Neonatal outcomes of congenital diaphragmatic hernia in full term versus early term deliveries: A systematic review and meta-analysis.

This systematic review and meta-analysis aimed to review the optimal timing of delivery at term for neonates with prenatally diagnosed congenital diaphragmatic hernia (CDH). We reviewed the literature up to December 19, 2022 using MEDLINE and the Cochrane Library databases. The inclusion criteria were original articles, comparative studies of CDH neonates delivered at an early term (37-38 weeks of gestation) and at full term (39 weeks of gestation or later), and comparative studies investigating outcomes of CDH neonates. Six studies met the inclusion criteria, including 985 neonates delivered at an early term and 629 delivered at full term. The cumulative rate of survival to discharge showed no significant difference between CDH neonates delivered at an early term (395/515; 76.7%) or at full term (345/467; 73.9%) (risk ratio [RR] 1.01; 95% confidence interval [CI], 0.89-1.16; p = 0.85). Furthermore, the number of neonates requiring oxygen therapy at discharge was not significantly different between CDH neonates delivered at an early term (32/370; 8.6%) and at full term (14/154; 9.1%) (RR, 0.99; 95% CI, 0.36-2.70; p = 0.99). Therefore, the optimal timing of delivery at term for neonates with CDH remains unclear.

Efficacy of discontinuing the use of low-dose aspirin at 28 weeks of gestation for preventing preeclampsia.

AIM: Low-dose aspirin (LDA) has been shown to reduce the incidence of preeclampsia (PE). Previous studies have focused on the timing of LDA initiation, but no study to date has assessed the timing of LDA discontinuation. This study aimed to evaluate the effect of LDA when LDA is initiated between 12 and 16 weeks of gestation and continued until 28 weeks of gestation. METHODS: This prospective cohort study with historical controls investigated singleton pregnancies that were at a high risk for PE. High-risk factors were defined as a history of hypertensive disorders of pregnancy, chronic hypertension, diabetes mellitus, autoimmune disease, obesity, and high normal blood pressure in the first trimester. We performed adjustments using propensity score matching (PSM) for each indication of LDA, maternal age, primiparity, and assisted reproductive technology. The primary outcome was the incidence of PE. Secondary outcomes were the incidence of preterm PE, fetal growth restriction (FGR), preterm birth, fetal malformation, and maternal postpartum hemorrhage (PPH). RESULTS: A total of 203 and 543 participants were assigned to the LDA and control group, respectively. After PSM, there was no significant difference in the incidence of PE (22.0% vs. 16.8%; p = 0.20), preterm PE (12.0% vs. 13.1%; p = 0.76), FGR (7.9% vs. 12.0%; p = 0.17), or preterm birth (17.3% vs. 15.7%; p = 0.68). There was also no significant increase in maternal PPH or in the incidence of fetal malformations. CONCLUSION: Discontinuing the use of LDA at 28 weeks of gestation did not result in a lower incidence of PE and FGR.

Maternal and Fetal Outcomes after Prior Mid-Trimester Uterine Rupture: A Systematic Review with Our Experience.

Background and Objectives: Since spontaneous uterine rupture in the mid-trimester is rare, maternal and fetal outcomes in subsequent pregnancies remain unclear. Therefore, this study aimed to examine the maternal and fetal outcomes of subsequent pregnancies after prior mid-trimester uterine rupture. Materials and Methods: A systematic review using PubMed, the Cochrane Central Register of Controlled Trials, and Scopus until 30 September 2021, was conducted in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The studies that clarified the maternal and fetal outcomes after prior mid-trimester uterine rupture and our case (n = 1) were included in the analysis. Results: Among the eligible cases, there were five women with eight subsequent pregnancies after prior mid-trimester uterine rupture. The timing of prior mid-trimester uterine rupture ranged from 15 to 26 weeks of gestation. The gestational age at delivery in subsequent pregnancies was 23-38 gestational weeks. Among the included cases (n = 8), those involving prior mid-trimester uterine rupture appeared to be associated with an increased prevalence of placenta accreta spectrum (PAS) (n = 3, 37.5%) compared with those involving term uterine rupture published in the literature; moreover, one case exhibited recurrent uterine rupture at 23 weeks of gestation (12.5%). No maternal deaths have been reported in subsequent pregnancies following prior mid-trimester uterine rupture. Fetal outcomes were feasible, except for one pregnancy with recurrent mid-trimester uterine rupture at 23 weeks of gestation, whose fetus was alive complicated by cerebral palsy. Conclusions: Our findings suggest that clinicians should be aware of the possibility of PAS and possible uterine rupture in pregnancies after prior mid-trimester uterine rupture. Further case studies are warranted to assess maternal and fetal outcomes in pregnancies following prior mid-trimester prior uterine rupture.

Congenital malformation and hemoglobin A1c in the first trimester among Japanese women with pregestational diabetes.

AIM: To investigate the incidence of major congenital malformations in Japanese women with pregestational diabetes, and to determine the cutoff value of hemoglobin A1c (HbA1c) in the first trimester associated with congenital malformations. METHODS: This retrospective cohort study included singleton pregnancies in Japanese women with pregestational diabetes, including type 1 and type 2 diabetes, and specific types of diabetes due to other causes. The primary outcome was the incidence of major congenital malformations. The secondary outcome was the incidence of all congenital malformations. The cutoff value of HbA1c for congenital malformations was calculated using receiver operating characteristic curve analysis. The adjusted odds ratios (aOR) of major congenital malformations were calculated using multiple logistic regression analyses. RESULTS: This study enrolled 292 patients, including 132 (45.2%) with type 1 diabetes, 156 (53.4%) with type 2 diabetes, and 4 (1.4%) with other specific types. The incidence rates of major congenital malformations and all congenital malformations were 7.2% (21/292) and 12.7% (37/292), respectively. The cutoff value of HbA1c in the first trimester for major malformations and for all congenital malformations was 6.5%. HbA1c ≥ 6.5% was significantly associated with major malformations (aOR 3.5; 95% confidence interval: 1.2-12.6; p = 0.018). CONCLUSION: The incidence of major congenital malformations significantly increased in pregnant Japanese women with HbA1c values of 6.5% or higher. The recommended HbA1c value during the first trimester used in other countries can be applied to pregnant Japanese women.

Fetal Outcomes Associated with the Sequence of Doppler Deterioration in Severely Growth-Restricted Fetuses.

OBJECTIVES: Various patterns of Doppler deterioration exist in fetal growth restriction (FGR). However, the factors that differentiate these patterns are still unknown. The purpose of this study was to clarify the perinatal outcomes and factors to determine the pattern of Doppler deterioration in severe FGR. MATERIALS AND METHODS: We conducted a retrospective cohort study of preterm severe FGR with Doppler abnormality, wherein the clinical features, including maternal characteristics, medical history, and sonographic findings, were compared between the patterns of Doppler deterioration. We used the multivariable logistic regression analyses to identify the factors associated with the pattern of Doppler deterioration. RESULTS: Of 322 eligible fetuses, 143 had Doppler abnormalities. Fetuses with Doppler deterioration from ductus venosus uniquely featured fetal and placental-umbilical abnormalities detected after birth. Gestational age (GA) at diagnosis of FGR and at the first diagnosis of Doppler abnormality in fetuses with Doppler deterioration from middle cerebral artery (MCA) were later than those from umbilical artery. In addition, the factor associated with Doppler deterioration from MCA was 31-week GA at the first diagnosis of Doppler abnormality (adjusted odds ratio [aOR]: 26.7; 95% CI: 8.35-103), not GA at diagnosis of FGR (aOR: 1.82; 95% CI: 0.50-5.96). CONCLUSIONS: Characteristics of each Doppler deterioration pattern might reflect FGR etiology. Undetectable anomalies and umbilical-placental abnormalities were found in fetuses with Doppler deterioration from the ductus venosus. Doppler deterioration from the MCA was observed after 31 weeks of gestation not only in the late-onset FGR but also in the early-onset FGR with normal umbilical artery Doppler findings.

Perinatal Determinants of Child Maltreatment in Japan.

Background: Child maltreatment induces significant health problems, both during childhood and into adulthood. To prevent child maltreatment, it is important to detect perinatal risk factors for earlier intervention. The aim of this study was to evaluate the perinatal risk factors associated with child maltreatment during pregnancy. Methods: A case-control study was conducted to compare perinatal data from the Maternal and Child Health Handbook between the case and control groups. Cases were collected from children registered in two Child Guidance Centers in Japan. The control group consisted of 3.5-year-old children in a city in Osaka Prefecture whose mothers responded to questionnaires containing information from the Maternal and Child Health Handbook. The association between perinatal factors and child maltreatment was assessed using multiple logistic regression analysis. Results: The data of 70 cases and 345 controls were collected. The following were found to be perinatal factors related to child maltreatment: teenage pregnancy (OR: 257.3, 95% CI: 17.3-3832.7), a mother aged 20-24 years (OR: 22.8, 95% CI: 4.4-117.8), a father who is older than the mother by 10 years or more (OR: 14.1, 95% CI: 2.1-94.8), an unmarried mother (OR: 15.7, 95% CI: 2.6-93.6), maternal mental disorder (OR: 48.9, 95% CI: 9.3-258.3), the first maternal prenatal visit being later than 20 weeks (OR: 132, 95% CI: 12.7-1384.7), little prenatal care (<10 visits) (OR: 21.4, 95% CI: 2.9-157.1), a low-birth-weight baby (OR: 5.1, 95% CI: 1.1-24.1), and congenital disease (OR: 7.9, 95% CI: 1.1-56.4). Conclusions: This study revealed that young mothers, fathers much older than mothers, unmarried mothers, and maternal mental disorder, mothers with late first visit or little perinatal care, and low-birth-weight babies and babies with congenital disease were associated with child maltreatment. These findings can be used to detect high-risk families for child maltreatment during or after pregnancy.

Clinical Characteristics of Jra Alloimmunization in Pregnancy: A Case Series.

Only few studies have reported on Jra alloimmunization in pregnancy, and its clinical course remains unclear. We reviewed our cases to clarify the change in the peak systolic velocity of the middle cerebral artery (MCA-PSV) during pregnancy and the critical anti-Jra antibody titer to predict fetal anemia. We collected the data of pregnant women with anti-Jra antibody from two hospitals between 2010 and 2017. We extracted data on maternal information, number of intrauterine blood transfusions (IUT), trend of anti-Jra antibody titer, changes of MCA-PSV, and neonatal outcome. We had 16 cases. IUTs were performed in 6 fetuses with severe anemia between 27 and 32 weeks' gestation. The MCA-PSV did not increase more than 1.5 multiples of the median (MoM) after 32 weeks' gestation. No significant difference was found in the maximum titer between cases with IUT and those without IUT. All pregnancies but one delivered at term. No neonates developed severe anemia or jaundice. MCA-PSV did not increase higher than 1.5 MoM later during the pregnancy. A critical titer to predict fetal anemia did not exist. Spontaneous term delivery could be expected even in fetuses who underwent IUT before 32 weeks' gestation.

Classification of factors involved in nonreportable results of noninvasive prenatal testing (NIPT) and prediction of success rate of second NIPT.

OBJECTIVE: To evaluate the reasons for nonreportable cell-free DNA (cfDNA) results in noninvasive prenatal testing (NIPT), we retrospectively studied maternal characteristics and other details associated with the results. METHODS: A multicenter retrospective cohort study in pregnant women undergoing NIPT by massively parallel sequencing (MPS) with failed cfDNA tests was performed between April 2013 and March 2017. The women's data and MPS results were analyzed in terms of maternal characteristics, test performance, fetal fraction (FF), z scores, anticoagulation therapy, and other details of the nonreportable cases. RESULTS: Overall, 110 (0.32%) of 34 626 pregnant women had nonreportable cfDNA test results after an initial blood sampling; 22 (20.0%) cases had a low FF (<4%), and 18 (16.4%) cases including those with a maternal malignancy, were found to have altered genomic profile. Approximately half of the cases with nonreportable results had borderline z score. Among the women with nonreportable results because of altered genomic profile, the success rate of retesting using a second blood sampling was relatively low (25.0%-33.3%). Thirteen (11.8%) of the women with nonreportable results had required hypodermic heparin injection. CONCLUSIONS: The classification of nonreportable results using cfDNA analysis is important to provide women with precise information and to reduce anxiety during pregnancy.

Impact of maternal methylenetetrahydrofolate reductase C677T polymorphism on intervillous and decidual pathology with pregnancy loss.

AIM: The association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and intervillous and decidual pathology in patients with pregnancy loss was investigated. METHODS: We performed a cross-sectional study on 243 patients presenting with pregnancy loss for the degree of intervillous fibrin and thrombosis (IT), and decidual fibrin and thrombosis (DT) and determined their MTHFR C677T genotypes. Overall differences in age, body mass index (BMI), gravidity, parity, number of pregnancy losses and gestational period when the pathologic samples were obtained, also were determined. RESULTS: There were no significant differences in age, BMI, gravidity, parity, number of pregnancy losses and gestational period, relative to MTHFR C677T genotype (TT vs CT vs CC). There were significantly more T allele carriers and TT genotype patients among patients with severe IT (odds ratio [OR] 1.653, P = 0.033 and OR 2.246, P = 0.032, respectively) and those with severe IT and decidual thrombosis (OR 2.602, P = 0.012 and OR 3.375, P = 0.035, respectively). The CC genotype was protective against the four studied pathologic grades. CONCLUSION: To our knowledge, this is the first study showing that the MTHFR C677T TT genotype and T allele are associated with severe intervillous and decidual pathologies in patients with pregnancy loss. Differences in pathologic grades of MTHFR C677T TT genotype could support the hypothesis that further periconceptional treatment for pregnancy loss could be customized depending on single nucleotide polymorphisms.

Fetal cell-free DNA fraction in maternal plasma for the prediction of hypertensive disorders of pregnancy.

OBJECTIVE: The purpose of this study is to compare the fetal fractions during non-invasive prenatal testing (NIPT) in singleton pregnancies according to gestational age and maternal characteristics to evaluate the utility of this parameter for the prediction of pregnancy complications including gestational diabetes mellitus (GDM) and hypertensive disorders of pregnancy (HDP). STUDY DESIGN: This study was a multicenter prospective cohort study. The present data were collected from women whose NIPT results were negative. The relationships between the fetal fractions and the gestational age, maternal weight and height, and incidences of miscarriage, preterm delivery, and pregnancy complications including GDM, HDP and placental abruption were assessed. RESULTS: A total of 5582 pregnant women with verified NIPT negative results were registered in the study. The demographic characteristics of the study populations were statistically analyzed, and the women with HDP tended to have a low fetal fraction in samples taken during early gestation. The area under the curve (AUC) in a receiver operating characteristic curve (ROC) analysis was 0.608 for women with HDP. CONCLUSION: A low fetal fraction on NIPT might be correlated with future HDP. However, predicting HDP during early pregnancy in women with a low fetal fraction might be difficult.

Transient amniotic fluid leakage after fetoscopic laser photocoagulation for twin-twin transfusion syndrome.

AIM: Iatrogenic premature rupture of membrane (PROM) is one of the major complications related to fetoscopic laser photocoagulation (FLP) for twin-twin transfusion syndrome (TTTS). However, amniotic fluid leakage (AFL) sometimes spontaneously disappears. This study evaluated the incidence and clinical characteristics of transient AFL after FLP. METHODS: We retrospectively reviewed pregnancies that underwent FLP for TTTS at a single center. Patients with apparent AFL within 2 weeks after FLP were divided into two groups: transient AFL, defined by the disappearance of fluid leakage within a week; and PROM, if AFL persisted continuously for more than a week or premature birth occurred, including miscarriage, within a week of the first symptom of AFL. RESULTS: Among 201 monochorionic twin pregnancies that underwent FLP during the study period, nine patients (4.5%) were diagnosed with AFL within a week after FLP. Four patients (2.0%) were classified as transient AFL and five as PROM. Median gestational age at FLP was not significantly different between the groups; operative time in the PROM group was significantly longer (P = 0.01). The surgery to delivery interval and median gestational age at delivery were greater in the transient AFL group (87.8 vs 17.6 days, P = 0.01; 32.5 vs 23.6 weeks, P = 0.01, respectively). CONCLUSIONS: The incidence of transient AFL after FLP was 2%. Perinatal outcomes of transient AFL might be better than that of PROM.

Prediction of sustained fetal toxicity induced by ketoprofen based on PK/PD analysis using human placental perfusion and rat toxicity data.

AIM: We encountered a case of fetal toxicity due to ductus arteriosus (DA) constriction in a 36-week pregnant woman who had applied multiple ketoprofen patches. The aim of the present study was to present the case and develop a model to predict quantitatively the fetal toxicity risk of transdermal administration of ketoprofen. METHODS: Human placenta perfusion studies were conducted to estimate transplacental pharmacokinetic (PK) parameters. Using a developed model and these parameters, human fetal plasma concentration profiles of ketoprofen administered to mothers were simulated. Using pregnant rats, DA constriction and fetal plasma drug concentration after ketoprofen administration were measured, fitted to an Emax model, and extrapolated to humans. RESULTS: Transplacental transfer value at the steady state of ketoprofen was 4.82%, which was approximately half that of antipyrine (passive marker). The model and PK parameters predicted almost equivalent mother and fetus drug concentrations at steady state after transdermal ketoprofen administration in humans. Maximum DA constriction and maximum plasma concentration of ketoprofen after administration to rat dams were observed at different times: 4 h and 1 h, respectively. The model accurately described the delay in DA constriction with respect to the fetal ketoprofen concentration profile. The model with effect compartment and the obtained parameters predicted that use of multiple ketoprofen patches could potentially cause severe DA constriction in the human fetus, and that fetal toxicity might persist after ketoprofen discontinuation by the mother, as observed in our case. CONCLUSION: The present approach successfully described the sustained fetal toxicity after discontinuing the transdermal administration of ketoprofen.

Current status of non-invasive prenatal testing in Japan.

AIM: The purpose of this study was to report the 3-year experience of a nationwide demonstration project to introduce non-invasive prenatal testing (NIPT) of maternal plasma for aneuploidy, and review the current status of NIPT in Japan. METHODS: Tests were conducted to detect aneuploidy in high-risk pregnant women, and adequate genetic counseling was provided. The clinical data, test results, and pregnancy outcomes were recorded. We discuss the problems of NIPT on the basis of published reports and meta-analyses. RESULTS: From April 2013 to March 2016, 30 613 tests were conducted at 55 medical sites participating in a multicenter clinical study. Among the 30 613 women tested, 554 were positive (1.81%) and 30 021 were negative (98.1%) for aneuploidy. Of the 289, 128, and 44 women who tested positive for trisomies 21, 18, and 13, respectively, and underwent definitive testing, 279 (96.5%), 106 (82.8%), and 28 (63.6%) were determined to have a true-positive result. For the 13 481 women with negative result and whose progress could be traced, two had a false-negative result (0.02%). The tests were performed on the condition that a standard level of genetic counseling be provided at hospitals. CONCLUSION: Here, we report on the 3-year nationwide experience with NIPT in Japan. It is important to establish a genetic counseling system to enable women to make informed decisions regarding prenatal testing. Moreover, a welfare system is warranted to support women who decide to give birth to and raise children with chromosomal diseases.

Prior uterine bleeding is associated with low visibility due to discolored amniotic fluid on fetoscopic laser photocoagulation.

AIM: To investigate the association between uterine bleeding preceding fetoscopic laser photocoagulation (FLP) and the presence of discolored amniotic fluid that impedes FLP. METHODS: A retrospective review of all multiple gestations requiring FLP at the present institution was conducted. The rate of low visibility because of discolored amniotic fluid at the beginning of FLP was compared between patients with and without a history of uterine bleeding, defined as either genital bleeding or ultrasonographically detected subchorionic hematoma. RESULTS: The prevalence of low visibility because of discolored amniotic fluid was 4.5% (seven in 156 patients). Two of the seven cases of low visibility resulted in double fetal death. The incidence of low visibility was significantly higher in the group with uterine bleeding before surgery compared with that without bleeding (28.6% vs 0.74%, P < 0.001). CONCLUSIONS: Patients with a history of uterine bleeding prior to FLP may encounter more technical difficulties owing to discolored amniotic fluid during FLP.

Prenatal and Postnatal Clinical Course of an Urachus Identified as an Allantoic Cyst in the Umbilical Cord.

PURPOSE: The aim of this study was to clarify the prenatal and postnatal clinical courses of an urachus identified as an allantoic cyst in the umbilical cord. METHODS: Allantoic cysts in the umbilical cord were identified in five fetuses over the past 12 years at our hospital. The prenatal and postnatal clinical courses of these patients were retrospectively reviewed. RESULTS: The presence of allantoic cysts in the umbilical cord was first detected at 15 to 27 weeks of gestation. The cysts subsequently became enlarged, reaching a maximum diameter of 34 to 61 mm at 17 to 32 weeks of gestation. The cysts then suddenly disappeared due to spontaneous rupture at 26 to 35 weeks of gestation. After being born at 38 (35-39) weeks of gestation, four patients were diagnosed with a patent urachus requiring surgery in the infantile period and one was diagnosed with an urachal cyst, which is currently being observed without surgery. CONCLUSION: The presence of an urachus identified as an allantoic cyst in the umbilical cord is frequently associated with spontaneous rupture during the prenatal period, resulting in a patent urachus after birth that requires surgical intervention.

Expression levels of ABCG2 on cord red blood cells and study of fetal anemia associated with anti-Jr(a).

BACKGROUND: The Jr(a) antigen of JR blood group systems is located on ABCG2 and Jr(a-) subjects whose red blood cells (RBCs) lack ABCG2 have been identified mostly among the Japanese. Although anti-Jr(a) can cause fetal anemia, little is known regarding its mechanism. STUDY DESIGN AND METHODS: We reviewed clinical courses of all reported cases with fetal anemia due to anti-Jr(a) . We analyzed the ABCG2 expressions of cord RBCs at various gestational ages. We examined the effects of sera containing anti-Jr(a) from three pregnancies with fetal anemia or monoclonal anti-Jr(a) on erythropoiesis and phagocytosis. We also examined epitopes of anti-Jr(a) . RESULTS: Case series suggested that the majority of fetal anemia with anti-Jr(a) may not be progressive in the later gestational ages. ABCG2 expression levels of cord RBCs were significantly higher than those of adults and neonates with high individual variation and gradually decreased with advancing gestational ages. Anti-Jr(a) did not significantly impact erythroid colony formation, although we detected a tendency toward the suppression of erythroid burst-forming unit formation by anti-Jr(a) using feline marrow cells. Anti-Jr(a) did not induce phagocytosis of sensitized RBCs by monocytes. While many anti-Jr(a) recognized the same regions as a monoclonal anti-ABCG2, 5D3, epitopes of anti-Jr(a) did not correlate with the incidence of fetal anemia. CONCLUSION: ABCG2 expression levels in cord RBCs are higher than those of adults, and the change of ABCG2 expression in erythroid lineage cells may influence the clinical course of fetal anemia with anti-Jr(a) , although we could not detect significant effects of anti-Jr(a) on erythroid colony formation or phagocytosis.

A Case Report and Literature Review of Midtrimester Termination of Pregnancy Complicated by Placenta Previa and Placenta Accreta.

Objective Concurrent placenta previa and placenta accreta increase the risk of massive obstetric hemorrhage. Despite extensive research on the management of placenta previa (including placenta accreta, increta, and percreta), the number and quality of previous studies are limited. We present a case of placenta accreta requiring an induced second-trimester abortion because of premature rupture of the membranes (PROM). Study Design Case report and review of the literature. Results A 41-year-old female presented at 20 weeks of gestation with placenta previa and PROM. Ultrasonography revealed placenta accreta with multiple placental lacunae. She then developed massive hemorrhaging just prior to a planned termination of pregnancy. We performed a hysterectomy with the intent of preserving life because of the failure of the placenta to detach and blood loss totaling 4,500 mL. Conclusion Previous studies suggest that second-trimester pregnancy terminations in cases of placenta previa which are not complicated with placenta accreta do not have a particularly high risk of hemorrhage. However, together with our case, the literature suggests that placenta previa complicated with placenta accreta presents a significant risk of hemorrhage both during delivery and intraoperatively. Further reports are needed to evaluate the most appropriate treatment options.