Matthew J. Garabedian

Uptake of noninvasive prenatal testing (NIPT) in women following positive aneuploidy screening

The aim of this study was to investigate how the introduction of noninvasive prenatal testing (NIPT) impacted womens testing choices following a positive prenatal screening (PNS) result.

Body mass index and operative times at cesarean delivery.

OBJECTIVE: To examine the relationship between body mass index (BMI, kg/m2) and incision-to-delivery interval and total operative time at cesarean delivery. METHODS: Women with singleton gestations undergoing uncomplicated primary and repeat cesarean deliveries were identified from the Maternal-Fetal Medicine Units Network Cesarean Registry. Women were classified by BMI category at time of delivery (normal 18.5–24.9, overweight 25.0–29.9, obese 30.0–39.9, and morbidly obese 40 or greater). Incision-to-delivery interval and total operative times during cesarean delivery were compared among the three groups. Primary outcome was prolonged incision-to-delivery interval as defined by 90th percentile or greater of the study population or 18 minutes or longer. RESULTS: Of the 21,372 women included in the analysis, 9,928 were obese (46.5%) and 2,988 (14.0%) were morbidly obese. Longer operative times were found among women with overweight (median [interquartile range] incision-to-delivery: 9.0 [6.0] and total operative time: 45.0 [21.0] minutes), obese (10.0 [7.0]; 48.0 [22.0] minutes), and morbidly obese BMIs (12.0 [8.0]; 55.0 [26.0] minutes) compared with women with normal BMI at delivery (9.0 [5.0]; 43.0 [20.0] minutes) (P<.001). Morbidly obese women had a more frequent incision-to-delivery interval that was 18 minutes or longer (n=602 [20%] compared with 127 [6%] in normal BMI). After adjustments including number of prior cesarean deliveries, incision-to-delivery interval 18 minutes or longer was significantly related to obese (odds ratio [OR] 1.62, 95% confidence interval [CI] 1.31–2.03) and morbidly obese (OR 2.81, 95% CI 2.24–3.56) BMI at delivery. CONCLUSION: Increasing BMI is related to increased incision-to-delivery interval and total operative time at cesarean delivery with morbidly obese BMI exposing women to the highest risk of prolonged incision-to-delivery interval. LEVEL OF EVIDENCE: II

Prenatal Diagnosis of Cystic Hygroma related to a Deletion of 16q24.1 with Haploinsufficiency of FOXF1 and FOXC2 Genes

We report the prenatal diagnosis of cystic hygroma that was subsequently identified to have haploinsufficiency of the FOXF1 and FOXC2 genes via array comparative genomic hybridization (aCGH). Deletion o f these genes has previously neither been associated with cystic hygroma nor prenatally diagnosed. The FOX gene cluster is involved in cardiopulmonary development. This case expands the phenotypic spectrum o f abnormalities of the FOXF1 and FOXC2 genes, as it seems within the spectrum of function that disruption of the FOX gene cluster would lead to include abnormalities of prenatal onset. Identification of this association would not be possible with conventional karyotype or targeted aCGH. This case highlights the power of whole genomic aCGH to further delineate the etiology of birth defects.

Maternal proteinuria in twin compared with singleton pregnancies.

OBJECTIVE: To compare 24-hour urinary protein excretion in twin and singleton pregnancies not complicated by hypertension. METHODS: We prospectively evaluated mean 24-hour urinary protein excretion in twin and singleton pregnancies between 24 0/7 weeks and 36 0/7 weeks of gestation. Women with urinary tract infections, chronic hypertension, pregestational diabetes, and renal or autoimmune diseases were excluded. Collection adequacy was assessed by urinary creatinine excretion adjusted for maternal weight. RESULTS: Adequate samples were obtained from 50 twin and 49 singleton pregnancies at a mean gestational age of 30 weeks. At collection, the two groups were similar with regard to maternal age, gestational age, body mass index, and blood pressure. Mean urinary protein excretion was higher in twin compared with singleton pregnancies (269.3±124.1 mg compared with 204.3±92.5 mg, P=.004). Proteinuria (300 mg/day protein or greater) occurred in 38.0% (n=19) of twin and 8.2% (n=4) of singleton pregnancies (P<.001). After adjusting for confounding variables, the difference in mean total protein excretion remained significant (P=.004) and twins were more likely to have proteinuria compared with singleton pregnancies (adjusted odds ratio 9.1, 95% confidence interval 2.1–38.5). Nineteen participants developed a hypertensive disorder at a mean of 7.7 weeks after the urine collection (range 2.6–14.5 weeks). After excluding these women, proteinuria was present in 43% of twin and 7% of singleton pregnancies (P<.001). CONCLUSION: Mean 24-hour urinary protein excretion in twin pregnancies is greater than in singletons. These data suggest a reevaluation of the diagnostic criteria for preeclampsia in twin pregnancies. LEVEL OF EVIDENCE: II

A new model for providing cell-free DNA and risk assessment for chromosome abnormalities in a public hospital setting.

Objective. Cell-free DNA (cfDNA) offers highly accurate noninvasive screening for Down syndrome. Incorporating it into routine care is complicated. We present our experience implementing a novel program for cfDNA screening, emphasizing patient education, genetic counseling, and resource management. Study Design. Beginning in January 2013, we initiated a new patient care model in which high-risk patients for aneuploidy received genetic counseling at 12 weeks of gestation. Patients were presented with four pathways for aneuploidy risk assessment and diagnosis: (1) cfDNA; (2) integrated screening; (3) direct-to-invasive testing (chorionic villus sampling or amniocentesis); or (4) no first trimester diagnostic testing/screening. Patients underwent follow-up genetic counseling and detailed ultrasound at 18–20 weeks to review first trimester testing and finalize decision for amniocentesis. Results. Counseling and second trimester detailed ultrasound were provided to 163 women. Most selected cfDNA screening (69%) over integrated screening (0.6%), direct-to-invasive testing (14.1%), or no screening (16.6%). Amniocentesis rates decreased following implementation of cfDNA screening (19.0% versus 13.0%, P < 0.05). Conclusion. When counseled about screening options, women often chose cfDNA over integrated screening. This program is a model for patient-directed, efficient delivery of a newly available high-level technology in a public health setting. Genetic counseling is an integral part of patient education and determination of plan of care.

Risk factors for classical hysterotomy by gestational age.

OBJECTIVE: To examine the likelihood of classical hysterotomy across preterm gestational ages and to identify factors that increase its occurrence. METHODS: This is a secondary analysis of a prospective observational cohort collected by the Maternal-Fetal Medicine Network of all women with singleton gestations who underwent a cesarean delivery with a known hysterotomy. Comparisons were made based on gestational age. Factors thought to influence hysterotomy type were studied, including maternal age, body mass index, parity, birth weight, small for gestational age (SGA) status, fetal presentation, labor preceding delivery, and emergent delivery. RESULTS: Approximately 36,000 women were eligible for analysis, of whom 34,454 (95.7%) underwent low transverse hysterotomy and 1,562 (4.3%) underwent classical hysterotomy. The median gestational age of women undergoing a classical hysterotomy was 32 weeks and the incidence peaked between 24 0/7 weeks and 25 6/7 weeks (53.2%), declining with each additional week of gestation thereafter (P for trend <.001). In multivariable regression, the likelihood of classical hysterotomy was increased with SGA (n=258; odds ratio [OR] 2.71; confidence interval [CI] 1.78–4.13), birth weight 1,000 g or less (n=467; OR 1.51; CI 1.03–2.24), and noncephalic presentation (n=783; OR 2.03; CI 1.52–2.72). The likelihood of classical hysterotomy was decreased between 23 0/7 and 27 6/7 weeks of gestation and after 32 weeks of gestation when labor preceded delivery, and increased between 28 0/7 and 31 6/7 weeks of gestation and after 32 weeks of gestation by multiparity and previous cesarean delivery. Emergent delivery did not predict classical hysterotomy. CONCLUSIONS: Fifty percent of women at 23–26 weeks of gestation who undergo cesarean delivery have a classical hysterotomy, and the risk declines steadily thereafter. This likelihood is increased by fetal factors, especially SGA and noncephalic presentation. LEVEL OF EVIDENCE: II

Current knowledge of prenatal diagnosis of mosaic autosomal trisomy in amniocytes: karyotype/phenotype correlations

Genetic counseling for prenatal diagnosis of autosomal trisomy is complex because of the uncertainty of outcome, which is important for management decisions. Compilation of cases of prenatally diagnosed autosomal trisomies in amniocytes has been done previously in an attempt to elucidate the clinical phenotype of these pregnancies. It has been greater than a decade since these studies were completed. To update this work, we reviewed cases reported in the literature since that time. These cases are correlated with the prior reports to increase knowledge about outcomes and to hopefully improve the data available for genetic counseling. The risk of abnormal outcome can be summarized as: very high risk (>60%) for 47,+2/46; 47,+9/46; 47,+16/46; 47,+20/46; and 47,+22/46; high risk (40–59%) for 47,+5/46; 47,+14/46; and 47,+15/46; moderately high risk (20–39%) for 47,+7/46 47,+12/46; and 47,+17/46; moderate risk (up to 19%) for 47,+6/46 and 47,+8/46, and none were low risk. 47,+6/46 was originally indeterminate, 47,+7/46 was originally moderate risk, 47,+9/46 was originally high risk, and 47,+17/46 was originally low risk.

Antenatal detection of maternal unipartental disomy of chromosome 2 in a fetus with non‐chromosomal, non‐syndromic alobar holoprosencephaly

Holoprosencephaly (HPE) refers to a group of disorders caused by incomplete division of the forebrain with awide range of associated phenotypes [Solomon et al., 2010]. It is themost common forebrain anomaly with a prevalence of 1:250 in embryos and 1:10,000 in liveborn infants [Bous et al., 2012]. Fetal development of HPE may be caused by genetic and teratogenic phenomena [Cohen and Shiota, 2002; Solomon et al., 2010], by aneuploidy (e.g., trisomy 13), or by other genetic syndromes with autosomal recessive, autosomal dominant, or X-linked mutations [Solomon et al., 2000; Cohen and Shiota, 2002]. Diabetes mellitus is a teratogenic risk factor for HPE [Solomon et al., 2000; Cohen and Shiota, 2002]. Mutations in 12 genes are known to cause apparently non-syndromic HPE [Solomon et al., 2010; Bous et al., 2012]. Mutations of four genes, SHH, ZIC2, SIX3, and TGIF, account for most non-chromosomal, non-syndromic HPE [Solomon et al., 2010]. This 24-year-old primigravidwomanpresented for prenatal care in her first trimester. Anatomic screening, performed at 18 6/7 weeks, showed the fetus to have hydrocephalus, alobar holoprosencephaly (HPE), mid-face hypoplasia with bilateral cleft lip and palate, a proboscis, a cervical meningocele, and post-axial polydactyly in the fetal feet (Fig. 1). The family history was unremarkable, and no known environmental or teratogenic exposures were identified. Her hemoglobin A1C was 4.8, suggesting a low likelihood of diabetes mellitus. An amniocentesis was performed and amniotic fluid was tested for karyotype, alpha fetoprotein, and single nucleotide polymorphism (SNP) chromosomal microarray (CMA). The karyotype was 46,XY. CMA showed evidence of isodisomy of chromosome 2 (UPD2) as (arr 2p25.3q37.3 (12, 771–243, 783, 384) 2 hmz). No deletions, mosaicism, or supernumerary chromosomes were noted. Ultrasonography was performed again at 21 4/7 weeks at the patient’s request and the above findings were confirmed. The patient was counseled about her options for continuation and termination of the pregnancy and she opted for termination by dilation and evacuation (D&E), which was performed at 22 weeks gestation. Counseling included that a D&E would preclude the

Pregnancy outcome in a woman with prune belly syndrome

Prune belly syndrome is a rare congenital syndrome that primarily affects male fetuses. Affected men are universally infertile; however, there is a paucity of information published on the reproductive potential of affected women. Pregnancy outcomes in affected women have not been described in the literature. We describe the case of pregnancy in an affected woman. Her pregnancy progressed without complication. Her fetus had no stigmata of the syndrome. Her labour and delivery were, however, complicated by a prolonged second stage of labour and need for vacuum-assisted vaginal delivery.

Maternal Safety Evaluation Following Implementation of Universal Delayed Cord Clamping [4R]

INTRODUCTION: In the term infant, there is evidence of delayed cord clamping (DCC) resulting in decreased anemia and improved cardiopulmonary adaptation. Despite the benefits, there are concerns regarding maternal safety, especially postpartum hemorrhage. This study evaluated the maternal safety outcomes following the departmental wide implementation of DCC. METHODS: A retrospective chart review was conducted of infants delivering between gestational age 34+0 weeks to 42+6 weeks. Outcomes were evaluated between the DCC and Immediate cord clamping (ICC) groups. Primary outcomes included estimated maternal blood loss (EBL) and hematocrit (Hct) decline following delivery. RESULTS: Of 817 deliveries, 763 (93%) underwent DCC. EBL for ICC group was 950 mL vs 300 mL in DCC group (<0.01 U); Hct decline was 6.2 vs 4.2 respectively (<0.01 t). 53% of the deliveries for the ICC were cesareans, while only 27% for the DCC. After controlling for mode of delivery, EBL in the vaginal delivery ICC group was 300 mL vs 300 mL in the DCC (P=.38); Hct decline was 3.1 and 3.7 (P=.76). In those undergoing cesareans, ICC EBL was 900 mL vs 1,000 mL (P=.93) for DCC; Hct decline 5.1 and 5.2 (0.92%). No blood transfusions in the vaginal delivery group. For those undergoing cesareans one (3.5%) transfusion was provided in the ICC group and 2 (1%) (P=.33) in the DCC group. CONCLUSION: Once controlling for mode of delivery there was no difference in primary maternal safety measures between the two groups. It is encouraged for Obstetricians to consider implementing universal DCC for all infants.