Laura L. Jelliffe-Pawlowski

Effect of magnitude and timing of maternal pregnancy blood lead (Pb) levels on birth outcomes

Objective:Associations between magnitude and timing of maternal pregnancy blood lead (Pb) levels (BLLs), birth weight, and total days of gestation were examined, as well as associations with related clinical diagnoses of low birth weight (LBW), preterm, and small-for-gestational-age (SGA) birth.Study Design:Among a sample of 262 mother–infant pairs studied retrospectively, one-way analysis of variance and regression statistics were used to measure the relationship between level of maternal pregnancy BLLs and birth outcomes while controlling for key maternal and newborn factors.Results:Women with maximum pregnancy BLLs (max-PBLLs) ⩾10 μg/dl tended to give birth earlier and their babies were at substantially increased risk for preterm and SGA birth. By holding other explanatory factors constant, each unit increase in max-PBLL above 10 μg/dl was found to be associated with a decrease of −0.3 in total days of gestation. Compared to women with lower levels, women with max-PBLLs ⩾10 μg/dl were at a threefold increased risk for preterm birth (adjusted OR=3.2, 95% CI 1.2–7.4) and more than a fourfold increased risk for having an SGA infant (adjusted OR=4.2, 1.3–13.9). Second trimester maximum BLLs ⩾10 μg/dl were associated with a steep decrease in total days of gestation (a decrease of −1.0 days per each unit increase above 10 μg/dl).Conclusions:These data provide evidence of the adverse effects of maternal pregnancy BLLs, particularly when levels are ⩾10 μg/dl. Prenatal Pb exposure at these levels was associated with significant decreases in total days of gestation and an increased risk of preterm and SGA birth.

Chromosome Abnormalities Detected by Current Prenatal Screening and Noninvasive Prenatal Testing

OBJECTIVE: To estimate how many additional chromosomal abnormalities can be detected by diagnostic testing compared with noninvasive prenatal testing in a high-risk prenatal population. METHODS: All karyotype results of invasive prenatal testing in singleton pregnancies performed in response to a positive prenatal screen through the California Prenatal Screening Program from April 2009 through December 2012 were examined. Abnormal karyotypes were categorized as to whether the abnormality is detectable by current noninvasive prenatal testing methods. RESULTS: Of 1,324,607 women who had traditional screening during the study period, 68,990 (5.2%) were screen-positive. Of screen-positive women, 26,059 (37.8%) underwent invasive diagnostic testing and 2,993 had an abnormal result (11.5%). Of these, 2,488 (83.1%) were predicted to be detectable with current noninvasive prenatal testing methods, and 506 (16.9%) were considered not currently detectable. Trisomy 21 accounted for 53.2% of the abnormal results (n=1,592). Common aneuploidies, detectable by noninvasive prenatal testing, comprised a higher percentage of abnormal results in older women (P<.01). CONCLUSION: For pregnant women with a positive aneuploidy screen who pursued diagnostic testing, 16.9% of chromosome abnormalities are not currently detectable by noninvasive prenatal testing. Undetectable aneuploidies range from relatively mild to those associated with significant disability. This is important information to be considered by patients, health care providers, and screening programs in evaluating the use of traditional screening and invasive prenatal diagnosis compared with noninvasive prenatal testing. LEVEL OF EVIEDENCE: III

A Genome-Wide Association Study (GWAS) for Bronchopulmonary Dysplasia

OBJECTIVE: Twin studies suggest that heritability of moderate-severe bronchopulmonary dysplasia (BPD) is 53% to 79%, we conducted a genome-wide association study (GWAS) to identify genetic variants associated with the risk for BPD. METHODS: The discovery GWAS was completed on 1726 very low birth weight infants (gestational age = 250–296/7 weeks) who had a minimum of 3 days of intermittent positive pressure ventilation and were in the hospital at 36 weeks’ postmenstrual age. At 36 weeks’ postmenstrual age, moderate-severe BPD cases (n = 899) were defined as requiring continuous supplemental oxygen, whereas controls (n = 827) inhaled room air. An additional 795 comparable infants (371 cases, 424 controls) were a replication population. Genomic DNA from case and control newborn screening bloodspots was used for the GWAS. The replication study interrogated single-nucleotide polymorphisms (SNPs) identified in the discovery GWAS and those within the HumanExome beadchip. RESULTS: Genotyping using genomic DNA was successful. We did not identify SNPs associated with BPD at the genome-wide significance level (5 × 10−8) and no SNP identified in previous studies reached statistical significance (Bonferroni-corrected P value threshold .0018). Pathway analyses were not informative. CONCLUSIONS: We did not identify genomic loci or pathways that account for the previously described heritability for BPD. Potential explanations include causal mutations that are genetic variants and were not assayed or are mapped to many distributed loci, inadequate sample size, race ethnicity of our study population, or case-control differences investigated are not attributable to underlying common genetic variation.

Neurodevelopmental Outcome at 8 Months and 4 Years among Infants Born Full-Term Small-for-Gestational-Age

OBJECTIVES: To examine the association between intrauterine growth restriction and neurodevelopmental outcome among full-term small-for-gestational-age (SGAT) infants at 8 months and 4 years of age.STUDY DESIGN: Growth parameters at birth and test scores on measures of neurodevelopmental function for 3922 children born SGAT were compared with those of 29,369 children born appropriately grown-for-gestational-age term from similar economic backgrounds. Additional within-SGAT/economic group comparisons were made for 1684 SGAT infants with symmetric undergrowth at birth and 2034 SGAT infants with asymmetric undergrowth at birth.RESULTS: Regardless of socioeconomic background, infants born SGAT were found to be at significantly increased risk for neurodevelopmental difficulties at 8 months and at 4 years of age. Few within SGAT/socioeconomic group differences in neurodevelopmental outcome appeared to be associated with specific pattern of growth restriction at birth.CONCLUSIONS: The present findings provide further evidence of the individual and public health impact of SGAT birth.

Triple-marker Prenatal Screening Program for Chromosomal Defects

OBJECTIVE: To examine screening performance of Californias triple-marker screening program, using data from a statewide registry for chromosomal defects. METHODS: This study included 752,686 women who received a screening risk and had an expected date of delivery between July 2005 and the end of June 2007. Follow-up diagnostic services for screen-positive women were performed at state-approved centers. Data on diagnostic outcomes from these visits were entered into the California Chromosomal Defect Registry (CCDR). Other CCDR sources include mandatory reporting by all cytogenetic laboratories and hospitals and outcome data forms submitted by prenatal care providers. RESULTS: The observed detection rate for Down syndrome (N=1,217) was 77.4%. It varied significantly by gestational dating method and maternal age. The rates for women aged younger than 35 years and 35 years and older were 62.4% and 94.0%, respectively. The detection rates were 81.3% for ultrasound-dated pregnancies and 67.5% for last menstrual period–dated pregnancies. For Turner syndrome, trisomy 18, triploidy, and trisomy 13, the detection rates were 79.4%, 82.5%, 98.1%, and 36.0%, respectively. The positive rate for Down syndrome was 5.4%. Of women with a Down syndrome fetus who were screen positive, only 49.5% opted for amniocentesis. Of women who obtained results from amniocentesis indicating a Down syndrome fetus, 61.4% had an elective termination, 26.2% had a live birth, 4.5% had a death or miscarriage, and 7.9% had an unknown outcome. CONCLUSION: The observed performance of this large triple-marker screening program exceeds generally predicted detection rates for Down syndrome. This study methodology will be used to measure the performance of subsequent screening enhancements. LEVEL OF EVIDENCE: III

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.

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.