Volume 49, Issue 9

Objectives To conduct a systematic literature review to evaluate the global incidence of intraventricular hemorrhage grade 2–4 among extremely preterm infants. Methods We performed searches in MEDLINE and Embase for intraventricular hemorrhage and prematurity cited in English language observational studies published from May 2006 to October 2017. Included studies analyzed data from infants born at ≤28 weeks’ gestational age and reported on intraventricular hemorrhage epidemiology. Results Ninety-eight eligible studies encompassed 39 articles from Europe, 31 from North America, 25 from Asia, five from Oceania, and none from Africa or South America; both Europe and North America were included in two publications. The reported global incidence range of intraventricular hemorrhage grade 3–4 was 5–52% (Europe: 5–52%; North America: 8–22%; Asia: 5–36%; Oceania: 8–13%). When only population-based studies were included, the incidence range of intraventricular hemorrhage grade 3–4 was 6–22%. The incidence range of intraventricular hemorrhage grade 2 was infrequently documented and ranged from 5–19% (including population-based studies). The incidence of intraventricular hemorrhage was generally inversely related to gestational age. Conclusions Intraventricular hemorrhage is a frequent complication of extremely preterm birth. Intraventricular hemorrhage incidence range varies by region, and the global incidence of intraventricular hemorrhage grade 2 is not well documented.

Objectives Clinical innovation and research on maternal–fetal interventions have become an essential for the development of perinatal medicine. In this paper, we present an ethical argument that the professional virtue of integrity should guide perinatal investigators. Methods We present an historical account of the professional virtue of integrity and the key distinction that this account requires between intellectual integrity and moral integrity. Results We identify implications of both intellectual and moral integrity for innovation, research, prospective oversight, the role of equipoise in randomized clinical trials, and organizational leadership to ensure that perinatal innovation and research are conducted with professional integrity. Conclusions Perinatal investigators and those charged with prospective oversight should be guided by the professional virtue of integrity. Leaders in perinatal medicine should create and sustain an organizational culture of professional integrity in fetal centers, where perinatal innovation and research should be conducted.

These practice guidelines follow the mission of the World Association of Perinatal Medicine in collaboration with the Perinatal Medicine Foundation, bringing together groups and individuals throughout the world, with the goal of improving the ultrasound assessment of the fetal Central Nervous System (CNS) anatomy. In fact, this document provides further guidance for healthcare practitioners for the evaluation of the fetal CNS during the mid-trimester ultrasound scan with the aim to increase the ability in evaluating normal fetal anatomy. Therefore, it is not intended to establish a legal standard of care. This document is based on consensus among perinatal experts throughout the world, and serves as a guideline for use in clinical practice.

Despite substantial improvement in reducing maternal mortality during the recent decades, we constantly face tragic fact that maternal mortality (especially preventable deaths) is still unacceptably too high, particularly in the developing countries, where 99% of all maternal deaths worldwide occur. Poverty, lack of proper statistics, gender inequality, beliefs and corruption-associated poor governmental policies are just few of the reasons why decline in maternal mortality has not been as sharp as it was wished and expected. Education has not yet been fully recognized as the way out of poverty, improvement of women’s role in the society and consequent better perinatal care and consequent lower maternal mortality. Education should be improved on all levels including girls, women and their partners, medical providers, religious and governmental authorities. Teaching the teachers should be also an essential part of global strategy to lower maternal mortality. This paper is mostly a commentary, not a systematic review nor a meta-analysis with the aim to rise attention (again) to the role of different aspects of education in lowering maternal mortality. The International Academy of Perinatal Medicine should play a crucial role in pushing the efforts on this issue as the influential instance that promotes reflection and dialog in perinatal medicine, especially in aspects such as bioethics, the appropriate use of technological advances, and the sociological and humanistic dimensions of this specific problem of huge magnitude. The five concrete steps to achieve these goals are listed and discussed.

Objectives Preterm birth clinics provide dedicated obstetric care to women at high risk of spontaneous preterm birth (SPTB). There remains a lack of conclusive evidence to support the overall utility of such clinics, attributable to a paucity and heterogeneity of primary data. This study audits Australia’s largest and oldest dedicated preterm birth clinic with the aim to add primary data to the area and offer opportunities for similar clinics to align practice. Methods A retrospective audit of referrals to the Preterm Labour Clinic at the Royal Women’s Hospital, Melbourne, Australia, between 2004 and 2018 was conducted. 1,405 singleton pregnancies met inclusion criteria. The clinic’s key outcomes, demographics, predictive tests and interventions were analysed. The primary outcomes were SPTB before 37, 34 and 30 weeks’ gestation. Results The overall incidence of SPTB in the clinic was 21.2% (n=294). Linear regression showed reductions in the adjusted rates of overall SPTB and pre-viable SPTB (delivery <24 weeks) from 2004 (108%; 8%) to 2018 (65%; 2% respectively). Neonatal morbidity and post-delivery intensive care admission concurrently declined (p=0.02; 0.006 respectively). Rates of short cervix (cervical length <25 mm) increased over time (2018: 30.9%) with greater uptake of vaginal progesterone for treatment. Fetal fibronectin, mid-trimester short cervix, and serum alkaline phosphatase were associated with SPTB on logistic regression. Conclusions Dedicated preterm birth clinics can reduce rates of SPTB, particularly deliveries before 24 weeks’ gestation, and improve short-term neonatal outcomes in pregnant women at risk of preterm birth.

Objectives To assess the risk of chorioamnionitis in nulliparous, term, singleton, vertex (NTSV) pregnancies with premature rupture of membranes (PROM) and an unfavorable cervix undergoing labor induction with either prostaglandin E2 (PGE2) or oxytocin only. Methods Retrospective cohort of NTSV pregnancies presenting with PROM who underwent labor induction with either PGE2 (n=94) or oxytocin (n=181) between October 2015 and March 2019. The primary outcome of chorioamnionitis was compared between the two groups. Statistical analysis included Chi-squared and Wilcoxon rank-sum tests, as well as logistic regression. For time to delivery, a Cox proportional hazard regression was used to determine the hazard ratio (HR) and adjusted HR (aHR). Results Baseline characteristics were similar between the two groups. Cervical ripening with PGE2 was associated with an increased rate of chorioamnionitis (18.1 vs. 6.1%; aOR 4.14, p=0.001), increased neonatal intensive care unit admissions (20.2 vs. 9.9%; aOR 2.4, p=0.02), longer time interval from PROM to delivery (24.4 vs. 17.9 h; aHR 0.56, p=<0.0001), and lower incidence of meconium (7.4 vs. 14.4%; aOR 0.26, p=0.01), compared to the oxytocin group. Conclusions Based on our data, the use of oxytocin appears both superior and safer compared to PGE2 in NTSV pregnancies with PROM undergoing labor induction.

Objectives Obstructive sleep apnea (OSA) is linked to many health comorbidities. We aimed to ascertain if OSA correlates with a rise in poor obstetrical outcomes. Methods Employing the United States’ Healthcare Cost and Utilization Project – National Inpatient Sample, we performed our retrospective cohort study including all women who delivered between 2006 and 2015. ICD-9 codes were used to characterize women as having a diagnosis of OSA. Temporal trends in pregnancies with OSA were studied, baseline features were evaluated among gravidities in the presence and absence of OSA, and multivariate logistic regression analysis was utilized in assessing consequences of OSA on patient and newborn outcomes. Results Of a total 7,907,139 deliveries, 3,115 belonged to patients suffering from OSA, resulting in a prevalence of 39 per 100,000 deliveries. Rates rose from 10.14 to 78.12 per 100,000 deliveries during the study interval (p<0.0001). Patients diagnosed with OSA were at higher risk of having pregnancies with preeclampsia, OR 2.2 (95% CI 2.0–2.4), eclampsia, 4.1 (2.4–7.0), chorioamnionitis, 1.4 (1.2–1.8), postpartum hemorrhage, 1.4 (1.2–1.7), venous thromboembolisms, 2.7 (2.1–3.4), and to deliver by caesarean section, 2.1 (1.9–2.3). Cardiovascular and respiratory complications were also more common among these women, as was maternal death, 4.2 (2.2–8.0). Newborns of OSA patients were at elevated risk of being premature, 1.3 (1.2–1.5) and having congenital abnormalities, 2.3 (1.7–3.0). Conclusions Pregnancies with OSA were linked to an elevated risk of poor maternal and neonatal outcomes. During pregnancy, OSA patients should receive attentive follow-up care in a tertiary hospital.

Objectives Preeclampsia is a dangerous pregnancy complication. The source of preeclampsia is unknown, though the placenta is believed to have a central role in its pathogenesis. An association between maternal infection and preeclampsia has been demonstrated, yet the involvement of the placental microbiome in the etiology of preeclampsia has not been determined. In this study, we examined whether preeclampsia is associated with an imbalanced microorganism composition in the placenta. Methods To this end, we developed a novel method for the identification of bacteria/viruses based on sequencing of small non-coding RNA, which increases the microorganism-to-host ratio, this being a major challenge in microbiome methods. We validated the method on various infected tissues and demonstrated its efficiency in detecting microorganisms in samples with extremely low bacterial/viral biomass. We then applied the method to placenta specimens from preeclamptic and healthy pregnancies. Since the placenta is a remarkably large and heterogeneous organ, we explored the bacterial and viral RNA at each of 15 distinct locations. Results Bacterial RNA was detected at all locations and was consistent with previous studies of the placental microbiome, though without significant differences between the preeclampsia and control groups. Nevertheless, the bacterial RNA composition differed significantly between various areas of the placenta. Viral RNA was detected in extremely low quantities, below the threshold of significance, thus viral abundance could not be determined. Conclusions Our results suggest that the bacterial and viral abundance in the placenta may have only limited involvement in the pathogenesis of preeclampsia. The evidence of a heterogenic bacterial RNA composition in the various placental locations warrants further investigation to capture the true nature of the placental microbiome.

Objectives To estimate the metformin failure rate in women with gestational diabetes. Methods The study was designed as a retrospective cohort of women diagnosed with gestational diabetes by the 75 g 2 h oral glucose tolerance test. Women were placed into two groups: metformin success (107 patients not requiring insulin therapy) or metformin failure (15 patients requiring the addition of, or, transition to insulin). Primary outcome: rate of metformin failure. Secondary outcomes: maternal and neonatal factors. Results The failure rate of metformin was 15% (19/122 women) in the study. The failure group was more likely to have 3 abnormal values on a 2-h 75 g oral glucose tolerance test (37% (n=7/19) vs. 15% (n=15/103), p=0.02). Patients who failed had higher average fasting blood glucose levels on the glucose tolerance test as well as on pretreatment fasting finger stick values. Those who failed metformin were diagnosed with gestational diabetes and started on metformin earlier in gestation. Conclusions Overall low rate of metformin failure in treatment of gestational diabetes.

Objectives This study examined predictive factors, in addition to Category II Fetal Herat Rate (FHR) monitoring that might imply fetal acidosis and risk of asphyxia. Methods This retrospective cohort study compared three groups of patients with Category II FHR monitoring indicating need for imminent delivery. Groups were divided based on fetal cord blood pH: pH≤7.0, 7.0<pH<7.2 and pH≥7.2. Demographics, medical history, delivery data and early neonatal outcomes were reviewed. Results The cohort included 417 women. Nine (2.2%) had cord pH≤7.0, 105 (25.2%) pH 7.0 to 7.2 and 303 (72.6%) ad pH≥7.2. Background characteristics, pregnancy follow-up and intrauterine fetal evaluation prior to delivery were similar in all groups. As expected, more patients in the low pH group had cesarean section (55.6%), than vaginal delivery or vacuum extraction (p=0.02). Five-minute Apgar scores were similar in all groups. Conclusions This retrospective study did not detect a specific parameter that could help predict the prognosis of fetal acidosis and risk of asphyxia. As we only included patients with a Category II tracing that was worrisome enough to lead to imminent delivery, it is reasonable to believe that this is due to patient selection, meaning that when the Category II FHR results in decision for prompt delivery, there is no added value in additional clinical characteristics. The evaluation should be expanded to all patients with Category II tracing for better interpretation tools for Category II FHR monitors, as well as a larger study population.

Objectives We aimed to establish new cut-off values for SIRS (Systemic Inflammatory Response Syndrome) variables in the obstetric population. Methods A prospective cohort study in pregnant and postpartum women admitted with systemic infections between December 2017 and January 2019. Patients were divided into three cohorts: Group A, patients with infection but without severe maternal outcomes (SMO); Group B, patients with infection and SMO or admission to the intensive care unit (ICU); and Group C, a control group. Outcome measures were ICU admission and SMO. The relationship between SIRS criteria and SMO was expressed as the area under the receiver operating characteristics curve (AUROC), selecting the best cut-off for each SIRS criterion. Results A total of 541 obstetric patients were enrolled, including 341 with infections and 200 enrolled as the reference group (Group C). The patients with infections included 313 (91.7%) in Group A and 28 (8.2%) in Group B. There were significant differences for all SIRS variables in Group B, compared with Groups A and C, but there were no significant differences between Groups A and C. The best cut-off values were the following: temperature 38.2 °C, OR 4.1 (1.8–9.0); heart rate 120 bpm, OR 2.9 (1.2–7.4); respiratory rate 22 bpm, OR 4.1 (1.6–10.1); and leukocyte count 16,100 per mcl, OR 3.5 (1.6–7.6). Conclusions The cut-off values for SIRS variables did not differ between healthy and infected obstetric patients. However, a higher cut-off may help predict the population with a higher risk of severe maternal outcomes.

Objectives Intra-amniotic infection, defined by the presence of microorganisms in the amniotic cavity, is often accompanied by intra-amniotic inflammation. Occasionally, laboratories report the growth of bacteria or the presence of microbial nucleic acids in amniotic fluid in the absence of intra-amniotic inflammation. This study was conducted to determine the clinical significance of the presence of bacteria in amniotic fluid samples in the absence of intra-amniotic inflammation. Methods A retrospective cross-sectional study included 360 patients with preterm labor and intact membranes who underwent transabdominal amniocentesis for evaluation of the microbial state of the amniotic cavity as well as intra-amniotic inflammation. Cultivation techniques were used to isolate microorganisms, and broad-range polymerase chain reaction coupled with electrospray ionization mass spectrometry (PCR/ESI-MS) was utilized to detect the nucleic acids of bacteria, viruses, and fungi. Results Patients whose amniotic fluid samples evinced microorganisms but did not indicate inflammation had a similar perinatal outcome to those without microorganisms or inflammation [amniocentesis-to-delivery interval (p=0.31), spontaneous preterm birth before 34 weeks (p=0.83), acute placental inflammatory lesions (p=1), and composite neonatal morbidity (p=0.8)]. Conclusions The isolation of microorganisms from a sample of amniotic fluid in the absence of intra-amniotic inflammation is indicative of a benign condition, which most likely represents contamination of the specimen during the collection procedure or laboratory processing rather than early colonization or infection.

Objectives To evaluate the association of intertwin differences in umbilical artery pulsatility index (DUAPI) and infant survival in twin-to-twin transfusion syndrome (TTTS). Methods Absolute DUAPI was calculated prior to laser surgery. Receiver-operating characteristics (ROC) curve analysis provided an intertwin DUAPI cutoff of 0.4 for the prediction of double twin survival to 30 days of life. Infant survival was compared between women with an intertwin DUAPI <0.4 and ≥0.4 in the whole cohort, in TTTS cases with Quintero stages I/II and in those with Quintero stages III/IV. Regression analyses were performed to evaluate the association of intertwin DUAPI <0.4 and infant survival adjusted for confounders. Results In total, 349 TTTS cases were included. Double twin survival to 30 days was observed in 67% (234/349) of cases. Significant differences in double twin survival was seen between intertwin DUAPI groups in the whole cohort (76.8 vs. 52.2%; p<0.001), in women with TTTS Quintero stage I or II (77.8 vs. 58.5%; p=0.015) as well as in women with TTTS Quintero stage III or IV (75 vs. 49.5%; p=0.001). Intertwin DUAPI <0.4 conferred a threefold increased chance for double twin survival. Conclusions Small intertwin DUAPI is associated with increased double infant survival in early and advanced TTTS stages.

Objectives The effects of lipid metabolism disorders (LMD) on pregnancy outcomes is not well known. The purpose of this study is to evaluate the impact of LMD on maternal and fetal outcomes. Methods Using the Healthcare Cost and Utilization Project – National Inpatient Sample from the United States, we carried out a retrospective cohort study of all births between 1999 and 2015 to determine the risks of complications in pregnant women known to have LMDs. All pregnant patients diagnosed with LMDs between 1999 and 2015 were identified using the International Classification of Disease-9 coding, which included all patients with pure hypercholesterolemia, pure hyperglyceridemia, mixed hyperlipidemia, hyperchylomicronemia, and other lipid metabolism disorders. Adjusted effects of LMDs on maternal and newborn outcomes were estimated using unconditional logistic regression analysis. Results A total of 13,792,544 births were included, 9,666 of which had an underlying diagnosis of LMDs for an overall prevalence of 7.0 per 10,000 births. Women with LMDs were more likely to have pregnancies complicated by diabetes, hypertension, and premature births, and to experience myocardial infarctions, venous thromboembolisms, postpartum hemorrhage, and maternal death. Their infants were at increased risk of congenital anomalies, fetal growth restriction, and fetal demise. Conclusions Women with LMDs are at significantly higher risk of adverse maternal and newborn outcomes. Prenatal counselling should take into consideration these risks and antenatal care in specialized centres should be considered.

Objectives To assess the frequency of antenatal corticosteroid (ACS) administration in cases with shortened cervical length by addition of placental alpha-microglobulin-1 (PAMG-1) testing to sonographic examination. Methods Single centre retrospective cohort study. Rate of ACS administration was compared between cases with cervical length between 15 and 25 mm and cases with positive PAMG-1 testing and cervical length between 15 and 25 mm. We evaluated the following outcome parameters: Rate of ACS administration, gestational age at delivery, time to delivery, delivery within seven days, delivery <34 and <37 weeks’ gestation, rate of admission to neonatal intensive care unit (NICU). Results In total, 130 cases were included. “PAMG-1 group” consisted of 68 women, 62 cases built the “historical control group”. ACS administration was performed less frequently in the “PAMG-1 cohort” (18 (26%) vs. 46 (74%); p<0.001). The rate of delivery within seven days did not differ (2 (3%) vs. 4 (6.5%); p=0.4239). The rates of delivery <34 weeks’ gestation (7 (10%) vs. 9 (15%); p=0.4643) and <37 weeks’ gestation (19 (28%) vs. 26 (42%); p=0.0939) did not differ. Time to delivery interval was longer in the PAMG-1 group (61.5 vs. 43 days, p=0.0117). NICU admission occurred more often in the “historical control group” (22 (38%) vs. 28 (60%); p=0.0272). Conclusions Addition of biomarker testing can help to avoid unnecessary ACS administrations in women with shortened cervical length.

Objectives Corticosteroids are administered to ventilator dependent infants with bronchopulmonary dysplasia (BPD) to improve respiratory function and facilitating extubation. Acutely, however, growth impairment can occur as a side effect of such therapy. We aimed to determine the effect of corticosteroids on postnatal growth during the entire neonatal intensive care unit (NICU) admission. Methods A whole population study of extremely preterm infants with BPD was undertaken. Corticosteroid therapy was classified as treatment with dexamethasone or hydrocortisone for a least five consecutive days. Growth was calculated as the difference in weight and head circumference z -score from birth to discharge. Results Six thousand, one hundred and four infants with BPD were included of whom 28.3% received postnatal corticosteroids. Infants receiving corticosteroids were less mature (GA 25.0 vs. 26.3 weeks) and of lower birthweight (0.70 vs. 0.84 kg) than those not receiving treatment. There were no significant differences between those who did and did not receive corticosteroids in weight gain (p=0.61) or head circumference growth (p=0.33) from birth to discharge. Single vs. multiple courses of postnatal corticosteroids did not result in significant differences in weight (p=0.62) or head circumference (p=0.13) growth. Conclusions Postnatal corticosteroid treatment did not affect the longer term growth of preterm infants with BPD.

Objectives Multiple pregnancies sustain the high pace of extreme prematurity. Little evidence is available about triplet gestation given the evolution in their management during the last decades . The aim of the study was to compare the neonatal outcomes of triplets with those of matched singletons in a cohort study. Methods An observational retrospective cohort study of triplets and matched singletons born between 2004 and 2017 matched by gestational age was conducted. Additionally, the investigation performed in regard to data from the overall Greek population of interest. The primary outcome was mortality or severe neonatal morbidity based on pregnancy type. Results A total of 237 triplets of 24–36 weeks’ gestation and 482 matched singletons were included. No differences in the primary outcome between triplets and singletons were found. Rates of severe neonatal morbidities did not differ significantly between triplets and singletons. A threshold of 1000 gr for birthweight and 28 weeks’ gestation for gestational age determined survival on triplets [OR: 0.08 (95% CI: 0.02–0.40, p=0.0020) and OR: 0.13 (95% CI: 0.03–0.57, p=0.0020) for gestational age and birthweight respectively]. In Greece stillbirths in triplets was 8 times higher than that of singletons (OR: 8.5, 95% CI: 6.9–10.5). From 3,375 triplets, 94 were stillborn, whereas in singletons, 4,659 out of 1,388,273. In our center 5 times more triplets than the expected average in Greece were delivered with no significant difference in stillbirths’ rates. Conclusions No significant differences were identified in mortality or major neonatal morbidities between triplets and matched singletons highlighting the significance of prematurity and birthweight for these outcomes.

Objectives Maternal race, marital status, and social environment impact risk of preterm delivery and size for gestational age. Although some paternal characteristics such as age are associated with pregnancy outcomes, the influence of the paternal presence, race/ethnicity and adverse life events is not well known. The objective of the study was to assess birth outcomes in mothers with a paternal presence compared to those without during the post-partum period. The secondary aim was to determine whether paternal race is associated with birth outcomes. Methods This was a cross-sectional study using parental surveys linked with birth certificate data from 2016 to 2018. Adverse birth composite outcomes (ABCO) including small for gestational age (SGA), prematurity or neonatal intensive care unit admission (NICU) were assessed. Results A total of 695 parents were analyzed (239 single mothers and 228 mother-father pairs). Compared to mothers with a father present, mothers without a father present exhibited increased odds of ABCO, prematurity and NICU. Non-Hispanic Black fathers had increased odds of ABCO and NICU compared to Non-Hispanic Whites (NHW). Hispanic fathers had increased odds of NICU compared to NHW. Conclusions Paternal absence in the post-partum period and paternal race were both independently associated with ABCO and NICU. Assessment of paternal presence and paternal race in clinical practice may help identify opportunities for additional support necessary to optimize birth outcomes.