Congenital hypotonia: systematic approach for prenatal detection.

OBJECTIVES: Congenital hypotonic conditions are rare and heterogeneous, and some are severely debilitating or lethal. Contrary to its prominent postnatal manifestation, the prenatal presentation of hypotonia is frequently subtle, inhibiting prenatal detection. We aimed to characterize the prenatal sonographic manifestation of congenital hypotonia throughout pregnancy, evaluate the yield of diagnostic tests and propose diagnostic models to increase its prenatal detection. METHODS: This was a retrospective observational study of singleton pregnancies with congenital hypotonia, diagnosed either prenatally or immediately after birth, at a single tertiary center between the years 2012 and 2020. Prenatally, hypotonia was diagnosed if a fetus showed sonographic or clinical signs suggestive of hypotonia and had a confirmed underlying genetic condition, or in the absence of a known genetic abnormality if the fetus exhibited multiple prominent signs suggestive of hypotonia. Postnatally, it was diagnosed in neonates displaying reduced muscle tone leading to reduced spontaneous movement, reduced swallowing or feeding difficulty. We reviewed the medical records of pregnant patients carrying fetuses subsequently diagnosed with congenital hypotonia and assessed the yield of ultrasound scans, fetal magnetic resonance imaging, computed tomography and genetic tests. The detection rate of sonographic signs suggesting fetal hypotonia was calculated. The prevalence of non-specific signs, including polyhydramnios, persistent breech presentation, intrauterine growth restriction and maternal perception of reduced fetal movement, were compared between the study group and the local liveborn singleton population. Potential detection rates of different theoretical semiotic diagnostic models, differing in the threshold for referral for a targeted scan, were assessed based on the cohort's data. RESULTS: The study group comprised 26 cases of congenital hypotonia, of which 10 (38.5%) were diagnosed prenatally, and the controls included 95 105 singleton live births, giving a prevalence of congenital hypotonia of 1:3658. Nuchal translucency thickness and the early anomaly scan at 13-17 weeks were normal in all 22 and 23 cases, respectively, in which this was performed. The mid-trimester scan performed at 19-25 weeks was abnormal in four of 24 (16.7%) cases. The overall prenatal detection rate of congenital hypotonic conditions in our cohort was 38.5%. Only cases which underwent a targeted scan were detected and, among the 16 cases which underwent this scan, the prenatal detection rate was 62.5% compared with 0% in pregnancies that did not undergo this scan (P = 0.003). An abnormal genetic diagnosis was obtained in 21 (80.8%) cases using the following modalities: chromosomal microarray analysis (CMA) in two (9.5%), whole-exome sequencing (WES) in 14 (66.7%) and methylation analysis in five (23.8%). CMA was abnormal in 8% (2/25) of the cases and WES detected a causative genetic mutation in 87.5% (14/16) of the cases in which these were performed. Comparison of non-specific signs in the study group with those in the local singleton population showed that hypotonic fetuses had significantly more polyhydramnios (64.0% vs 3.0%, P < 0.0001), persistent breech presentation (58.3% vs 4.2%, P < 0.0001), intrauterine growth restriction (30.8% vs 3.0%, P < 0.0001) and maternal perception of reduced fetal movement (32.0% vs 4.7%, P < 0.0001). Prenatally, the most commonly detected signs supporting a diagnosis of hypotonia were structural anomaly (62.5%, 10/16), reduced fetal movement (46.7%, 7/15), joint contractures (46.7%, 7/15) and undescended testes ≥ 30 weeks (42.9%, 3/7 males). Proposed diagnostic strategies that involved performing a targeted scan for a single non-specific ultrasound sign or two such signs, and then carrying out a comprehensive genetic evaluation for any additional sign, offered theoretical detection rates in our cohort of 88.5% and 57.7%, respectively. CONCLUSIONS: Congenital hypotonic conditions are rare and infrequently detected prenatally. Sonographic signs are visible from the late second trimester. A targeted scan increases prenatal detection significantly. Comprehensive genetic testing, especially WES, is the cornerstone of diagnosis in congenital hypotonia. Theoretical diagnostic models which may increase prenatal detection are provided. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Adnexal torsion recurrence-is the adnexal twist degree a risk factor? A retrospective cohort study.

OBJECTIVE: To evaluate whether the adnexal twist degree is related to torsion recurrence and whether there is a dose-dependent correlation. DESIGN: A retrospective cohort study. SETTING: Single tertiary medical centre. POPULATION: The study includes non-pregnant patients operated, for the first time, for adnexal torsion, between 2011 and 2018. METHODS: Information regarding the degree of adnexal twist was collected from surgical reports. Recurrence was identified using a computerised database and ascertained via telephone with a response rate of 87.2% (253/290). MAIN OUTCOME MEASURES: Adnexal torsion recurrence rate. RESULTS: A total of 182 women who had undergone laparoscopic detorsion met the inclusion criteria. Twenty-two had torsion recurrence (12.1%). Adnexal twist degree in the primary event was associated with a higher recurrence risk: 4.3% of women with twist degree ≤360 (n = 3/70), 14.5% of women with twist degree of 361-720 (n = 9/62) and 20% of women with twist degree >720 (n = 10/50) (P = 0.03). The median twist degree was 540 (interquartile range [IQR] 360-855) and 720 (IQR 675-1080) degrees in the control and study groups, respectively (P = 0.005). Additional possibly associated factors for recurrence were evaluated. Age emerged as a possible risk factor, with a median age of 19 years in the recurrence group (IQR 14-27 years) versus 28.5 (IQR 19-36 years) in the non-recurrence group (P < 0.01). Logistic regression analysis revealed that together with age, adnexal twist degree remained significantly associated with torsion recurrence (odds ratio [OR] 1.98, 95% CI 1.09-3.61; P = 0.02). CONCLUSION: Adnexal twist degree was found to be positively associated with the risk of torsion recurrence. TWEETABLE ABSTRACT: Adnexal twist degree was found to be positively associated with the risk of torsion recurrence.

Optimal timing of fetal reduction from twins to singleton: earlier the better or later the better?

OBJECTIVES: To determine the rate of pregnancy complications and adverse obstetric and neonatal outcomes of twin pregnancies that were reduced to singleton at an early compared with a later gestational age. METHODS: This was a historical cohort study of dichorionic diamniotic twin pregnancies that underwent fetal reduction to singletons in a single tertiary referral center between January 2005 and February 2017. The study population was divided into two groups according to gestational age at fetal reduction: those performed at 11-14 weeks' gestation, mainly at the patient's request or as a result of a complicated medical or obstetric history; and selective reductions performed at 15-23 weeks for structural or genetic anomalies. The main outcome measures compared between pregnancies that underwent early reduction and those that underwent late reduction included rates of pregnancy complications, pregnancy loss, preterm delivery and adverse neonatal outcome. RESULTS: In total, 248 dichorionic diamniotic twin pregnancies were included, of which 172 underwent early reduction and 76 underwent late reduction. Although gestational age at delivery was not significantly different between the late- and early-reduction groups (38 weeks, (interquartile range (IQR), 36-40 weeks) vs 39 weeks (IQR, 38-40 weeks); P = 0.2), the rates of preterm delivery < 37 weeks (28.0% vs 14.0%; P = 0.01), < 34 weeks (12.0% vs 1.8%; P = 0.002) and < 32 weeks (8.0% vs 1.8%; P = 0.026) were significantly higher in pregnancies that underwent late reduction. Regression analysis revealed that late reduction of twins was an independent risk factor for preterm delivery, after adjustment for maternal age, parity, body mass index and the location of the reduced sac. Rates of early complications linked to the reduction procedure itself, such as infection, vaginal bleeding and leakage of fluids, were comparable between the groups (7.0% for early reduction vs 9.2% for late reduction; P = 0.53). There was no significant difference in the rate of pregnancy loss before 24 weeks (0.6% for early reduction vs 1.3% for late reduction; P = 0.52), and no cases of intrauterine fetal death at or after 24 weeks were documented. There was no significant difference in the prevalence of gestational diabetes mellitus, hypertensive disorders of pregnancy, preterm prelabor rupture of membranes or small-for-gestational age. The rates of respiratory distress syndrome (6.7% vs 0%; P = 0.002), need for mechanical ventilation (6.7% vs 0.6%; P = 0.01) and composite neonatal morbidity (defined as one or more of respiratory distress syndrome, sepsis, necrotizing enterocolitis, intraventricular hemorrhage, need for respiratory support or neonatal death) (10.7% vs 2.9%; P = 0.025) were higher in the late- than in the early-reduction group. Other neonatal outcomes were comparable between the groups. CONCLUSIONS: Compared with late first-trimester reduction of twins, second-trimester reduction is associated with an increased rate of prematurity and adverse neonatal outcome, without increasing the rate of procedure-related complications. Technological advances in sonographic diagnosis and more frequent use of chorionic villus sampling have enabled earlier detection of fetal anatomic and chromosomal abnormalities. Therefore, efforts should be made to complete early fetal assessment to allow reduction during the first trimester. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Perinatal outcome of monochorionic diamniotic twin pregnancy complicated by selective intrauterine growth restriction according to umbilical artery Doppler flow pattern: single-center study using strict fetal surveillance protocol.

OBJECTIVE: To determine the perinatal outcome of monochorionic diamniotic (MCDA) twin pregnancies complicated by selective intrauterine growth restriction (sIUGR), which were classified according to the umbilical artery (UA) Doppler flow pattern of the IUGR twin. METHODS: This was a retrospective cohort study of all MCDA twin pregnancies diagnosed with sIUGR and managed at a single tertiary referral center between 2012 and 2018. Cases were classified according to the UA Doppler flow pattern of the IUGR twin as Type I (positive end-diastolic flow), Type II (persistently absent/reversed end-diastolic flow) or Type III (intermittently absent/reversed end-diastolic flow). Patients with Type-II or -III sIUGR were hospitalized at 26-28 weeks of gestation for increased fetal surveillance. Perinatal and immediate and long-term neurodevelopmental outcomes were stratified according to the UA Doppler flow pattern at the final examination. Intact survival rate was defined as the number of infants surviving without neurological impairment, divided by the total number of fetuses. Composite adverse outcome, defined as any mortality, presence of severe brain lesions on postnatal transcranial ultrasound or severe neurological morbidity, was also assessed. RESULTS: Of 88 MCDA twin pregnancies with sIUGR included in the study, 28 underwent selective termination by cord occlusion using radiofrequency ablation, resulting in a perinatal survival rate of 89.3% and a median gestational age (GA) at delivery of 33.8 (interquartile range (IQR), 28.8-38.2) weeks for the large cotwin. Expectant management was employed in 60 cases. In 26 (43.3%) cases in the expectant-management group, the classification according to the UA Doppler flow pattern changed during gestation, resulting in 26 (43.3%) cases of Type-I, 22 (36.7%) cases of Type-II and 12 (20.0%) cases of Type-III sIUGR at the final examination. The perinatal survival rate of both twins with sIUGR Types I, II and III at the final examination was 100%, 81.8% and 75.0%, respectively (P = 0.04). Two cases of double fetal death and one case of single fetal death occurred 1-4 weeks after the Doppler pattern had changed from Type I or Type II to Type III. The median GA at delivery was 34.8 (IQR, 33.1-35.7) weeks in Type I, 30.3 (IQR, 28.6-32.1) weeks in Type II and 32.0 (IQR, 31.3-32.6) weeks in Type III (P < 0.01). The total intact survival rate was 100% for Type I, 77.3% for Type II and 75.0% for Type III (P < 0.001). Multivariate analysis demonstrated that early GA at diagnosis (odds ratio (OR), 0.83 (95% CI, 0.69-0.99); P = 0.04) and the presence of Type II or III vs Type I at the last examination (OR, 13.16 (95% CI, 1.53-113.32); P = 0.02) were associated with preterm birth < 32 weeks' gestation. Early GA at diagnosis was also associated with the composite adverse outcome (OR, 0.60 (95% CI, 0.36-0.99); P = 0.04). CONCLUSIONS: The classification system of MCDA pregnancy complicated by sIUGR, according to the UA Doppler flow pattern of the IUGR twin at final examination, is associated with perinatal outcome. Importantly, the UA Doppler flow pattern can change during gestation, which has an impact on the risk of fetal death. Nevertheless, under strict fetal surveillance, the perinatal outcome of these pregnancies is favorable. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Cephalic extraction versus breech extraction in second-stage caesarean section: a retrospective study.

OBJECTIVE: Our primary objective was to compare maternal and neonatal outcomes based on the attempted mode of extraction. Our secondary objective was to compare the outcomes based on the actual mode of extraction. DESIGN: A retrospective cohort study at a single tertiary centre between the years 2011 and 2019. SETTING: The study included 1028 cases of term pregnancies in vertex presentation that were delivered by caesarean section at the second stage of delivery. POPULATION: Patients were grouped according to the attempted mode of extraction: attempted cephalic extraction (674) and breech extraction (354). A subgroup analysis was conducted, comparing successful cephalic extraction (615), failed cephalic extraction (59) and breech extraction (354). METHODS: Both maternal and neonatal complication rates were compared between the groups. RESULTS: There were significantly more uterine incision extensions (27.4 versus 11.9%, P < 0.001) and increased need for blood transfusion (10.7 versus 6.2%, P = 0.018) in the cephalic extraction compared with the breech extraction group. The highest rate of uterine incision extensions (45.8%) and need for blood transfusion (22%) was in the subgroup of failed cephalic extraction. The rate of adverse neonatal outcomes was comparable between the two groups. However, in the subgroup of failed cephalic extraction, there were higher rates of low 1-minute Apgar scores, NICU hospitalisation and limb fractures compared with successful cephalic extractions and breech extractions (P = 0.016, 0.01, <0.001, respectively). CONCLUSIONS: Breech extraction in second-stage caesarean section is associated with fewer maternal complications compared wiith attempted cephalic extraction without increasing neonatal complication rates. TWEETABLE ABSTRACT: In breech versus cephalic extraction, breech extraction was found to have better outcomes in second-stage caesarean section.

Disparity in fetal growth between twin and singleton gestation: the role of adipokines.

OBJECTIVE: Twin pregnancies are characterized by unique pattern of attenuated fetal weight gain during late gestation compared with singleton gestation. The mechanism(s) responsible for regulating twin growth has not yet elucidated. Leptin and adiponectin are two adipocytokines implicated in metabolism and energy balance of fetuses, newborns and adults. Moreover, these hormones have been suggested to play a role in fetal growth. The objective of the study was to determine cord blood adiponectin and leptin in twins and singletons, with and without growth impairment. STUDY DESIGN: This was a case-control study. It included two groups of newborns, matched for gestational age and birth weight percentile: singleton (n=60 newborns) and twins (n=44 newborns). Adiponectin and leptin were determined in cord blood, and compared between the groups according to clinical and demographic characteristics. Non-parametric and parametric statistical methods were employed. RESULTS: Median adiponectin and leptin concentrations were lower in twins vs singletons (P<0.001 for both comparisons). Among small for gestational age newborns (SGA), median concentration of adiponectin (P=0.04), but not leptin (P=0.1), was lower in twins compared to singletons. In pooled analysis (singleton plus twins), cord blood adiponectin and leptin were strongly correlated with gestational age (P<0.001 and P=0.005, respectively) and birth weight (P<0.001 and P<0.001, respectively). Regression analysis revealed that plurality (P=0.02) was significantly and independently associated with cord blood adiponectin concentrations, after adjustment for confounding variables. Similar regression in which leptin was the independent variable revealed that only birth weight (P=0.01) was significantly and independently associated with cord blood leptin concentrations. CONCLUSIONS: Twin pregnancies are associated with lower cord blood concentrations of adiponectin and leptin compared with singleton gestations. However, only cord blood adiponectin, but not leptin, was lower in SGA neonates. Collectively, these data suggest that adiponectin may be implicated in the mechanism accounting for the growth disparity between twins and singletons.

Choosing between bad, worse and worst: what is the preferred mode of delivery for failure of the second stage of labor?

OBJECTIVE: To determine the preferred mode of delivery (vacuum, forceps or cesarean delivery) for second-stage dystocia. METHODS: Retrospective cohort study of women delivered by forceps, vacuum or cesarean delivery due to abnormalities of the second stage of labor. Primary outcome included neonatal and maternal composite adverse effects. RESULTS: A total of 547 women were included: 150 (27.4%) had forceps delivery, 200 (36.5%) had vacuum extraction, and 197 (36.1%) had cesarean section. The rate of neonatal composite outcome was significantly increased in vacuum extraction (27%) compared to forceps delivery (14.7%) or cesarean section (9.7%) (p < 0.001). There was no difference in the rate of maternal composite outcome among the groups. Both operative vaginal delivery modes were associated with significantly lower rate of postpartum infection compared to cesarean delivery (0% versus 3%, p = 0.004). CONCLUSION: Operative vaginal delivery was associated with reduced postpartum infection compared to cesarean section. Forceps delivery was associated with reduced risk for adverse neonatal outcome compared to vacuum extraction, with no increase in the risk of composite maternal complications.

Can middle cerebral artery peak systolic velocity predict polycythemia in monochorionic-diamniotic twins? Evidence from a prospective cohort study.

OBJECTIVE: The antenatal diagnosis of twin anemia-polycythemia sequence (TAPS) in monochorionic-diamniotic (MCDA) twin pregnancies is based on elevated peak systolic velocity in the middle cerebral artery (MCA-PSV) in the donor twin and decreased MCA-PSV in the recipient twin. However, the association between these parameters and polycythemia has not yet been established. The aim of this study was to determine whether MCA-PSV can predict polycythemia in MCDA pregnancies. METHODS: This was a prospective cohort study of MCDA pregnancies recruited at 14-18 weeks' gestation from a single tertiary care center between January 2011 and June 2014. Fetal MCA Doppler waveforms were recorded every 2 weeks from 18 weeks' gestation until delivery. Only those with an MCA-PSV measurement within 1 week of delivery were included in the analysis. Neonatal hematocrit level was determined in all twins from venous blood obtained within 4 h of delivery. Polycythemia was defined as a hematocrit of > 65%, and anemia as a hematocrit of < 45%. TAPS was diagnosed when an intertwin hemoglobin difference of > 8 g/dL and reticulocyte count ratio of > 1.7 were observed. RESULTS: Of 162 MCDA pregnancies followed during the study period, 69 had an MCA-PSV measurement within 1 week of delivery and were included in the study. Twenty-five neonates were diagnosed with polycythemia and nine twin pairs met the criteria for TAPS. In a pooled analysis, MCA-PSV was negatively correlated with neonatal hematocrit (P = 0.017, r = -0.215) and was significantly higher in anemic fetuses than in normal controls (1.15 multiples of the median (MoM) vs 1.02 MoM, respectively; P = 0.001). However, MCA-PSV was similar among polycythemic and normal fetuses (0.95 MoM vs 1.02 MoM, respectively; P = 0.47). Intertwin difference in MCA-PSV (delta MCA-PSV) was positively correlated with intertwin hematocrit difference (P = 0.002, r = 0.394). Moreover, twin pregnancies with an intertwin hematocrit difference of > 24% had a significantly greater delta MCA-PSV than did those with an intertwin hematocrit difference of ≤ 24% (delta MCA-PSV, 19 vs 5 cm/s; P < 0.001). CONCLUSIONS: MCA-PSV is not significantly decreased in polycythemic MCDA twins. However, delta MCA-PSV is associated with a large intertwin difference in hematocrit, and its use may be better than conventional methods for the risk assessment of TAPS. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Low molecular weight heparin therapy during pregnancy is associated with elevated circulatory levels of placental growth factor.

INTRODUCTION: Low molecular weight heparin (LMWH) has been shown to be effective in decreasing the recurrence of placenta-mediated complications of pregnant women. The aim of this study was to determine the effect of LMWH on circulating levels of soluble fms-like tyrosine kinase-1 (sFlt-1), soluble endoglin (sEng) and placental growth factor (PLGF) in pregnant women who required anticoagulation therapy. METHODS: A longitudinal prospective cohort study was performed including pregnant women in whom anticoagulation therapy by LMWH during pregnancy was clinically indicated (n = 33). Healthy pregnant women, matched for gestational age, who did not require thromboprophylaxis served as controls (n = 29). Maternal plasma samples were obtained throughout gestation every 4 weeks and stored at -70 °C. Maternal plasma concentrations of sFlt-1, sEng and PLGF were determined by ELISA and compared between the two groups. RESULTS: Patients treated with LMWH had significantly increased circulatory levels of PLGF during the third trimester compared with controls (28-34 weeks: 719.2 pg/ml vs 558.6 pg/ml at, p < 0.01; 35-40 weeks: 975.6 pg/ml vs 511.2 pg/ml, p < 0.01, respectively). In contrast, circulatory levels of sFlt-1 and sEng were similar between the LMWH treatment group and controls throughout gestation. Consistent with these findings, the ratio of sFlt-1/PLGF was lower in patients treated with LMWH compared to controls (28-34 weeks: 1.9 vs 7.2, p < 0.05; 35-40 weeks: 5 vs 12.9, p < 0.05, respectively). DISCUSSION: Anticoagulation treatment of pregnant women with LMWH is associated with a pro-angiogenic state. These findings may explain the effectiveness of LMWH in the prevention of placenta-mediated complications of pregnancy.

Current debate on the use of antibiotic prophylaxis for caesarean section.

Caesarean delivery is frequently complicated by surgical site infections, endometritis and urinary tract infection. Most surgical site infections occur after discharge from the hospital, and are increasingly being used as performance indicators. Worldwide, the rate of caesarean delivery is increasing. Evidence-based guidelines recommended the use of prophylactic antibiotics before surgical incision. An exception is made for caesarean delivery, where narrow-range antibiotics are administered after umbilical cord clamping because of putative neonatal benefit. However, recent evidence supports the use of pre-incision, broad-spectrum antibiotics, which result in a lower rate of maternal morbidity with no disadvantage to the neonate.

Parvovirus B19 infection in human pregnancy.

Human parvovirus B19 infection is widespread. Approximately 30-50% of pregnant women are nonimmune, and vertical transmission is common following maternal infection in pregnancy. Fetal infection may be associated with a normal outcome, but fetal death may also occur without ultrasound evidence of infectious sequelae. B19 infection should be considered in any case of nonimmune hydrops. Diagnosis is mainly through serology and polymerase chain reaction. Surveillance requires sequential ultrasound and Doppler screening for signs of fetal anaemia, heart failure and hydrops. Immunoglobulins, antiviral and vaccination are not yet available, but intrauterine transfusion in selected cases can be life saving.

Clinical significance of early (< 20 weeks) vs. late (20-24 weeks) detection of sonographic short cervix in asymptomatic women in the mid-trimester.

OBJECTIVE: The aim of this study was to determine whether the risk of early spontaneous preterm delivery (PTD) in asymptomatic women with a sonographic cervical length of ≤ 15 mm in the mid-trimester changes as a function of gestational age at diagnosis. METHODS: This cohort study included 109 asymptomatic patients with a sonographic cervical length of ≤ 15 mm diagnosed at 14-24 weeks of gestation. Women with a multifetal gestation, cerclage and a cervical dilatation of > 2 cm were excluded. The study population was stratified by gestational age at diagnosis (< 20 weeks vs. 20-24 weeks) and by cervical length (≤ 10 mm vs. 11-15 mm). The primary outcome variables were PTD at < 28 and < 32 weeks of gestation and the diagnosis-to-delivery interval. RESULTS: The median gestational age at diagnosis of a short cervix before 20 weeks and at 20-24 weeks was 18.9 and 22.7 weeks, respectively. Women diagnosed before 20 weeks had a higher rate of PTD at < 28 weeks (76.9% vs. 30.9%; P < 0.001) and at < 32 weeks (80.8% vs. 48.1%; P = 0.004), and a shorter median diagnosis-to-delivery interval (21 vs. 61.5 days, P = 0.003) than those diagnosed at 20-24 weeks. The rate of amniotic fluid sludge was higher among patients diagnosed with a short cervix at < 20 weeks of gestation than in those in whom it was diagnosed between 20 and 24 weeks (92.3% vs. 48.2%; P < 0.001). CONCLUSIONS: Asymptomatic women with a sonographic cervical length of ≤ 15 mm diagnosed before 20 weeks of gestation have a dramatic and significantly higher risk of early preterm delivery than women diagnosed at 20-24 weeks. These findings can be helpful to physicians in counseling these patients, and may suggest different mechanisms of disease leading to a sonographic short cervix before or after 20 weeks of gestation.

Plasma soluble endoglin concentration in pre-eclampsia is associated with an increased impedance to flow in the maternal and fetal circulations.

OBJECTIVES: To examine the relationship between abnormalities in uterine (UtA) and/or umbilical artery (UA) Doppler velocimetry and maternal plasma concentrations of soluble endoglin (sEng) in patients with pre-eclampsia (PE). METHODS: A cross-sectional study was conducted in 135 normal pregnant women and 69 patients with PE. Patients with PE were subclassified into four groups: those who had Doppler abnormalities in both the UtA and UA, patients who had Doppler abnormalities in the UtA alone, those who had Doppler abnormalities in the UA alone, and patients without Doppler abnormalities in either vessel. Plasma concentrations of sEng were determined by enzyme-linked immunosorbent assay. RESULTS: Among patients with PE, those with abnormal UtA and UA Doppler velocimetry had the highest median plasma concentration of sEng compared with any other group (P < 0.001, Kruskal-Wallis test). Women with PE with normal Doppler velocimetry in both vessels had the lowest median plasma concentration of sEng. There was a significant relationship between plasma concentrations of sEng and mean UtA resistance index (Spearman Rho = 0.5, P < 0.001) as well as UA pulsatility index (Spearman Rho = 0.4, P = 0.002). Multiple regression analysis suggested that Doppler abnormalities in the UtA and UA as well as gestational age at blood sampling contributed to plasma sEng concentrations (P < 0.001). CONCLUSIONS: Abnormalities of impedance to blood flow in the UtA and UA are associated with an excess of sEng in the circulation of mothers with PE. These findings suggest that the 'antiangiogenic state' in PE is partially reflected in abnormalities of Doppler velocimetry.

Adiponectin multimers in maternal plasma.

OBJECTIVE: Adiponectin is an anti-diabetic, anti-atherogenic, anti-inflammatory, and angiogenic adipokine that circulates in oligomeric complexes including: low molecular weight (LMW) trimers, medium molecular weight (MMW) hexamers, and high molecular weight (HMW) isoforms. The aim of this study was to determine whether there are changes in adiponectin multimers in pregnancy and as a function of maternal weight. STUDY DESIGN: In this cross-sectional study, plasma concentrations of total, HMW, MMW, and LMW adiponectin were determined in women included in three groups: (1) normal pregnant women of normal body mass index (BMI) (n = 466), (2) overweight pregnant women (BMI >or=25; n = 257), and (3) non-pregnant women of normal weight (n = 40). Blood samples were collected once from each woman between 11 and 42 weeks of gestation. Plasma adiponectin multimer concentrations were determined by enzyme-linked immunosorbent assay (ELISA). Non-parametric statistics were used for analysis. RESULTS: (1) The median HMW adiponectin concentration and the median HMW/total adiponectin ratio were significantly higher, and the median LMW adiponectin concentration was significantly lower in pregnant women than in non-pregnant women. (2) Among pregnant women, the median plasma concentration of total, HMW, and MMW adiponectin was significantly higher in normal weight women than in overweight patients. (3) Maternal HMW was the most prevalent adiponectin multimer regardless of gestational age or BMI status. (4) There were no significant differences in the median concentration of total, MMW, and LMW adiponectin and their relative distribution with advancing gestation. CONCLUSION: Human pregnancy is characterized by quantitative and qualitative changes in adiponectin multimers, especially the most active isoform, HMW adiponectin.

The effect of gestational age and labor on placental growth hormone in amniotic fluid.

OBJECTIVE: Placental growth hormone (PGH) is produced by trophoblast. This hormone becomes detectable in maternal serum during the first trimester of pregnancy. Its concentration increases as term approaches and becomes undetectable within one hour of delivery. PGH has important biological properties, including somatogenic (growth promotion), lactogenic, and lipolytic activity. Recently, PGH has been detected in amniotic fluid (AF) of midtrimester pregnancies. The purpose of this study was to determine whether PGH concentrations in AF change with advancing gestational age and in labor at term. DESIGN: AF was assayed for PGH concentrations in samples obtained from patients undergoing genetic amniocentesis between 14 and 18 weeks of gestation (n=67), normal patients at term not in labor (n=24), and pregnant women at term in labor (n=51). PGH concentrations were determined by ELISA. Non-parametric statistics were used for analysis. RESULTS: (1) PGH was detected in all AF samples; (2) patients in the midtrimester had a higher median concentration of PGH in AF than those at term (midtrimester: median: 3140.5 pg/ml; range: 1124.2-13886.5 vs. term: median: 2021.1pg/ml; range: 181.6-8640.8; p<0.01); (3) there was no difference in the median concentration of PGH between women at term, not in labor, and those in labor (term not in labor: median: 2113.4pg/ml; range: 449.3-8640.8 vs. term in labor: median: 2004.1pg/ml; range: 181.6-8531.5; p=0.73). CONCLUSIONS: (1) PGH is detectable in AF at both mid- and third trimesters; (2) the median AF concentration of PGH is significantly lower at term when compared to the second trimester; (3) labor at term is not associated with changes in the AF concentration of PGH. The role of this unique placental hormone now found in the fetal compartment requires further investigation.

Clinical significance of the presence of amniotic fluid 'sludge' in asymptomatic patients at high risk for spontaneous preterm delivery.

OBJECTIVES: To determine the clinical significance of the presence of amniotic fluid (AF) 'sludge' among asymptomatic patients at high risk for spontaneous preterm delivery. METHODS: This retrospective case-control study included 281 patients with (n = 66) or without (n = 215) AF 'sludge', who underwent transvaginal ultrasound examination between 13 and 29 completed weeks of gestation. Patients with threatened preterm labor, multiple gestation, fetal anomalies, placenta previa or uterine contractions were excluded. RESULTS: The prevalence of AF 'sludge' in the study population was 23.5% (66/281). The rates of spontaneous preterm delivery at < 28 weeks, < 32 weeks, < 35 weeks and < 37 weeks of gestation were 14.7% (29/197), 21.3% (46/216), 28.7% (62/216) and 42.1% (91/216), respectively. Patients with 'sludge' had: (1) a higher rate of spontaneous preterm delivery at < 28 weeks (46.5% (20/43) vs. 5.8% (9/154); P < 0.001), < 32 weeks (55.6% (25/45) vs. 12.3% (21/171); P < 0.001) and < 35 weeks (62.2% (28/45) vs. 19.9% (34/171); P < 0.001); (2) a higher frequency of clinical chorioamnionitis (15.2% (10/66) vs. 5.1% (11/215); P = 0.007), histologic chorioamnionitis (61.5% (40/65) vs. 28% (54/193); P < 0.001) and funisitis (32.3% (21/65) vs. 19.2% (37/193); P = 0.03); (3) a higher frequency of preterm prelabor rupture of membranes (PROM) (39.4% (26/66) vs. 13.5% (29/215); P < 0.001), lower gestational age at preterm PROM (median 24.7 (interquartile range (IQR), 22.3-28.1) weeks vs. 32.3 (IQR, 27.7-34.8) weeks; P < 0.001); and (4) shorter median ultrasound-to-delivery interval ('sludge' positive 127 days (95% CI, 120-134 days) vs. 'sludge' negative 161 days (95% CI, 153-169 days); P < 0.001) and ultrasound-to-preterm PROM interval ('sludge' positive 23 days (95% CI, 7-39 days) vs. 'sludge' negative 57 days (95% CI, 38-77 days); P = 0.003) than those without 'sludge'. AF 'sludge' was an independent explanatory variable for the occurrence of spontaneous preterm delivery at < 28 weeks, < 32 weeks and < 35 weeks, preterm PROM, microbial invasion of the amniotic cavity (MIAC) and histologic chorioamnionitis. Moreover, the combination of a cervical length < 25 mm and 'sludge' conferred an odds ratio of 14.8 and 9.9 for spontaneous preterm delivery at < 28 weeks and < 32 weeks, respectively. CONCLUSIONS: AF 'sludge' is an independent risk factor for spontaneous preterm delivery, preterm PROM, MIAC and histologic chorioamnionitis in asymptomatic patients at high risk for spontaneous preterm delivery. Furthermore, the combination of 'sludge' and a short cervix confers a higher risk for spontaneous preterm delivery at < 28 weeks and < 32 weeks than a short cervix alone.

Fetal thymus size as a predictor of chorioamnionitis in women with preterm premature rupture of membranes.

OBJECTIVE: Emerging evidence indicates that chorioamnionitis is associated with a significant decrease in thymic size at birth in very low birth weight (VLBW) preterm infants. The aim of this study was to determine whether decreased fetal thymus size is associated with histological or clinical chorioamnionitis in patients with preterm premature rupture of membranes (PROM). METHODS: Twenty-one patients between 24 and 35 weeks of gestation with preterm PROM were included. Serial ultrasound examinations were performed during the latency period, and measurements of the fetal thymus size were obtained. Small thymus was defined as a thymus perimeter < or = 5th percentile according to a fetal thymus nomogram, which was based on measurements of 403 fetuses. Diagnosis of chorioamnionitis was made using neonatal clinical parameters and histological examinations of the placentas. RESULTS: In our study 13 patients presented with thymus size below the 5th percentile. Among the 13 patients with small thymus, nine (69%) had clinical or histological findings consistent with the diagnosis of chorioamnionitis. All eight women with a normal-sized thymus had no evidence of clinical or histological chorioamnionitis. Fetal thymus perimeter < or = 5th percentile yielded a sensitivity of 100%, specificity of 66.7%, a positive predictive value of 69% and a negative predictive value of 100% for identifying chorioamnionitis in patients with preterm PROM. CONCLUSIONS: Fetal thymus size is decreased in women with preterm PROM and chorioamnionitis. Measurement of the fetal thymus might allow an early diagnosis of chorioamnionitis in cases of preterm PROM. Normal thymus size might be used to rule out latent intrauterine infection.

Maternal serum adiponectin levels during human pregnancy.

OBJECTIVE: Pregnancy is a unique situation characterized by insulin resistance. The role of adiponectin, an insulin-sensitizing hormone, has not been completely clarified during pregnancy. The aim of this cross-sectional study was to evaluate adiponectin levels during pregnancy and postpartum. STUDY DESIGN: Adiponectin and leptin levels were tested in 80 pregnant women, 20 in each trimester (mean gestational age 10.5+/-1.9; 19.3+/-4.9; 39.3+/-0.8 weeks,) as well as 4 days postpartum. RESULTS: Adiponectin levels during first (13.3+/-3.6 micro g/ml), second (12.6+/-4.4 micro g/ml) and third trimester (11.2+/-3.7 micro g/ml) did not differ and were significantly higher than postpartum levels (8.8+/-2.1 micro g/ml; P<0.0001, P<0.004 and P<0.02, respectively). CONCLUSION: Despite increased insulin resistance during pregnancy, no significant alterations in adiponectin levels were observed. This may imply that the regulation of adiponectin during gestation is altered. The elevated gestational adiponectin levels are consistent with increased 'adiponectin resistance' during pregnancy.

The use of high-dimensional biology (genomics, transcriptomics, proteomics, and metabolomics) to understand the preterm parturition syndrome.

High-dimensional biology (HDB) refers to the simultaneous study of the genetic variants (DNA variation), transcription (messenger RNA [mRNA]), peptides and proteins, and metabolites of an organ, tissue, or an organism in health and disease. The fundamental premise is that the evolutionary complexity of biological systems renders them difficult to comprehensively understand using only a reductionist approach. Such complexity can become tractable with the use of "omics" research. This term refers to the study of entities in aggregate. The current nomenclature of "omics" sciences includes genomics for DNA variants, transcriptomics for mRNA, proteomics for proteins, and metabolomics for intermediate products of metabolism. Another discipline relevant to medicine is pharmacogenomics. The two major advances that have made HDB possible are technological breakthroughs that allow simultaneous examination of thousands of genes, transcripts, and proteins, etc., with high-throughput techniques and analytical tools to extract information. What is conventionally considered hypothesis-driven research and discovery-driven research (through "omic" methodologies) are complementary and synergistic. Here we review data which have been derived from: 1) genomics to examine predisposing factors for preterm birth; 2) transcriptomics to determine changes in mRNA in reproductive tissues associated with preterm labour and preterm prelabour rupture of membranes; 3) proteomics to identify differentially expressed proteins in amniotic fluid of women with preterm labour; and 4) metabolomics to identify the metabolic footprints of women with preterm labour likely to deliver preterm and those who will deliver at term. The complementary nature of discovery science and HDB is emphasised.