Factors related to fetal demise in cases with congenital heart defects.

BACKGROUND: Congenital heart defects are the most common congenital anomaly. Despite the increasing survival of these children, there is still an increased incidence of fetal demise, frequently attributed to cardiac failure. Considering that abnormal placental development has been described in congenital heart disease, our hypothesis is that placental insufficiency may contribute to fetal death in congenital heart disease. OBJECTIVE: This study aimed to assess cases with fetal congenital heart disease and intrauterine demise, and analyze factors that are related to the demise. STUDY DESIGN: All congenital heart disease cases diagnosed prenatally during the period January 2002 to January 2021 were selected from the regional prospective congenital heart disease registry, PRECOR. Multiple pregnancies and pregnancies with fetal trisomy 13 or 18, triploidy, and Turner's syndrome were excluded from the analysis, because fetal demise is attributed to the chromosomal abnormality in these cases. Cases were categorized into 4 groups based on the possible cause of fetal death as follows: cardiac failure, additional (genetic) diagnosis, placental insufficiency, and a group in which no cause was found. A separate analysis was performed for isolated congenital heart disease cases. RESULTS: Of the 4806 cases in the PRECOR registry, 112 had fetal demise, of which 43 were excluded from the analysis (13 multiple pregnancies, 30 genetic). Of these, 47.8% were most likely related to cardiac failure, 42.0% to another (genetic) diagnosis, and 10.1% to placental insufficiency. No cases were allocated to the group with an unknown cause. Only 47.8% of the cases had isolated congenital heart disease, and in this group 21.2% was most likely related to placental insufficiency. CONCLUSION: This study shows that in addition to cardiac failure and other (genetic) diagnoses, placental factors play an important role in fetal demise in congenital heart disease, especially in cases of isolated heart defects. Therefore, these findings support the importance of regular ultrasonographic assessment of fetal growth and placental function in fetal congenital heart disease.

Early Childhood Growth Parameters in South African Children with Exposure to Maternal HIV Infection and Placental Insufficiency.

Maternal HIV exposure and intrauterine growth restriction (IUGR) due to placental insufficiency both carry major risks to early child growth. We compared the growth outcomes of children aged 18 months who had abnormal umbilical artery resistance indices (UmA-RI), as a marker of placental insufficiency, with a comparator group of children with normal UmA-RI during pregnancy, as mediated by maternal HIV infection. The cross-sectional study included 271 children, grouped into four subgroups based on HIV exposure and history of normal/abnormal UmA-RI, using available pregnancy and birth information. Standard procedures were followed to collect anthropometric data, and z-scores computed as per World Health Organization growth standards. Lower length-for-age z-scores (LAZ) were observed in children who were HIV-exposed-uninfected (CHEU) (-0.71 ± 1.23; p = 0.004) and who had abnormal UmA-RI findings (-0.68 ± 1.53; p < 0.001). CHEU with abnormal UmA-RI had lower LAZ (-1.3 ± 1.3; p < 0.001) and weight-for-age z-scores (WAZ) (-0.64 ± 0.92; p = 0.014) compared to the control group. The prevalence of stunting was 40.0% in CHEU with abnormal UmA-RI and 16.0% in CHEU with normal UmA-RI (p < 0.001; p = 0.016, respectively). In conclusion, maternal HIV exposure and placental insufficiency are independent risk factors for childhood stunting, with this risk potentiated when these two risk factors overlap.

Persistence of abnormal uterine artery flow postpartum: Case-control study.

Cohort study of singleton pregnancies with risk factors for placental insufficiency, managed at St. Michael's Hospital in Toronto, Canada. Patients undergone UA Doppler assessment at 18-22 weeks' gestation and 6 weeks postpartum. 15 pregnancies complicated by preeclampsia or intrauterine growth restriction (IUGR) (cases) were compared to 17 unaffected pregnancies (controls). Cases with preeclampsia and/or IUGR had higher UA PI at 18-22 weeks than controls. By 6 weeks' postpartum, the corresponding mean values were 2.60 and 2.14 (p = 0.20). This preliminary study suggests a potential different trajectory for physiologic recovery of UA flow after a pregnancy affected by placental insufficiency.

Maternal circulating SPINT1 is reduced in small-for-gestational age pregnancies at 26 weeks: Growing up in Singapore towards health outcomes (GUSTO) cohort study.

Fetal growth restriction arising from placental insufficiency is a leading cause of stillbirth. We recently identified low maternal circulating SPINT1 concentrations as a novel biomarker of poor fetal growth. Here we measured SPINT1 in a prospective cohort in Singapore. Circulating SPINT1 concentrations were significantly lower among 141 pregnant women destined to deliver small-for-gestational age infants (birthweight <10th centile), compared to 772 controls (p < 0.01) at as early as 26 weeks' gestation. There were no correlations between infant body composition and circulating SPINT1 concentrations at 26 weeks. This provides validation that low maternal SPINT1 concentration is associated with poor fetal growth.

Abnormal Fetal Growth: Small for Gestational Age, Fetal Growth Restriction, Large for Gestational Age: Definitions and Epidemiology.

Abnormal fetal growth (growth restriction and overgrowth) is associated with perinatal morbidity, mortality, and lifelong risks to health. To describe abnormal growth, "small for gestational age" and "large for gestational age" are commonly used terms. However, both are statistical definitions of fetal size below or above a certain threshold related to a reference population, rather than referring to an abnormal condition. Fetuses can be constitutionally small or large and thus healthy, whereas fetuses with seemingly normal size can be growth restricted or overgrown. Although golden standards to detect abnormal growth are lacking, understanding of both pathologic conditions has improved significantly.

Fetal Growth and Stillbirth.

Fetal growth restriction (FGR) is a common clinical manifestation of placental insufficiency. As such, FGR is a risk factor for stillbirth. This association has been demonstrated in numerous studies but is prone to overestimation because of the possibility of prolonged in utero retention before the recognition of the fetal death. Stillbirth risk reduction by optimizing maternal medical conditions and exposures and appropriate antenatal testing and delivery timing are essential to pregnancies affected by FGR. It is important to evaluate stillbirths with FGR with fetal autopsy, placental pathology, genetic testing, and assessment of antiphospholipid antibodies and fetal-maternal hemorrhage.

Antenatal Fetal Adrenal Measurements at 22 to 30 Weeks' Gestation, Fetal Growth Restriction, and Perinatal Morbidity.

OBJECTIVE: Our objective was to test the association of fetal adrenal size with perinatal morbidity among fetuses with fetal growth restriction (FGR; estimated fetal weight [EFW] < 10th percentile). STUDY DESIGN: This was a secondary analysis of the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be (nuMoM2b) adrenal study, which measured fetal adrenal gland size at 22 to 30 weeks' gestation. We analyzed the transverse adrenal area (TAA) and fetal zone area (absolute measurements and corrected for fetal size) and the ratio of the fetal zone area to the total transverse area using a composite perinatal outcome of stillbirth, neonatal intensive care unit admission, respiratory distress syndrome, necrotizing enterocolitis, retinopathy of prematurity, sepsis, mechanical ventilation, seizure, or death. Among fetuses with FGR, adrenal measurements were compared between those that did and did not experience the composite perinatal outcome. RESULTS: There were 1,709 eligible neonates. Seven percent (n = 120) were diagnosed with FGR at the time of adrenal measurement, and 14.7% (n = 251) experienced perinatal morbidity. EFW-corrected and absolute adrenal measurements were similar among fetuses with and without FGR as well as among those who did and did not experience morbidity. The area under the curve for corrected TAA was 0.52 (95% confidence interval 0.38-0.67). CONCLUSION: In our cohort, adrenal size was not associated with risk of morbidity among fetuses with FGR.

Residential proximity to roadways and placental-associated stillbirth: a case-control study.

We conducted a retrospective case-control study of 1,097 women in Massachusetts and Rhode Island, USA, to examine the association between stillbirth related to placental abruption or placental insufficiency and maternal exposure to traffic-related air pollution. We utilized distance to nearest roadway proximity metrics as a proxy for traffic-related air pollution exposure. No meaningful increase in the overall odds of placental-associated stillbirths was observed (adjusted OR: 1.1, 95% CI: 0.5-2.8). However, mothers living within 50 m of a roadway had a 60% increased odds of experiencing a stillbirth related to placental abruption compared to mothers living greater than 200 m away. This suggestive finding was imprecise due to the small case number in the highest exposure category (95% CI: 0.6-4.0). Future studies of placental abruption with more precise exposure assessments are warranted.

Reduced growth velocity from the mid-trimester is associated with placental insufficiency in fetuses born at a normal birthweight.

BACKGROUND: Fetal growth restriction (FGR) due to placental insufficiency is a major risk factor for stillbirth. While small-for-gestational-age (SGA; weight < 10th centile) is a commonly used proxy for FGR, detection of FGR among appropriate-for-gestational-age (AGA; weight ≥ 10th centile) fetuses remains an unmet need in clinical care. We aimed to determine whether reduced antenatal growth velocity from the time of routine mid-trimester ultrasound is associated with antenatal, intrapartum and postnatal indicators of placental insufficiency among term AGA infants. METHODS: Three hundred and five women had biometry measurements recorded from their routine mid-trimester (20-week) ultrasound, at 28 and 36 weeks' gestation, and delivered an AGA infant. Mid-trimester, 28- and 36-week estimated fetal weight (EFW) and abdominal circumference (AC) centiles were calculated. The EFW and AC growth velocities between 20 and 28 weeks, and 20-36 weeks, were examined as predictors of four clinical indicators of placental insufficiency: (i) low 36-week cerebroplacental ratio (CPR; CPR < 5th centile reflects cerebral redistribution-a fetal adaptation to hypoxia), (ii) neonatal acidosis (umbilical artery pH < 7.15) after the hypoxic challenge of labour, (iii) low neonatal body fat percentage (BF%) reflecting reduced nutritional reserve and (iv) placental weight < 10th centile. RESULTS: Declining 20-36-week fetal growth velocity was associated with all indicators of placental insufficiency. Each one centile reduction in EFW between 20 and 36 weeks increased the odds of cerebral redistribution by 2.5% (odds ratio (OR) = 1.025, P = 0.001), the odds of neonatal acidosis by 2.7% (OR = 1.027, P = 0.002) and the odds of a < 10th centile placenta by 3.0% (OR = 1.030, P < 0.0001). Each one centile reduction in AC between 20 and 36 weeks increased the odds of neonatal acidosis by 3.1% (OR = 1.031, P = 0.0005), the odds of low neonatal BF% by 2.8% (OR = 1.028, P = 0.04) and the odds of placenta < 10th centile by 2.1% (OR = 1.021, P = 0.0004). Falls in EFW or AC of > 30 centiles between 20 and 36 weeks were associated with two-threefold increased relative risks of these indicators of placental insufficiency, while low 20-28-week growth velocities were not. CONCLUSIONS: Reduced growth velocity between 20 and 36 weeks among AGA fetuses is associated with antenatal, intrapartum and postnatal indicators of placental insufficiency. These fetuses potentially represent an important, under-recognised cohort at increased risk of stillbirth. Encouragingly, this novel fetal assessment would require only one additional ultrasound to current routine care, and adds to the potential benefits of routine 36-week ultrasound.

Association of abnormal placental perfusion with the risk of male hypospadias: a hospital-based retrospective cohort study.

BACKGROUND: The effect and extent of abnormal placental perfusion (APP) on the risk of male hypospadias are poorly understood. We compared the prevalence of male hypospadias in the offspring of women with APP and quantify the extent of the APP effect on the anomaly. METHODS: A hospital-based retrospective analysis of births from 2012 to 2016 was conducted in 2018. Women of singleton pregnancy and male infants born to them were included (N = 21,447). A multivariate analysis was performed to compare the prevalence of male hypospadias in infants exposed to APP with those that were not exposed to APP. RESULTS: Compared with the infants of women without APP, infants of women with APP showed an increased risk of male hypospadias (odds ratio, 2.40; 95% confidence interval, 1.09-5.29). The male hypospadias cumulative risk increased with the severity of APP. Infants exposed to severe APP had a significantly higher risk of male hypospadias than those without APP exposure (9.2 versus 1.7 per 1000 infants, P < 0.001). A path analysis indicated that 28.18-46.61% of the risk of hypospadias may be attributed to the effect of APP. CONCLUSIONS: Male hypospadias risk was associated with APP and increased with APP severity, as measured in the second trimester. APP had an important role in the development of the anomaly.

Association between in vitro fertilization and ischemic placental disease by gestational age.

OBJECTIVE: To evaluate the association between in vitro fertilization (IVF) and ischemic placental disease (IPD), stratified by gestational age. DESIGN: We performed a secondary analysis of a retrospective cohort study of deliveries. SETTING: Deliveries were performed over 15 years at a single tertiary hospital. PATIENT(S): We included all parturients who had a live born infant or an intrauterine fetal demise (IUFD). INTERVENTION(S): We compared pregnancies resulting from IVF cycles to non-IVF pregnancies. MAIN OUTCOME MEASURE(S): The primary outcomes were preterm and term IPD (preeclampsia, placental abruption, small-for-gestational age infant [SGA], or an intrauterine fetal demise [IUFD] due to placental insufficiency). RESULT(S): Of the 69,084 deliveries during the study period, 3,763 (5.4%) were conceived with IVF. The incidence of preterm delivery was 32.6% in IVF pregnancies and 10.8% in non-IVF pregnancies. Multiple gestations were more common in IVF pregnancies. Compared to non-IVF pregnancies, IVF pregnancies were more likely to develop both preterm and term IPD, even after adjustment for maternal age and parity. The risk of preterm IPD was 4 times higher (95% confidence interval, 3.7-4.4) in patients who underwent IVF compared with those who did not undergo IVF. Among parturients who delivered at ≥37 weeks of gestation, IVF pregnancies had 1.7 times the risk of term IPD (95% confidence interval, 1.6-1.9) compared with non-IVF pregnancies. CONCLUSION(S): IVF was strongly associated with preterm IPD. We found a similar, but attenuated, association between IVF and term IPD. The stronger association with preterm IPD suggests an association between IVF and placental insufficiency.

Roles of the underlying cause of delivery and gestational age on long-term child health.

BACKGROUND: Clinical conditions leading to delivery are heterogeneous. However, most studies examining the short- and long-term consequences of birth on child health only consider gestational age at delivery, not the underlying cause. OBJECTIVE: To examine the effect of both gestational age at delivery and underlying cause of delivery on child health outcomes. METHODS: This population-based retrospective cohort study of singleton infants born in Alberta (April 2004-March 2005) used linked administrative and perinatal data to identify birth subtypes by underlying cause (infection/inflammation (I/I), placental dysfunction (PD), both, or neither), gestational age at delivery, and child health outcomes (neonatal morbidity and mortality, paediatric complex chronic conditions, and neurodevelopmental disorders and disabilities). Poisson regression with robust variance was used to assess differences in the (adjusted) risk ratio (RR) of each outcome by gestational age, and by cause of delivery. The roles of gestational age and cause of delivery were examined using mediation analysis methods. RESULTS: A total of 38,192 children were included, with 66.7% experiencing neither I/I nor PD (I/I: 4.0%, PD: 27.5%, both: 1.8%). Infants born preterm had higher risk of all outcomes compared to those born at term and late-term. Infants with exposure to both causes had higher risk of all outcomes (neonatal morbidity, RR 8.96, 95% confidence interval [CI] 7.55, 10.63; paediatric complex chronic conditions, RR 3.94, 95% CI 3.08, 5.05; and neurodevelopmental disorders, RR 1.58, 95% CI 1.37, 1.84). The effect of underlying cause of delivery on child health outcomes was partially explained by gestational age, more in cases involving I/I than in those involving PD alone. CONCLUSIONS: Short- and long-term child health outcomes differ by the underlying cause leading to delivery, as well as the gestational age at delivery. Having a clearer prognosis for infants may promote the use of clinical interventions earlier for children at increased risk.

Postmortem examination protocol and systematic re-evaluation reduce the proportion of unexplained stillbirths.

Background Stillbirth often remains unexplained, mostly due to a lack of any postmortem examination or one that is incomplete and misinterpreted. Methods This retrospective cohort study was conducted at the Department of Obstetrics and Gynecology, Helsinki University Hospital, Finland, and comprised 214 antepartum singleton stillbirths from 2003 to 2015. Maternal and fetal characteristics and the results of the systematic postmortem examination protocol were collected from medical records. Causes of death were divided into 10 specific categories. Re-evaluation of the postmortem examination results followed. Results Based on our systematic protocol, the cause of death was originally defined and reported as such to parents in 133 (62.1%) cases. Re-evaluation of the postmortem examination results revealed the cause of death in an additional 43 (20.1%) cases, with only 23 (10.7%) cases remaining truly unexplained. The most common cause of stillbirth was placental insufficiency in 56 (26.2%) cases. A higher proportion of stillbirths that occurred at ≥39 gestational weeks remained unexplained compared to those that occurred earlier (24.1% vs. 8.6%) (P = 0.02). Conclusion A standardized postmortem examination and a re-evaluation of the results reduced the rate of unexplained stillbirth. Better knowledge of causes of death may have a major impact on the follow-up and outcome of subsequent pregnancies. Also, closer examination and better interpretation of postmortem findings is time-consuming but well worth the effort in order to provide better counseling for the grieving parents.

Achieving orphan designation for placental insufficiency: annual incidence estimations in Europe.

OBJECTIVE: To determine whether a novel therapy for placental insufficiency could achieve orphan drug status by estimating the annual incidence of placental insufficiency, defined as an estimated fetal weight below the 10th centile in the presence of abnormal umbilical artery Doppler velocimetry, per 10 000 European Union (EU) population as part of an application for European Medicines Agency (EMA) orphan designation. DESIGN: Incidence estimation based on literature review and published national and EU statistics. SETTING AND POPULATION: European Union. METHODS: Data were drawn from published literature, including national and international guidelines, international consensus statements, cohort studies and randomised controlled trials, and published national and EU statistics, including birth rates and stillbirth rates. Rare disease databases were also searched. RESULTS: The proportion of affected pregnancies was estimated as 3.17% (95% CI 2.93-3.43%), using a weighted average of the results from two cohort studies. Using birth rates from 2012 and adjusting for a pregnancy loss rate of 1/100 gave an estimated annual incidence of 3.33 per 10 000 EU population (95% CI 3.07-3.60 per 10 000 EU population). This fell below the EMA threshold of 5 per 10 000 EU population. CONCLUSIONS: Maternal vascular endothelial growth factor gene therapy for placental insufficiency was granted EMA orphan status in 2015 after we demonstrated that it is a rare, life-threatening or chronically debilitating and currently untreatable disease. Developers of other potential obstetric therapies should consider applying for orphan designation, which provides financial and regulatory benefits. TWEETABLE ABSTRACT: Placental insufficiency meets the European Medicines Agency requirements for orphan disease designation.

Incidence and Management of Umbilical Artery Flow Abnormalities during Open Fetal Surgery.

INTRODUCTION: Umbilical artery (UA) Doppler ultrasound is used to assess uteroplacental insufficiency. Absent or reversed end diastolic flow (AREDF) in the UA is associated with increased perinatal mortality in fetuses with intrauterine growth restriction. We describe the incidence of UA Doppler abnormalities during open fetal surgery. METHODS: We conducted a retrospective review of patients undergoing open in utero myelomeningocele (MMC) repair between 2008 and 2015. Intermittent UA Dopplers were performed during key portions of all cases. Our primary outcome was the rate of any AREDF. Secondary outcomes included analysis of absent versus reversed end diastolic flow (EDF), vasopressor use, and volatile anesthetic and clinical outcomes. RESULTS: Thirty-four of 47 fetuses developed UA Doppler abnormalities intraoperatively. Nineteen had absent EDF and 15 had reversed EDF. No AREDF was present before induction, and all AREDF resolved by postoperative day 1. Ten of 19 (52.6%) patients who received sevoflurane had reversed EDF, versus 5/28 (17.9%) for desflurane, odds ratio (95% CI) 5.11 (1.36-19.16), p = 0.02. One intraoperative fetal death occurred in the AREDF group. DISCUSSION: AREDF is a common phenomenon during open MMC repair. Anesthetic agent choice may influence this risk. Future studies of UA flow during fetal surgery are needed to further evaluate the impact of intraoperative AREDF on fetal well-being.

Underlying mechanisms of retained placenta: Evidence from a population based cohort study.

OBJECTIVE: To determine risk factors for retained placenta, and to identify supporting epidemiologic evidence for the three previously-proposed mechanisms: (i) invasive placentation, (ii) placental hypo-perfusion, and (iii) inadequate uterine contractility. DESIGN: A retrospective population-based cohort study. SETTING AND POPULATION: Israeli population in the southern district. METHODS: Data were analyzed from a tertiary hospital database, between 1989 and 2014, using univariate tests and generalized estimating equation (GEE) multivariable models. MAIN OUTCOME MEASURES: Prevalence of retained placenta. RESULTS: The study population included 205,522 vaginal deliveries of which 4.8% (n=9870) were complicated with retained placenta. Previous intra-uterine procedures and placenta-related pregnancy complications were found to be significant risk factors for retained placenta (history of cesarean section aOR=8.82, 95%CI 8.35-9.31; history of curettage aOR=12.80, 95%CI 10.57-15.50; pre-eclampsia aOR=1.25, 95%CI 1.14-1.38; delivery of a small for gestational age neonate aOR=1.08, 95%CI 1.01-1.16; stillbirth aOR=2.34, 95%CI 1.98-2.77). During labour, the risk for retained placenta was increased in presence of arrest of dilatation (aOR=2.03, 95%CI 1.08-3.82) or arrest of descent (aOR=1.55, 95%CI 1.22-1.96). Infections of the uterine cavity during labour were also found to be strongly associated with increased risk of retained placenta (endometritis aOR=2.21, 95%CI 1.64-2.97; chorioamnionitis aOR=3.35, 95% CI 2.78-4.04). CONCLUSIONS: Supporting epidemiologic evidence were found for all three underlying mechanisms. In addition, there is evidence to suggest that intrauterine infection and inflammation may also be a possible pathology associated with retained placenta. TWEETABLE ABSTRACT: Risk factors for retained placenta support previously proposed mechanisms in a large cohort study.

Placenta associated pregnancy complications in pregnancies complicated with placenta previa.

OBJECTIVES: The purpose of our study was to examine the hypothesis that pregnancies complicated with placenta previa have an increased risk of placental insufficiency associated pregnancy complications (IUGR, preeclampsia, placental abruption and perinatal mortality). MATERIALS AND METHODS: Our study included all deliveries that occurred at Soroka University Medical Center (Beer Sheva, Israel) between January 1998 and December 2013. Of them 1,249 were complicated by placenta previa and represented our study group. A composite outcome was created to include conditions associated with placental insufficiency. It included hypertensive disorders (i.e. gestational hypertension, mild and severe preeclampsia, HELLP and eclampsia), small for gestational age neonates and placental abruption. RESULTS: Patients with pregnancy complicated by placenta previa had significantly different obstetrical characteristics including bad obstetric history (8% vs. 4%, p < 0.001), recurrent abortions (11% vs. 5%, p < 0.001). Patients with placenta previa had higher rates of vaginal bleeding in the second half of pregnancy (3% vs. 0%, p < 0.001), gestational diabetes (8% vs. 5.5%, p < 0.001), placental abruption (10% vs. 1%, p < 0.001), adherent placenta (4% vs. 0.5%, p < 0.001), preterm delivery (52% vs. 8%, p < 0.001), with a median gestational age of 36 vs. 39 weeks, p < 0.001. The composite outcome was significantly more prevalent in the placenta previa group (21% vs. 13%, p < 0,001). CONCLUSIONS: Our study demonstrated an increased rate of placental insufficiency associated complications in women with placenta previa. This is of clinical relevance and suggests that a careful surveillance for women with placenta previa may help in minimizing maternal, fetal and neonatal complications.

Short-term outcome of periviable small-for-gestational-age babies: is our counseling up to date?

OBJECTIVE: There are limited data for counseling on and management of periviable small-for-gestational-age (SGA) fetuses. We therefore aimed to investigate the short-term outcome of periviable SGA fetuses in relation to the likely underlying cause. METHODS: This was a retrospective study of data from three London tertiary fetal medicine centers obtained between 2000 and 2015. We included viable singleton pregnancies with a severely small fetus, defined as those with an abdominal circumference ≤ 3rd percentile, identified between 22 + 0 and 25 + 6 weeks' gestation. Data obtained included fetal biometry, presence of placental anomalies, uterine and fetal Doppler and neonatal outcome. We excluded cases with structural abnormalities, proven or suspected abnormal karyotype or genetic syndromes. Cases were classified according to the suspected underlying cause of the small fetal size into one of the following categories: uteroplacental insufficiency, evidence of placental damage with normal uterine artery Doppler, viral infection, or unclassied. RESULTS: There were 245 cases included in the study. Of these, at diagnosis of SGA, 201 (82%) were categorized as uteroplacental cause, 13 (5%) as suspected placental cause, one (0.4%) as suspected viral cause and 30 (12%) could not be assigned to any of these categories. Overall, 101 (41%) cases survived the neonatal period; 89 (36%) underwent in-utero fetal demise, 22 (9%) died neonatally and 33 (14%) pregnancies were terminated. The diagnosis-to-delivery interval was 8.1 weeks in those that survived and 4.5 weeks in those that died neonatally. CONCLUSIONS: Almost 90% of periviable SGA cases are associated with uteroplacental insufficiency or intraplacental damage. Survival is related to gestational age at delivery, with outcomes better than might be assumed at diagnosis and some pregnancies reaching term. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Placental insufficiency among high-risk pregnancies with a normal umbilical artery resistance index after 32weeks.

OBJECTIVE: To determine the incidence of abnormal multi-vessel Doppler values among advanced pregnancies at risk of suboptimal placentation but with a normal umbilical artery resistance index (RI), and to assess whether clinical and ultrasonography findings can identify them. METHODS: In a prospective cross-sectional study at Tygerberg Hospital, South Africa, women with high-risk pregnancies but normal umbilical artery RI after 32weeks underwent ultrasonography (fetal biometry, liquor, and placenta maturation) and Doppler assessment (uterine, umbilical, and middle cerebral arteries) between February 11 and October 21, 2013. Study data were compared among four groups: fetuses with normal uterofetoplacental Doppler values and those with any abnormal pulsatility index, each subdivided into small for gestational age (SGA) and appropriate for gestational age (AGA) by estimated fetal weight. RESULTS: Of 210 participants, 72 (36.2%) had abnormal Doppler results, and 60 (28.6%) fetuses were SGA (38 [63.3%] with abnormal Doppler results). Clinical characteristics did not differ between groups with normal or abnormal Doppler values; however, among normal Doppler results, SGA pregnancies demonstrated poorer fundal growth (P=0.006). Significant associations existed between abnormal Doppler results and asymmetric growth, inappropriately advanced placental maturation, and reduced liquor volume (all P≤0.04), but with very low sensitivities (3.9%, 4.8%, and 14.5%, respectively). CONCLUSION: Maternal characteristics and imaging variables did not reliably identify more than one-third of pregnancies with evidence of suboptimal placentation.

Apelin in Normal Pregnancy and Pregnancies Complicated by Placental Insufficiency.

INTRODUCTION: Apelin is a potent inotropic agent and causes endothelium-mediated vasodilation. Its cardiovascular profile suggests a role in the regulation of gestational hemodynamics. METHODS: We longitudinally assessed maternal serum apelin levels and hemodynamics (cardiac output and total peripheral resistance) between 20 and 34 weeks gestation in 18 women at high risk of placental dysfunction. Placental apelin staining was assessed by immunohistochemistry in placentas from uncomplicated pregnancies (n = 6), preterm deliveries (n = 6), preeclampsia (PET, n = 8), and isolated intrauterine growth restriction (IUGR, n = 8). Placental apelin gene expression was assessed by quantitative polymerase chain reaction. RESULTS: In the high-risk cohort, 4 fetuses developed isolated IUGR and 6 women developed PET. We obtained a median of 5 (range 2-9) hemodynamic and apelin measurements per woman. Apelin levels throughout gestation were best fitted by a quadratic curve. Apelin levels between 20 and 26 weeks gestation correlated with total peripheral resistance (r = .57, P = .01) and showed a trend toward an inverse correlation with stroke volume (r = -.42, P = .08). Apelin serum levels were 30% lower in pregnancies complicated by IUGR than in uncomplicated pregnancies or in women with preeclampsia (P = .009). Placental apelin gene expression was similar in IUGR, PET, preterm, and term normal placentas. Apelin staining was seen both in syncytiotrophoblast and stroma of the placental villi. In IUGR placentas, apelin staining was strongly decreased in both compartments compared to normals. Preeclamptic placentas showed an intermediate staining. CONCLUSIONS: Apelin levels mirror the cardiovascular changes seen in pregnancy. Serum and placental apelin levels are decreased in IUGR.