Inflammatory markers in relation to maternal lifestyle and adverse pregnancy outcomes in twin pregnancies.

It is well known that inflammatory markers play an important role in the development and maintenance of healthy pregnancies. However, the literature regarding inflammation in relation to lifestyle and adverse pregnancy outcomes in twin pregnancies is remarkably uncovered. Therefore, this study aimed at evaluating the concentration of inflammatory markers in dried capillary blood spot samples from 523 women with twin pregnancies, included at a median gestational age of 21+1 weeks. The relationship between inflammatory markers and maternal lifestyle (current smoking status and pre-pregnancy body mass index) in addition to adverse pregnancy outcomes (preeclampsia, gestational diabetes mellitus, and small for gestational age) was analyzed. The study showed that active smoking at inclusion was associated with an elevated concentration of interleukin-8. Furthermore, maternal obesity was associated with an elevated concentration of C-reactive protein and monocyte chemoattractant protein-1. Analysis of the data showed no statistically significant variations in the concentration of the assessed inflammatory markers for neither preeclampsia, gestational diabetes mellitus, nor small for gestational age. The current study promotes future research on the pathophysiology of twin pregnancies in relation to adverse pregnancy outcomes, as the literature within the area remains scarce.

Fetal Growth Restriction Is Associated with Pregnancy Associated Plasma Protein A and Uterine Artery Doppler in First Trimester.

Fetal growth restriction (FGR) is a major cause of stillbirth and poor neurodevelopmental outcomes. The early prediction may be important to establish treatment options and improve neonatal outcomes. The aim of this study was to assess the association of parameters used in first-trimester screening, uterine artery Doppler pulsatility index and the development of FGR. In this retrospective cohort study, 1930 singleton pregnancies prenatally diagnosed with an estimated fetal weight under the third percentile were included. All women underwent first-trimester screening assessing maternal serum pregnancy-associated plasma protein A (PAPP-A), free beta-human chorionic gonadotrophin levels, fetal nuchal translucency and uterine artery Doppler pulsatility index (PI). We constructed a Receiver Operating Characteristics curve to calculate the sensitivity and specificity of early diagnosis of FGR. In pregnancies with FGR, PAPP-A was significantly lower, and uterine artery Doppler pulsatility index was significantly higher compared with the normal birth weight group (0.79 ± 0.38 vs. 1.15 ± 0.59, p < 0.001 and 1.82 ± 0.7 vs. 1.55 ± 0.47, p = 0.01). Multivariate logistic regression analyses demonstrated that PAPP-A levels and uterine artery Doppler pulsatility index were significantly associated with FGR (p = 0.009 and p = 0.01, respectively). To conclude, these two parameters can predict FGR < 3rd percentile.

Neutrophil Gelatinase-Associated Lipocalin and Hypertensive Disorders of Pregnancy: A Cohort Study in Twin Pregnancies.

Hypertensive disorders complicate more than 10% of twin pregnancies. Several studies showed increased neutrophil gelatinase-associated lipocalin (NGAL) values in women with singleton pregnancies and preeclampsia. This study aimed to assess NGAL values in twin pregnancies complicated by hypertensive disorders. We conducted a study of 242 consecutive twin pregnancies at the Medical University of Vienna. Serum NGAL was evaluated twice during pregnancy and once in the postpartum period. Furthermore, serum NGAL values were compared between women who developed hypertensive disorders and those who had normal blood pressure. In all twin pregnancies, mean NGAL values increased significantly from the first to the second visit (p = 0.004) and, further, after delivery (p < 0.001). NGAL was significantly higher in pregnancies that developed pregnancy hypertension or preeclampsia when compared to the control group at the first visit (109.2 ± 48.9 ng/mL vs. 91.9 ± 29.4 ng/mL, p = 0.04, respectively). The predictive power of first visit NGAL values for development of pregnancy hypertension or preeclampsia was evaluated. When using a cut-off value of 115 ng/mL, we obtained a sensitivity of 45% with a specificity of 77%. We conclude that women with twin pregnancies who develop hypertensive disorders of pregnancy showed increased NGAL values at 11−16 weeks.

Notching and Pulsatility Index of the Uterine Arteries and Preeclampsia in Twin Pregnancies.

Increased uterine artery Doppler indices have been shown to be associated with preeclampsia and adverse pregnancy outcomes in singleton and twin pregnancies. At 20-22 weeks of gestation, we assessed the use of notching, the highest, lowest, and mean pulsatility index (PI), and the combination of notching and PI of the uterine arteries to screen for preeclampsia. This was done in a cohort of 380 twin pregnancies. The results showed that the combination of notching and the highest PI above the 95th centile of the uterine arteries gives the best screening characteristics for preeclampsia in twin pregnancies. We calculated sensitivities for preeclampsia for notching, highest PI, and the combination of notching and the highest PI of 50%, 45% and 91%, with specificities of 96%, 96% and 93%, respectively. The present findings demonstrate that notching, increased highest PI, and the combination of notching and the highest PI of the uterine arteries is associated with an increased risk of preeclampsia in twin pregnancies. We observed the highest sensitivity and specificity by using the combination of notching and the highest PI of the uterine arteries.

Plasma progesterone, estradiol, and unconjugated estriol concentrations in twin pregnancies: Relation with cervical length and preterm delivery.

INTRODUCTION: The aim of this study was to examine the association between plasma hormone concentrations, cervical length, and preterm delivery in twin pregnancies, including the effect of progesterone treatment. MATERIAL AND METHODS: This study included 191 women pregnant with twins from a randomized placebo-controlled trial. A baseline blood sample was collected at 18-24 weeks before treatment with vaginal progesterone (n = 95) or placebo pessaries (n = 96), and 167 (87.4%) women had a second sample collected after 4-8 weeks of treatment. At baseline, 155 (81.2%) women had their cervical length measured. Progesterone, estradiol, and unconjugated estriol concentration was measured, and the association between hormone concentrations, cervical length, and gestational age at delivery was examined. Hormone concentrations were compared in the placebo and progesterone group. Statistical analysis included Spearman's rho, Mann-Whitney U test, Cuzick's test for trends, and linear regression analyses. RESULTS: A short cervical length was associated with preterm delivery. Cervical length and hormone concentrations were not associated (Spearman's rho; progesterone -.05, estradiol .04, estriol .08). Decreasing gestational age at delivery was associated with higher progesterone and estradiol concentrations at baseline (P trend; progesterone 0.04, estradiol 0.02) but not in the second sample or in the weekly change between samples. Progesterone treatment did not increase the progesterone concentration. CONCLUSIONS: Plasma concentrations of progesterone, estradiol, and unconjugated estriol at 18-24 weeks are not associated with cervical length or preterm delivery in twin pregnancies. Vaginal progesterone treatment does not increase the circulating progesterone concentration in twin pregnancies. Cervical length, but not hormone concentration, is predictive of preterm delivery in twin gestations.

Maternal and neonatal omentin-1 levels in gestational diabetes.

PURPOSE: To evaluate the effect of gestational diabetes on omentin-1 in maternal and cord plasma. As a potent mediator of insulin resistance, Omentin-1, an adipokine derived from human adipose and placental tissue, may be an important player in the pathophysiology of gestational diabetes. METHODS: This was a prospective case-control study. The study included 96 women with gestational diabetes and 96 pregnant women without. Omentin-1 was measured at the time of the oral glucose tolerance test, at 32 weeks in maternal plasma and right after delivery in umbilical cord blood by ELISA assay. RESULTS: Over a period of 2 years, 200 patients were enrolled. Omentin-1 levels did not significantly differ between both groups throughout the pregnancy: omentin-1 levels were 157 ± 83 ng/ml in women with gestational diabetes and 158 ± 93 ng/ml in women without gestational diabetes (p = 0.94) at time of the oral glucose tolerance test and 118 ± 77 ng/ml in women with diabetes and 150 ± 89 ng/ml in women without (p = 0.12) at 32 weeks, respectively. Both groups showed a decrease in omentin-1 levels throughout pregnancy, with a more pronounced decrease in diabetic women (13 ± 53 versus 4 ± 48 ng/ml; p = 0.5). Neonatal omentin-1 levels were significantly lower in offspring of diabetic mothers: 106 ± 61 versus 134 ± 45 ng/ml (p = 0.03). CONCLUSIONS: There was no significant difference in omentin-1 levels between healthy and diabetic mothers throughout the pregnancy. However, we found significantly lower omentin-1 levels in offspring of diabetic mothers. This may indicate a risk for the development of insulin resistance in later life.

Randomized controlled trial of induction at 38 weeks versus 40 weeks gestation on maternal and infant outcomes in women with insulin-controlled gestational diabetes.

OBJECTIVE: To compare the impact of induction of labor at 38 weeks of gestation with the induction of labor at 40 weeks of gestation in women with insulin-treated gestational diabetes on maternal and fetal outcome. STUDY DESIGN: In this study 100 pregnant women with insulin-treated gestational diabetes were randomized to either induction of labor at 38 (group I) or 40 weeks (group II) to evaluate the rate of large for gestational age newborns, neonatal hypoglycemia, success rate of deliveries within 48 h and cesarean section rate after induction in both groups. RESULTS: The difference of large for gestational age newborns was not significant between the two groups (6.8% vs. 12.8%, p = 0.49), 16 (36.4%) newborns in group I and 8 (17.0%) newborns in group II developed hypoglycemia <35 mg/dl (p = 0.04). The success rate for deliveries within 48 h after induction of labor for groups I and II was 77.3% and 92.3%, respectively (p = 0.25). The cesarean section rate after induction of labor was not significantly different between the two groups (24.1% vs. 18.7%, p = 0.49). CONCLUSION: In a cohort of women with insulin-treated gestational diabetes, induction of labor at 38 weeks did not significantly reduce the rate of large for gestational age newborns compared to induction at 40 weeks but seems to increase the rate of neonatal hypoglycemia.

Short- and long-term perinatal outcome in twin pregnancies affected by weight discordance.

INTRODUCTION: The objective was to investigate the association between chorionicity-specific intertwin birthweight discordance and adverse outcomes including long-term follow up at 6, 18, and 48-60 months after term via Ages and Stages Questionnaire. MATERIAL AND METHODS: In this secondary analysis of a cohort study (Oldenburg et al., n = 1688) and a randomized controlled trial (PREDICT study, n = 1045) twin pairs were divided into three groups according to chorionicity-specific birthweight discordance: <75th percentile, 75th-90th percentile and >90th percentile. Information on infant mortality, admittance to neonatal intensive care units, and gestational age at delivery was available for all pairs. Detailed neonatal outcomes were available for 656 pairs from PREDICT, of which 567 pairs had at least one Ages and Stages Questionnair follow-up. Logistic regression models were used for dichotomous outcomes. Ages and Stages Questionnair scores were compared using the method of generalized estimating equation to account for the correlation within twins. RESULTS: The 75th and 90th percentiles for birthweight discordance were 14.8 and 21.4% for monochorionic and 16.0 and 23.8% for dichorionic twins. After adjustment for small for gestational age and gender, birthweight discordance >75th and >90th percentile was associated with induced delivery <34 weeks [odds ratio 1.71 (95% confidence interval 1.11-2.65) and odds ratio 2.83 (95% confidence interval 1.73-4.64), respectively]. Discordance >75th-percentile was associated with an increased risk of infant mortality after 28 days [odds ratio 4.69 (95% confidence interval 1.07-20.45)] but not with major neonatal complications or with low mean Ages and Stages Questionnair scores at 6, 18, and 48-60 months after term. CONCLUSION: Chorionicity-specific intertwin birthweight discordance is a risk factor for induced preterm delivery and infant mortality, but not for lower scores for neurophysiological development at 6, 18, and 48-60 months.

Prospective risk of stillbirth and neonatal complications in twin pregnancies: systematic review and meta-analysis.

OBJECTIVE: To determine the risks of stillbirth and neonatal complications by gestational age in uncomplicated monochorionic and dichorionic twin pregnancies. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline, Embase, and Cochrane databases (until December 2015). REVIEW METHODS: Databases were searched without language restrictions for studies of women with uncomplicated twin pregnancies that reported rates of stillbirth and neonatal outcomes at various gestational ages. Pregnancies with unclear chorionicity, monoamnionicity, and twin to twin transfusion syndrome were excluded. Meta-analyses of observational studies and cohorts nested within randomised studies were undertaken. Prospective risk of stillbirth was computed for each study at a given week of gestation and compared with the risk of neonatal death among deliveries in the same week. Gestational age specific differences in risk were estimated for stillbirths and neonatal deaths in monochorionic and dichorionic twin pregnancies after 34 weeks' gestation. RESULTS: 32 studies (29 685 dichorionic, 5486 monochorionic pregnancies) were included. In dichorionic twin pregnancies beyond 34 weeks (15 studies, 17 830 pregnancies), the prospective weekly risk of stillbirths from expectant management and the risk of neonatal death from delivery were balanced at 37 weeks' gestation (risk difference 1.2/1000, 95% confidence interval -1.3 to 3.6; I(2)=0%). Delay in delivery by a week (to 38 weeks) led to an additional 8.8 perinatal deaths per 1000 pregnancies (95% confidence interval 3.6 to 14.0/1000; I(2)=0%) compared with the previous week. In monochorionic pregnancies beyond 34 weeks (13 studies, 2149 pregnancies), there was a trend towards an increase in stillbirths compared with neonatal deaths after 36 weeks, with an additional 2.5 per 1000 perinatal deaths, which was not significant (-12.4 to 17.4/1000; I(2)=0%). The rates of neonatal morbidity showed a consistent reduction with increasing gestational age in monochorionic and dichorionic pregnancies, and admission to the neonatal intensive care unit was the commonest neonatal complication. The actual risk of stillbirth near term might be higher than reported estimates because of the policy of planned delivery in twin pregnancies. CONCLUSIONS: To minimise perinatal deaths, in uncomplicated dichorionic twin pregnancies delivery should be considered at 37 weeks' gestation; in monochorionic pregnancies delivery should be considered at 36 weeks. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014007538.

Abnormal maternal echocardiographic findings in triplet pregnancies presenting with dyspnoea.

OBJECTIVE: The objective of our study was to evaluate the prevalence of abnormal maternal echocardiographic findings in triplet pregnancies presenting with dyspnoea. STUDY DESIGN: Between 2003 and 2013, patients' records of 96 triplet pregnancies at our department were analysed including maternal and fetal outcome, echocardiographic parameters and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. After exclusion of triplet pregnancies with fetal demise before 23 + 0 weeks, selective feticide or missing outcome data, the study population consisted of 60 triplet pregnancies. All women with dyspnoea underwent echocardiography and measurement of NT-proBNP. RESULTS: Dyspnoea towards the end of pregnancy was observed in 13.3% (8/60) of all women with triplet pregnancies, and all of these women underwent echocardiography. The prevalence of abnormal echocardiographic findings in women with dyspnoea was 37.5% (3/8) with peripartum cardiomyopathy in one woman. Median serum NT-proBNP was significantly higher in women with abnormal echocardiographic findings compared with those without (1779 ng/ml, range 1045-6076 ng/ml vs 172 ng/ml, range 50-311 ng/ml; p < 0.001 by Mann-Whitney-U Test). CONCLUSION: We conclude that triplet pregnancies presenting with dyspnoea show a high prevalence of abnormal echocardiographic findings. Since dyspnoea is a common sign in triplet pregnancies and is associated with a high rate of cardiac involvement, echocardiography and evaluation of maternal NT-proBNP could be considered to improve early diagnosis and perinatal management.

Cerebral Lesions at Fetal Magnetic Resonance Imaging and Neurologic Outcome After Single Fetal Death in Monochorionic Twins.

BACKGROUND: Single fetal death (sFD) in monochorionic twin pregnancies is associated with substantial morbidity and mortality in the survivor. The aim of our study was to evaluate the rate of cerebral lesions detected at fetal Magnetic Resonance Imaging (MRI) and to correlate the results with the neurologic outcome of the survivors of monochorionic twin pregnancies after sFD. METHODS: Between 2005 and 2012, 11 monochorionic twin pregnancies with sFD and subsequent fetal MRI of the survivor were included. All neonates underwent neurologic assessment after birth and 56% of surviving infants underwent long-term neurologic assessment. MRI findings and neurologic outcome of the survivors were evaluated. RESULTS: Gestational age at sFD was 20.9 (±2.9) weeks; 55% (6/11) of survivors of monochorionic twin pregnancies after sFD showed cerebral lesions at fetal MRI; 72% (8/11) of all survivors had normal neonatal neurologic outcome: all survivors with normal fetal MRI and 50% of survivors with cerebral lesions at fetal MRI. Long-term neurologic assessment was normal in all tested patients with normal fetal MRI and in one of three tested patients with cerebral lesions at fetal MRI. CONCLUSION: Survivors of monochorionic twin pregnancies after sFD show a high rate of cerebral lesions at fetal MRI. The importance of cerebral lesions at fetal MRI in survivors after sFD in monochorionic twin pregnancies is uncertain. All tested survivors with normal fetal MRI showed normal neurologic outcome but only one of three survivors with cerebral lesions at fetal MRI showed normal long-term neurologic outcome.

Isolated Short Fetal Femur Length in the Second Trimester and the Association with Adverse Perinatal Outcome: Experiences from a Tertiary Referral Center.

OBJECTIVE: To determine the association between isolated mid-trimester short fetal femur length and adverse perinatal outcome. METHODS: This is a retrospective cohort study of patients with singleton gestations routinely assessed by second trimester ultrasound examination during 2006-2013. A fetal isolated short femur was defined as a femur length (FL) below the 5th percentile in a fetus with an abdominal circumference greater than the 10th percentile. Cases of aneuploidy, skeletal dysplasia and major anomalies were excluded. Primary outcomes of interest included the risk of small for gestational age neonates, low birth weight and preterm birth (PTB). Secondary outcome parameters were a 5-min Apgar score less than 7 and a neonatal intensive care unit admission. A control group of 200 fetuses with FL ≥ 5th percentile was used to compare primary and secondary outcome parameters within both groups. Chi-square and Student's t-tests were used where appropriate. RESULTS: Out of 608 eligible patients with a short FL, 117 met the inclusion criteria. Isolated short FL was associated with an increased risk for small for gestational age (19.7% versus 8.0%, p = 0.002) neonates, low birth weight (23.9% versus 8.5%, p<0.001), PTB (19.7% versus 6.0%, p<0.001) and neonatal intensive care unit admissions (13.7% versus 3.5%, p = 0.001). The incidence of a 5-min Apgar score less than 7 was similar in both groups. CONCLUSION: Isolated short FL is associated with a subsequent delivery of small for gestational age and Low birth weight neonates as well as an increased risk for PTB. This information should be considered when counseling patients after mid-trimester isolated short FL is diagnosed.

Individualized assessment of preterm birth risk using two modified prediction models.

OBJECTIVES: To construct two prediction models for individualized assessment of preterm delivery risk within 48h and before completed 32 weeks of gestation and to test the validity of modified and previously published models. STUDY DESIGN: Data on 617 consecutive women with preterm labor transferred to a tertiary care center for threatened preterm delivery between 22 and 32 weeks of gestation were analysed. Variables predicting the risk of delivery within 48h and before completed 32 weeks of gestation were assessed and applied to previously published prediction models. Multivariate analyses identified variables that were incorporated into two modified models that were subsequently validated. RESULTS: Two modified prediction models were developed and internally validated, incorporating four and six of the following variables to predict the risk of delivery within 48h and before completed 32 weeks of gestation, respectively: presence of preterm premature rupture of membranes and/or vaginal bleeding, sonographic cervical length, week of gestation, fetal fibronectin, and serum C-reactive protein. The correspondence between the actual and the predicted preterm birth rates suggests excellent calibration of the models. Internal validation analyses for the modified 48h and 32 week prediction models revealed considerably high concordance-indices of 0.8 (95%CI: [0.70-0.81]) and 0.85 (95%CI: [0.82-0.90]), respectively. CONCLUSIONS: Two modified prediction models to assess the risk of preterm birth were constructed and validated. The models can be used for individualized prediction of preterm birth and allow more accurate risk assessment than based upon a single risk factor. An online-based risk-calculator was constructed and can be assessed through: http://cemsiis.meduniwien.ac.at/en/kb/science-research/software/clinical-software/prematurebirth/.

Isolated single umbilical artery: evaluating the risk of adverse pregnancy outcome.

OBJECTIVE: To evaluate if isolated single umbilical artery (SUA) diagnosed on second-trimester ultrasound has an independent risk association with adverse pregnancy outcomes. STUDY DESIGN: We compared 136 singleton pregnancies with isolated SUA with 500 consecutive singleton pregnancies with a three-vessel cord (3 VC). Pregnancies complicated by chromosomal abnormalities and other congenital malformations were excluded. The rates of intrauterine growth restriction (IUGR) defined as birth weight less than the 3rd percentile, small for gestational age (SGA) fetuses, defined as a birth weight lower than the 10th percentile and the incidence of very preterm deliveries before 34 weeks of gestation were compared between the two groups. Multivariable logistic regression analysis was performed to evaluate the risk association between SUA and adverse pregnancy outcomes, while controlling for potential confounders. RESULTS: Fetuses with isolated SUA had significantly lower birth weight (2942.5 ± 783.7 vs. 3243.7 ± 585.6 g, p = 0.002), and were delivered at an earlier gestational age (38.7 ± 3.4 vs. 39.5 ± 2.2 weeks, p < 0.001), when compared to fetuses with a 3 VC. Fetuses with isolated SUA were at higher risk for IUGR (15.4% vs. 1.8%, p < 0.001), SGA (20.6% vs. 4.4%, p < 0.001) and very preterm delivery (6.6% vs. 1.4%, p = 0.002). Using a multiple logistic regression model, isolated SUA was shown to be an independent risk factor for IUGR (adjusted OR = 11.3, 95% CI 4.8-25.6; p < 0.001) and very preterm delivery (adjusted OR = 5.0, 95% CI 1.8-13.8; p = 0.002). CONCLUSIONS: The presence of isolated SUA is independently associated with an increased risk for IUGR, SGA and very preterm delivery.

Congenital heart disease in monochorionic twins with and without twin-to-twin transfusion syndrome.

OBJECTIVE: This study aims to evaluate the prevalence of congenital heart disease (CHD) in monochorionic (MC) twin pregnancies with and without twin-to-twin transfusion syndrome (TTTS) in an unselected cohort, which underwent prenatal and postnatal echocardiography. METHOD: This was a retrospective cohort study including 451 MC twin pregnancies between 2002 and 2012. Complete outcome data were available for 381 pregnancies. All patients had prenatal echocardiography, and postnatal echocardiography was performed in all newborns with symptoms or to follow-up on prenatal findings. Data from prenatal and postnatal echocardiography and autopsy were analyzed. The classification of Houyel et al. was used for structural CHD. RESULTS: Structural CHD was diagnosed in 5.5% of all MC twins (42/762). Twins with TTTS showed a significant higher rate of CHD than unaffected twins (9.3% vs 4.7%; p = 0.03). Prenatal detection rate of CHD was 48%. Most common abnormalities were ventricular septal defects (VSD) (2.1%) followed by anomalies of the ventricular outflow tracts (1.3%) in the overall population and VSD (2.9%) and anomalies of the great arteries (2.9%) in the group with TTTS. CONCLUSION: MC twin pregnancies show a high prevalence of structural CHD (5.5%), especially those affected by TTTS. A detailed prenatal and postnatal echocardiography could be considered in these pregnancies.