Development of phenotyping algorithms for hypertensive disorders of pregnancy (HDP) and their application in more than 22,000 pregnant women.

Recently, many phenotyping algorithms for high-throughput cohort identification have been developed. Prospective genome cohort studies are critical resources for precision medicine, but there are many hurdles in the precise cohort identification. Consequently, it is important to develop phenotyping algorithms for cohort data collection. Hypertensive disorders of pregnancy (HDP) is a leading cause of maternal morbidity and mortality. In this study, we developed, applied, and validated rule-based phenotyping algorithms of HDP. Two phenotyping algorithms, algorithms 1 and 2, were developed according to American and Japanese guidelines, and applied into 22,452 pregnant women in the Birth and Three-Generation Cohort Study of the Tohoku Medical Megabank project. To precise cohort identification, we analyzed both structured data (e.g., laboratory and physiological tests) and unstructured clinical notes. The identified subtypes of HDP were validated against reference standards. Algorithms 1 and 2 identified 7.93% and 8.08% of the subjects as having HDP, respectively, along with their HDP subtypes. Our algorithms were high performing with high positive predictive values (0.96 and 0.90 for algorithms 1 and 2, respectively). Overcoming the hurdle of precise cohort identification from large-scale cohort data collection, we achieved both developed and implemented phenotyping algorithms, and precisely identified HDP patients and their subtypes from large-scale cohort data collection.

Perioperative risk factors of preterm delivery after fetoscopic laser photocoagulation for twin-twin transfusion syndrome.

OBJECTIVE: To identify risk factors for preterm delivery (PTD) in patients who received fetoscopic laser photocoagulation (FLP) of placental anastomoses for twin-twin transfusion syndrome (TTTS). METHODS: This retrospective cohort study prospectively analyzed and recorded perioperative data in a cohort of patients who had FLP for TTTS, identifying perioperative risk factors for PTD using a Cox proportional hazard regression model. RESULTS: Of 304 patients included, 26 (8.6%) delivered within 4 weeks of FLP. Independent predictors of delivery within 4 weeks of FLP were a history of PTD (hazard ratio [HR]: 5.91, 95% confidence interval [CI]:1.21-28.82, p = 0.03), vaginal bleeding in the second trimester (HR: 6.62, 95% CI: 1.76-24.90, p < 0.01), and amnioreduction ≥1715 mL (HR: 3.16, 95% CI: 1.11-9.05, p < 0.03). CONCLUSION: Patients with a history of PTD, preoperative vaginal bleeding, and amnioreduction ≥1715 mL were more likely to deliver prematurely.

Re-evaluation of the predictive value of Quintero staging of twin-twin transfusion syndrome for fetal death after fetoscopic laser photocoagulation.

OBJECTIVE: To elucidate the significance of sonographic indices, including Doppler waveforms, that constitute the Quintero classification for predicting death of the recipient or donor after fetoscopic laser photocoagulation (FLP) for twin-twin transfusion syndrome (TTTS). METHODS: Prospectively collected data of twins who underwent FLP for TTTS were reviewed. Among the abnormal indices of ultrasound performed just before FLP, factors that were significantly associated with fetal and neonatal deaths in the log-rank test, including fetal demise of co-twins and preterm birth before 28 weeks of gestation, were introduced into the Cox proportional-hazards model to calculate risk ratio (RR). RESULTS: We included 235 cases with a prevalence of recipient and donor deaths of 7% and 14%, respectively. In the proportional-hazards model, absent or reversed umbilical artery end-diastolic velocity (UA AREDV) of recipients (n = 7) was independently associated with recipient death (RR = 6.97). In recipients without UA AREDV, reversed ductus venosus (DV) a-wave of recipients (RR = 3.55) was independently associated with recipient death. In donors, UA AREDV with a visible bladder (stage III atypical donor) was independently associated with donor death (RR = 4.24). CONCLUSION: Some individual components of the Quintero stage are associated with death of either recipient or donor twins following FLP.

Analysis of HLA-G long-read genomic sequences in mother-offspring pairs with preeclampsia.

Preeclampsia is a pregnancy-induced disorder that is characterized by hypertension and is a leading cause of perinatal and maternal-fetal morbidity and mortality. HLA-G is thought to play important roles in maternal-fetal immune tolerance, and the associations between HLA-G gene polymorphisms and the onset of pregnancy-related diseases have been explored extensively. Because contiguous genomic sequencing is difficult, the association between the HLA-G genotype and preeclampsia onset is controversial. In this study, genomic sequences of the HLA-G region (5.2 kb) from 31 pairs of mother-offspring genomic DNA samples (18 pairs from normal pregnancies/births and 13 from preeclampsia births) were obtained by single-molecule real-time sequencing using the PacBio RS II platform. The HLA-G alleles identified in our cohort matched seven known HLA-G alleles, but we also identified two new HLA-G alleles at the fourth-field resolution and compared them with nucleotide sequences from a public database that consisted of coding sequences that cover the 3.1-kb HLA-G gene span. Intriguingly, a potential association between preeclampsia onset and the poly T stretch within the downstream region of the HLA-G*01:01:01:01 allele was found. Our study suggests that long-read sequencing of HLA-G will provide clues for characterizing HLA-G variants that are involved in the pathophysiology of preeclampsia.

Low birth weight and abnormal pre-pregnancy body mass index were at higher risk for hypertensive disorders of pregnancy.

Low birth weight is known to be associated with hypertension, cardiovascular disease and hypertensive disorders of pregnancy (HDP); however, this association might vary by race/ethnicity. This study aimed to clarify the association between women's own birth weight and their subsequent risk for HDP in a Japanese population, in combination with pre-pregnancy body mass index (BMI). We conducted a cohort study as part of the Tohoku Medical Megabank Birth and Three-Generation Cohort Study in Miyagi, Japan. Our study's population included 4810 women. A multivariate logistic regression analysis was performed to calculate the adjusted odds ratio (aOR) and the 95% confidence interval (CI) of the women's own birth weight for HDP, in the combination categories of birth weight and pre-pregnancy BMI. As a result, the group with a low birth weight of <2500 g had a significant association with HDP (the aOR, 1.50; 95% CI, 1.02-2.21). In the subtype analysis, the odds ratio for only preeclampsia was significantly increased in the low birth weight group (aOR, 3.37; 95% CI, 1.84-6.16). In the group with a low birth weight, the prevalence of HDP was higher in both the underweight and overweight groups. In conclusion, there was a significant association between low birth weight and subsequent HDP in Japanese women. Furthermore, a significant association with HDP was found for women born with a low birth weight who were underweight or overweight as adults. Maintaining a normal weight may be effective for preventing HDP even if a woman was born small.

Hypertensive disorders of pregnancy, obesity, and hypertension in later life by age group: a cross-sectional analysis.

We investigated whether the association between a history of hypertensive disorders of pregnancy (HDP) and hypertension in later life varies by age group and the effect of obesity on the association between a history of HDP and hypertension in later life. This cross-sectional population-based study was conducted at the Tohoku Medical Megabank Project in Miyagi and Iwate, Japan. The study subjects were 33,412 parous women of 20 years of age and older. We used multivariate logistic regression analysis to assess the association between a history of HDP and hypertension. We constructed a composite variable that combined a history of HDP (±) and overweight/obesity (BMI ≥ 25 kg/m2) (±), resulting in four categories, and analyzed the risks of each category by multivariate logistic regression analysis. In total, 1585 (4.7%) women had a history of HDP. The prevalence of hypertension was higher in women with HDP (51.4%) than in those without HDP (36.8%; p < 0.01). The adjusted odds ratios (ORs) for hypertension in women with HDP in their 30s, 40s, 50s, 60s, and 70s or older were 3.63, 1.84, 2.15, 1.48, and 1.86, respectively. In the interaction analysis, the association between a history of HDP and hypertension was stronger in women in their 30s-50s than in women who were 60 or older (p = 0.057). The adjusted ORs for hypertension were higher in overweight/obese women with HDP than in their nonoverweight/obese counterparts in all age groups (30s: 27.17 vs. 2.22; 70s: 4.75 vs. 1.90). In conclusion, the association between HDP and later hypertension was stronger in younger women and in obese women in the 30-70 age group.

Maternity Log study: a longitudinal lifelog monitoring and multiomics analysis for the early prediction of complicated pregnancy.

PURPOSE: A prospective cohort study for pregnant women, the Maternity Log study, was designed to construct a time-course high-resolution reference catalogue of bioinformatic data in pregnancy and explore the associations between genomic and environmental factors and the onset of pregnancy complications, such as hypertensive disorders of pregnancy, gestational diabetes mellitus and preterm labour, using continuous lifestyle monitoring combined with multiomics data on the genome, transcriptome, proteome, metabolome and microbiome. PARTICIPANTS: Pregnant women were recruited at the timing of first routine antenatal visits at Tohoku University Hospital, Sendai, Japan, between September 2015 and November 2016. Of the eligible women who were invited, 65.4% agreed to participate, and a total of 302 women were enrolled. The inclusion criteria were age ≥20 years and the ability to access the internet using a smartphone in the Japanese language. FINDINGS TO DATE: Study participants uploaded daily general health information including quality of sleep, condition of bowel movements and the presence of nausea, pain and uterine contractions. Participants also collected physiological data, such as body weight, blood pressure, heart rate and body temperature, using multiple home healthcare devices. The mean upload rate for each lifelog item was ranging from 67.4% (fetal movement) to 85.3% (physical activity), and the total number of data points was over 6 million. Biospecimens, including maternal plasma, serum, urine, saliva, dental plaque and cord blood, were collected for multiomics analysis. FUTURE PLANS: Lifelog and multiomics data will be used to construct a time-course high-resolution reference catalogue of pregnancy. The reference catalogue will allow us to discover relationships among multidimensional phenotypes and novel risk markers in pregnancy for the future personalised early prediction of pregnancy complications.

Radiofrequency Ablation with an Internally Cooled Electrode for Twin Reversed Arterial Perfusion Sequence.

OBJECTIVE: The study aims to evaluate the efficacy of radiofrequency ablation (RFA) with an internally cooled electrode for twin reversed arterial perfusion (TRAP) sequence. METHODS: From April 2008 through December 2014, we retrospectively reviewed all patients who underwent RFA with an internally cooled electrode for TRAP sequence at 3 tertiary referral centers in Japan. RESULTS: Twenty-five monochorionic diamniotic twin pregnancies underwent RFA with an internally cooled electrode for TRAP sequence at 16-27 weeks of gestation. In all cases, umbilical cord blood flow cessation in the acardiac twin was confirmed by ultrasonography with color Doppler. There were 2 cases of procedure-related complications: 1 case of unintentional septostomy and 1 case of anemia in a pump twin. Fetal demise of the pump twin occurred in 3 (12%) cases. Twenty-two (88%) of 25 pump twins were delivered alive. The median gestational age at delivery was 36 + 3 weeks (range 25 + 2-40 + 5 weeks). There were 14 cases (64%) of premature deliveries before 37 weeks and 5 (23%) before 32 weeks. CONCLUSION: RFA with an internally cooled electrode is a feasible and effective procedure for the treatment of TRAP sequence.

Case with a Nonreassuring Fetal Status Induced by Massive Hematemesis due to Mallory-Weiss Tear That Required Emergency Cesarean Section at 38 Weeks' Gestation.

We describe a rare case of Mallory-Weiss tear with massive hematemesis at 38 weeks' gestation. A 35-year-old woman presented with epigastralgia followed by massive hematemesis. An emergency endoscopy indicated active pulsatile bleeding at the esophagocardial junction. Although an emergency endoscopic hemostasis was successful, late decelerations without acceleration on cardiotocogram were observed. Therefore, the patient underwent emergency cesarean section, along with blood transfusion, following the endoscopic hemostasis. The hemoglobin level just before the operation was 5.1 g/dL. We suspected that massive hematemesis induced maternal acute anemia and hypovolemia, which resulted in a nonreassuring fetal status. Hence, urgent endoscopic hemostasis, adequate blood transfusion, and emergency cesarean section were needed. Mallory-Weiss tear during the third trimester may have a possibility of massive hematemesis and urgent blood transfusion, emergency endoscopic hemostasis, and emergency cesarean section may be needed.