We describe the neuropathologic procedure utilized in the Stillbirth Collaborative Research Network (SCRN), focusing on the examination of central nervous system (CNS) in stillbirth (SB). The SCRN was organized to perform a case-control study to determine the scope and causes of SB. Pathologists at all the participating centers agreed on and used the same standardized neuropathologic techniques. Standardized sections were taken and detailed data were collected. Fresh brain tissue was saved for investigative purposes. A total of 663 women with SB were enrolled into the case-control study: 620 delivered a single stillborn, 42 delivered twins, and 1 delivered triplets. Of the 560 (84.5%) who consented to postmortem examination, 465 (70.1%) also gave consent to the examination of the CNS. In the 440 stillborn infants in whom CNS examination was possible, 248 (56.4%) of the brains were intact, 72 were fragmented (16.4%), and 120 (27.3%) were liquefied. In summary, this is the largest prospective study dedicated to investigate the causes of SB and collect essential information and biological samples in the United States. A protocol for neuropathologic examination was instituted, and a brain tissue repository was created to provide samples and related data for future investigations.
SCRN; neuropathology; stillbirth; central nervous system
After reviewing the state of knowledge about the scope and causes of stillbirth (SB) in a special workshop sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the participants determined that there is little guidance regarding the best use of postmortem examination (PM) to address the pathogenesis of stillbirth. In this report, we describe the PM procedure designed and used in the NICHD-supported Stillbirth Cooperative Research Network (SCRN). Perinatal pathologists, clinicians, epidemiologists, and biostatisticians at four tertiary care centers, a data coordinating center, and NICHD developed a standardized approach to perinatal PM, which was applied to a population-based study of stillbirth as part of the SCRN. The SCRN PM protocol was successfully instituted and used at the four medical centers. A total of 663 women with stillbirth were included: 620 delivered a single stillborn infant, 42 delivered twins, and one delivered triplets for a total of 676 stillborn infants. Of these women, 560 (84.5%) consented to PM (572 stillborn infants) that was conducted according to the SCRN protocol. A standardized PM protocol was developed to evaluate stillbirth consistently across centers in the United States. Novel testing and approaches that increase the yield of the PM can be developed using this model.
SCRN; postmortem examination; stillbirth; perinatal pathology
The Stillbirth Collaborative Research Network (SCRN) was organized to study the scope and causes of stillbirth (SB) in the United States. The objective of this report is to describe the approach used for the placental examination performed as part of the study. The SCRN consists of a multidisciplinary team of investigators from five clinical sites, the National Institute of Child Health and Human Development, and the Data Coordination and Analysis Center. The study is a population-based cohort and nested case-control study, with prospective enrollment of women with SB and live births (LB) at the time of delivery. Detailed and standardized postmortem examination was performed on SB and placental examination in both groups. A total of 663 women with SB and 1932 women with LB were enrolled into the case-control study. In the SB group, there were 707 fetuses. Of these cases, 654 (98.6%) had placental examination. Of these LB controls, 1804 (93.4%) had placental examination. This is the largest prospective study to include population-based SB and LB, using standardized postmortem and placental examination, medical record review, maternal interview, collection of samples, and a multidisciplinary team of investigators collaborating in the analyses. Thus it has the potential to provide high-level evidence regarding the contribution of placental abnormalities to stillbirth.
Stillbirth; placenta; umbilical cord; cause of death
To determine whether maternal body mass index (BMI) influences the beneficial effects of diabetes treatment in women with gestational diabetes (GDM).
Secondary analysis of a multicenter randomized treatment trial of women with GDM. Outcomes of interest were elevated umbilical cord c-peptide levels (>90th percentile 1.77 ng/mL), LGA birth weight (>90th percentile), and neonatal fat mass (g). Women were grouped into five BMI categories adapted from the WHO International Classification of normal, overweight, and obese adults. Outcomes were analyzed according to treatment group assignment.
A total of 958 women were enrolled (485 treated and 473 controls). Maternal BMI at enrollment was not related to umbilical cord c-peptide levels. However, treatment of women in the overweight, Class I, and Class II obese categories was associated with a reduction in both LGA birth weight and neonatal fat mass. Neither measure of excess fetal growth was reduced with treatment in normal weight (BMI <25) or Class III (BMI ≥ 40) obese women.
There was a beneficial effect of treatment on fetal growth in women with mild GDM who were overweight or Class I and II obese. These effects were not apparent for normal weight and very obese women.
Gestational diabetes; BMI; Treatment effect
To test whether elevated umbilical cord serum inflammatory cytokine levels predicted subsequent cerebral palsy (CP) or neurodevelopmental delay (NDD).
Nested case-control analysis within a clinical trial of antenatal magnesium sulfate (MgSO4) before anticipated PTB for prevention of CP, with evaluation of surviving children at age 2. NDD was defined as a Bayley Psychomotor Developmental Index (PDI) and/or Mental Developmental Index (MDI) <70. Controls, defined as surviving children without CP and with Bayley PDI and MDI ≥85, were matched by race and gestational age. Cord serum was analyzed for IL-8, IL-1 β and TNF-α levels. Elevated cytokine levels were defined as ≥75th percentile in placebo-exposed controls. Analyses compared case/control cytokine levels, adjusting for MgSO4 exposure, gestational age, race/ethnicity and sociodemographic differences.
Logistic regression analysis with 339 cases and 276 controls showed that elevated IL-8 and IL-1β were more common in cord blood serum from infants with subsequent low MDI compared with controls. After adjusting for additional confounders, the significant differences were no longer evident. Cytokine levels (IL-8, IL-1β, and TNF-α) were not elevated with CP or low PDI.
Cord serum IL-8, IL-1β, and TNF-α levels in preterm infants are not associated with subsequent CP or NDD.
Cytokines; Cerebral Palsy; Neurodevelopmental Outcomes; Prematurity; Magnesium Sulfate
To compare apnea events recorded by bedside cardiorespiratory monitor and nursing documentation with those detected by visual inspection of continuous electronic cardiorespiratory waveform.
In a prospective observational study, 20 nonventilated infants of 28 to 33 weeks’ gestational age were monitored for apnea during the first 2 postnatal weeks. Apnea was defined as a respiratory pause > 20 seconds or > 15 seconds if associated with a heart rate < 80/min or oxygen saturation < 85%. True apnea was defined as one for which visual inspection of continuous electronic cardiorespiratory waveform on the central monitor verified apnea.
The number of apnea episodes recorded by nursing documentation and bedside monitors were 207 and 418, respectively. Only 7.7% of apnea events recorded by nursing documentation were confirmed as true apnea compared with 50.4% of apnea recorded by bedside monitors and the difference was statistically significant. Of true apnea (n = 211) episodes recorded on central monitors, 99% were recorded by bedside monitors but only 7.6% of apnea occurrences were recorded by nursing personnel.
Nursing documentation does not provide accurate monitoring of apnea. Although bedside monitors have better sensitivity and specificity than nursing documentation, future research should be directed to improve the specificity of bedside monitoring.
neonatal intensive care unit; bradycardia; desaturation; premature infants
To describe latency for patients with preterm premature membrane rupture (PPROM) between 24 0/7 and 31 6/7 weeks’ gestation.
Secondary analysis of data collected prospectively in a multicenter clinical trial of magnesium sulfate for cerebral palsy prevention. Women with PPROM and fewer than 6 contractions per hour at enrollment who were candidates for expectant management (n=1377) were included in this analysis. Length of latency was calculated in days by subtracting the time of delivery from the time of membrane rupture.
At each week of gestation, median latency between 24-28 weeks was similar at approximately 9 days, but was significantly shorter with PPROM at 29, 30, and 31 weeks (p<0.001). In addition, the percentage of patients remaining undelivered at 7 days and 14 days was similar for PPROM between 24-28 weeks, but decreased significantly after that. For each gestational age, the proportion of patients remaining pregnant declined in a fashion similar to exponential pattern.
Median latency after PPROM is similar from 24-28 weeks’ gestation, but shortens with PPROM at and after 29 weeks.
latency; premature rupture of membranes; preterm birth
To determine whether genetic variants associated with glucose homeostasis are associated with gestational diabetes (GDM).
We genotyped 899 self-identified Caucasian women and 386 self-identified African-American women in the Pregnancy, Infection and Nutrition (PIN) Studies cohorts for 36 single-nucleotide polymorphisms (SNPs) associated with type 2 diabetes (T2DM) and/or glucose homeostasis in European populations.
GDM was diagnosed in 56 of 899 (6.2%) Caucasian and 24 of 386 (6.2%) African-American women. Among Caucasian women, GDM was associated with carriage of TCF7L2 rs7901695, MTNR1B rs10830963 and GCKR rs780094 alleles associated with T2DM and fasting glucose in non-pregnant populations. Among African-American participants, we found an increased risk among TSPAN8 rs7961581 C allele homozygotes and reduced risk among carriers of the JAZF1 rs864745 T allele.
We found several SNPs that are associated with GDM risk in the PIN cohorts. Maternal genotyping may identify women at risk for impaired gestational glucose tolerance.
diabetes; gestational diabetes; genetics; single nucleotide polymorphisms
Prenatal diagnosis provides valuable information regarding a variety of congenital heart defects. Some defects occur early in gestation with little change throughout pregnancy, whereas others evolve during mid and late gestation. Fetal cardiac intervention (FCI) affords the opportunity to interrupt progression of disease in this latter category, resulting in improved perinatal and lifelong outcomes.
This chapter addresses three lesions for which percutaneous FCI can be utilized: (1) aortic stenosis with evolving hypoplastic left heart syndrome, for which aortic valvuloplasty may prevent left ventricular hypoplasia and has yielded a biventricular circulation in approximately one third of cases; (2) hypoplastic left heart syndrome with intact atrial septum, for which relief of atrial restriction has potential to improve perinatal survival; and (3) pulmonary atresia with intact ventricular septum and evolving right ventricular hypoplasia, for which pulmonary valvuloplasty has resulted in a biventricular circulation in the majority of patients. The pathophysiology, rationale for intervention, patient selection criteria, procedural technique, and outcomes for each lesion will be reviewed. This chapter will also review complications of FCI and their treatment, and maternal and fetal anesthesia specific to FCI. The importance of a specialized center with experience managing infants delivered after FCI will also be addressed.
congenital heart disease; fetal cardiac intervention; aortic stenosis; hypoplastic left heart syndrome; pulmonary atresia with intact ventricular septum
To characterize the incidence, management and short term outcomes of cardiovascular insufficiency (CVI) in mechanically ventilated newborns, evaluating 4 separate pre-specified definitions.
Multicenter, prospective cohort study of infants ≥34 weeks gestational age (GA) and on mechanical ventilation during the first 72 hours. CVI was prospectively defined as either (1) mean arterial pressure (MAP)
Of 647 who met inclusion criteria, 419 (65%) met ≥1 definition of CVI. Of these, 98% received fluid boluses, 36% inotropes and 17% corticosteroids. Of treated infants, 46% did not have CVI as defined by a MAP < GA ± signs of inadequate perfusion. Inotrope therapy was associated with increased mortality (11.1% vs. 1.3%; P < 0.05).
More than half of the infants met at least one definition of CVI. However, almost half of the treated infants met none of the definitions. Inotropic therapy was associated with increased mortality. These findings can help guide the design of future studies of CVI in newborns.
blood pressure; cardiovascular insufficiency; mechanical ventilation; inotrope; fluid bolus; glucocorticoid; outcomes; newborn
Infection-related neonatal mortality due to omphalitis in developing country home births is an important public health problem. Three cluster randomized trials of 4% chlorhexidine applied to the umbilical cord stump from 1 to multiple times in the days following a home birth have evaluated this intervention compared to other types of cord care on the development of omphalitis and neonatal mortality. Each of the 3 studies showed significant reductions in either omphalitis, neonatal mortality, or both with the 4% chlorhexidine. However, the optimal dosing schedule remains uncertain. While further studies are needed to clarify this issue, from the 3 studies it is now clear that with a minimum of one application of 4% chlorhexidine to the umbilical cord stump following delivery, the incidence of omphalitis and neonatal mortality can be reduced, especially in preterm newborns. This intervention, which is safe, inexpensive and requires minimal training and skill, should strongly be considered for adoption wherever home births occur.
To compare the ability of customized versus normalized population fetal growth norms in identifying neonates at risk for adverse perinatal outcomes (APOs) associated with fetal overgrowth and gestational diabetes (GDM).
Secondary analysis of a multicenter treatment trial of mild GDM. The primary outcome was a composite of neonatal outcomes associated with fetal overgrowth and GDM. Birthweight percentiles were calculated using ethnicity- & gender-specific population norms and customized norms (Gardosi).
203 (9.8%) and 288 (13.8%) neonates were LGA by population (LGApop) and customized (LGAcust) norms, respectively. Both LGApop and LGAcust were associated with the primary outcome and neonatal hyperinsulinemia, while neither was associated with hypoglycemia or hyperbilirubinemia. The ability of customized and population birthweight percentiles for predicting APOs were poor (receiver operating characteristic area under the curve <0.6 for 6 out of 8 APOs).
Neither customized nor normalized-population norms better identify neonates at risk of APOs related to fetal overgrowth and GDM.
customized growth; adverse neonatal outcomes; gestational diabetes; large for gestational age
To examine maternal dietary intake and preterm delivery.
Data included 5738 deliveries from the National Birth Defects Prevention Study. Odds ratios (ORs) reflected risks of delivery at <32, 32–34, or 35–36 versus ≥37 weeks for maternal intake in the lowest or highest quartile of nutrient intake compared with the middle two.
Among deliveries < 32 weeks, many ORs were ≥1.5 or ≤0.7, but few confidence intervals excluded one. ORs were 1.5 for lowest quartiles of protein, thiamin, riboflavin, choline, vitamin A, α-carotene, β-carotene, vitamin E, iron, copper, and zinc and for highest quartiles of carbohydrate, glycemic index, and Mediterranean Diet Score. ORs were ≤0.7 for lowest quartiles of glycemic index and betaine and for highest quartiles of protein, alanine, methionine, vitamin B6, betaine, and calcium. Few ORs met these criteria for later preterm deliveries.
Results suggested an association of nutrient intake with earlier preterm deliveries.
nutrition; pregnancy; preterm delivery
To study the relationship between fetal station and successful vaginal delivery in nulliparous women.
This was a secondary analysis from a previously reported trial of pulse oximetry. Vaginal delivery rates were evaluated and compared with respect to the fetal station. Spontaneous labor and induction of labor groups were evaluated separately. Multivariable logistic regression analysis was performed to adjust for confounding factors.
Successful vaginal delivery was more frequent with an engaged vertex for spontaneous labor (86.2% versus 78.6%; p = 0.01) and induced labor (87.7% versus 66.1%; p < 0.01). After adjustment, engaged fetal vertex was not associated with vaginal delivery for spontaneous labor (odds ratio [OR] 1.5; 95% confidence interval [CI] 0.95 to 2.3; p = 0.08) or for women with induced labor (OR 2.2; 95% CI 0.96 to 5.1; p = 0.06).
Among nulliparous women enrolled in the FOX randomized trial in spontaneous labor or for labor induction, an engaged fetal vertex does not affect their vaginal delivery rate.
labor; fetal station; vaginal delivery
To estimate the cost-effectiveness of a trial of labor after one previous cesarean delivery (TOLAC).
A model comparing TOLAC with elective repeat cesarean delivery (ERCD) was developed for a hypothetical cohort with no contraindication to a TOLAC. Probabilistic estimates were obtained from women matched on their baseline characteristics using propensity scores. Cost data, quality adjusted-life-years (QALYs) and data on cerebral palsy were incorporated from the literature.
The TOLAC strategy dominated the ERCD strategy at baseline, with $138.6 million saved and 1703 QALYs gained per 100,000 women. The model was sensitive to five variables; the probability of uterine rupture, the probability of successful TOLAC, the QALY of failed TOLAC, the cost of ERCD and the cost of successful TOLAC without complications. When the probability of TOLAC success was at the base value, 68.5%, TOLAC was preferred if the probability of uterine rupture was 4.2% or less. When the probability of uterine rupture was at the base value, 0.8%, the TOLAC strategy was preferred as long as the probability of success was 42.6% or more.
A TOLAC is less expensive and more effective than an ERCD in a group of women with balanced baseline characteristics.
cost-effectiveness; elective repeat cesarean; trial of labor; propensity scores
We analyzed the role of environmental risk factors, socio-demographic characteristics, clinical characteristics, and reproductive history in preterm births and their associated perinatal outcomes in families classified according to their histories of preterm recurrence among siblings.
A retrospective study was conducted at “Nuestra Señora de la Merced” Maternity Hospital in the city of Tucumán, Argentina. A total of 348 preterm, non-malformed, singleton children born to multipara women were reviewed. The family history score described by Khoury was applied, and families were classified as having no, medium or high genetic aggregation.
Families with no familial aggregation showed a higher rate of short length of cohabitation, maternal urinary tract infections during the current pregnancy and maternal history of miscarriage during the previous pregnancy. Families with a high level of aggregation had a significantly higher incidence of pregnancy complications, such as diabetes, hypertension and immunological disorders.
Reproductive histories clearly differed between the groups, suggesting both a different response to environmental challenges based on genetic susceptibility, and the activation of different pathophysiological pathways to determine the duration of pregnancy in each woman.
preterm birth; familial aggregation; pregnancy
To characterize the pharmacokinetics and pharmacogenetics of nifedipine in pregnancy.
Pregnant women receiving oral nifedipine underwent steady-state pharmacokinetic testing over one dosing interval. DNA was obtained and genotyped for cytochrome P450 (CYP) 3A5, and CYP3A4*1B. Nifedipine and oxidized nifedipine concentrations were measured in plasma and pharmacokinetic parameters were compared between those women who expressed a CYP3A5*1 allele and those who expressed only variant CYP3A5 alleles (*3,*6, or *7).
Fourteen women had complete data to analyze. Four women (29%) expressed variant CYP3A5; three of these women were also CYP3A4*1B allele carriers. The mean half-life of nifedipine was 1.68±1.56 hours. AUC0–6 for the women receiving nifedipine every 6 hours was 207±138μg·h/L. Oral clearance was different between high expressers and low expressers (232.0±37.8 μg/mL vs. 85.6±45.0 μg/mL, respectively; p=0.007).
CYP3A5 genotype influences the oral clearance of nifedipine in pregnant women.
nifedipine; pharmacokinetics; pharmacogenetics; pregnancy; tocolysis
To assess the relationship between a low 50-g 1-hour glucose loading test (GLT) and maternal and neonatal outcomes in women without diabetes.
This was a secondary analysis of a multicenter observational cohort from a randomized trial of treatment for mild gestational diabetes. Maternal and neonatal outcomes were compared between women with GLT values < 90 mg/dL and those with results 90 to 119 mg/dL.
Of 436 enrolled women, 297 (68.1%) had a GLT result of 90 to 119 mg/dL and 139 (31.9%) had a result of < 90 mg/dL. There was a lower incidence of neonatal hypoglycemia in those with a GLT < 90 mg/dL (5.7% versus 16.5%, p = 0.006). Other outcomes were not associated with test results.
A GLT result < 90 mg/dL compared with 90 to 119 mg/dL is associated with a lower risk of neonatal hypoglycemia, but no other significant findings.
low glucose screening test; neonatal hypoglycemia
To evaluate factors impacting selection to delayed pushing in the second stage of labor.
This case-control study was a secondary analysis of a large retrospective cohort study. Cases included women who delayed pushing for 60 minutes or more in the second stage of labor. Controls began pushing prior to 60 minutes from the time of diagnosis of complete dilation. Demographic, labor, and nonmedical factors were compared among cases and controls. Logistic regression modelling was used to identify factors independently associated with delayed pushing.
We identified 471 women who delayed pushing and 4,819 controls. Nulliparity, maternal body mass index > 25, high fetal station at complete dilation, regional anesthesia use, and start of second stage during staffing shift change were independent factors associated with increased use of delayed pushing. On the other hand, black race and second stage management during night shift were associated with lower odds of employing delayed pushing. Delayed pushing was more commonly employed in nulliparous women, but 38.9% of multiparous women also delayed pushing.
We identified multiple factors associated with use of delayed pushing. This study helps to define current patterns of second stage labor management.
Delayed pushing; labor management; second stage
To compare population versus customized fetal growth norms in identifying neonates at risk for adverse outcomes (APO) associated with small for gestational age (SGA).
Secondary analysis of an intrapartum fetal pulse oximetry trial in nulliparous women at term. Birthweight percentiles were calculated using ethnicity- & gender-specific population norms and customized norms (Gardosi).
508 (9.9%) and 584 (11.3%) neonates were SGA by population (SGApop) and customized (SGAcust) norms. SGApop infants were significantly associated with a composite adverse neonatal outcome, neonatal intensive care admission, low fetal oxygen saturation and reduced risk of cesarean delivery; while both SGApop and SGAcust were associated with a 5-minute Apgar score < 4. The ability of customized and population birthweight percentiles in predicting APO was poor (12 out of 14 APOs had AUC <0.6).
In this intrapartum cohort, neither customized nor normalized-population norms adequately identify neonates at risk of APO related to SGA.
customized norm; fetal growth; small for gestational age; adverse outcomes
This prospective observational study explored the association of hypertensive disorders of pregnancy and small-for-gestational age (SGA) with obstructive sleep apnea (OSA) as determined by screening measures for OSA and sleep studies.
Two symptom-based screening questionnaires, the Berlin Questionnaire (BQ) and the Epworth Sleepiness Scale (ESS), were administered to enroll 1509 gravidae. Screen positive subjects were referred for polysomnography (PSG). The primary outcome was the occurrence of either gestational hypertension or preeclampsia. [a1]Generalized linear models (GLM) were used to estimate the relative risks of associations.
1157 subjects were available for outcomes analysis. Screening positive on the BQ was positively associated with hypertensive disorders in GLM models (aRR=1.90, 95%CI 1.52–2.37).
In this large prospective trial, GLM modeling suggest that the BQ but not the ESS demonstrated significant association with measured adverse pregnancy outcomes, and specific items predicted these outcomes better than others. However, causative association of BQ with OSA cannot be assumed.
Obesity; Obstructive Sleep Apnea; Preeclampsia; Sleep-Disordered Breathing
To determine if tobacco use increases the incidence of preterm premature rupture of the membranes (pPROM) or alters perinatal outcomes after pPROM.
This is a secondary analysis of the databases of three completed Eunice Kennedy Shriver National Institute of Child Health and Human Development–supported Maternal Fetal Medicine Units Network studies. Self-reported tobacco exposure data was obtained. Its relationship with the incidence of pPROM and associated neonatal outcome measures were assessed.
There was no difference in the incidence of pPROM when comparing non-smokers to those using tobacco. Although a trend was seen between the incidence of pPROM and the amount smoked, this did not reach statistical significance. Among the patients with pPROM, the use of tobacco was not associated with an increase in perinatal morbidity.
Our data do not support a significant relationship between tobacco use and pPROM.
tobacco; premature rupture of the membranes
Newborns are at increased risk of infection due to genetic, epigenetic, and environmental factors. Herein we examine the roles of the neonatal innate immune system in host defense against bacterial and viral infections. Full-term newborns express a distinct innate immune system biased towards TH2/TH17-polarizing and anti-inflammatory cytokine production with relative impairment in TH1-polarizing cytokine production that leaves them particularly vulnerable to infection with intracellular pathogens. In addition to these distinct features, preterm newborns also have fragile skin, impaired TH17-polarizing cytokine production and deficient expression of complement and of antimicrobial proteins and peptides (APPs) that likely contribute to susceptibility to pyogenic bacteria. Ongoing research is identifying APPs, including bacterial/permeability-increasing protein and lactoferrin, as well as pattern recognition receptor (PRR) agonists that may serve to enhance protective newborn and infant immune responses as stand alone immune response modifiers or vaccine adjuvants.
adjuvants; neonatal sepsis; pathogen recognition receptors; innate immunity