Risk of pre-eclampsia in patients with a maternal genetic predisposition to common medical conditions: a case-control study.

OBJECTIVE: To assess whether women with a genetic predisposition to medical conditions known to increase pre-eclampsia risk have an increased risk of pre-eclampsia in pregnancy. DESIGN: Case-control study. SETTING AND POPULATION: Pre-eclampsia cases (n = 498) and controls (n = 1864) in women of European ancestry from five US sites genotyped on a cardiovascular gene-centric array. METHODS: Significant single-nucleotide polymorphisms (SNPs) from 21 traits in seven disease categories (cardiovascular, inflammatory/autoimmune, insulin resistance, liver, obesity, renal and thrombophilia) with published genome-wide association studies (GWAS) were used to create a genetic instrument for each trait. Multivariable logistic regression was used to test the association of each continuous scaled genetic instrument with pre-eclampsia. Odds of pre-eclampsia were compared across quartiles of the genetic instrument and evaluated for significance. MAIN OUTCOME MEASURES: Genetic predisposition to medical conditions and relationship with pre-eclampsia. RESULTS: An increasing burden of risk alleles for elevated diastolic blood pressure (DBP) and increased body mass index (BMI) were associated with an increased risk of pre-eclampsia (DBP, overall OR 1.11, 95% CI 1.01-1.21, P = 0.025; BMI, OR 1.10, 95% CI 1.00-1.20, P = 0.042), whereas alleles associated with elevated alkaline phosphatase (ALP) were protective (OR 0.89, 95% CI 0.82-0.97, P = 0.008), driven primarily by pleiotropic effects of variants in the FADS gene region. The effect of DBP genetic loci was even greater in early-onset pre-eclampsia cases (at <34 weeks of gestation, OR 1.30, 95% CI 1.08-1.56, P = 0.005). For other traits, there was no evidence of an association. CONCLUSIONS: These results suggest that the underlying genetic architecture of pre-eclampsia may be shared with other disorders, specifically hypertension and obesity. TWEETABLE ABSTRACT: A genetic predisposition to increased diastolic blood pressure and obesity increases the risk of pre-eclampsia.

Mid-trimester amniotic fluid pro-inflammatory biomarkers predict the risk of spontaneous preterm delivery in twins: a retrospective cohort study.

OBJECTIVE: To evaluate the association between the concentrations of immune-related proteins in mid-trimester amniotic fluid (AF) and the subsequent risk of spontaneous preterm delivery in twins. STUDY DESIGN: The study population consisted of consecutive women with a twin pregnancy who underwent clinically indicated genetic amniocentesis at 15 to 20 weeks, and had a subsequent spontaneous delivery in the early preterm period (<32 weeks (cases)) or at term (37 to 42 weeks (controls)). AF was analyzed for cytokines (interleukin (IL)-1ß, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13 and IL-15, interferon-γ, tumor necrosis factor-α), matrix metalloproteinases (MMP-1, MMP-2, MMP-3, MMP-8, MMP-9 and MMP-12), and chemokines (complement factor-D/Adipsin, Serpin E1/PAI-1, Adiponectin/Acrp30, C-Reactive Protein, CCL2/MCP-1, Leptin, Resistin) using multiplex immunoassay kits. The association between AF protein levels and subsequent early preterm birth were examined. RESULT: A total of 96 sets of twins were enrolled, including 17 early preterm birth cases and 79 term controls. AF concentrations of IL-6, IL-8, MMP-3, MMP-8 and MMP-9, and CCL2/MCP-1 were significantly higher in cases than controls. Among these analytes, the combination of AF IL-8 and MMP-9 values had the highest predictive value for early preterm birth. The risk was 8% (10/132) for IL-8<1200 pg ml(-1) and MMP-9<1000 pg ml(-1), 30% (15/50) for IL-8>1200 pg ml(-1) or MMP-9>1000 pg ml(-1), and 90% (9/10) for IL-8>1200 pg ml(-1) and MMP-9>1000 pg ml(-1) (P<0.001). CONCLUSION: High concentrations of IL-8 and MMP-9 in mid-trimester AF in twins predicted well the risk of early preterm birth.

Single- and double-stranded viral RNA generate distinct cytokine and antiviral responses in human fetal membranes.

There has been growing interest in the role of viral infections and their association with adverse pregnancy outcomes. However, little is known about the impact viral infections have on the fetal membranes (FM). Toll-like receptors (TLR) are thought to play a role in infection-associated inflammation at the maternal-fetal interface. Therefore, the objective of this study was to characterize the cytokine profile and antiviral response in human FMs exposed to viral dsRNA, which activates TLR3, and viral ssRNA, which activates TLR8; and to determine the mechanisms involved. The viral dsRNA analog, Poly(I:C), induced up-regulated secretion of MIP-1α, MIP-1ß, RANTES and TNF-α, and down-regulated interleukin (IL)-2 and VEGF secretion. In contrast, viral ssRNA induced a broader panel of cytokines in the FMs by up-regulating the secretion of IL-1ß, IL-2, IL-6, G-CSF, MCP-1, MIP-1α, MIP-1ß, RANTES, TNF-α and GRO-α. Using inhibitory peptides against TLR adapter proteins, FM secretion of MIP-1ß and RANTES in response to Poly(I:C) was MyD88 dependent; MIP-1α secretion was dependent on MyD88 and TRIF; and TNF-α production was independent of MyD88 and TRIF. Viral ssRNA-induced FM secretion of IL-1ß, IL-2, IL-6, G-CSF, MIP-1α, RANTES and GRO-α was dependent on MyD88 and TRIF; MIP-1ß was dependent upon TRIF, but not MyD88; and TNF-α and MCP-1 secretion was dependent on neither. Poly(I:C), but not ssRNA, induced an FM antiviral response by up-regulating the expression of IFNß, myxovirus-resistance A, 2',5'-oligoadenylate synthetase and apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3G. These findings demonstrate that human FMs respond to two viral signatures by generating distinct inflammatory cytokine/chemokine profiles and antiviral responses through different mechanisms.

Prenatal diagnosis of criss-cross heart: sonographical and pathological features of five cases.

OBJECTIVE: To describe the sonographical and pathological features of fetal criss-cross heart (CCH). STUDY DESIGN: All cases of fetal CCH diagnosed by fetal echocardiogram from May 2003-May 2011 were identified at a single referral center using an established perinatal database. Demographic and genetic information, sonographical images and autopsy reports were reviewed. Sonographical and pathological features are described. RESULT: Five cases of fetal CCH were identified, all of which were confirmed by autopsy. Characteristic sonographical findings include: (1) the inability to obtain four-chamber view at standard transverse plane through the fetal chest; (2) appreciation of the misaligned spatial atrial-ventricle connection with the interventricular septum in a 'spiraling' orientation; (3) orientation of the two ventricular inlets in a superior-inferior and crossing position; and (4) a four-chamber-like view seen in the sagittal plane of the fetal chest. Doppler ultrasound demonstrates the 'criss-cross' arrangement of the inflow tracts into the two ventricles simultaneously in the transverse plane of the fetal chest. CONCLUSION: CCH is a rare developmental disorder that can be accurately diagnosed prenatally. Early diagnosis will allow for more targeted counseling and early intervention.

Admission uric acid levels and length of expectant management in preterm preeclampsia.

OBJECTIVE: Uric acid is known to be elevated in preeclampsia. We sought to determine if uric acid levels on admission correlate with the length of expectant management in preterm patients with preeclampsia. STUDY DESIGN: A retrospective chart review was conducted on singleton preeclamptic pregnancies delivered between 24 0/7 and 37 0/7 weeks' gestation at Tufts Medical Center between January 2005 and December 2007. Patients with a multiple gestation and those transferred or discharged before delivery were excluded. Data regarding signs and symptoms of preeclampsia, laboratory values, pregnancy complications and outcome were abstracted from the medical records. Correlation between admission uric acid level and days of expectant management was assessed. The relative risk (RR) was used to estimate the effect of uric acid levels on expectant management length >7 days. Mantel-Haenszel χ(2) values were used to construct 95% confidence intervals (CIs) around the RR. RESULT: Four hundred seventy-one charts were reviewed. Of these, 190 met inclusion criteria. In all, 55 patients (28.9%) were managed expectantly for >1 week. Admission uric acid level correlated with days of expectant management (P<0.0001). Uric acid levels at admission were categorized as ≤4.0 mg dl(-1) (low uric acid level), 4.1 to 6.0 mg dl(-1) (medium) and ≥6.1 mg dl(-1) (high). Relative to women with high uric acid levels at admission, we observed a sevenfold higher rate of extending expectant management for >1 week among women with low uric acid level (7.0; 95% CI: 3.34 to 14.68). Women with medium uric acid levels at admission also had a higher likelihood of prolonging pregnancy relative to women with high uric acid levels (RR: 2.81; 95% CI: 1.32 to 5.96) (P-value for trend <0.0001). CONCLUSION: Admission uric acid levels correlate with the length of expectant management in preterm patients with preeclampsia. Pregnancy prolongation for >1 week is significantly more likely in patients with low and medium uric acid levels at the time of admission. Uric acid levels may be helpful in assessing disease severity and counseling preeclamptic patients regarding likelihood of extended expectant management.

Expression of extracellular signal-regulated kinase1/2 and p38 mitogen-activated protein kinase in the invasive trophoblasts at the human placental bed.

BACKGROUND: Mitogen-activated protein kinases (MAP kinases) participate in signal transduction pathways that control embryogenesis, cell differentiation, cell proliferation and cell death. The roles of extracellular signal-regulated kinase1/2 (ERK1/2) and p38 MAP kinase in the differentiation and invasion of human trophoblasts have been studied. However, the in vivo expression and activation of ERK1/2 and p38 at the placental bed have not been elucidated. METHODS: The study group consisted of placental bed biopsy tissues obtained from the pregnancies without preeclampsia (n=24) and with preeclampsia (n=8) between 31 and 40 weeks of gestation. We evaluated the expressions and phosphorylations of ERK1/2 and p38 MAP kinase in the invasive trophoblasts in the placental bed tissues using immunohistochemistry. RESULTS: p38 and phospho-p38 MAP kinase were not detected in invasive trophoblasts in cases or controls. ERK1/2 and phospho-ERK1/2 were positive in invasive trophoblasts albeit with variable staining. Phosphorylation of ERK1/2 was significantly less frequent in invasive trophoblasts in placental bed biopsies from women with preeclampsia compared with normotensive controls. CONCLUSION: These findings suggest that preeclampsia is associated with decreased activation of ERK1/2 in invasive trophoblasts in vivo.

Placental growth factor in the cerebrospinal fluid of women with preeclampsia.

OBJECTIVE: Recent data suggest that excess circulating soluble fms-like tyrosine kinase-1 (sFlt-1) may causally relate to preeclampsia. This study investigates the levels of sFlt-1, VEGF, and PlGF in cerebrospinal fluid (CSF) of patients with preeclampsia and normotensive controls. METHODS: CSF was collected from preeclamptic patients (n=15) and controls (n=7) at the time of spinal anesthesia and assayed for PlGF, sFlt-1, and VEGF (total and free) by specific immunoassays. RESULTS: All sought angiogenic factors were measurable. Levels of free PlGF but not sFlt-1 or VEGF (total or free) were increased in CSF of preeclamptic women. There was no significant difference in the ratios of angiogenic factors in the CSF of women with preeclampsia. There was no correlation between levels of angiogenic factors and CSF cell counts or severity of symptoms. CONCLUSION: Elevated levels of PlGF in CSF preeclamptic women may promote vascular permeability and contribute to the hypertensive encephalopathy seen in such patients.

Role of cytokines in preterm labor and birth.

Preterm birth (defined as delivery prior to 37 weeks' gestation) complicates 5-10% of all births. It is a major cause of perinatal mortality and morbidity. Approximately 20% of all preterm births are iatrogenic resulting from obstetric intervention for maternal and/or fetal indications. Of the remainder, 2/3 are spontaneous preterm labor with or without preterm premature rupture of the membranes (pPROM). Preterm labor is a syndrome rather than a diagnosis since the etiologies are varied. Risk factors include, among others, pPROM, cervical insufficiency, pathologic uterine distention (polyhydramnios, multiple gestation), uterine anomalies, intrauterine infection/inflammation, and social factors (stress, smoking, heavy work). The final common pathway appears to be activation of the inflammatory cascade. Bacterial colonization and/or inflammation of the choriodecidual interface induces production of pro-inflammatory cytokines that, in turn, lead to neutrophil activation and the synthesis and release of uterotonins such as prostaglandins (which cause uterine contractions) and metalloproteinases (that weaken fetal membranes and remodel cervical collagen). This monograph reviews the role of cytokines in the pathophysiology of preterm labor and delivery.

Prenatal diagnosis of pyruvate dehydrogenase deficiency using magnetic resonance imaging.

INTRODUCTION: Pyruvate dehydrogenase deficiency is an inherited inborn error of metabolism associated with early neonatal death and long-term neurologic sequelae in survivors. Prenatal diagnosis currently relies on isolation of fetal cells for subsequent genetic and/or biochemical studies. Magnetic resonance imaging and magnetic resonance spectroscopy have been used on occasion for both postnatal diagnosis and management of pyruvate dehydrogenase deficiency. We illustrate a case in which these non-invasive modalities also prove useful for prenatal diagnosis of this condition. CASE: A 31-year-old multipara with a history of two prior infants affected with pyruvate dehydrogenase deficiency presented with a spontaneous dichorionic, diamniotic twin pregnancy. Magnetic resonance imaging and magnetic resonance spectroscopy were performed on both fetuses. Magnetic resonance imaging of the presenting (male) fetus demonstrated mild ventriculomegaly, increased extracerebrospinal fluid, and decreased cortical sulcation and gyration. The non-presenting (female) fetus was structurally normal. Magnetic resonance spectroscopy spectra were obtained for both fetuses, and were normal. The diagnosis of pyruvate dehydrogenase deficiency was made in the presenting fetus after delivery on the basis of subsequent mortality from severe lactic acidosis. CONCLUSION: Prenatal MR imaging of the fetal brain can be used for prenatal diagnosis in fetuses at risk for pyruvate dehydrogenase deficiency. Prenatal MR spectroscopy, although technically feasible, does not appear to have a role in the prenatal diagnosis of this condition.

Placenta percreta and uterine rupture associated with prior whole body radiation therapy.

BACKGROUND: Injury to reproductive organs including the uterus is a known complication of ionizing radiation, but the risks to the mother and fetus during subsequent pregnancies are not well defined. CASE: A young woman with a remote history of whole body irradiation for childhood leukemia had uterine rupture at 17 weeks' gestation. Pathologic examination of the supracervical hysterectomy specimen revealed a posterior-fundal placenta percreta with a diffusely thinned myometrium (1-6 mm). The clinicopathologic findings were consistent with prior radiation injury. CONCLUSION: Uterine irradiation may predispose to abnormal placentation and uterine rupture in a subsequent pregnancy.

The epidemiology of preterm labor.

There are many factors that are associated with preterm labor and delivery. These include maternal conditions such as medical illness, anemia and uterine malformation. They may be related to past events such as prior obstetric complication, previous preterm labor, cervical surgery or induced abortion. They may be intrinsic to the current pregnancy, such as reproductive tract infection, multifetal gestation, maternal age, short interpregnancy interval or prolonged menstrual conception interval. Maternal behaviors such as smoking and substance abuse can be risk factors for a short gestation. Demographic variables such as race, employment and socioeconomic status can also be associated with preterm labor. This article briefly reviews these subjects.

A systematic approach to the management of preterm labor.

Preterm birth occurs in 7% to 12% of all deliveries, but accounts for over 85% of all perinatal morbidity and mortality. Although the ability of obstetric care providers to identify women at risk for preterm delivery has improved, the overall incidence of preterm birth has remained unchanged for the past 30 years. Preterm birth remains the single greatest challenge for physician-researchers in the field of maternal-fetal medicine in the 21st century. This article reviews in detail the current state of the literature as regards the etiology, pathophysiology, prevention, and treatment of premature labor and preterm birth. A better understanding of the molecular mechanisms responsible for the process of labor, both at term and preterm, will improve our ability to identify and manage women at risk of premature delivery.

Neonatal outcome of infants born at 23 weeks' gestation.

OBJECTIVE: To determine the neonatal outcome in accurately dated 23-week deliveries. METHODS: We reviewed the records of consecutive births between 23 0/7 and 23 6/7 weeks at Brigham & Women's Hospital, Boston, Massachusetts, from January 1995 to December 1999. Women were excluded if they presented for elective termination or had known fetal death or poor dating criteria. Neonatal records were abstracted for mortality and short-term morbidity, including the respiratory distress syndrome (RDS), intraventricular hemorrhage, chronic lung disease, necrotizing enterocolitis, periventricular leukomalacia, and retinopathy of prematurity. Survival was defined as discharge from neonatal intensive care. RESULTS: Thirty-three singleton pregnancies met criteria for inclusion, 11 of whom survived to discharge (survival rate 0.33; 95% CI 0.18, 0.52). More advanced gestational age was associated with increased likelihood of survival: 0 of 12 at 23 0/7 to 23 2/7 weeks, 4 of 10 at 23 3/7 to 23 4/7 weeks, and 7 of 11 at 23 5/7 to 23 6/7 weeks (P =.02). All 11 survivors developed RDS and chronic lung disease. One of 11 survivors had necrotizing enterocolitis, and 2 of 11 had severe retinopathy of prematurity. One survivor had periventricular leukomalacia on head ultrasonography, compared with 7 of the nonsurvivors who had head ultrasonography (P =.03). One survivor developed severe intraventricular hemorrhage (grade 3 or 4) compared with 8 of the 12 at-risk nonsurvivors who had head ultrasonography (P =.01). CONCLUSION: About one third of infants delivered at 23 weeks' gestation survived to be discharged from neonatal intensive care. More advanced gestational age was associated with increased likelihood of survival. No neonates survived free of substantial morbidity.

Prenatal ultrasonography and the diagnosis of fetal cleft lip.

OBJECTIVE: To determine the efficacy of obstetric ultrasonography in the detection of fetal cleft lip. METHODS: The study population included all women who had a fetal anatomic survey with adequate visualization of the face and who gave birth at Brigham and Women's Hospital between January 1, 1990, and January 31, 2000. All neonates born with cleft lip were identified from the Brigham and Women's Active Malformation Surveillance Program. Confirmation of the anatomic defect was obtained from the pediatric record or from the pathologic report if the pregnancy was terminated or ended in miscarriage. Cases of isolated cleft palate were excluded. An ultrasonography database was used to identify all cases of cleft lip diagnosed before delivery. Maternal information regarding the pregnancy was abstracted from the medical record. Statistical significance was determined using the chi2 statistic for categorical variables and the t test for continuous variables. RESULTS: A total of 56 confirmed cases of cleft lip were identified in the study population. Overall, 73% of the cases (41 of 56) were identified antenatally. Additional fetal anomalies were present in 54% of the cases (30 of 56). A comparison between those cases that were detected and those in which the diagnosis was missed showed that there was a significantly lower detection rate if the ultrasonography was performed before 20 weeks (12 [57%] of 21 versus 29 [83%] of 35; P = .035). There was no difference between the 2 groups in terms of maternal age or weight. Maternal parity, prior maternal abdominal surgery, the presence of a multiple gestation, or coexisting fetal anomalies did not significantly affect the detection rate. There was no difference in detection rate in the first half of the study period (1990-1995; 23 [72%] of 32) compared with the second half (1996-2000; 18 [76%] of 24; P = .79). CONCLUSIONS: In this cohort of women, the rate of detection of fetal cleft lip was significantly lower when the anatomic survey was performed before 20 weeks' gestation. This difference could not be accounted for by such variables as prior maternal abdominal surgery, coexisting fetal anomalies, or improvements in ultrasonographic detection with time. We recommend that the anatomic survey for fetuses at high risk for this condition be performed after 20 weeks' gestation.

Post-term induction of labor revisited.

Post-term pregnancy (longer than 42 weeks or 294 days) occurs in approximately 10% of all singleton gestations. The adverse outcomes of post-term pregnancy include a substantial increase in perinatal mortality and morbidity. ACOG currently recommends induction of labor for low-risk pregnancy during the 43rd week of gestation. However, that recommendation dates from 1989. Recent reports mandate reconsideration of the management of post-term pregnancy, including reinterpretation of the statistical risk of stillbirth in post-term pregnancies using ongoing (undelivered) rather than delivered pregnancies as the denominator, which shows a far higher risk to post-term fetuses than believed. Recent data also suggest that the risk of cesarean delivery after induction of labor at term is lower than reported, possibly because of improvements in methods for cervical ripening. Those findings provide rationale for earlier labor induction in low-risk pregnancies.