Rebecca J. Baer

Risk of selected structural abnormalities in infants after increased nuchal translucency measurement

OBJECTIVE We sought to examine the association between increased first-trimester fetal nuchal translucency (NT) measurement and major noncardiac structural birth defects in euploid infants. STUDY DESIGN Included were 75,899 singleton infants without aneuploidy or critical congenital heart defects born in California in 2009 through 2010 with NT measured between 11-14 weeks of gestation. Logistic binomial regression was employed to estimate relative risks (RRs) and 95% confidence intervals (CIs) for occurrence of birth defects in infants with an increased NT measurement (by percentile at crown-rump length [CRL] and by ≥3.5 mm compared to those with measurements <90th percentile for CRL). RESULTS When considered by CRL adjusted percentile and by measurement ≥3.5 mm, infants with a NT ≥95th percentile were at risk of having ≥1 major structural birth defects (any defect, RR, 1.6; 95% CI, 1.3-1.9; multiple defects, RR, 2.1; 95% CI, 1.3-3.4). Infants with a NT measurement ≥95th percentile were at particularly high risk for pulmonary, gastrointestinal, genitourinary, and musculoskeletal anomalies (RR, 1.6-2.7; 95% CI, 1.1-5.4). CONCLUSION Our findings demonstrate that risks of major pulmonary, gastrointestinal, genitourinary, and musculoskeletal structural birth defects exist for NT measurements ≥95th percentile. The ≥3-fold risks were observed for congenital hydrocephalus; agenesis, hypoplasia, and dysplasia of the lung; atresia and stenosis of the small intestine; osteodystrophies; and diaphragm anomalies.

Interpregnancy interval after live birth or pregnancy termination and estimated risk of preterm birth: a retrospective cohort study

We assessed whether interpregnancy interval (IPI) length after live birth and after pregnancy termination was associated with preterm birth (PTB).

Association of early-preterm birth with abnormal levels of routinely collected first- and second-trimester biomarkers

OBJECTIVE The purpose of this study was to examine the relationship between typically measured prenatal screening biomarkers and early-preterm birth in euploid pregnancies. STUDY DESIGN The study included 345 early-preterm cases (<30 weeks of gestation) and 1725 control subjects who were drawn from a population-based sample of California pregnancies who had both first- and second-trimester screening results. Logistic regression analyses were used to compare patterns of biomarkers in cases and control subjects and to develop predictive models. Replicability of the biomarker early-preterm relationships that was revealed by the models was evaluated by examination of the frequency and associated adjusted relative risks (RRs) for early-preterm birth and for preterm birth in general (<37 weeks of gestation) in pregnancies with identified abnormal markers compared with pregnancies without these markers in a subsequent independent California cohort of screened pregnancies (n = 76,588). RESULTS The final model for early-preterm birth included first-trimester pregnancy-associated plasma protein A in the ≤5th percentile, second-trimester alpha-fetoprotein in the ≥95th percentile, and second-trimester inhibin in the ≥95th percentile (odds ratios, 2.3-3.6). In general, pregnancies in the subsequent cohort with a biomarker pattern that were found to be associated with early-preterm delivery in the first sample were at an increased risk for early-preterm birth and preterm birth in general (<37 weeks of gestation; adjusted RR, 1.6-27.4). Pregnancies with ≥2 biomarker abnormalities were at particularly increased risk (adjusted RR, 3.6-27.4). CONCLUSION When considered across cohorts and in combination, abnormalities in routinely collected biomarkers reveal predictable risks for early-preterm birth.

Detection Rates for Aneuploidy by First-Trimester and Sequential Screening.

OBJECTIVE: To estimate detection rates for aneuploidy by first-trimester and sequential screening. METHODS: The study included women with singleton pregnancies who participated in the California Prenatal Screening Program with estimated delivery dates from August 2009 to December 2012 who had first- or first- and second-trimester (sequential) screening. Detection rates were measured for target (trisomies 21 and 18) and other aneuploidies identified from the California Chromosome Defect Registry. RESULTS: Of 452,901 women screened, 17,435 (3.8%) were screen-positive for Down syndrome only; 433 (0.1%) for trisomy 18 only; 1,689 (0.4%) for both Down syndrome and trisomy 18; and 2,947 (0.7%) for neural tube defects, Smith-Lemli-Opitz syndrome, or for multiple conditions. The detection rates were Down syndrome—92.9% (95% confidence interval [CI] 91.4–94.2); trisomy 18—93.2% (95% CI 90.5–95.9); trisomy 13—80.4% (95% CI 73.9–86.9); 45,X—80.1% (95% CI 73.9–86.3), and triploidy—91.0% (95% CI 84.2–97.9). Overall, the detection rate for chromosome abnormalities was 81.6% (95% CI 80.0–83.1) at an overall false-positive rate of 4.5%. CONCLUSION: First-trimester and sequential screening are sensitive and specific for the broad range of karyotype abnormalities seen in the population. LEVEL OF EVIDENCE: II

Persistent Pulmonary Hypertension of the Newborn in Late Preterm and Term Infants in California

BACKGROUND AND OBJECTIVES: There are limited epidemiologic data on persistent pulmonary hypertension of the newborn (PPHN). We sought to describe the incidence and 1-year mortality of PPHN by its underlying cause, and to identify risk factors for PPHN in a contemporary population-based dataset. METHODS: The California Office of Statewide Health Planning and Development maintains a database linking maternal and infant hospital discharges, readmissions, and birth and death certificates from 1 year before to 1 year after birth. We searched the database (2007–2011) for cases of PPHN (identified by International Classification of Diseases, Ninth Revision codes), including infants ≥34 weeks’ gestational age without congenital heart disease. Multivariate Poisson regression was used to identify risk factors associated with PPHN; results are presented as risk ratios, 95% confidence intervals. RESULTS: Incidence of PPHN was 0.18% (3277 cases/1 781 156 live births). Infection was the most common cause (30.0%). One-year mortality was 7.6%; infants with congenital anomalies of the respiratory tract had the highest mortality (32.0%). Risk factors independently associated with PPHN included gestational age <37 weeks, black race, large and small for gestational age, maternal preexisting and gestational diabetes, obesity, and advanced age. Female sex, Hispanic ethnicity, and multiple gestation were protective against PPHN. CONCLUSIONS: This risk factor profile will aid clinicians identifying infants at increased risk for PPHN, as they are at greater risk for rapid clinical deterioration.

Gestational dating by metabolic profile at birth: a California cohort study

Background Accurate gestational dating is a critical component of obstetric and newborn care. In the absence of early ultrasound, many clinicians rely on less accurate measures, such as last menstrual period or symphysis-fundal height during pregnancy, or Dubowitz scoring or the Ballard (or New Ballard) method at birth. These measures often underestimate or overestimate gestational age and can lead to misclassification of babies as born preterm, which has both short- and long-term clinical care and public health implications. Objective We sought to evaluate whether metabolic markers in newborns measured as part of routine screening for treatable inborn errors of metabolism can be used to develop a population-level metabolic gestational dating algorithm that is robust despite intrauterine growth restriction and can be used when fetal ultrasound dating is not available. We focused specifically on the ability of these markers to differentiate preterm births (PTBs) (<37 weeks) from term births and to assign a specific gestational age in the PTB group. Study Design We evaluated a cohort of 729,503 singleton newborns with a California birth in 2005 through 2011 who had routine newborn metabolic screening and fetal ultrasound dating at 11–20 weeks’ gestation. Using training and testing subsets (divided in a ratio of 3:1) we evaluated the association among PTB, target newborn characteristics, acylcarnitines, amino acids, thyroid-stimulating hormone, 17-hydroxyprogesterone, and galactose-1-phosphate-uridyl-transferase. We used multivariate backward stepwise regression to test for associations and linear discriminate analyses to create a linear function for PTB and to assign a specific week of gestation. We used sensitivity, specificity, and positive predictive value to evaluate the performance of linear functions. Results Along with birthweight and infant age at test, we included 35 of the 51 metabolic markers measured in the final multivariate model comparing PTBs and term births. Using a linear discriminate analyses-derived linear function, we were able to sort PTBs and term births accurately with sensitivities and specificities of ≥95% in both the training and testing subsets. Assignment of a specific week of gestation in those identified as PTBs resulted in the correct assignment of week ±2 weeks in 89.8% of all newborns in the training and 91.7% of those in the testing subset. When PTB rates were modeled using the metabolic dating algorithm compared to fetal ultrasound, PTB rates were 7.15% vs 6.11% in the training subset and 7.31% vs 6.25% in the testing subset. Conclusion When considered in combination with birthweight and hours of age at test, metabolic profile evaluated within 8 days of birth appears to be a useful measure of PTB and, among those born preterm, of specific week of gestation ±2 weeks. Dating by metabolic profile may be useful in instances where there is no fetal ultrasound due to lack of availability or late entry into care.

Second trimester serum predictors of preterm birth in a population‐based sample of low‐risk pregnancies

To examine the relationship between typically collected second trimester maternal serum biomarkers and preterm birth among pregnancies without intrauterine‐growth‐retardation or other specific risk factors.

Survival and Major Morbidity of Extremely Preterm Infants: A Population-Based Study.

OBJECTIVES: To assess the rates of mortality and major morbidity among extremely preterm infants born in California and to examine the rates of neonatal interventions and timing of death at each gestational age. METHODS: A retrospective cohort study of all California live births from 2007 through 2011 linked to vital statistics and hospital discharge records, whose best-estimated gestational age at birth was 22 through 28 weeks. Major morbidities were based on International Classification of Diseases, Ninth Revision, Clinical Modification codes. Survival beyond the first calendar day of life and procedure codes were used to assess attempted resuscitation after birth. RESULTS: A total of 6009 infants born at 22 through 28 weeks’ gestation were included. Survival to 1 year for all live births ranged from 6% at 22 weeks to 94% at 28 weeks. Seventy-three percent of deaths occurred within the first week of life. Major morbidity was present in 80% of all infants, and multiple major morbidities were present in 66% of 22- and 23-week infants. Rates of resuscitation at 22, 23, and 24 weeks were 21%, 64%, and 93%, respectively. Survival after resuscitation was 31%, 42%, and 64% among 22-, 23-, and 24-week infants, respectively. Improved survival was associated with increased birth weight, female sex, and cesarean delivery (P < .01) for resuscitated 22-, 23-, and 24-week infants. CONCLUSIONS: In a population-based study of extreme prematurity, infants ≤24 weeks’ gestation are at highest risk of death or major morbidity. These data can help inform recommendations and decision-making for extremely preterm births.

Maternal characteristics and mid-pregnancy serum biomarkers as risk factors for subtypes of preterm birth.

To examine the relationship between maternal characteristics, serum biomarkers and preterm birth (PTB) by spontaneous and medically indicated subtypes.

Obstetric, perinatal, and fetal outcomes in pregnancies with false-positive integrated screening results.

OBJECTIVE: To assess the risk of adverse obstetric, perinatal, and fetal outcomes for pregnant women participating in prenatal sequential integrated screening through the California Prenatal Screening Program who had a false-positive screening result. METHODS: Women who underwent first- and second-trimester prenatal integrated screening plus nuchal translucency measurement with outcome information available were included. Fetuses and neonates with chromosomal or neural tube defects were excluded. We compared the risk of adverse outcomes for all women with a positive screening result compared with a 10% random sample of women with a negative screening result. Logistic binomial regression was used to compare adverse outcomes in screen-positive compared with screen-negative women. RESULTS: We identified 9,051 screen-positive and 30,928 screen-negative pregnancies with outcome information available. Compared with screen-negative pregnancies, screen-positive women were more likely to be diagnosed with preeclampsia, placenta previa, or abruption (7.6% screen-positive, 3.8% screen-negative; relative risk 1.7, 95% confidence interval [CI] 1.6–1.8) or experience fetal loss before 20 weeks of gestation (1.9% screen-positive, 0.2% screen-negative; relative risk 3.5, 95% CI 3.2–3.8). Women with positive results for more than one screened condition were at substantially greater risk of fetal and neonatal mortality (relative risks 33.6–156.7, 95% CIs 21.8–194.4). CONCLUSION: Among pregnancies without chromosomal or neural tube defects, prenatal sequential integrated screening provides information regarding risk across a variety of adverse pregnancy outcomes. LEVEL OF EVIDENCE: II