Cell-Free DNA Screening: Complexities and Challenges of Clinical Implementation

Screening for fetal aneuploidy in pregnant women using cell-free DNA has increased dramatically since the technology became commercially available in 2011. Since that time, numerous trials have demonstrated high sensitivity and specificity to screen for common aneuploidies in high-risk populations. Studies assessing the performance of these tests in low-risk populations have also demonstrated improved detection rates compared with traditional, serum-based screening strategies. Concurrent with the increased use of this technology has been a decrease in invasive procedures (amniocentesis and chorionic villus sampling). As the technology becomes more widely understood, available, and utilized, challenges regarding its clinical implementation have become apparent. Some of these challenges include test failures, false-positive and false-negative results, limitations in positive predictive value in low-prevalence populations, and potential maternal health implications of abnormal results. In addition, commercial laboratories are expanding screening beyond common aneuploidies to include microdeletion screening and whole genome screening. This review article is intended to provide the practicing obstetrician with a summary of the complexities of cell-free DNA screening and the challenges of implementing it in the clinical setting

How Low Is Too Low? Postpartum Hemorrhage Risk among Women with Thrombocytopenia

Objective To estimate the association between severity of thrombocytopenia and postpartum hemorrhage. Study Design We performed a secondary analysis of a prospective cohort of women delivering by cesarean or vaginal birth after cesarean conducted by the National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Unit. Women delivering ≥ 20 weeks with platelets < 400,000/mL were included. Thrombocytopenia was defined as predelivery platelets of < 150,000/mL. Primary outcomes were (1) laboratory evidence of hemorrhage, defined as a decrease in hemoglobin ≥ 4 mg/dL and (2) clinical evidence of hemorrhage, a composite of atony, transfusion, coagulopathy, hysterectomy, laparotomy, or intensive care unit admission. Odds ratios were calculated for primary outcomes using thrombocytopenia as a dichotomous and ordinal variable. Results A total of 54,597 women were included; 5,611 (10.3%) had antepartum thrombocytopenia, 1,976 (3.6%) women had laboratory evidence of hemorrhage, and 3,862 (7.1%) had clinical evidence of hemorrhage. Thrombocytopenia was associated with both laboratory evidence of hemorrhage (adjusted odds ratio [aOR]: 1.60, 95% CI: 1.38-1.86) and clinical evidence of hemorrhage (aOR: 1.68, 95% CI: 1.52-1.83). The odds of laboratory and clinical evidence of hemorrhage increased incrementally with severity of thrombocytopenia. Conclusion Thrombocytopenia is associated with both laboratory and clinical evidence of hemorrhage; risk increases dramatically as platelet count decreases

Principles of Anti-infective Dosing in Pregnancy

AbstractPurposeAnti-infectives are among the most commonly prescribed medications in pregnancy. However, detailed information on the pharmacokinetics and pharmacodynamics of these medications in pregnancy is limited, leading to uncertainty among clinicians regarding the tolerability and efficacy of treatments. The purposes of this review were to highlight key physiologic changes during pregnancy that influence drug behavior, and to discuss areas of active research related to anti-infective drugs in pregnancy.MethodsA review of literature in PubMed was performed for topics related to physiologic changes of pregnancy, postcesarean surgical site infections, vaccines in pregnancy, and intrauterine infections. The literature was reviewed and pertinent sources were utilized for this article.FindingsPhysiologic changes during pregnancy may impact drug disposition and efficacy. Cefazolin regimens are the current prophylactic treatment of choice for postcesarean surgical site infections. Vaccines are provided in pregnancy for both maternal and neonatal benefit. Broad-spectrum antibiotics continue to be used as first-line therapy for intrauterine infections.ImplicationsContinued efforts to broaden the knowledge base on anti-infective drug behavior in pregnancy will result in increased therapeutic options for this population

Risk of neonatal and childhood morbidity among preterm infants exposed to marijuana

Background: Limited data exist regarding the neonatal and neurodevelopmental outcomes of infants exposed to marijuana (MJ) in-utero, particularly among preterm infants. We hypothesized that MJ-exposed preterm infants would have worse neonatal and childhood developmental outcomes compared to MJ-unexposed infants. Methods: Secondary analysis of multicenter randomized-controlled trial of antenatal magnesium sulfate for the prevention of cerebral palsy was conducted. Singleton nonanomalous infants delivered <35 weeks exposed to MJ in-utero were compared to MJ-unexposed. Primary neonatal outcome was death, grade 3/4 intraventricular hemorrhage, periventricular leukomalacia, bronchopulmonary dysplasia, and/or stage II/III necrotizing enterocolitis before discharge. Primary childhood outcome was death, moderate/severe cerebral palsy, or/and Bayley II Scales <70 at age 2. Backward-stepwise regression used to estimate odds of primary outcomes. Results: 1867 infants met inclusion criteria; 135(7.2%) were MJ-exposed. There were no differences in neonatal (20% vs. 26%, p = 0.14) or childhood (26% vs. 21%, p = 0.21) outcomes in MJ-exposed infants compared to MJ-unexposed infants. In adjusted models, MJ-exposure was not associated with adverse neonatal outcomes (aOR 0.83 95% CI 0.47,1.44) or early childhood outcomes (aOR 1.47, 95% CI 0.97,2.23). Conclusions: Among infants born <35 weeks of gestation, MJ-exposure was not associated with adverse neonatal or childhood outcomes. Long-term follow-up studies are needed to assess later childhood neurodevelopmental outcomes following MJ-exposure

Birthweight Extremes and Neonatal and Childhood Outcomes after Preterm Premature Rupture of Membranes

Objective To determine the association between birthweight extremes and risk of adverse neonatal and childhood outcomes following preterm premature rupture of membranes (PPROM). Study Design This is a secondary analysis of data from the Beneficial Effects of Antenatal Magnesium Sulfate Trial. Women with nonanomalous singletons and PPROM delivering ≥24.0 weeks were included. Birthweight was classified as small for gestational age (SGA), appropriate for gestational age (AGA), or large for gestational age (LGA). Composite severe neonatal morbidity and childhood outcomes at age 2, were compared between these groups. Results One thousand five hundred and ninety-eight infants were included (58 SGA, 1,354 AGA, and 186 LGA). There was an inverse relationship between birthweight and rate of composite major neonatal morbidity (55.2% of SGA, 31.5% of AGA, 18.3% of LGA, p < 0.001). Former-SGA children were more likely to be diagnosed with major composite childhood morbidity at age 2 (25.9% of SGA, 8.3% of AGA, 5.9% of LGA, p < 0.001). In multivariate models, LGA infants had improved initial neonatal outcomes compared with AGA infants (adjusted odds ratio [aOR], 0.44; 95% confidence interval [CI], 0.28-0.71; p = 0.001). Conclusion Among infants delivered following PPROM, those who were LGA at delivery had improved composite adverse neonatal outcomes. SGA increases the risk of severe neonatal morbidity, early childhood death, and moderate/severe cerebral palsy at age 2

Factors Associated with Previable Delivery following Second Trimester Rupture of Membranes

Objective To identify factors associated with previable delivery in second trimester preterm rupture of membranes (PROM). Study Design We conducted a single-center retrospective cohort study of women with pregnancies complicated by second trimester PROM (14.0-21.9 weeks' gestation) from 2000 to 2015 who elected expectant pregnancy management and achieved at least 24 hours latency. Maternal characteristics and clinical factors were compared among pregnancies that reached viability (≥ 23.0 weeks) and pregnancies delivered before viability ( 1cm, Group B streptococcus carrier status, bacterial vaginosis, and chlamydial infection during pregnancy were similar between groups. Median time to delivery was significantly shorter in women who delivered < 23 weeks compared with those who reached ≥ 23 weeks (6 vs. 46 days, p < 0.01). Conclusion Previable delivery occurred in the majority of women with second trimester PROM. No maternal or clinical factors were associated with delivery prior to viability. Counseling women with second trimester PROM should include the inability to determine which pregnancies will reach viability

Maternal super obesity and neonatal morbidity after term cesarean delivery

Objective To estimate the association between maternal super obesity (body mass index [BMI] ≥ 50 kg/m2) and neonatal morbidity among neonates born via cesarean delivery (CD). Methods Retrospective cohort of singleton neonates delivered via CD ≥ 37 weeks in the Maternal-Fetal Medicine Unit Cesarean Registry. Maternal BMI at delivery was stratified as 18.5 to 29.9 kg/m2, 30 to 39.9 kg/m2, 40 to 49.9 kg/m2, and ≥ 50 kg/m2. Primary outcomes included acute (5-minute Apgar score &lt; 5, cardiopulmonary resuscitation and ventilator support &lt; 24 hours, neonatal injury, and/or transient tachypnea of the newborn) and severe (grade 3 or 4 intraventricular hemorrhage, necrotizing enterocolitis, seizure, respiratory distress syndrome, hypoxic ischemic encephalopathy, meconium aspiration, ventilator support ≥ 2 days, sepsis and/or neonatal death) neonatal morbidity. Odds of neonatal morbidity were estimated for each BMI category adjusting for clinical and operative characteristics. Results Of 41,262 maternal-neonatal dyads, 36% of women were nonobese, 49% had BMI of 30 to 39.9 kg/m2, 12% had BMI of 40 to 49.9 kg/m2, and 3% were super obese. Compared with nonobese women, super obese women had twofold odds of acute (5 vs. 10%; adjusted odds ratio [aOR]: 1.81, 95% confidence interval [CI]: 1.59-2.73) and severe (3 vs. 6%; aOR: 2.08; 95% CI: 1.59-2.73) neonatal morbidity. Conclusion Among term infants delivered via CD, maternal super obesity is associated with increased risk of neonatal morbidity

Gestational age at initiation of 17-alpha hydroxyprogesterone caproate and recurrent preterm birth

Background Preterm birth is the leading cause of neonatal morbidity and mortality in nonanomalous neonates in the United States. Women with a previous early spontaneous preterm birth are at highest risk for recurrence. Weekly intramuscular 17-alpha hydroxyprogesterone caproate reduces the risk of recurrent prematurity. Although current guidelines recommend 17-alpha hydroxyprogesterone caproate initiation between 16 and 20 weeks, in clinical practice, 17-alpha hydroxyprogesterone caproate is started across a spectrum of gestational ages. Objective The objective of the study was to examine the relationship between the gestational age at 17-alpha hydroxyprogesterone caproate initiation and recurrent preterm birth among women with a prior spontaneous preterm birth 16–28 weeks’ gestation. Study Design This was a retrospective cohort study of women from a single tertiary care center, 2005–2016. All women with ≥1 singleton preterm births because of a spontaneous onset of contractions, preterm prelabor rupture of membranes, or painless cervical dilation between 16 and 28 weeks followed by a subsequent singleton pregnancy treated with 17-alpha hydroxyprogesterone caproate were included. Women were grouped based on quartiles of gestational age of 17-alpha hydroxyprogesterone caproate initiation (quartile 1, 140/7 to 161/7; quartile 2, 162/7 to 170/7; quartile 3, 171/7 to 186/7; and quartile 4, 190/7 to 275/7). Women with a gestational age of 17-alpha hydroxyprogesterone caproate initiation in quartiles 1 and 2 were considered to have early-start 17-alpha hydroxyprogesterone caproate; those in quartiles 3 and 4 were considered to have late-start 17-alpha hydroxyprogesterone caproate. The primary outcome was recurrent preterm birth &lt;37 weeks’ gestation. Secondary outcomes included recurrent preterm birth &lt;34 and &lt;28 weeks’ gestation and composite major neonatal morbidity (diagnosis of grade III or IV intraventricular hemorrhage, periventricular leukomalacia, bronchopulmonary dysplasia, necrotizing enterocolitis stage II or III, or death). Gestational age at delivery was compared by quartile of 17-alpha hydroxyprogesterone caproate initiation using Kaplan-Meier survival curves and the log-rank test. Logistic regression models estimated odds ratios for the association between gestational age at 17-alpha hydroxyprogesterone caproate initiation and preterm birth &lt;37 weeks’ gestation, adjusting for demographics, prior pregnancy and antenatal characteristics. Results A total of 132 women met inclusion criteria; 52 (39.6%) experienced recurrent preterm birth &lt;37 weeks in the studied pregnancy. 17-Alpha hydroxyprogesterone caproate was initiated at a mean 176/7 ± 2.5 weeks. Demographic and baseline characteristics were similar between women with early-start 17-alpha hydroxyprogesterone caproate (quartiles 1 and 2) compared with those with late-start 17-alpha hydroxyprogesterone caproate (quartiles 3 and 4). Women with early-start 17-alpha hydroxyprogesterone caproate trended toward lower rates of recurrent preterm birth &lt;37 weeks compared with those with late-start 17-alpha hydroxyprogesterone caproate (41.3% vs 57.7%, P =.065). Delivery gestational age was inversely proportional to gestational age at 17-alpha hydroxyprogesterone caproate initiation (quartile 1, 374/7 weeks vs quartile 2, 365/7 vs quartile 3, 361/7 weeks vs quartile 4, 340/7, P =.007). In Kaplan-Meier survival analyses, these differences in delivery gestational age by 17-alpha hydroxyprogesterone caproate initiation quartile persisted across pregnancy (log-rank P &lt;.001). In regression models, later initiation of 17-alpha hydroxyprogesterone caproate was significantly associated with increased odds of preterm birth &lt;37 weeks. Women with early 17-alpha hydroxyprogesterone caproate initiation also had lower rates of major neonatal morbidity than those with later 17-alpha hydroxyprogesterone caproate initiation (1.5% vs 14.3%, P =.005). Conclusion Rates of recurrent preterm birth among women with a prior spontaneous preterm birth 16–28 weeks are high. Women beginning 17-alpha hydroxyprogesterone caproate early deliver later and have improved neonatal outcomes. Clinicians should make every effort to facilitate 17-alpha hydroxyprogesterone caproate initiation at 16 weeks