Abnormalities of placental development and function are associated with the different fetal growth patterns of hypoplastic left heart syndrome and transposition of the great arteries.

BACKGROUND: Birthweight is a critical predictor of congenital heart disease (CHD) surgical outcomes. Hypoplastic left heart syndrome (HLHS) is cyanotic CHD with known fetal growth restriction and placental abnormalities. Transposition of the great arteries (TGA) is cyanotic CHD with normal fetal growth. Comparison of the placenta in these diagnoses may provide insights on the fetal growth abnormality of CHD. METHODS: Clinical data and placental histology from placentas associated with Transposition of the Great Arteries (TGA) were analyzed for gross pathology, morphology, maturity and vascularity and compared to both control and previously analyzed HLHS placentas [1]. RNA was isolated from HLHS, TGA and control placentas and sequenced by Illumina HiSeq.Transcriptome analysis was performed using AltAnalyze. Immunohistochemistry was utilized to assess placental nutrient transporter expression in all three groups. RESULTS: Placental weight was reduced in TGA cases, and demonstrated reduced villous vasculature, immature terminal villi in the parenchyma compared to controls and reflected our previous data from HLHS placentas. However, birth weight was not reduced in TGA cases compared to controls in contrast to the HLHS cohort and birthweight:placental weight ratio was significantly increased in TGA cases but not HLHS compared to control. Transcriptomic and histologic analysis demonstrates reduced cell activity and nutrient transport capability in HLHS but not TGA placentas which appear to increase/maintain these mechanisms. CONCLUSIONS: Despite common vascular disturbances in placentas from HLHAs and TGA, these do not account for the disparities in birthweights frequently seen between these CHD subtypes, in contrast our transcriptomic and histologic analyses reveal differentially regulated mechanisms between the subtypes that may explain these disparities.

Hypoplastic left heart syndrome is associated with structural and vascular placental abnormalities and leptin dysregulation.

INTRODUCTION: Hypoplastic left heart syndrome (HLHS) is a severe cardiovascular malformation (CVM) associated with fetal growth abnormalities. Genetic and environmental factors have been identified that contribute to pathogenesis, but the role of the placenta is unknown. The purpose of this study was to systematically examine the placenta in HLHS with and without growth abnormalities. METHODS: HLHS term singleton births were identified from a larger cohort when placenta tissue was available. Clinical data were collected from maternal and neonatal medical records, including anthropometrics and placental pathology reports. Placental tissues from cases and controls were analyzed to assess parenchymal morphology, vascular architecture and leptin signaling. RESULTS: HLHS cases (n = 16) and gestational age-matched controls (n = 18) were analyzed. Among cases, the average birth weight was 2993 g, including 31% that were small for gestational age. When compared with controls, gross pathology of HLHS cases demonstrated significantly reduced placental weight and increased fibrin deposition, while micropathology showed increased syncytial nuclear aggregates, decreased terminal villi, reduced vasculature and increased leptin expression in syncytiotrophoblast and endothelial cells. DISCUSSION: Placentas from pregnancies complicated by fetal HLHS are characterized by abnormal parenchymal morphology, suggesting immature structure may be due to vascular abnormalities. Increased leptin expression may indicate an attempt to compensate for these vascular abnormalities. Further investigation into the regulation of angiogenesis in the fetus and placenta may elucidate the causes of HLHS and associated growth abnormalities in some cases.

Somatic growth trajectory in the fetus with hypoplastic left heart syndrome.

BACKGROUND: Fetal growth abnormalities in hypoplastic left heart syndrome (HLHS) have been documented primarily by birth measurements. Fetal growth trajectory has not been described. We hypothesized that fetal growth trajectory declines across late gestation in this population. METHODS: Infants with a prenatal diagnosis of HLHS and no history of prematurity or a genetic syndrome were identified. Fetal ultrasound measurements and birth anthropometrics were obtained from clinical records. z-Scores for estimated fetal weight (EFWz) and birth weight (BWTz) were compared. BWTz for three neonatal standards were compared. RESULTS: Paired fetal and neonatal data were identified in 33 cases of HLHS. Mean gestational age at ultrasound and birth were 27 and 38 wk, respectively. BWTz was lower than EFWz by a mean of 0.82 (SD: 0.72, P < 0.0001), with 64% of subjects demonstrating a decrease in z-score of >0.5. Umbilical artery (UA) Doppler found no evidence of significant placental insufficiency. Modest differences in BWTz were seen across BWT standards in this cohort. CONCLUSION: The majority of fetuses with HLHS demonstrate decreased growth velocity during later pregnancy, suggesting growth abnormalities manifest in utero. The potential relationship to future clinical outcomes warrants further study.

Microcephaly is associated with early adverse neurologic outcomes in hypoplastic left heart syndrome.

BACKGROUND: Hypoplastic left heart syndrome (HLHS) is associated with significant mortality and morbidity. Fetal head growth abnormalities have been identified in a subset of HLHS fetuses, but it is unclear whether specific patterns of maladaptive growth affect clinical outcomes. We hypothesized that poor fetal head growth is associated with an increased frequency of adverse clinical outcomes. METHODS: We retrospectively examined a cohort of HLHS patients from midgestation to 1 y of age. Fetal and birth anthropometric measurements were analyzed using the Olsen standard, and clinical outcomes were obtained. RESULTS: A total of 104 HLHS patients were identified over a 12-y period; fetal data were available in 38 cases. HLHS neonates demonstrated a high incidence of microcephaly (12%), small head size (27%), and poor head growth (32%). All-cause mortality was 31% at 30 d and 43% at 1 y. Neurologic outcomes were observed in 12% of patients and were significantly increased with microcephaly (43 vs. 4%; P = 0.02). The average length of hospital stay following stage I palliation was 33.4 ± 33 d, correcting for early death. CONCLUSION: In term nonsyndromic HLHS, fetal and neonatal microcephaly are associated with early adverse neurologic outcomes but not mortality.

Hormonal regulation of prostaglandin E2 receptors: localization and expression in rat cervical tissue.

Prostaglandin E2 (PGE2) may regulate uterine activation and cervical ripening for labor through specific contractile and relaxatory receptors (EP1-4). The aim of this study was to determine the expression of PGE2 receptor isoforms in pregnant rat cervix during RU486-induced labor and progesterone supplementation to delay labor. Localization and expression of cervical PGE2 receptors were evaluated, and quantitative real-time polymerase chain reaction (PCR) for EP1-4 was performed. EP1-4 were found in both cervical epithelium and smooth muscle. RU486 treatment increased EP2 and EP4 messenger RNA (mRNA) and protein expression. Progesterone treatment had no effect on EP2 and EP4 mRNA expression but decreased EP4 protein. Hormonal manipulation resulted in differences in cellular localization of EP1 and EP3 in cervical epithelial cells, suggesting a specific role in that cell. Progesterone differentially regulates the expression of PGE2 receptor isoforms in the cervix. Elucidating the regulation of PGE2 receptors may facilitate improved approaches to the prevention and treatment of preterm labor.

Prenatal head growth and white matter injury in hypoplastic left heart syndrome.

Children with hypoplastic left heart syndrome (HLHS) have an increased prevalence of central nervous system (CNS) abnormalities. The extent to which this problem is due to CNS maldevelopment, prenatal ischemia, postnatal chronic cyanosis and/or multiple exposures to cardiopulmonary bypass is unknown. To better understand the etiology of CNS abnormalities in HLHS, we evaluated 68 neonates with HLHS; in 28 cases, both fetal ultrasound and echocardiogram data were available to assess head size, head growth and aortic valve anatomy (atresia or stenosis). In addition, we evaluated neuropathology in 11 electively aborted HLHS fetuses. The mean head circumference percentile in HLHS neonates was significantly smaller than HLHS fetuses (22 +/- 2% versus 40 +/- 4%, p < 0.001). A significant decrease in head growth, defined as a 50% reduction in head circumference percentile, was observed in half (14/28) of HLHS fetuses and nearly a quarter (6/28) were already growth restricted (

Maternal and perinatal outcome in women with a history of stroke.

OBJECTIVE: The purpose of this study was to determine recurrence risk and pregnancy outcome in 23 women with a history of stroke. STUDY DESIGN: We conducted a descriptive study of 23 women (35 pregnancies) with a history of stroke. Charts were reviewed from 1990 through 2002. The data were analyzed for the antenatal treatment strategies, recurrence risk for stroke, and pregnancy outcome. RESULTS: There were 23 study patients with 35 subsequent pregnancies. Associated risk factors of the stroke were thrombophilia (5 women), sickle cell disease (3 women), maternal cardiac malformations (3 women), hypertension (3 women), oral contraceptive use (2 women), cerebral arteriovenous malformations (2 women), head trauma (1 woman), meningitis (1 woman), endocarditis (1 woman), and idiopathic reason (2 women). Four women with 9 subsequent pregnancies had a stroke that was associated with a previous pregnancy or postpartum incident. Two of these 9 pregnancies received anticoagulation (heparin, 1 pregnancy; heparin plus aspirin, 1 pregnancy). Nineteen women with 26 subsequent pregnancies had a stroke before pregnancy. Nine of these 26 pregnancies received anticoagulation (heparin, 5 pregnancies; aspirin, 3 pregnancies; heparin plus aspirin, 1 pregnancy). The remaining pregnancies did not receive prophylactic anticoagulation. Overall, there were 21 term deliveries, 8 preterm deliveries, 5 miscarriages, and 1 fetal death. Three of 34 pregnancies (9%) were small for gestational age infants. There were no recurrent thrombotic episodes during pregnancy or after delivery. Maternal complications included admission to the intensive care unit for uncontrolled hypertension in 1 patient. CONCLUSION: Women with a history of stroke have a low risk of recurrent stroke (0%). This information is useful for the prepregnancy counseling of such individuals. The need for prophylactic anticoagulation in patients with a previous stroke cannot be answered by this study.