Implementation of First-trimester Screening and Prevention of Preeclampsia: a Stepped Wedge Cluster-randomized Trial in Asia.

BACKGROUND: This trial aimed to assess the efficacy, acceptability and safety of a first-trimester screen-and-prevent strategy for preterm preeclampsia (PE) in Asia. METHODS: Between 1st August 2019 and 28th February 2022, this multicenter stepped wedge cluster randomized trial included maternity/diagnostic units from ten regions in Asia. The trial started with a period where all recruiting centers provided routine antenatal care without study-related intervention. At regular six-week intervals, one cluster was randomized to transit from non-intervention phase to intervention phase. In the intervention phase, women underwent first-trimester screening for preterm PE using a Bayes theorem-based triple-test. High-risk women, with adjusted risk for preterm PE ≥ 1 in 100, received low-dose aspirin from <16 weeks until 36 weeks. RESULTS: Overall, 88.04% (42,897/48,725) of women agreed to undergo first-trimester screening for preterm PE. Among those identified as high-risk in the intervention phase, 82.39% (2,919/3,543) received aspirin prophylaxis. There was no significant difference in the incidence of preterm PE between the intervention and non-intervention phases (adjusted odds ratio [aOR] 1.59; 95% confidence interval [CI] 0.91 to 2.77). However, among high-risk women in the intervention phase, aspirin prophylaxis was significantly associated with a 41% reduction in the incidence of preterm PE (aOR 0.59; 95%CI 0.37 to 0.92). Additionally, it correlated with 54%, 55% and 64% reduction in the incidence of PE with delivery at <34 weeks (aOR 0.46; 95%CI 0.23 to 0.93), spontaneous preterm birth <34 weeks (aOR 0.45; 95%CI 0.22 to 0.92) and perinatal death (aOR 0.34; 95%CI 0.12 to 0.91), respectively. There was no significant between-group difference in the incidence of aspirin-related severe adverse events. CONCLUSIONS: The implementation of the screen-and-prevent strategy for preterm PE is not associated with a significant reduction in the incidence of preterm PE. However, low-dose aspirin effectively reduces the incidence of preterm PE by 41% among high-risk women. The screen-and-prevent strategy for preterm PE is highly accepted by a diverse group of women from various ethnic backgrounds beyond the original population where the strategy was developed. These findings underpin the importance of the widespread implementation of the screen-and-prevent strategy for preterm PE on a global scale.

Probiotics including Clostridium butyricum, Enterococcus faecium, and Bacillus subtilis may prevent recurrent spontaneous preterm delivery.

AIM: A large cohort study of Japanese women reported that the rate of recurrent spontaneous preterm delivery (sPTD) in the next pregnancy was 22.3%; therefore, it is important to prevent recurrent sPTD. The present study investigated the rate of recurrent sPTD in pregnant women treated with probiotics. METHODS: This was a retrospective study. Fifty-one pregnant women with a history of sPTD and who had been taking probiotics before 14 weeks of gestation were selected. The rate of sPTD in the next pregnancy among 255 pregnant women with a history of sPTD who had not taken probiotics was compared with that in the probiotics group. RESULTS: The rate of recurrent sPTD was 9.8% (5/51), which was lower than previously reported values. Furthermore, the rate of recurrent sPTD was significantly lower in the probiotics group (9.8%) than in the nonprobiotics group (31.0% [79/255]; p = 0.002). CONCLUSIONS: Probiotics may reduce the rate of recurrent sPTD.

Risk factors for spontaneous miscarriage above 12 weeks or premature delivery in patients undergoing cervical polypectomy during pregnancy.

BACKGROUND: It currently remains unknown whether the resection of cervical polyps during pregnancy leads to miscarriage and/or preterm birth. This study evaluated the risk of spontaneous PTB below 34 or 37 weeks and miscarriage above 12 weeks in patients undergoing cervical polypectomy during pregnancy. METHODS: This was a retrospective monocentric cohort study of patients undergoing cervical polypectomy for clinical indication. Seventy-three pregnant women who underwent polypectomy were selected, and risk factors associated with miscarriage above 12 weeks or premature delivery below 34 or 37 weeks were investigated. A multivariable regression looking for predictors of spontaneous miscarriage > 12 weeks and PTB < 34 or 37 weeks were performed. RESULTS: Sixteen patients (21.9%, 16/73) had spontaneous delivery at < 34 weeks or miscarriage above 12 weeks. A univariate analysis showed that bleeding before polypectomy [odds ratio (OR) 7.7, 95% confidence interval (CI) 1.6-37.3, p = 0.004], polyp width ≥ 12 mm (OR 4.0, 95% CI 1.2-13.1, p = 0.005), the proportion of decidual polyps (OR 8.1, 95% CI 1.00-65.9, p = 0.024), and polypectomy at ≤10 weeks (OR 5.2, 95% CI 1.3-20.3, p = 0.01) were significantly higher in delivery at < 34 weeks than at ≥34 weeks. A logistic regression analysis identified polyp width ≥ 12 mm (OR 11.8, 95% CI 2.8-77.5, p = 0.001), genital bleeding before polypectomy (OR 6.5, 95% CI 1.2-55.7, p = 0.025), and polypectomy at ≤10 weeks (OR 5.9, 95% CI 1.2-45.0, p = 0.028) as independent risk factors for predicting delivery at < 34 weeks. Polyp width ≥ 12 mm and bleeding before polypectomy are risk factors for PTB < 37 wks. CONCLUSIONS: Our cohort of patients undergoing polypectomy in pregnancy have high risks of miscarriage or spontaneous premature delivery. It is unclear whether these risks are given by the underlying disease, by surgical treatment or both. This study establishes clinically relevant predictors of PTB are polyp size> 12 mm, bleeding and first trimester polypectomy. PTB risks should be exposed to patients and extensively discussed with balancing against the benefits of intervention in pregnancy.

Fermented foods and preterm birth risk from a prospective large cohort study: the Japan Environment and Children's study.

BACKGROUND: The dietary pattern of pregnant women is known to be associated with preterm birth (PTB). We investigated whether PTB was associated with intake of fermented food by using data from the Japan Environment and Children's Study. METHODS: From a data set of 103,099 pregnancies, 77,667 cases at low risk for PTB were analyzed. The primary outcome measurements were based on PTB. Fermented food (miso soup, yogurt, cheese, and fermented soybeans) consumption was assessed by using a semi-quantitative food frequency questionnaire. RESULTS: Intake of miso soup, yogurt, and fermented soybeans before pregnancy significantly reduced the risk of early PTB (< 34 weeks). The adjusted odds ratio (OR) for early PTB in women who had miso soup 1-2 days/week, 3-4 days/week, or ≥ 5 days/week were 0.58, 0.69, and 0.62, respectively, compared with those who had miso soup < 1 day/week (95% confidence interval (CI) 0.40-0.85, 0.49-0.98, and 0.44-0.87). The adjusted OR for early PTB in women who ate yogurt ≥ 3 times/week was 0.62 (95% CI, 0.44-0.87) compared to those who ate yogurt < 1 time/week. The adjusted OR for early PTB in women who ate fermented soybeans ≥ 3 times/week was 0.60 (95% CI, 0.43-0.84) compared to those who ate < 1 time/week. However, the incidence of overall PTB and late PTB (34-36 weeks) was not associated with fermented food intake. CONCLUSION: PTB low-risk women with a high consumption of miso soup, yogurt, and fermented soybeans before pregnancy have a reduced risk of early PTB.

A Yolk Sac Larger Than 5 mm Suggests an Abnormal Fetal Karyotype, Whereas an Absent Embryo Indicates a Normal Fetal Karyotype.

OBJECTIVES: It is very hard to estimate an abnormal or normal fetal karyotype in miscarriage before surgery. We investigated whether the abnormal fetal karyotype in early miscarriage could be estimated by comprehensive ultrasonographic findings by a multivariate analysis. METHODS: One hundred fifty-one patients with early miscarriage (<12 weeks' gestation) were selected in our hospital. The clinical characteristics were compared between pregnant women carrying a fetus with an abnormal karyotype and those with a normal one, and the size and configuration of the gestational sac, yolk sac, and embryo at diagnosis of early miscarriage were also evaluated. RESULTS: The rate of abnormal fetal karyotypes was 66.2 % (100 of 151). A maternal age older than 35 years (odds ratio, 3.2; 95% confidence interval, 1.4-7.4; P = .005), yolk sac larger than 5 mm (odds ratio, 6.2; 95% confidence interval, 2.2-22.7, P < .001), and absent embryo (odds ratio, 0.40; 95% confidence interval, 0.16-0.95; P = .038) were independent markers for predicting an abnormal fetal karyotype by multiple logistic regression analysis. CONCLUSIONS: At the point of early miscarriage diagnosis, a yolk sac larger than 5 mm suggests an abnormal fetal karyotype, whereas an absent embryo indicates a normal fetal karyotype.

In which preterm labor-patients is intravenous maintenance tocolysis effective?

AIM: We evaluated whether maintenance tocolysis (intravenous ritodrine hydrochloride and/or magnesium sulfate) was effective in cases of spontaneous preterm labor with intact membranes. METHODS: One hundred and thirty preterm labor patients who reached 36 weeks of gestation by maintenance tocolysis were selected. Immediate delivery (ID) after ceasing maintenance tocolysis was defined as an 'effective case'. The correlated factors between ID and no immediate delivery (NID) were statistically analyzed. RESULTS: Thirty-six patients delivered < two days after ceasing maintenance tocolysis (27.7%) and were defined as effective cases. Multiple logistic regression analysis revealed that amniotic fluid interleukin-8 at admission (≥ 2.3 ng/mL; odds ratio [OR] 5.6, 95% confidence interval [CI] 2.1-17.6; P < 0.001), pre-pregnancy body mass index (≤ 21.4; OR 5.3, 95% CI 2.0-16.2; P < 0.001) and cerclage (OR 3.6, 95% CI 1.1-11.8; P = 0.028) were independent factors correlated with ID (< 2 days). CONCLUSION: Maintenance tocolysis may be effective in limited cases with mild intra-amniotic inflammation, in lean women and in cerclage cases. Maintenance tocolysis should be ceased in cases without these clinical factors when clinical symptoms disappear.

Effectiveness of Helicobacter pylori eradication in pregnant women with idiopathic thrombocytopenic purpura.

Platelet counts increase after eradication of Helicobacter pylori (Hp) infection in non-pregnant patients with Hp-associated idiopathic thrombocytopenic purpura (ITP); however, improvement in pregnant patients has not yet been reported. We treated four pregnant women for Hp-positive ITP after Hp eradication. In three of four cases, platelet counts increased to levels exceeding 10 × 109 /L two weeks after eradication, and these levels were maintained until delivery. Vaginal deliveries were uncomplicated, and no excessive blood loss occurred in any of the cases. There were no remarkable side effects of Hp eradication in pregnant women or fetuses. In pregnant women with Hp-associated ITP, Hp eradication might be worthwhile prior to considering steroid administration.

Multiple pregnancy, short cervix, part-time worker, steroid use, low educational level and male fetus are risk factors for preterm birth in Japan: a multicenter, prospective study.

AIM: To examine the relationship between preterm birth and socioeconomic factors, past history, cervical length, cervical interleukin-8, bacterial vaginosis, underlying diseases, use of medication, employment status, sex of the fetus and multiple pregnancy. METHODS: In a multicenter, prospective, observational study, 1810 Japanese women registering their future delivery were enrolled at 8⁺° to 12⁺6 weeks of gestation. Data on cervical length and delivery were obtained from 1365 pregnant women. Multivariate logistic regression analysis was performed. RESULTS: Short cervical length, steroid use, multiple pregnancy and male fetus were risk factors for preterm birth before 34 weeks of gestation. Multiple pregnancy, low educational level, short cervical length and part-timer were risk factors for preterm birth before 37 weeks of gestation. CONCLUSION: Multiple pregnancy and cervical shortening at 20-24 weeks of gestation was a stronger risk factor for preterm birth. Any pregnant woman being part-time employee or low educational level, having a male fetus and requiring steroid treatment should be watched for the development of preterm birth.

Comparison of risk factors for gestational hypertension and preeclampsia in Japanese singleton pregnancies.

AIM: To demonstrate the difference between risk factors for gestational hypertension (GH) and preeclampsia (PE). MATERIAL AND METHODS: Using data from women with no essential hypertension and with singleton births between 2001 and 2005 delivering after 22 weeks of gestation at 125 centers in Japan (Japan Perinatal Registry Network) (n =241 292), we compared risk factors for GH and PE. Odds ratios were calculated using multivariate logistic regression analyses. RESULTS: Of 241 292 women, 2808 (1.2%) developed GH and 6423 (2.7%) developed PE. Thirty-five years or older, primiparity, diabetes mellitus, and renal disease increased the risk of both hypertensive conditions. Forty years or older was a risk factor only for GH, while primiparity, female baby, and renal disease were risk factors only for PE. Early-onset was a common risk factor for small-for-gestational-age (SGA) in GH and PE, but in late-onset only PE was a risk factor for SGA. The main population of SGA infants was composed of PE cases because PE accounted for 83.3% of early-onset type before 32 weeks. Girl preponderance in the PE women was observed (sex ratio: boys/girls=0.904), while slight boy preponderance was seen in normotensive women (1.06) and GH (1.02). CONCLUSION: Preeclampsia is associated with lower fetal sex ratio (girl preponderance) compared to GH or normotensive. Presence of hypertension is a risk factor for SGA in early-onset GH and PE, and hypertension and proteinuria are risk factors for SGA in late-onset group.

Aberrant methylation of H19-DMR acquired after implantation was dissimilar in soma versus placenta of patients with Beckwith-Wiedemann syndrome.

Gain of methylation (GOM) at the H19-differentially methylated region (H19-DMR) is one of several causative alterations in Beckwith-Wiedemann syndrome (BWS), an imprinting-related disorder. In most patients with epigenetic changes at H19-DMR, the timing of and mechanism mediating GOM is unknown. To clarify this, we analyzed methylation at the imprinting control regions of somatic tissues and the placenta from two unrelated, naturally conceived patients with sporadic BWS. Maternal H19-DMR was abnormally and variably hypermethylated in both patients, indicating epigenetic mosaicism. Aberrant methylation levels were consistently lower in placenta than in blood and skin. Mosaic and discordant methylation strongly suggested that aberrant hypermethylation occurred after implantation, when genome-wide de novo methylation normally occurs. We expect aberrant de novo hypermethylation of H19-DMR happens to a greater extent in embryos than in placentas, as this is normally the case for de novo methylation. In addition, of 16 primary imprinted DMRs analyzed, only H19-DMR was aberrantly methylated, except for NNAT DMR in the placental chorangioma of Patient 2. To our knowledge, these are the first data suggesting when GOM of H19-DMR occurs.

Exponential increase of the gestational-age-specific incidence of preeclampsia onset (COPE study): a multicenter retrospective cohort study in women with maternal check-ups at <20 weeks of gestation in Japan.

According to the 2004 Japanese definition, early-onset (EO) preeclampsia (PE) is defined as PE occurring at <32 weeks of gestation. This was based on the presence of "dual peaks" (30-31 and 34-35 weeks) in the prevalence of severe forms of hypertension. In contrast, the international definition adopted a cutoff of 34 weeks based on the consensus. Our aim was to investigate whether there were "dual peaks" in the gestational-age-specific incidence or prevalence of PE onset in pregnant women who underwent maternal check-ups at <20 weeks of gestation in a multicenter retrospective cohort study. Diagnoses of PE and superimposed preeclampsia (SPE) were based on the new Japanese definition. A total of 26,567 pregnant women with singleton pregnancy were investigated. The best fitting equations for the distribution of the onset of gestational-age-specific incidence (hazard) rates of PE/SPE, PE, and PE with severe hypertension (a systolic blood pressure ≥160 and/or a diastolic blood pressure ≥110 mmHg) were investigated using the curve estimation function in SPSS. PE/SPE occurred in 1.83% of the patients. EO-PE/SPE with onset at <32 and <34 weeks of gestation and preterm PE/SPE occurred in 0.38, 0.56, and 1.07% of the patients, respectively. Gestational-age-specific incidence rates of PE/SPE, PE, and PE with severe hypertension showed exponential increases, with very high R2 values (0.975, 0.976, and 0.964, respectively). There were no "dual peaks" in the prevalence rates of women with SPE/PE, PE, and PE with severe hypertension. In conclusion, the absence of "dual peaks" refutes the previous rationale of EO-PE being defined as PE at <32 weeks of gestation. Further studies to determine an appropriate definition of EO-PE/SPE are needed.

Smoking during pregnancy increases risks of various obstetric complications: a case-cohort study of the Japan Perinatal Registry Network database.

BACKGROUND: The adverse effects of maternal smoking on the health of pregnant women have been examined mostly on a disease-by-disease basis. The aims of this study were to evaluate simultaneously the effects of smoking during pregnancy on various obstetric complications, using data from a large medical database, and to investigate the expediency of using a case-cohort design for such an analysis. METHODS: A case-cohort study was conducted within the Japan Perinatal Registry Network database. Perinatal information on infant deliveries was entered into the database at 125 medical centers in Japan. The base population of the study was 180 855 pregnant women registered in the database from 2001 through 2005. The outcome measures were the incidences of 11 different obstetric complications. Logistic regression models were used to estimate age-adjusted risk ratios (aRRs) and relative excess incidence proportions (REIs). RESULTS: The overall prevalence of smoking during pregnancy was 5.8% in the base cohort, and the prevalence was higher among younger women. A comparison of the cases and control cohort showed that smokers during pregnancy had statistically significant higher risks for preterm rupture of the membrane (aRR: 1.67, 95% confidence interval [CI]: 1.43-1.96; REI: 40.2%, 95% CI: 29.9%-49.1%), chorioamnionitis (1.65, 1.36-2.00; 39.4%, 26.4%-50.0%), incompetent cervix (1.63, 1.35-1.96; 38.5%, 25.8%-49.1%), threatened premature delivery (1.38, 1.17-1.64; 27.7%, 14.5%-38.9%), placental abruption (1.37, 1.10-1.72; 27.1%, 8.8%-41.7%), and pregnancy-induced hypertension (1.20, 1.01-1.41; 16.4%, 1.2%-29.3%). CONCLUSIONS: Maternal smoking was associated with a number of obstetric complications. This highlights the importance of smoking cessation during pregnancy. In addition, case-cohort analysis proved useful in estimating RRs for multiple outcomes in a large database.

Comparison of risk factors for major obstetric complications between Western countries and Japan: a case-cohort study.

AIM: The aim of this study was to demonstrate the differences in risk factors for obstetrical complications between Japan and Western countries. MATERIAL AND METHODS: Using the Perinatal Database of the Japan Society for Obstetrics and Gynecology, we studied singleton deliveries after 22 weeks of gestation (n = 242 715) at 125 centers of the perinatal network in Japan from 2001 through 2005 as a base cohort. In total, 3749 births (1.5% of the base cohort) were randomly selected as a subcohort. We compared the rate of risk factors in the cases with ten obstetrical complications with that in the subcohort (case-cohort study). RESULTS: Almost all of the evaluated risk factors were common between Western countries and Japan. Older age at pregnancy was a common risk factor for pregnancy-induced hypertension, placental abruption, placenta previa, and placenta accreta/increta/percreta. On the other hand, younger age at pregnancy was a common risk factor for eclampsia and preterm delivery. Smoking during pregnancy was a common risk factor for pregnancy-induced hypertension, preterm premature rupture of the membranes, preterm delivery, cervical insufficiency, chorioamnionitis, and placental abruption. In vitro fertilization and embryo transfer was a common risk factor for cervical insufficiency, placenta previa, and placenta accreta/increta/percreta. CONCLUSION: This case-cohort study in Japan clarified the common risk factors between Western countries and Japan as well as the risk factors indigenous to Japanese women. To identify the risk factors for a disease in a specific country, we should use data derived from its population.

Impact of maternal age on the incidence of obstetrical complications in Japan.

AIM: To clarify the effect of maternal age on obstetrical complications through a cohort and case-cohort study. METHODS: We studied 242 715 births at 125 centers of a perinatal network in Japan from 2001 through 2005 as a base cohort. Women with single pregnancies who delivered after 22 weeks of gestation were included in the study. Six classes of maternal age were selected: <20; 20-24; 25-29; 30-34; 35-39; and ≥40 years. The cohort study was used to investigate whether age is related to obstetrical complications. By random selection 3749 births were determined as a subcohort. Risk ratio (RR) was determined using multivariate analysis in the case-cohort study. RESULTS: The incidence proportion (per 100 births) of pregnancy-induced hypertension, cervical insufficiency, placenta previa, and placental abruption increased with age, whereas the incidence proportion of preterm labor and chorioamnionitis were higher at younger maternal age. The RR of women in the age groups 35-39 years and ≥40 years (with the reference of 1.0 for women in the age group of 20-34 years) were determined: pregnancy-induced hypertension, 1.66, 2.55; placenta previa, 1.76, 2.19; and placental abruption, 1.18, 1.5. The RR of preterm labor for women in the age group of <20 years was 1.78. CONCLUSION: The effect of maternal age differs for each obstetrical complication, and thus, it is important to understand these differences for management of individual pregnant patients.

Comparison of risk factors for placental abruption and placenta previa: case-cohort study.

AIM: A case-cohort study was performed to clarify and compare the risk factors for placental abruption and placenta previa. MATERIAL & METHODS: This study reviewed 242,715 births at 125 centers of the perinatal network in Japan from 2001 through to 2005 as a base-cohort. Women with singleton pregnancies delivered after 22 weeks of gestation were included. The evaluation determined the risk factors for placental abruption and placenta previa. Five thousand and thirty-six births (2.1%) were determined as the subcohort by random selection. Acute-inflammation-associated clinical conditions (premature rupture of membranes and clinical chorioamnionitis) and chronic processes associated with vascular dysfunction or chronic inflammation (chronic and pregnancy-induced hypertension, pre-existing or gestational diabetes and maternal smoking) was examined between the two groups. RESULTS: Placental abruption and placenta previa were recorded in 10.1 per 1000 and 13.9 per 1000 singleton births. Risk factors for abruption and previa, respectively, included maternal age over 35 years (adjusted risk ratios [RRs]=1.20 and 1.78), IVF-ET (RRs = 1.38 and 2.94), preterm labor (RRs = 1.63 and 3.09). Smoking (RRs = 1.37), hypertension (RRs = 2.48), and pregnancy-induced hypertension (RR = 4.45) were risk factors for abruption but not for previa. On the other hand, multiparity (RR= 1.18) was a risk factor for previa but not for abruption. The rates of acute-inflammation-associated conditions and chronic processes were higher among women with abruption than with previa. (RR 2.0 and 4.08, respectively). CONCLUSION: The case-cohort study technique elucidated the difference in the risk factors for placental abruption and placenta previa.

Beckwith-Wiedemann syndrome with placental chorangioma due to H19-differentially methylated region hypermethylation: a case report.

Beckwith-Wiedemann syndrome (BWS) is a common overgrowth syndrome that involves abdominal wall defects, macroglossia, and gigantism. It is sometimes complicated by placental tumor and polyhydramnios. We report a case of BWS, prenatally diagnosed with ultrasonography. A large and well-circumscribed tumor also existed on the fetal surface of the placenta, which was histologically diagnosed as chorangioma after delivery. Polyhydramnios was obvious and the fetal heart enlarged progressively during pregnancy. Because the biophysical profiling score dropped to 4 points at 33 weeks of gestation, we carried out cesarean section. By epigenetic analysis, H19-differentially methylated region hypermethylation was observed in the placental tumor, normal placental tissue, and cord blood mononuclear cells. This is the first report of BWS with placental tumor due to H19-differentially methylated region hypermethylation.

Prediction of exact delivery time in patients with preterm labor and intact membranes at admission by amniotic fluid interleukin-8 level and preterm labor index.

AIM: To examine whether delivery time for preterm labor can be predicted by clinical and biochemical markers at admission. METHODS: It has previously been reported that interleukin (IL)-8 and glucose in the amniotic fluid, fetal fibronectin (fFN) in vaginal secretions and the preterm labor index (PLI) are independent risk factors for delivery before 34 weeks' gestation. Using these four markers, we developed an equation model to predict the remaining gestation period after amniocentesis by step-wise multiple regression analysis in 126 preterm delivery cases (retrospective section of the study). We also evaluated whether this equation model could predict delivery time in 65 new preterm labor patients (prospective section of the study). Finally, we investigated the risk factors for delivery within three days after amniocentesis. RESULTS: The period from amniocentesis until delivery was calculated using the following equation by step-wise multiple regression analysis: predicted period until delivery (days) = 77.1 - 15.8 × log (amniotic IL-8 level [ng/mL]) - 9.2 × PLI (points). The calculated period until delivery correlated significantly with the actual period until delivery in the prospective study. When a high score of PLI (≥5 points) and a high level of vaginal fFN (≥90 ng/mL) or a high level of amniotic IL-8 (≥25.5 ng/mL) were present, the positive predictive values were 88.2% and 80.9% in predicting delivery within three days, respectively. CONCLUSIONS: Using markers reflecting inflammation in the uterus (amniotic IL-8 or vaginal fFN) and clinical symptoms (PLI), we may be able to predict the exact delivery time in preterm labor patients with intact membranes.

Pre-eclampsia Complicated With Maternal Renal Dysfunction Is Associated With Poor Neurological Development at 3 Years Old in Children Born Before 34 Weeks of Gestation.

Objective: The purpose of this study was to investigate perinatal factors associated with a poor neurodevelopmental outcome in preterm infants. Methods: A retrospective study was conducted by searching our clinical database between January 2006 and December 2016. A total of 165 singleton children who were born between 23 and 33 weeks of gestation were included. We defined poor neurological development outcomes as follows: cerebral palsy; intellectual disability; developmental disorder including autism and attention-deficit/hyperactivity disorder; low score (<85 points) on Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III); or low score of Kyoto Scale of Psychological Development corrected at 3 years old. We diagnosed maternal renal dysfunction according to the Clinical Practice Guideline for chronic kidney disease 2018 and the Best Practice Guide 2015 for Care and Treatment of Hypertension in Pregnancy. Results: The rate of poor neurological development was 25/165 (15.2%): cerebral palsy (n = 1), intellectual disability (n = 1), developmental disorder (n = 2), low score of Bayley-III (n = 20), and low score of Kyoto Scale of Psychological Development (n = 1). Preeclampsia complicated with maternal renal dysfunction (P = 0.045) and delivery at <30 weeks of gestation (P = 0.007) were independent risk factors for poor neurological development. Conclusions: In addition to previous risk factors such as delivery at <30 weeks of gestation, preeclampsia complicated with renal dysfunction was also associated with poor neurodevelopmental outcomes corrected at 3 years old.

Fetal Megalencephaly with Cortical Dysplasia at 18 Gestational Weeks Related to Paternal UPD Mosaicism with PTEN Mutation.

The phosphatase and tensin homolog (PTEN) gene is a tumor-suppressor gene located on 10q22-23. Since the introduction of molecular genetics in prenatal diagnostics, various birth defects associated with gene mutations have been diagnosed. However, no reports on fetal cases related to PTEN mutation have been found, so far. We encountered a rare case of fetal PTEN mutation. Fetal macrocephaly was noted at 16 weeks. At 18 and 20 weeks, neurosonography revealed megalencephaly with an asymmetrical structure and multifocal polygyria. The head circumference (HC) was +6.2 SD at 18 weeks and +8.1 SD at 20 weeks. The parents opted for pregnancy termination, and the male fetus was delivered at 21 weeks, with HC +9.3 SD. Single-nucleotide polymorphism (SNP) array for amniotic cells showed paternal uniparental disomy (UPD) 10q mosaicism, and the mosaic ratio was calculated as 56% from B-allele frequency. Exome sequencing revealed the pathogenic PTEN mutation with mosaicism. The heterozygous PTEN mutation may not cause early manifestations from the fetal period, and an abnormal phenotype may appear after birth. This may be the reason why fetal defects associated with PTEN mutation are not detected. Since this case had homozygous and heterozygous mutations, survival was possible, exhibiting an incredibly huge head with cortical dysplasia from early pregnancy.

Granulysin produced by uterine natural killer cells induces apoptosis of extravillous trophoblasts in spontaneous abortion.

Immune changes are known to occur in recurrent spontaneous abortion, but it is unclear whether either maternal natural killer (NK) cells or T cells attack fetus-derived trophoblasts. To clarify the immunological causes of spontaneous abortion, we examined the relationship between cytotoxic granule proteins in decidual lymphocytes, such as granulysin, granzyme B, and perforin, and the induction of apoptosis in extravillous trophoblasts (EVTs). The number of granulysin-positive CD56(bright) NK cells increased significantly in the decidua basalis during spontaneous abortion compared with normal pregnancy; however, granzyme B- and perforin-positive cells did not change. Interestingly, the expression of granulysin was also detected in the nuclei of EVTs in spontaneous abortion samples. When IL-2-stimulated CD56(bright) NK cells were cocultured with EVT cells (HTR-8/SV40neo), granulysin was found initially in the cytoplasm and then accumulated in the nuclei of the HTR-8/SV40neo cells. Furthermore, transfected cells expressing a GFP-granulysin fusion protein induced apoptosis in HTR-8/SV40neo cells independently of caspases. Our results suggest that granulysin-positive uterine NK cells attack EVTs; subsequently, the uNK-derived granulysin actively accumulates in the nuclei of EVTs, causing the death of EVTs due to apoptosis. These data support a new apoptosis pathway for trophoblasts via uNK-derived granulysin, suggesting that granulysin is involved in spontaneous abortion.