The use of vaginal progesterone as a maintenance therapy in women with arrested preterm labor: a double-blind placebo-randomized controlled trial.

BACKGROUND: The efficacy of maintenance tocolytic therapy after successful arrest of preterm labor remains controversial. The purpose of this study was to evaluate the efficacy of 400 mg of daily vaginal progesterone (cyclogest) after successful parenteral tocolysis to increase latency period and improvement of neonatal outcomes in women with threatened preterm labor. MATERIALS AND METHODS: In this randomized, double-blind, placebo-controlled trial, 85 participants were randomly allocated to either 400 mg daily of vaginal progesterone (n = 45) or placebo (n = 40) until 34 weeks of gestation. The primary outcomes were the time until delivery (latency period) and cervical length after 1 week of treatment. Secondary outcome were GA on delivery, type of delivery, incidence of low birth weight, perinatal morbidity and mortality. RESULTS: Longer mean latency until delivery (53.6 ± 16.8 versus 34.5 ± 12.9) days p = .0001; longer mean of gestational age on delivery (37.5 ± 2.2 versus 34.2 ± 2.1) weeks p = .0001; cervical length after 1 week of treatment (27.5 ± 5.5 versus 20.7 ± 3.1) mm p = .0001; low birth weight 12 (29.3%) versus 19 (57.6%) p = .01; and NICU admission 9 (22%) versus 15 (45.5%), were significantly different between the two groups. No significant differences were found between neonatal death 1 (2.4%) versus 2 (6.1%), p = .43; RDS 5 (12.2%) versus 8 (24.2%), p = .17; and need to mechanical ventilator 2 (5.4%) versus 6 (18.2%) p = .136, for the progesterone and placebo groups, respectively. CONCLUSION: Daily administration of 400 mg vaginal progesterone after successful parenteral tocolysis may increase latency preceding delivery and improves cervical shortening and neonatal outcome in women with preterm labor. Further confirmatory studies are warranted.

Consensus on Training and Assessment of Competence in Performing Chorionic Villus Sampling and Amniocentesis: An International Delphi Survey.

INTRODUCTION: The aim of this study was to obtain expert consensus on the content of a curriculum for learning chorionic villus sampling (CVS) and amniocentesis (AC) and the items of an assessment tool to evaluate CVS and AC competence. METHODS: We used a 3-round iterative Delphi process. A steering committee supervised all processes. Seven international collaborators were identified to expand the breadth of the study internationally. The collaborators invited fetal medicine experts to participate as panelists. In the first round, the panelists suggested content for a CVS/AC curriculum and an assessment tool. The steering committee organized and condensed the suggested items and presented them to the panelists in round 2. In the second round, the panelists rated and commented on the suggested items. The results were processed by the steering committee and presented to the panelists in the third round, where final consensus was obtained. Consensus was defined as support by more than 80% of the panelists for an item. RESULTS: Eighty-six experts agreed to participate in the study. The panelists represented 16 countries across 4 continents. The final list of curricular content included 12 theoretical and practical items. The final assessment tool included 11 items, systematically divided into 5 categories: pre-procedure, procedure, post-procedure, nontechnical skills, and overall performance. These items were provided with behavioral scale anchors to rate performance, and an entrustment scale was used for the final overall assessment. CONCLUSION: We established consensus among international fetal medicine experts on content to be included in a CVS/AC curriculum and on an assessment tool to evaluate CVS/AC skills. These results are important to help transition current training and assessment methods from a time- and volume-based approach to a competency-based approach which is a key step in improving patient safety and outcomes for the 2 most common invasive procedures in fetal medicine.

Circulating syndecan-1 is reduced in pregnancies with poor fetal growth and its secretion regulated by matrix metalloproteinases and the mitochondria.

Fetal growth restriction is a leading cause of stillbirth that often remains undetected during pregnancy. Identifying novel biomarkers may improve detection of pregnancies at risk. This study aimed to assess syndecan-1 as a biomarker for small for gestational age (SGA) or fetal growth restricted (FGR) pregnancies and determine its molecular regulation. Circulating maternal syndecan-1 was measured in several cohorts; a large prospective cohort collected around 36 weeks' gestation (n = 1206), a case control study from the Manchester Antenatal Vascular service (285 women sampled at 24-34 weeks' gestation); two prospective cohorts collected on the day of delivery (36 + 3-41 + 3 weeks' gestation, n = 562 and n = 405 respectively) and a cohort who delivered for preterm FGR (< 34 weeks). Circulating syndecan-1 was consistently reduced in women destined to deliver growth restricted infants and those delivering for preterm disease. Syndecan-1 secretion was reduced by hypoxia, and its loss impaired proliferation. Matrix metalloproteinases and mitochondrial electron transport chain inhibitors significantly reduced syndecan-1 secretion, an effect that was rescued by coadministration of succinate, a mitochondrial electron transport chain activator. In conclusion, circulating syndecan-1 is reduced among cases of term and preterm growth restriction and has potential for inclusion in multi-marker algorithms to improve detection of poorly grown fetuses.

Placental Growth Factor and Adverse Obstetric Outcomes in a Mixed-Risk Cohort of Women Screened for Preeclampsia in the First Trimester of Pregnancy.

OBJECTIVE: The study aimed to investigate the association between placental growth factor (PlGF) and adverse obstetric outcomes in a mixed-risk cohort of pregnant women screened for preeclampsia (PE) in the first trimester. METHODS: We included women with singleton pregnancies screened for PE between April 2014 and September 2016. Outcome data were retrieved from the New South Wales Perinatal Data Collection (NSW PDC) by linkage to the prenatal cohort. Adverse outcomes were defined as spontaneous preterm birth (sPTB) before 37-week gestation, birth weight (BW) below the 3rd centile, PE, gestational hypertension (GH), stillbirth, and neonatal death. RESULTS: The cohort consisted of 11,758 women. PlGF multiple of the median (MoM) was significantly associated with maternal sociodemographic characteristics (particularly smoking status and parity) and all biomarkers used in the PE first trimester screening model (notably pregnancy-associated plasma protein A MoM and uterine artery pulsatility index [PI] MoM). Low levels of PlGF (<0.3 MoM and <0.5 MoM) were independently associated with sPTB, low BW, PE, GH, and a composite adverse pregnancy outcome score, with odds ratios between 1.81 and 4.44 on multivariable logistic regression analyses. CONCLUSIONS: Low PlGF MoM levels are independently associated with PE and a range of other adverse pregnancy outcomes. Inclusion of PlGF should be considered in future models screening for adverse pregnancy outcomes in the first trimester.

Maternal cardiovascular risk after hypertensive disorder of pregnancy.

BACKGROUND AND OBJECTIVE: Hypertensive disorders of pregnancy (HDPs) affect 5%-10% of pregnancies and have been associated with excess maternal cardiovascular disease (CVD) risk. The primary aim of this study was to reliably estimate absolute and relative risks of CVD after HDP. METHODS: A retrospective cohort of women who had singleton pregnancies in New South Wales, Australia, between 2002 and 2016 and identified using linked population health administrative databases. The primary exposure was new-onset HDP (pre-eclampsia/eclampsia and gestational hypertension), and the endpoint was hospitalisation or death due to ischaemic or hypertensive heart disease, or stroke. Kaplan-Meier analysis estimated risks among mothers following their first birth, and multivariable time-dependent Cox regression estimated the association between HDP and CVD. RESULTS: Among 528 106 women, 10.3% experienced HDP in their first pregnancy. The 10-year estimated risk of CVD was 2.1 per 1000 if no HDP and 5.5 per 1000 following HDP. Adjusting for demographics, gestational diabetes, small for gestational age and preterm birth, we found that there was an interaction between smoking and HDP, and a larger effect of early-onset (<34 weeks) HDP, compared with late-onset HDP. The HR for women with early-onset HDP who did not smoke was 4.90 (95% CI 3.00 to 7.80) and the HR for those who did smoke was 23.5 (95% CI 13.5 to 40.5), each compared with women without HDP who did not smoke. CONCLUSION: In this nationally representative Australian cohort, HDP, especially early onset, conferred a clear increase in the risk of CVD, with amplification by smoking. Targeted preventive health, during and after pregnancy, could prevent a substantial burden of CVD among childbearing women.

Cesarean delivery: Trend in indications over three decades within a major city hospital network.

INTRODUCTION: The cesarean delivery rate has been increasing globally in recent decades. The reasons for this are complex and subject to ongoing debate. Investigation of the indications for cesarean delivery and how these have changed over an extended period of time could provide insight into the reasons for changing obstetric practice. Our objective was to explore contributing factors to the increasing rate of cesarean delivery by examining the incidence of and indications for cesarean delivery over the past three decades at our institutions. MATERIAL AND METHODS: We conducted a retrospective observational study of all cesarean deliveries, from 24 weeks' gestational age onwards, within an inner-city hospital network in Sydney, Australia, between August 1989 and December 2016. The primary outcome measures were the rates of and indications for emergency and planned cesarean delivery. We also examined our data within the Robson 10-Group Classification system. RESULTS: There were 147 722 births over the study period, with 37 309 cesarean deliveries for an overall rate of 25.3%. The rate of cesarean delivery increased from 18.7% in 1989-1994 (8.7% emergency, 10% planned) to 30.4% in 2010-2016 (11.4% emergency, 19% planned). Emergency cesarean delivery for slow progress increased from 3.4% to 5.5% of all births (a relative increase of 62%) and other emergency cesareans mainly performed for suspected intrapartum fetal compromise increased from 5.2% to 5.6% (a relative increase of 8%). Previous uterine surgery (predominantly cesarean section) was the largest contributor to the increase in planned procedures from 3.8% to 9.0% of all births, and 29% of all cesarean deliveries. Primary cesarean delivery for planned antenatal fetal indications, previous pregnancy problems, multiple gestation and maternal choice all increased substantially in combined rate from 0.7% to 4.9%. Cesarean rates in Robson groups 6, 7 and 8 (term breech and multiple gestations) increased most over time. CONCLUSIONS: The increased rate of cesarean delivery is mainly attributable to a greater number of procedures performed for slow progress in labor, breech presentation or repeat cesarean section.

Epigenetic aging in newborns: role of maternal diet.

BACKGROUND: Epigenetic aging is associated with higher risk of cardiovascular disease, cancer, and all-cause mortality and may be a mechanistic link between early-life exposures, such as maternal dietary characteristics during pregnancy, and risk of adult disease. OBJECTIVES: We sought to determine the early-life risk factors for newborn epigenetic aging, specifically maternal dietary macronutrient intake, and whether epigenetic aging is associated with cardiovascular health markers in the newborn. METHODS: Epigenetic age acceleration of 169 newborns was measured from saliva using the Horvath age calculator. Maternal diet during pregnancy was assessed using food-frequency questionnaires. RESULTS: Newborns with positive age acceleration were more likely to be female and have greater body fatness. Maternal intakes of saturated fat [6.2 wk epigenetic age acceleration (95% CI: 1.0, 11.3) per 5% of energy; P = 0.02] and monounsaturated fat [12.4 wk (95% CI: 4.2, 20.5) per 5% of energy; P = 0.003] were associated with higher epigenetic age acceleration in the newborn. The strongest association of individual fatty acids were for palmitoleic acid (25.3 wk; 95% CI: 11.4, 39.2; P = 0.0004), oleic acid (2.2 wk; 95% CI: 0.8, 3.6; P = 0.002), and palmitic acid (2.9 wk; 95% CI: 1.0, 4.9; P = 0.004) per 1% of energy intake. Vitamin D supplementation was associated with lower epigenetic age acceleration (-8.1 wk; 95% CI: -14.5, -1.7; P = 0.01). Epigenetic age acceleration was associated with aortic intima-media thickness in preterm infants [1.0 µm (95% CI: 0.2, 1.8) per week of epigenetic age acceleration; P = 0.01], but not among those born at term (P = 0.78). Epigenetic age acceleration was not associated with heart rate variability in either preterm or term born infants (both P > 0.2). CONCLUSIONS: This study provides evidence of maternal dietary characteristics that are associated with epigenetic aging in the offspring. Prospective intervention studies are required to determine whether such associations are causal.

A Novel Early Pregnancy Risk Prediction Model for Gestational Diabetes Mellitus.

INTRODUCTION: Accurate early risk prediction for gestational diabetes mellitus (GDM) would target intervention and prevention in women at the highest risk. We evaluated novel biomarker predictors to develop a first-trimester risk prediction model in a large multiethnic cohort. METHODS: Maternal clinical, aneuploidy and pre-eclampsia screening markers (PAPP-A, free hCGß, mean arterial pressure, uterine artery pulsatility index) were measured prospectively at 11-13+6 weeks' gestation in 980 women (248 with GDM; 732 controls). Nonfasting glucose, lipids, adiponectin, leptin, lipocalin-2, and plasminogen activator inhibitor-2 were measured on banked serum. The relationship between marker multiples-of-the-median and GDM was examined with multivariate regression. Model predictive performance for early (< 24 weeks' gestation) and overall GDM diagnosis was evaluated by receiver operating characteristic curves. RESULTS: Glucose, triglycerides, leptin, and lipocalin-2 were higher, while adiponectin was lower, in GDM (p < 0.05). Lipocalin-2 performed best in Caucasians, and triglycerides in South Asians with GDM. Family history of diabetes, previous GDM, South/East Asian ethnicity, parity, BMI, PAPP-A, triglycerides, and lipocalin-2 were significant independent GDM predictors (all p < 0.01), achieving an area under the curve of 0.91 (95% confidence interval [CI] 0.89-0.94) overall, and 0.93 (95% CI 0.89-0.96) for early GDM, in a combined multivariate prediction model. CONCLUSIONS: A first-trimester risk prediction model, which incorporates novel maternal lipid markers, accurately identifies women at high risk of GDM, including early GDM.

A first trimester prediction model for gestational diabetes utilizing aneuploidy and pre-eclampsia screening markers.

OBJECTIVE: We examined whether first trimester aneuploidy and pre-eclampsia screening markers predict gestational diabetes mellitus (GDM) in a large multi-ethnic cohort and the influence of local population characteristics on markers. METHODS: Clinical and first trimester markers (mean arterial pressure (MAP), uterine artery pulsatility index (UtA PI), pregnancy associated plasma protein A (PAPP-A), free-ß human chorionic gonadotropin (free-hCGß)) were measured in a case-control study of 980 women (248 with GDM, 732 controls) at 11 to 13 + 6 weeks' gestation. Clinical parameters, MAP-, UtA PI-, PAPP-A-, and free-hCGß-multiples-of-the-median (MoM) were compared between GDM and controls; stratified by ethnicity, parity, and GDM diagnosis <24 versus ≥24 weeks' gestation. GDM model screening performance was evaluated using AUROC. RESULTS: PAPP-A- and UtA PI-MoM were significantly lower in GDM versus controls (median ((IQR) PAPP-A-MoM 0.81 (0.58-1.20) versus 1.00 (0.70-1.46); UtA PI-MoM 1.01 (0.82-1.21) versus 1.05 (0.84-1.29); p < .05). Previous GDM, family history of diabetes, south/east Asian ethnicity, parity, BMI, MAP, UtA PI, and PAPP-A were significant predictors in multivariate analysis (p < .05). The AUC for a model based on clinical parameters was 0.88 (95%CI 0.85-0.92), increasing to 0.90 (95%CI 0.87-0.92) with first trimester markers combined. The combined model best predicted GDM <24 weeks' gestation (AUC 0.96 (95%CI 0.94-0.98)). CONCLUSIONS: Addition of aneuploidy and pre-eclampsia markers is cost-effective and enhances early GDM detection, accurately identifying early GDM, a high-risk cohort requiring early detection, and intervention. Ethnicity and parity modified marker association with GDM, suggesting differences in pathophysiology and vascular risk.

First trimester prediction and prevention of adverse pregnancy outcomes related to poor placentation.

PURPOSE OF REVIEW: To summarize recent research findings related to first trimester prediction and prevention of adverse pregnancy outcomes associated with poor placentation. Recent publications related to prediction and prevention of preeclampsia, intrauterine growth restriction (IUGR) and stillbirth were reviewed. RECENT FINDINGS: Researchers continue to identify markers that will help predict pregnancies that go on to develop preeclampsia through screening at 11-13 weeks. A number of multivariate algorithms describing risks for preeclampsia have been published and some of these have been validated in independent populations. A large randomized controlled trial has proven the efficacy of a first trimester prediction - prevention programme for preeclampsia with an 80% reduction in prevalence of disease leading to delivery less than 34 weeks. Screening tools for IUGR and stillbirth are less advanced and require further validation in other populations. The value of these models in preventing disease still needs to be demonstrated. SUMMARY: Significant progress has been made in developing predictive and preventive strategies which can affect the prevalence of severe early-onset preeclampsia. This approach could be adopted for population-based screening aiming to prevent this disease.

Fly Thru imaging: Feasibility study and comparison with outpatient hysteroscopy.

BACKGROUND: In the investigation of abnormal uterine bleeding, hysteroscopy with endometrial biopsy is considered the gold standard. Fly Thru™ imaging is a new application used to generate virtual hysteroscopy clips. AIMS: We aimed to investigate the feasibility and diagnostic accuracy of sonohysterogram with virtual hysteroscopy as an alternative to outpatient diagnostic hysteroscopy. MATERIALS AND METHODS: Two separate cohorts of women were recruited. The first cohort was to assess feasibility of the application. The second cohort included women recruited to undergo a sonohysterogram, with virtual hysteroscopy, prior to their scheduled outpatient hysteroscopy. Pain scores were recorded after each procedure. RESULTS: Sixteen women were recruited to the feasibility cohort and virtual hysteroscopy post-processing was successfully applied in 14/16 (88%). Clips were produced in less than one minute in 12/16 (75%). Both tubal ostia were identified in 12/16 (75%). Twenty-nine women were enrolled in the correlation cohort with two women excluded as they did not proceed to hysteroscopy according to study protocol. Virtual hysteroscopy, successfully generated in 23/27 women (85%), detected all intra-cavitary pathologies (9/27) detected on outpatient hysteroscopy. Tubal ostia were visualised less often with virtual hysteroscopy (37%) when compared with outpatient hysteroscopy (74%). Sonohysterogram with virtual hysteroscopy was associated with less pain with a median difference in pain score of 2 (interquartile range 1.0-4.0, P < 0.0001). CONCLUSIONS: Sonohysterogram with virtual hysteroscopy is feasible; however, the addition of virtual hysteroscopy to sonohysterogram alone has limited value. Larger studies are required to determine whether it can be used as a diagnostic alternative to outpatient hysteroscopy.

First trimester ultrasound assessment for fetal aneuploidy.

Screening tests for trisomy 21 have gradually become more refined and now involve complex statistical models that combine demographic, biophysical, and biochemical parameters to produce individualized risk estimates for pregnant women. An understanding of the evolution of the principles, methods, and statistical techniques applied to Down syndrome screening is valuable as these processes can be transferred to other, more prevalent, adverse pregnancy outcomes. First trimester ultrasound forms the foundation of this process.

Auditing ultrasound assessment of fetal nuchal translucency thickness: a review of Australian National Data 2002-2008.

BACKGROUND: Nuchal translucency (NT) measurement is the ultrasound component of first trimester combined screening for Down syndrome. In 2002, a NT ultrasound education and monitoring program was established in Australia. Between 2002 and 2008, a total of 728,502 NT scans were audited through this process. OVERALL AIM: To audit the availability and performance of certified operators measuring NT following implementation of the Australian education and monitoring program in 2002. METHODS: Retrospective review of the central database that is used to monitor performance of individuals and practices performing NT scans in both public and private practice settings throughout Australia between 2002 and 2008. The performance of operators was assessed by a widely used international standard - that 40-60% of NT measurements should be above the median value for gestational age. RESULTS: The number of certified operators has increased (from 184 in 2002 to 477 in 2008). There is wide variation between states in the number of operators per birth. The percentage of certified operators with a measurement distribution meeting the international standard has increased from 40% in 2002 to 55% in 2008. Greatest improvement has been seen in operators performing 30-199 scans per year. There has been no overall improvement in performance over the last three audit cycles. CONCLUSIONS: The number of operators certified to perform the NT scan has increased since 2002, although availability in some states remains low. An initial improvement in performance of operators appears to have reached a plateau. It is time to become more proactive in engaging operators in the audit cycle.

Intra-abdominal masses: prenatal differential diagnosis and management.

Intra-abdominal masses and cystic lesions are not commonly identified during the routine 20-week anomaly scan but are not infrequently seen as incidental findings during a third trimester scan assessing fetal growth and well being. This review looks at the potential differential diagnosis of masses and cysts seen prenatally and aims to define a method of assessment that will help limit the differential diagnosis before delivery.

Outcome of antenatally diagnosed sacrococcygeal teratomas: single-center experience (1993-2004).

AIMS: Sacrococcygeal teratomas (SCTs) are the commonest neonatal tumors with an incidence of approximately 1:30,000. There are few large single-center series and even fewer describing both their antenatal and postnatal course. We report the outcome of all fetuses investigated at a tertiary fetal medicine center with this diagnosis. METHOD: Demographic details were obtained from a prospectively maintained database. Patient records were examined for additional data including antenatal and postnatal interventions. Data were described as median (range). RESULTS: Forty-one SCTs were diagnosed antenatally during the period 1993 to 2004. Twelve were excluded from subsequent analysis (single antenatal visit or attending for second opinion [n = 6] and termination of pregnancy [n = 6]). Twelve underwent fetal intervention (laser vessel ablation [n = 4], alcohol sclerosis [n = 3], cyst drainage [n = 2], amniodrainage [n = 2], vesicoamniotic shunt [n = 1]) for fetal hydrops and polyhydramnios to aid in delivery and to prevent obstructive uropathy developing in the fetus. Of these, 3 died in utero and 9 survived to be born (median gestational age, 33 weeks [27-37 weeks]). A further 3 died in the neonatal period. There are 6 long-term survivors (50%) from this group. Seventeen infants, without intervention, were born at median gestational age 38 weeks (26-40 weeks). One infant with severe cardiac anomalies died on the day of birth. All surviving infants had definitive excisional surgery at a median of 2 days (1-16 days). Current median follow-up of survivors is 39 months (8-86 months). There have been no recurrences. One child has mild constipation, and 3 are awaiting cosmetic revision of their scars. CONCLUSIONS: The overall survival of antenatally diagnosed SCT is approximately 77%, with the development of hydrops and others requiring in utero intervention carrying a poor prognosis. Otherwise, the outcome after surgical excision is excellent.

Does nuchal translucency have a role in fetal cardiac screening?

Increased nuchal translucency is the strongest single marker for chromosomal abnormality. Consequently, it is currently becoming established as the foundation of most early screening programmes for Down syndrome. In the absence of chromosomal abnormality, increased nuchal translucency has been shown to be associated with other congenital anomalies including cardiac defects. Several datasets have now reported this association and here these are reviewed to assess the effectiveness of nuchal translucency measurement as a screening tool for the prenatal detection of congenital heart disease.