Nir Melamed

Serum MicroRNAs Are Promising Novel Biomarkers

Background Circulating nucleic acids (CNAs) offer unique opportunities for early diagnosis of clinical conditions. Here we show that microRNAs, a family of small non-coding regulatory RNAs involved in human development and pathology, are present in bodily fluids and represent new effective biomarkers. Methods and Results After developing protocols for extracting and quantifying microRNAs in serum and other body fluids, the serum microRNA profiles of several healthy individuals were determined and found to be similar, validating the robustness of our methods. To address the possibility that the abundance of specific microRNAs might change during physiological or pathological conditions, serum microRNA levels in pregnant and non pregnant women were compared. In sera from pregnant women, microRNAs associated with human placenta were significantly elevated and their levels correlated with pregnancy stage. Conclusions and Significance Considering the central role of microRNAs in development and disease, our results highlight the medically relevant potential of determining microRNA levels in serum and other body fluids. Thus, microRNAs are a new class of CNAs that promise to serve as useful clinical biomarkers.

Pregnancy outcome at extremely advanced maternal age

OBJECTIVE The purpose of this study was to evaluate pregnancy outcome in women at extremely advanced maternal age (≥ 45 years). STUDY DESIGN We compared the condition of women aged ≥ 45 years (n = 177) in a 10:1 ratio (20-29, 30-39, and 40-44 years.). Subgroup analysis compared the condition of women aged 45-49 years with those women aged ≥ 50 years. RESULTS The rates of gestational diabetes mellitus and hypertensive complications were higher for the study group, compared with the whole group (17.0% vs 5.6% and 19.7% vs 4.5%, respectively; P < .001), as was the rate of preterm delivery at <37 and <34 weeks of gestation (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.2-3.6 and OR, 3.5; 95% CI, 1.4-9.0, respectively). The rates of cesarean delivery (OR, 31.8; 95% CI, 18.0-56.1), placenta previa, postpartum hemorrhage, and adverse neonatal outcome were significantly higher among the study group. The risk for gestational diabetes mellitus, preeclampsia toxemia, preterm delivery, and neonatal intensive care unit admission was increased for women aged ≥ 50 years. CONCLUSION Pregnancy at extreme advanced maternal age is associated with increased maternal and fetal risk.

Short-term Neonatal Outcome in Low-Risk, Spontaneous, Singleton, Late Preterm Deliveries

OBJECTIVE: To estimate the effect of gestational age on short-term neonatal morbidity in cases of spontaneous, low-risk singleton late preterm deliveries and to identify predictors of adverse neonatal outcome. METHODS: This was a retrospective study of all spontaneous, low-risk late preterm deliveries (34 0/7 to 36 6/7 weeks of gestation) during the years 1997 to 2006 (n=2,478). Multiple gestations and pregnancies complicated by preterm premature rupture of membranes (PROM) or maternal or fetal complications were excluded. Short-term neonatal outcome was compared with a control group of full-term deliveries in a 3:1 ratio (n=7,434). Logistic regression analysis was used to identify risk factors for neonatal morbidity among late preterm infants. RESULTS: Compared with full-term infants, spontaneous late preterm delivery was independently associated with an increased risk of neonatal morbidity, including respiratory distress syndrome (4.2% compared with 0.1%, P<.001), sepsis (0.4% compared with 0.04%, P<.001), intraventricular hemorrhage (0.2% compared with 0.02%, P<.001), hypoglycemia (6.8% compared with 0.4%, P<.001), and jaundice requiring phototherapy (18% compared with 2.5%, P<.001). Cesarean delivery (odds ratio [OR] 2.1, 95% confidence interval [CI] 1.6–2.6), male sex (OR 1.4, 95% CI 1.1–1.8), and multiparity (OR 2.2, 95% CI 1.7–2.8) were independent risk factors for neonatal respiratory morbidity in cases of late preterm deliveries. The relationship between gestational age and neonatal morbidity was of continuous nature with a nadir at about 39 weeks rather than a term–preterm threshold phenomenon and was unrelated to birth weight. CONCLUSION: Late prematurity is associated with significant neonatal morbidity in cases of spontaneous low-risk singleton deliveries. This information is important for appropriate counseling and should stimulate efforts to decrease the rate of late preterm deliveries. LEVEL OF EVIDENCE: II

Fetal gender and pregnancy outcome

Objective. To assess the effect of fetal gender on pregnancy outcome. Methods. Retrospective study of all singleton pregnancies at a tertiary hospital during 1995–2006. Results. Of the 66,387 women studied, 34,367 (51.8%) delivered male and 32,020 (48.2%) delivered female neonates. The rate of preterm delivery (as early as 29 weeks) was higher for male fetuses and was attributed to an increased incidence of spontaneous preterm labor and preterm premature rupture of membranes. Women carrying male fetuses were at increased risk for operative vaginal delivery (OVD) for non-reassuring fetal heart rate, failed OVD and cesarean delivery. Female fetuses were more likely to experience fetal growth restriction (FGR). Conclusion.  Fetal gender is independently associated with adverse pregnancy outcome. Although the added risk is relatively small, further investigation of the mechanisms underlying this association may contribute to our understanding of the pathophysiology of pregnancy complications such as preterm delivery and FGR.

Sonographic Fetal Weight Estimation Which Model Should Be Used

Objective. The purpose of this study was to compare the accuracy of different sonographic models for fetal weight estimation. Methods. We evaluated 26 different models using 3705 sonographic weight estimations performed less than 3 days before delivery. Models were ranked on the basis of systematic and random errors and were grouped according to the combination of biometric indices in each model. Cluster analysis was used to compare the accuracy of the different model groups. Results. A considerable variation in the accuracy of the different models was found. For birth weights (BWs) in the range of 1000 to 4500 g, models based on 3 or 4 fetal biometric indices were significantly more accurate than models that incorporated only 1 or 2 indices. The accuracy of weight estimation decreased at the extremes of BWs, leading to overestimation in low‐BW categories as opposed to underestimation when the BW exceeded 4000 g. The precision of most models was lowest in the low‐BW groups. Conclusions. To improve the accuracy of fetal weight estimation, sonographic models that are based on 3 or 4 fetal biometric indices should be preferred. Recognizing the accuracy and the tendency for underestimation or overestimation of each of the available models is important for the judicious interpretation of fetal weight estimations, especially at the extremes of fetal weight.

Screening and Diagnosis of Gestational Diabetes Mellitus:: Critical appraisal of the new International Association of Diabetes in Pregnancy Study Group recommendations on a national level

OBJECTIVE To study the implications of implementing the International Association of Diabetes in Pregnancy Study Group (IADPSG) recommendations for screening and diagnosis of gestational diabetes mellitus (GDM) in Israel and explore alternative methods for identifying women at risk for adverse pregnancy outcomes. RESEARCH DESIGN AND METHODS We analyzed data of the Israeli Hyperglycemia and Adverse Pregnancy Outcomes study participants (N = 3,345). Adverse outcome rates were calculated and compared for women who were positive according to 1) IADPSG criteria, 2) IADPSG criteria with risk stratification, or 3) screening with BMI or fasting plasma glucose (FPG). RESULTS Adopting IADPSG recommendations would increase GDM diagnosis by ∼50%. One-third of IADPSG-positive women were at low risk for adverse outcomes and could be managed less intensively. FPG ≥89 mg/dL or BMI ≥33.5 kg/m2 at 28–32 weeks of gestation detected proportions of adverse outcomes similar to IADPSG criteria. CONCLUSIONS Implementing IADPSG recommendations will substantially increase GDM diagnosis. Risk stratification in IADPSG-positive women may reduce over-treatment. Screening with FPG or BMI may be a practical alternative.

Sonographic prediction of fetal macrosomia: the consequences of false diagnosis.

Objective. The purpose of this study was to determine the effect of false diagnosis of macrosomia (<4500 g) on maternal/perinatal outcomes. Methods. We conducted a case‐control study of women (n = 1938) in whom sonographically estimated fetal weight (EFW) was determined up to 3 days before delivery and actual birth weight (BW) was 3500 to 4499 g. Women with false‐positive and ‐negative findings for macrosomia were compared, respectively, with women with true‐negative and ‐positive findings for outcome variables. Results. The cesarean delivery (CD) rate was 2 to 2.5 times higher when EFW was 4000 to 4499 g, regardless of actual BW. Failure to detect macrosomia was associated with higher rates of perineal trauma, 5‐minute Apgar scores less than 7, and neonatal trauma, mostly related to the higher rate of surgical vaginal deliveries. The use of another sonographic model with a lower false‐positive rate could theoretically reduce the CD rate by approximately 5%. Conclusions. False diagnosis of macrosomia substantially increases the CD rate and leads to maternal/neonatal complications.

Expectant management of preterm premature rupture of membranes: is it all about gestational age?

OBJECTIVE We sought to compare neonatal outcome in cases of uncomplicated preterm premature rupture of membranes (PPROM) (ie, no evidence of clinical chorioamnionitis, placental abruption, or fetal distress) with that of spontaneous preterm deliveries (PTDs) and to determine the effect of the latency period. STUDY DESIGN The study group included women with PPROM at gestational age 28⁰(/)⁷-33⁶(/)⁷ weeks (n = 488). Neonatal outcome was compared with a matched control group of women with spontaneous PTD (n = 1464). RESULTS Neonates in the uncomplicated PPROM group were at increased risk for composite adverse outcome (53.7% vs 42.0%; P < .001), mortality (1.6% vs 0.0%; P < .001), respiratory morbidity (32.8% vs 26.4%; P = .006), necrotizing enterocolitis, jaundice, hypoglycemia, hypothermia, and polycythemia. Neonatal adverse outcome was more likely in cases of latency period >7 days, oligohydramnios, male fetus, and nulliparity. CONCLUSION Consultation regarding prematurity-related morbidity in infants exposed to uncomplicated PPROM cannot be extrapolated from PTDs and should be stratified by the duration of the latency period and the other risk factors identified in the current study.

Factors affecting the duration of the latency period in preterm premature rupture of membranes.

Objective. To investigate the natural course of preterm premature rupture of membranes (PPROM) at <34 + 0 weeks and to identify factors that affect the duration of the latency period. Design. A retrospective cohort study of all women diagnosed with PPROM prior to 34 + 0 weeks during 1998–2006. Latency period was defined as the time between onset of PPROM to either spontaneous delivery, labor induction at 34 + 0 weeks, or indicated delivery prior to 34 + 0 weeks because of suspected chorioamnionitis or nonreassuring fetal heart rate. Results. The overall rate of PPROM was 1.4% (905/66,775), of which 46% (417/905) occurred at <34 + 0 weeks. Overall, the latency period exceeded 48 h in about 73.4% of cases (306/471). Women with short latency periods (<48 h) were characterised by higher degree of cervical dilatation and higher gestational age at admission and were more likely to be nulliparous. The duration of the latency period ranged between 0 and 59 days and was inversely related to gestational age at admission (r = −0.63, P < 0.001). Using Cox proportional hazards model, gestational age at admission (HR = 1.29, 95% CI = 1.22–1.37), oligohydroamnios (HR = 1.49, 95% CI = 1.18–1.87), cervical dilatation >1 cm (HR = 0.65, 95% CI = 0.52–0.83), fetal growth restriction (HR = 2.94, 95% CI = 1.24–6.94) and nulliparity (HR = 1.28, 95% CI = 1.12–1.63) were significantly associated with shorter duration of the latency period. Conclusion. In this study, we have identified several predictive factors for the duration of the latency period in cases of PPROM. This information may assist clinicians in risk stratification and in providing consultation for women presenting with PPROM prior to 34 weeks of gestation.

Sonographic Diagnosis of Ovarian Torsion Accuracy and Predictive Factors

The purpose of this study was to determine the accuracy of sonographic diagnosis of ovarian torsion and the predictive value of typical sonographic signs.