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1.  Differences in risk factors for incident and recurrent small-for-gestational-age birthweight: a hospital-based cohort study 
Examine whether small-for-gestational-age (SGA) risk factors differed by prior SGA birth.
Hospital-based cohort study.
Utah, US.
Electronic medical record data from 25,241 women who were nulliparous at study entry with ≥2 subsequent consecutive singleton deliveries (2002–2010).
Estimated adjusted relative risks (RR) and 95% confidence intervals (95%CI) for the association between second pregnancy characteristics and SGA risk. Tested for risk factor differences between recurrence and incidence (Pdifference).
Main outcome measures
Second pregnancy incident (n=1,067) and recurrent SGA (n=484) determined using a population-based reference.
SGA complicated 20.3% and 4.5% of deliveries to women with and without a prior SGA birth, respectively. Young maternal age (Pdifference=.01) and pregnancy hypertensive diseases (Pdifference=.03) were associated with incident, but not recurrent SGA. Significant risk factors for incidence and recurrence were smoking [Incident RR=1.64 (95%CI 1.22–2.19); Recurrent RR=1.59 (95%CI 1.17–2.17)], short stature [Incident RR=1.34 (95%CI 1.16–1.54); Recurrent RR=1.54 (95%CI 1.31–1.82)], prepregnancy underweight [Incident RR=1.32 (95%CI 1.07–1.64); Recurrent RR=1.30 (95%CI 1.03–1.64)], and inadequate weight gain [Incident RR=1.41 (95%CI 1.22–1.64); Recurrent RR=1.33 (95%CI 1.10–1.60)]. Race-ethnicity, marital or insurance status, alcohol, diabetes, asthma, thyroid disease, depression, or interpregnancy interval were not associated with incidence or recurrence.
There was considerable overlap in the risk factors for SGA recurrence and incidence. Recurrence and incidence risk factors included smoking, short stature, underweight, and inadequate weight gain. Maternal age and hypertensive diseases increased the risk for incidence only. Regardless of the SGA definition, some potentially modifiable risk factors for recurrence were identified.
PMCID: PMC4108555  PMID: 24702952
small-for-gestational-age; fetal growth restriction
2.  Changes in Diabetes Status Between Pregnancies and Impact on Subsequent Newborn Outcomes 
American journal of obstetrics and gynecology  2013;210(5):431.e1-431.e14.
Pregnancies complicated by gestational (GDM) or preexisting diabetes mellitus (DM) are at high risk for adverse newborn outcomes. Whether GDM history, recurrence, or transition to DM modifies such risks is unknown.
Study Design
Medical record data on 62,013 repeat singleton pregnancies were collected retrospectively from women who delivered at least twice in Utah (2002-2010). Poisson regression models with robust variance estimators were used to estimate relative risks (RR) and 95% confidence intervals (CI) associated with GDM/DM status at the previous and/or current pregnancy relative to those without GDM/DM at either. Large for gestational age (LGA), shoulder dystocia, preterm birth (<37wks; PTB), respiratory distress syndrome (RDS), and other neonatal morbidities were examined adjusting for study site, maternal age, race, parity, interpregnancy interval, prepregnancy body mass index (BMI), and smoking status.
GDM in the previous pregnancy alone increased the risk of LGA in the current pregnancy (RR=1.20, 95% CI:1.05-1.38). Recurrent GDM increased the risks of LGA (RR=1.76, 95% CI:1.56-1.98), shoulder dystocia (RR=1.98, 95% CI:1.46-2.70), and PTB (RR=1.68, 95% CI:1.44-1.96) beyond that observed for pregnancies with current GDM alone. Women with GDM in a previous pregnancy that transitioned to DM in the current pregnancy and women with DM prior to the previous pregnancy had increased risks of all above outcomes.
GDM in a previous pregnancy alone without recurrence may still confer an increased LGA risk. Pregnancies complicated by GDM that transition to DM and those with DM prior to the previous pregnancy have the highest risks of adverse newborn outcomes.
PMCID: PMC4011935  PMID: 24361790
diabetes; large for gestational age; macrosomia; shoulder dystocia; respiratory distress
3.  The association between parity and birthweight in a longitudinal consecutive pregnancy cohort 
Nulliparity is associated with lower birthweight, but few studies have examined how within mother changes in risk-factors impact this association.
We used longitudinal electronic medical record data from a hospital-based cohort of consecutive singleton live births from 2002–2010 in Utah. To reduce bias from unobserved pregnancies primary analyses were limited to 9,484 women who entered nulliparous from 2002–2004 with 23,380 pregnancies up to parity 3. Unrestricted secondary analyses used 101,225 pregnancies from 45,212 women with pregnancies up to parity 7. We calculated gestational age and sex-specific birthweight z-scores with nulliparas as the reference. Using linear mixed models, we estimated birthweight z-score by parity adjusting for pregnancy-specific sociodemographics, smoking, alcohol, prepregnancy body mass index, gestational weight gain, and medical conditions.
Compared to nulliparas, infants of primiparas were larger by 0.20 unadjusted z-score units [95% confidence interval (CI) 0.18, 0.22]; the adjusted increase was similar at 0.18 z-score units [95% CI 0.15, 0.20]. Birthweight continued to increase up to parity 3, but with a smaller difference, (parity 3 vs. 0 β=0.27 [95% CI 0.20, 0.34]). In the unrestricted secondary sample, there was significant departure in linearity from parity 1 to 7 (P<0.001); birthweight increased only up to parity 4, (parity 4 vs. 0 β=0.34 [95% CI 0.31, 0.37]).
The association between parity and birthweight was non-linear with the greatest increase observed between first and second-born infants of the same mother. Adjustment for changes in weight or chronic diseases did not change the relationship between parity and birthweight.
PMCID: PMC3922415  PMID: 24320682
pregnancy; birthweight; parity; siblings; birth order
4.  Mortality and Morbidity of VLBW Infants With Trisomy 13 or Trisomy 18 
Pediatrics  2014;133(2):226-235.
Little is known about how very low birth weight (VLBW) affects survival and morbidities among infants with trisomy 13 (T13) or trisomy 18 (T18). We examined the care plans for VLBW infants with T13 or T18 and compared their risks of mortality and neonatal morbidities with VLBW infants with trisomy 21 and VLBW infants without birth defects.
Infants with birth weight 401 to 1500 g born or cared for at a participating center of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network during the period 1994–2009 were studied. Poisson regression models were used to examine risk of death and neonatal morbidities among infants with T13 or T18.
Of 52 262 VLBW infants, 38 (0.07%) had T13 and 128 (0.24%) had T18. Intensity of care in the delivery room varied depending on whether the trisomy was diagnosed before or after birth. The plan for subsequent care for the majority of the infants was to withdraw care or to provide comfort care. Eleven percent of infants with T13 and 9% of infants with T18 survived to hospital discharge. Survivors with T13 or T18 had significantly increased risk of patent ductus arteriosus and respiratory distress syndrome compared with infants without birth defects. No infant with T13 or T18 developed necrotizing enterocolitis.
In this cohort of liveborn VLBW infants with T13 or T18, the timing of trisomy diagnosis affected the plan for care, survival was poor, and death usually occurred early.
PMCID: PMC3904274  PMID: 24446439
trisomy 13; trisomy 18; trisomy 21; very low birth weight; preterm infants
5.  Developmental Origins of Cardiovascular Disease 
Although cardiovascular disease has traditionally been viewed as a condition of aging individuals, increasing focus has turned to its developmental origins. Since birthweight has been related to cardiovascular disease risk, research into factors such as gravid conditions that affect fetal growth have grown. Associations between maternal diabetes and childhood obesity from sibling studies suggest a causal role but prospective studies of gestational diabetes remain mixed. Preeclampsia and increased offspring blood pressure has been consistently observed but evidence for other cardiovascular outcomes is lacking. While maternal obesity is associated with childhood obesity, causality remains unclear and paternal obesity should be investigated as an independent risk factor. Environmental chemical exposures in utero, particularly obesogens, are now emerging as another concern, as is conception by infertility treatment. Few studies have investigated subclinical measures of endothelial function or atherosclerosis and more research in these areas may help reveal the underlying pathogenesis.
PMCID: PMC4214855  PMID: 25364653
developmental origins; cardiovascular disease; birthweight; preterm birth; gestational diabetes; preeclampsia; maternal obesity; environmental chemicals
6.  Ten-Year Review of Major Birth Defects in VLBW Infants 
Pediatrics  2013;132(1):49-61.
Birth defects (BDs) are an important cause of infant mortality and disproportionately occur among low birth weight infants. We determined the prevalence of BDs in a cohort of very low birth weight (VLBW) infants cared for at the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) centers over a 10-year period and examined the relationship between anomalies, neonatal outcomes, and surgical care.
Infant and maternal data were collected prospectively for infants weighing 401 to 1500 g at NRN sites between January 1, 1998, and December 31, 2007. Poisson regression models were used to compare risk of outcomes for infants with versus without BDs while adjusting for gestational age and other characteristics.
A BD was present in 1776 (4.8%) of the 37 262 infants in our VLBW cohort. Yearly prevalence of BDs increased from 4.0% of infants born in 1998 to 5.6% in 2007, P < .001. Mean gestational age overall was 28 weeks, and mean birth weight was 1007 g. Infants with BDs were more mature but more likely to be small for gestational age compared with infants without BDs. Chromosomal and cardiovascular anomalies were most frequent with each occurring in 20% of affected infants. Mortality was higher among infants with BDs (49% vs 18%; adjusted relative risk: 3.66 [95% confidence interval: 3.41–3.92]; P < .001) and varied by diagnosis. Among those surviving >3 days, more infants with BDs underwent major surgery (48% vs 13%, P < .001).
Prevalence of BDs increased during the 10 years studied. BDs remain an important cause of neonatal morbidity and mortality among VLBW infants.
PMCID: PMC3691532  PMID: 23733791
birth defects; prematurity; Neonatal Research Network; low birth weight
7.  Late-Onset Sepsis in Very Low Birth Weight Infants from Singleton and Multiple Gestation Births 
The Journal of pediatrics  2013;162(6):1120-1124.e1.
To describe and compare incidence of late-onset sepsis (LOS) and demographic and clinical characteristics associated with LOS in very low birth weight (VLBW) infants from singleton and multiple births and to examine the heritability in susceptibility to LOS among VLBW twins by comparing same-sex with unlike-sex twin pairs.
Study design
We studied infants with birth weight 401–1500 grams cared for at clinical centers of the NICHD Neonatal Research Network 2002–2008. Only the first episode of LOS was examined. Stepwise logistic regression models were fitted separately for singleton and multiple pregnancies to examine the maternal and neonatal factors associated with LOS. LOS due to only gram-negative bacteria among singleton and multiple pregnancies was also examined in separate models. The heritability of LOS was estimated by examining concordance of LOS between twins from same-sex and unlike-sex pairs.
LOS occurred in 25.0% (3797/15,178) of singleton and 22.6% (1196/5294) of multiple VLBW infants. Coagulase-negative staphylococci were the most common infecting organisms, accounting for 53.2% of all LOS episodes in singletons and 49.2% in multiples. E. coli and Klebsiella species were the most commonly isolated gram-negative organisms, and Candida albicans was the most commonly isolated fungus. Concordance of LOS was not significantly different between same-sex and unlike-sex twin pairs.
LOS remains a common problem in VLBW infants. The incidence of LOS is similar for singleton and multiple infants. Similar concordance of LOS in same-sex and unlike-sex twin pairs provided no evidence that susceptibility to LOS among VLBW infants is genetically determined.
PMCID: PMC3633723  PMID: 23324523
Heredity; preterm infants; twins
8.  Outcome of Extremely Low Birth Weight Infants with Congenital Heart Defects in the Eunice Kennedy Shriver NICHD Neonatal Research Network 
Pediatric cardiology  2012;33(8):1415-1426.
Little is known about the outcomes of extremely low birth weight (ELBW) preterm infants with congenital heart defects (CHDs). The aim of this study was to assess the mortality, morbidity, and early childhood outcomes of ELBW infants with isolated CHD compared with infants with no congenital defects. Participants were 401–1,000 g infants cared for at National Institute of Child Health and Human Development Neonatal Research Network centers between January 1, 1998 and December 31, 2005. Neonatal morbidities and 18–22 months’ corrected age outcomes were assessed. Neurodevelopmental impairment (NDI) was defined as moderate to severe cerebral palsy, Bayley II mental or psychomotor developmental index < 70, bilateral blindness, or hearing impairment requiring aids. Poisson regression models were used to estimate relative risks for outcomes while adjusting for gestational age, small for gestational-age status, and other variables. Of 14,457 ELBW infants, 110 (0.8 %) had isolated CHD, and 13,887 (96 %) had no major birth defect. The most common CHD were septal defects, tetralogy of Fallot, pulmonary valve stenosis, and coarctation of the aorta. Infants with CHD experienced increased mortality (48 % compared with 35 % for infants with no birth defect) and poorer growth. Surprisingly, the adjusted risks of other short-term neonatal morbidities associated with prematurity were not significantly different. Fifty-seven (52 %) infants with CHD survived to 18–22 months’ corrected age, and 49 (86 %) infants completed follow-up. A higher proportion of surviving infants with CHD were impaired compared with those without birth defects (57 vs. 38 %, p = 0.004). Risk of death or NDI was greater for ELBW infants with CHD, although 20% of infants survived without NDI.
PMCID: PMC3687358  PMID: 22644414
heart defects; congenital; follow-up studies
9.  Adherence to the Mediterranean diet and body fat distribution in reproductive aged women 
Adherence to the Mediterranean Diet (MD) high in fruits, vegetables and monounsaturated fats, has been associated with lower body mass index. Associations with measured body fat, including regional adiposity, have not been previously investigated. We examined the associations between the alternate Mediterranean Diet Score (aMED), anthropometry and measured adiposity by dual energy x-ray absorptiometry.
This study included 248 healthy females, aged 18–44 years from the BioCycle Study. Each woman’s aMED (range 0–9) was calculated from up to eight 24-hr dietary recalls over 1–2 menstrual cycles (>97% had ≥7 recalls). Multiple linear regression was used to determine whether aMED and its specific components were associated with total and regional adiposity after adjusting for age, race, education, physical activity and energy intake.
Participants had an average (SD) aMED of 4.2 (1.7) and percent body fat of 29.5 (6.0)%. Significant inverse associations were found between aMED and all the examined adiposity measures except waist to hip ratio. Among the DXA measures, a 1-unit increment in aMED was associated with a 0.06 (95% CI:−0.09,−0.02) lower trunk-to-leg fat ratio (T/L), a measure of upper to lower body fat. In an analysis examining T/L as an outcome with the separate components of the aMED, T/L was lower with increased legume consumption (β=−0.280, 95% CI:−0.550,−0.010) but was higher with increased consumption of red and processed meat (β=0.060, 95% CI:0.002,0.117).
Adherence to the aMED was associated with lower total and regional adiposity, adding to the mounting evidence of the health benefits of the MD.
PMCID: PMC3594052  PMID: 23388669
Mediterranean Diet; body fat; trunk fat; regional adiposity; obesity; body mass index; DXA
10.  Maternal Dietary Patterns during Third Trimester in Association with Birthweight Characteristics and Early Infant Growth 
Scientifica  2013;2013:786409.
Our analysis examined the impact of maternal dietary patterns and lifestyle factors on markers of fetal growth, specifically birthweight and size for gestational age (small- (SGA) or large-for-gestational age (LGA)). The Infant Feeding Practices Study II, a prospective cohort study, surveyed pregnant women during their 3rd trimester, of which a subgroup (n = 893) completed a food frequency questionnaire. Maternal dietary patterns were evaluated by diet scores (Alternative Healthy Eating Index for Pregnancy and alternate Mediterranean diet) and by carbohydrate quality (glycemic index and glycemic load). Poisson regression with robust standard errors was used to examine the relative risk of SGA and separately LGA, with dietary patterns and other lifestyle factors. Linear regression was used to determine the association of birthweight and early infant growth with better dietary patterns. Relative risk of SGA and LGA was not associated with dietary patterns. Birthweight and infant growth were not associated with maternal diet. Smoking, however, increased the risk of delivering an SGA infant (RR = 2.92, 95% CI: 1.58–5.39), while higher prepregnancy BMI increased the risk of delivering an LGA infant (RR = 1.06, 95% CI: 1.03–1.09). Future studies are needed to evaluate whether deficiencies in more specific maternal dietary nutrients play a role in fetal growth.
PMCID: PMC3893866  PMID: 24490111
11.  Survival and Morbidity Outcomes of Very Low Birth Weight Infants with Down Syndrome 
Pediatrics  2010;126(6):1132-1140.
Individuals with Down syndrome (DS) are at increased risk of several morbidities with lifelong health consequences. Little is known about mortality or morbidity risks in early infancy among very-low-birth-weight (VLBW) infants with DS. Our objective was to compare survival and neonatal morbidities between VLBW infants with DS and VLBW infants with other non-DS chromosomal anomalies, other non-chromosomal birth defects, and VLBW infants without major birth defects.
Data were collected prospectively for infants weighing 401-1500 grams born and/or cared for at one of the study centers participating in the NICHD Neonatal Research Network from 1994 through 2008. Risk of death and morbidities including patent ductus arteriosus (PDA), necrotizing enterocolitis (NEC), late onset sepsis (LOS), retinopathy of prematurity (ROP), and bronchopulmonary dysplasia (BPD), were compared between VLBW infants with DS and infants in the other groups.
Infants with DS were at increased risk of death (adjusted relative risk [RR] 2.47, 95% confidence interval [CI] 2.00-3.07), PDA, NEC, LOS, and BPD relative to infants with no birth defects. Decreased risk of death (RR 0.40, 95% CI 0.31-0.52) and increased risks of NEC and LOS were observed when comparing infants with DS to infants with other non-DS chromosomal anomalies. Relative to infants with non-chromosomal birth defects, infants with DS were at increased risk of PDA and NEC.
The increased risk of morbidities among VLBW infants with DS provides useful information for counseling parents and for caretakers in anticipating the need for enhanced surveillance for prevention of these morbidities.
PMCID: PMC3059605  PMID: 21098157
neonatal mortality; neonatal morbidity; preterm infants; Down syndrome; trisomy 21

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