no bone fractures were reported to have occurred; 12/368 creatinines and seven out of 305 phosphates were grade one (16) or two (three) in 14 children with no effect of in utero tenofovir (p>0.1). There was no evidence that in utero tenofovir affected growth after 2 years (p = 0.38). Attained height- and weight for age were similar to general (HIV-uninfected) Ugandan populations. Study limitations included relatively small size and lack of randomisation to maternal ART regimens.
Conclusions
Overall 1-year 5% infant mortality was similar to the 2%–4% post-neonatal mortality observed in this region. No increase in congenital, renal, or growth abnormalities was observed with in utero tenofovir exposure. Although some infants died untested, absence of recorded HIV infection with combination ART in pregnancy is encouraging. Detailed safety of tenofovir for pre-exposure prophylaxis will need confirmation from longer term follow-up of larger numbers of exposed children.
Trial registration
www.controlled-trials.com ISRCTN13968779
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Currently, about 34 million people (mostly in low- and middle-income countries) are infected with HIV, the virus that causes AIDS. At the beginning of the epidemic, more men than women were infected with HIV but now about half of all people living with HIV/AIDS are women, most of who became infected through unprotected sex with an infected partner. In sub-Saharan Africa alone, 12 million women are HIV-positive. Worldwide, HIV/AIDS is the leading cause of death among women of child-bearing age. Moreover, most of the 400,000 children who become infected with HIV every year acquire the virus from their mother during pregnancy or birth, or through breastfeeding, so-called mother-to-child transmission (MTCT). Combination antiretroviral therapy (ART)—treatment with cocktails of powerful antiretroviral drugs—reduces HIV-related illness and death among women, and ART given to HIV-positive mothers during pregnancy and delivery and to their newborn babies greatly reduces MTCT.
Why Was This Study Done?
Because of ongoing international efforts to increase ART coverage, more HIV-positive women in Africa have access to ART now than ever before. However, little is known about pregnancy outcomes among HIV-infected African women taking ART throughout pregnancy for their own health or about the long-term outcomes of their offspring. In particular, few studies have examined the effect of taking tenofovir (an antiretroviral drug that is now recommended as part of first-line ART) throughout pregnancy. Tenofovir readily crosses from mother to child during pregnancy and, in animal experiments, high doses of tenofovir given during pregnancy caused bone demineralization (which weakens bones), kidney problems, and impaired growth among offspring. In this study, the researchers analyze data collected on pregnancy and infant outcomes among Ugandan and Zimbabwean HIV-positive women who took ART throughout pregnancy in the Development of AntiRetroviral Therapy in Africa (DART) trial. This trial was designed to test whether ART could be safely and effectively delivered in Africa without access to the expensive laboratory tests that are routinely used to monitor ART toxicity and efficacy in developed countries.
What Did the Researchers Do and Find?
The pregnancy outcomes of 302 women who became pregnant during the DART trial and information on birth defects among their babies were collected as part of the DART protocol; information on the survival, growth, and development of the infants born to these women was collected in a separate infant study. Most of the women who became pregnant were taking tenofovir-containing ART before and throughout their pregnancies. 58% of the pregnancies resulted in a live birth, 7% resulted in a stillbirth (birth of a dead baby at any time from 22 weeks gestation to the end of pregnancy), and 35% resulted in a termination or miscarriage (before 22 weeks gestation). Of the 226 live births, seven infants died within 2 weeks and seven had birth defects. Similar proportions of the infants exposed and not exposed to tenofovir during pregnancy died soon after birth or had birth defects. Of the 182 surviving infants who were enrolled in the infant study, 14 subsequently died at an average age of 9 months, giving a 1-year mortality of 5%. None of the surviving children who were tested (172 infants) were HIV infected. No bone fractures or major kidney problems occurred during follow-up and prebirth exposure to tenofovir in utero had no effect on growth or weight gain at 2 years (in contrast to a previous US study).
What Do These Findings Mean?
By showing that prebirth tenofovir exposure does not affect pregnancy outcomes or increase birth defects, growth abnormalities, or kidney problems, these findings support the use of tenofovir-containing ART during pregnancy among HIV-positive African women, and suggest that it could also be used to prevent women of child-bearing age acquiring HIV-infection heterosexually. Notably, the observed 5% 1-year infant mortality is similar to the 2%–4% infant mortality normally seen in the region. The absence of HIV infection among the infants born to the DART participants is also encouraging. However, this is a small study (only 111 infants were exposed to tenofovir throughout pregnancy) and women were not randomly assigned to receive tenofovir-containing ART. Consequently, more studies are needed to confirm that tenofovir exposure during pregnancy does not affect pregnancy outcomes or have any long-term effects on infants. Such studies are essential because the use of tenofovir as a treatment for women who are HIV-positive is likely to increase and tenofovir may also be used in the future to prevent HIV acquisition in HIV-uninfected women.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001217.
Information is available from the US National Institute of Allergy and infectious diseases on all aspects of HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS, and summaries of recent research findings on HIV care and treatment (in several languages)
Information is available from Avert, an international AIDS nonprofit on many aspects of HIV/AIDS, including detailed information on HIV/AIDS treatment and care, women, HIV and AIDS, children, HIV and AIDS, and on HIV/AIDS and pregnancy (some information in English and Spanish); personal stories of women living with HIV are available
More information about the DART trial is available
Additional patient stories about living with HIV/AIDS are available through the nonprofit website Healthtalkonline
doi:10.1371/journal.pmed.1001217
PMCID: PMC3352861  PMID: 22615543
21.  SOCIAL SUPPORT, PSYCHOLOGICAL DISTRESS, AND PARENTING STRAINS IN MOTHERS OF VERY LOW BIRTHWEIGHT INFANTS* 
Family relations  1996;45(3):343-350.
This study investigated maternal psychological distress, perceptions of social supports, and parenting strains after the birth of a very low birthweight (VLBW) infant. Compared to mothers of term infants, mothers of VLBW infants had significantly higher incidence of psychological distress during the neonatal period, but did not differ from mothers of term infants in their feelings of role restriction, parenting competence, or social supports. Lower general social support predicted high distress levels, but only for mothers of VLBW infants. Mothers with a low sense of parenting competence, but support from spouse/partners reported lower maternal distress.
doi:10.2307/585507
PMCID: PMC4244282  PMID: 25431508
bronchopulmonary dysplasia; high-risk infants; parenting; psychological distress; social support
22.  The Origins of 12-Month Attachment: A Microanalysis of 4-Month Mother-Infant Interaction 
Attachment & human development  2010;12(0):3-141.
A detailed microanalysis of 4-month mother-infant face-to-face communication revealed a fine-grained specification of essential communication processes that predicted 12-month insecure attachment outcomes, particularly resistant and disorganized classifications. An urban community sample of 84 dyads were videotaped at 4 months during a face-to-face interaction, and at 12 months during the Ainsworth Strange Situation. Four-month mother and infant communication modalities of attention, affect, touch, and spatial orientation were coded from split-screen videotape on a 1s time base; mother and infant facial-visual “engagement” variables were constructed. We used contingency measures (multi-level time-series modeling) to examine the dyadic temporal process over time, and specific rates of qualitative features of behavior to examine the content of behavior. Self-contingency (auto-correlation) measured the degree of stability/lability within an individual’s own rhythms of behavior; interactive contingency (lagged cross-correlation) measured adjustments of the individual’s behavior that were correlated with the partner’s previous behavior.
We documented that both self- and interactive contingency, as well as specific qualitative features, of mother and infant behavior were mechanisms of attachment formation by 4 months, distinguishing 12-month insecure, resistant, and disorganized attachment classifications from secure; avoidant were too few to test. All communication modalities made unique contributions. The separate analysis of different communication modalities identified intermodal discrepancies or conflict, both intrapersonal and interpersonal, that characterized insecure dyads. Contrary to dominant theories in the literature on face-to-face interaction, measures of maternal contingent coordination with infant yielded the fewest associations with 12-month attachment, whereas mother and infant self-contingency, and infant contingent coordination with mother, yielded comparable numbers of findings. Rather than the more usual hypothesis that more contingency is “better,” we partially supported our hypothesis that 12-month insecurity is associated with both higher and lower 4-month self- and interactive contingency values than secure, as a function of mother vs. infant and communication modality. Thus, in the origins of attachment security, more contingency is not necessarily better.
A remarkable degree of differentiation was identified in the 4-month patterns of “future” C and D infants, classified as resistant and disorganized, respectively, at 12 months. Only future D infants were emotionally distressed, with simultaneous positive and negative discrepant affect; only their mothers showed difficulty in sharing infant affect, particularly distress, and lowered their contingent coordination with infant facial-visual engagement. This lowered contingent coordination makes it more difficult for infants to come to expect that their emotional/attentional states can influence mothers to coordinate with them and thus compromises the infant’s sense of interactive efficacy. Only future C dyads showed the spatial approach/avoid pattern of “chase and dodge;” only mothers of future D infants showed the spatial intrusion pattern of “looming” into the infant’s face. Both future C and D dyads showed patterns of touch dysregulation. Future C infants inhibited their emotional coordination with mothers’ less affectionate touch, as if tuning it out. Future D dyads showed a dyadic touch dysregulation, in which mothers lowered their coordination with infant touch, while infants had a lowered ability to use their own touch. Both mothers of future C and D infants disturbed the stability of the spatial “frame” of the encounter by transitioning among upward, forward and loom orientations in less predictable ways than mothers of future B infants. Only mothers of future D infants disturbed the attentional “frame” as well, by looking and looking away from the infant’s face in less predictable ways than mothers of future B infants. Only mothers of future D infants showed methods of managing their own state which distanced them from their infants, such as extensive looking away and “closing up” their faces.
The intact interactive contingency of the mother of the future C infant overall safeguards the infant’s interactive agency, and the infant’s expectation that mother will match the direction of infant affective change, sharing infant states. However, we proposed that the future C infant will have difficulty feeling sensed and known by mother during her spatial/tactile intrusions.
The central feature of future D dyads is intrapersonal and interpersonal discordance or conflict in the context of intensely distressed infants. Lowered maternal contingent coordination, and failures of maternal affective correspondence, constitute maternal emotional withdrawal from distressed infants, compromising infant interactive agency and emotional coherence. The level of dysregulation in future D dyads is thus of an entirely different order than that of future C dyads. We proposed that the future D infant represents not being sensed and known by the mother, particularly in states of distress. We proposed that the emerging internal working model of future D infants includes confusion about their own basic emotional organization, about their mothers’ emotional organization, and about their mothers’ response to their distress, setting a trajectory in development which may disturb the fundamental integration of the person.
The findings have rich implications for clinical intervention, with remarkable specificity for different kinds of mother and infant distress. The concepts of heightened and lowered self- and interactive contingency, in different modalities, as well as the specific behavioral qualities identified, provide a more differentiated set of concepts to guide clinical intervention.
doi:10.1080/14616730903338985
PMCID: PMC3763737  PMID: 20390524
23.  Using parent questionnaires to assess neurodevelopment in former preterm infants: a validation study 
Background
Former preterm and very low birth weight (VLBW) infants require close neurodevelopmental surveillance after hospital discharge, but in-person professional testing is resource-intensive and inconvenient for families. A standardised developmental questionnaire completed by parents offers an alternative to in-person testing, but few such questionnaires have been validated. Our aim was to validate the Motor and Social Development (MSD) scale in a sample of former preterm infants.
Methods
We studied 321 visits to a neonatal follow-up clinic. Parents completed the MSD, which measures cognitive, motor, and social abilities. Psychologists and physical therapists administered the Bayley Scales of Infant Development, 3rd edition (Bayley-III) cognitive and motor scales.
Results
The median (range) gestational age was 28 (23, 34) weeks and birthweight 980 (400, 2700) g. Corrected age at study participation ranged 5–35 months. The mean (standard deviation) Bayley-III motor score was 94 (16); cognitive 98 (16); and MSD 91 (18). Internal consistency of the MSD was moderate to high (Cronbach alpha of 0.65 to 0.88). The MSD was moderately correlated with the Bayley-III motor (Pearson r=0.49, P<0.001) and cognitive (r=0.45, P<0.001) scales. The area under the receiver operating characteristic curve was 0.88 (95% confidence interval [CI] 0.81, 0.95) for the MSD to detect a low Bayley-III motor score (<70); and 0.88 (95% CI 0.82, 0.95) for a low cognitive score, indicating good discrimination.
Conclusions
The MSD has good internal and concurrent validity, and may be useful for neurodevelopmental assessment of former preterm and VLBW infants in clinical and research settings.
doi:10.1111/ppe.12025
PMCID: PMC3564502  PMID: 23374065
24.  Behavioural and emotional problems in very preterm and very low birthweight infants at age 5 years 
Background
Children born very preterm (VP; <32 weeks' gestation) or with very low birth weight (VLBW, <1500 g; hereafter called VP/VLBW) are at risk for behavioural and emotional problems during school age and adolescence. At school entrance these problems may hamper academic functioning, but evidence on their occurrence at this age in VP/VLBW children is lacking.
Aim
To provide information on academic functioning of VP/VLBW children and to examine the association of behavioural and emotional problems with other developmental problems assessed by paediatricians.
Design, setting and participants
A cohort of 431 VP/VLBW children aged 5 years (response rate 76.1%) was compared with two large national samples of children of the same age (n = 6007, response rate 86.9%).
Outcome measures
Behavioural and emotional problems measured by the Child Behavior Checklist (CBCL), and paediatrician assessment of other developmental domains among VP/VLBW children.
Results
The prevalence rate of a CBCL total problems score in the clinical range was higher among VP/VLBW children than among children of the same age from the general population (13.2% v 8.7%, odds ratio 1.60 (95% confidence interval 1.18 to 2.17)). Mean differences were largest for social and attention problems. Moreover, they were larger in children with paediatrician‐diagnosed developmental problems at 5 years, and somewhat larger in children with severe perinatal problems.
Conclusion
At school entrance, VP/VLBW children are more likely to have behavioural and emotional problems that are detrimental for academic functioning. Targeted and timely help is needed to support them and their parents in overcoming these problems and in enabling them to be socially successful.
doi:10.1136/adc.2006.093674
PMCID: PMC2672756  PMID: 16877476
25.  Increased incidence of intraventricular hemorrhage and developmental delay in cocaine-exposed, very low birth weight infants 
The Journal of pediatrics  1994;124(5 0 1):765-771.
This study sought to determine whether very low birth weight (VLBW) infants (<1500 gm) with fetal cocaine exposure differed from non-cocaine-exposed VLBW infants in incidence of neonatal medical complications and in later developmental outcome. Forty-one cocaine-exposed, VLBW infants, followed in a longitudinal study, were compared with 41 non-cocaine-exposed, VLBW infants of comparable race, social class, age, and incidence of bronchopulmonary dysplasia. Cocaine-exposed infants were identified on the basis of combined findings of maternal and/or infant urine immunoassay and on the basis of maternal self-report. At birth, groups did not differ on medical risk factors except that cocaine-exposed infants had a higher incidence of mild (grades I to II) intraventricular hemorrhage. Cocaine-using women were also more likely to use other drugs, especially alcohol, marijuana, and tobacco. At follow-up, at mean corrected ages of 16.5 ± 8 months for 30 cocaine-exposed infants and 18.5 ± 7 months for 37 non-cocaine-exposed infants, standardized assessments of cognitive (Mental Development Index) and motor (Psychomotor Development Index) development were administered. Cocaine-exposed infants had lower mean cognitive (83 ± 27 vs 91 ± 19), and motor (85 ± 25 vs 96 ± 18) scores; the incidence of developmental delay was significantly higher even after control for the effects of intraventricular hemorrhage and chronologic age. Cocaine-exposed VLBW infants were also more likely to be living with relatives or in foster homes. We conclude that these VLBW, cocaine-exposed infants were at increased risk of intraventricular hemorrhage, were more likely to be placed outside maternal care, and had higher incidences of cognitive and motor delays at follow-up.
PMCID: PMC4181569  PMID: 7513757

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