Changes in preterm and extremely preterm birth rates in Japan after the introduction of obstetrical practice guidelines in 2008.

AIM: Obstetrical guidelines were established in Japan in 2008, and obstetrical diagnoses and treatments were subsequently standardized nationally. We examined changes in the preterm birth rate (PTBR) and extremely preterm birth rate (EPTBR) following the introduction of such guidelines. METHODS: Information on 50 706 432 live births in Japan between 1979 and 2021, including Japanese reproductive medicine, the childbearing age of pregnant women, and the employment status of reproductive-age women between 2007 and 2020, were obtained from the Japanese government and academic societies. Regression analysis was used to compare chronological changes nationally and those of eight Japanese regions. Regional and national average PTBRs and EPTBRs from 2007 to 2020 were compared by using a repeated measures analysis of variance. RESULTS: From 1979 to 2007, PTBRs and EPTBRs in Japan increased significantly. However, from 2008, the national PTBR and EPTBR decreased until 2020 (p < 0.001) and 2019 (p = 0.02), respectively. From 2007 to 2020, overall PTBR and EPTBR were 5.68% and 0.255%, respectively. A significant difference in the PTBR and EPTBR existed between the eight Japanese regions. During this period, the number of pregnancies using assisted reproductive technology increased from 19 595 to 60 381, pregnant women became older, the employment rate of those of reproductive age increased, and nonregular employment was 54%, which was 2.5 times higher than for men. CONCLUSIONS: In Japan, after obstetrical guidelines were enacted in 2008, PTRBs decreased significantly even under the pressure of increasing preterm births. Countermeasures may be necessary for regions showing high PTBRs.

Prenatal alcohol exposure and adverse fetal growth restriction: findings from the Japan Environment and Children's Study.

BACKGROUNDS: Japanese studies on the association between maternal alcohol consumption and fetal growth are few. This study assessed the effect of maternal alcohol consumption on fetal growth. METHODS: This prospective birth cohort included 95,761 participants enrolled between January 2011 and March 2014 in the Japan Environment and Children's Study. Adjusted multiple linear and logistic regression models were used to assess the association between prenatal alcohol consumption and infant birth size. RESULTS: Consumption of a weekly dose of alcohol in the second/third trimester showed a significant negative correlation with standard deviation (SD; Z) scores for body weight, body length, and head circumference at birth, respectively. Consumption of a weekly dose of alcohol during the second/third trimester had a significant positive correlation with incidences of Z-score ≤ -1.5 for birth head circumference. Associations between alcohol consumption in the second/third trimester and Z-score ≤ -1.5 for birth weight or birth length were not significant. Maternal alcohol consumption in the second/third trimester above 5, 20, and 100 g/week affected body weight, body length, and head circumference at birth, respectively. CONCLUSION: Low-to-moderate alcohol consumption during pregnancy might affect fetal growth. Public health policies for pregnant women are needed to stop alcohol consumption during pregnancy. IMPACT: This study examined the association between maternal alcohol consumption and fetal growth restriction in 95,761 pregnant Japanese women using the prospective birth cohort. Maternal alcohol consumption in the second/third trimester more than 5, 20, and 100 g/week might affect fetal growth in body weight, body length, and head circumference, respectively. The findings are relevant and important for educating pregnant women on the adverse health effects that prenatal alcohol consumptions have on infants.

Population Attributable Fractions of Modifiable Risk Factors for Nonsyndromic Orofacial Clefts: A Prospective Cohort Study From the Japan Environment and Children's Study.

BACKGROUND: Population impact of modifiable risk factors on orofacial clefts is still unknown. This study aimed to estimate population attributable fractions (PAFs) of modifiable risk factors for nonsyndromic cleft lip with or without cleft palate (CL±P) and cleft palate only (CP) in Japan. METHODS: We conducted a prospective cohort study using data from the Japan Environment and Children's Study, which recruited pregnant women from 2011 to 2014. We estimated the PAFs of maternal alcohol consumption, psychological distress, maternal active and passive smoking, abnormal body mass index (BMI) (<18.5 and ≥25 kg/m2), and non-use of a folic acid supplement during pregnancy for nonsyndromic CL±P and CP in babies. RESULTS: A total of 94,174 pairs of pregnant women and their single babies were included. Among them, there were 146 nonsyndromic CL±P cases and 41 nonsyndromic CP cases. The combined adjusted PAF for CL±P of the modifiable risk factors excluding maternal alcohol consumption was 34.3%. Only maternal alcohol consumption was not associated with CL±P risk. The adjusted PAFs for CL±P of psychological distress, maternal active and passive smoking, abnormal BMI, and non-use of a folic acid supplement were 1.4% (95% confidence interval [CI], -10.7 to 15.1%), 9.9% (95% CI, -7.0 to 26.9%), 10.8% (95% CI, -9.9 to 30.3%), 2.4% (95% CI, -7.5 to 14.0%), and 15.1% (95% CI, -17.8 to 41.0%), respectively. We could not obtain PAFs for CP due to the small sample size. CONCLUSIONS: We reported the population impact of the modifiable risk factors on CL±P, but not CP. This study might be useful in planning the primary prevention of CL±P.

Mediating Factors Between Parental Socioeconomic Status and Small for Gestational Age in Infants: Results from the Hokkaido Study on Environment and Children's Health.

OBJECTIVES: Previous studies indicated a significant association between small for gestational age (SGA) in infants and their parents' socioeconomic status (SES). Thus, this study aimed to examine if parental factors, such as maternal smoking, and the pre-pregnancy body mass index (BMI) could mediate the associations between parental SES and SGA. METHODS: The participants of this study were pregnant women who enrolled in an ongoing birth cohort study, the Hokkaido study, during the first trimester of their pregnancies. A total of 14,593 live singleton births were included in the statistical analysis, of which 1011 (6.9%) were SGA. Two structural equation models were employed to evaluate the associations between parental SES, parental characteristics, and SGA. RESULTS: The effect of low SES on SGA was directly mediated by maternal pre-pregnancy BMI, smoking during the third trimester, and alcohol consumption during the first trimester in the first model, which was based the assumption of independent associations between mediating factors. In the second model, which additionally considered the mediating factors from the first model, smoking during pregnancy mediated decline in parental SES, consequently increased SGA. Moreover, an increase in pregnancy smoking status increased the prevalence of lower maternal pre-pregnancy BMI and its effect on SGA. CONCLUSIONS FOR PRACTICE: In this study, we observed the independent mediating effect of maternal pre-pregnancy BMI, smoking, and alcohol consumption during pregnancy on low SES and, consequently, SGA, with the additional mediating pathway of SES to smoking to low BMI on SGA.

Trajectories of the Psychological Status of Mothers of Infants With Nonsyndromic Orofacial Clefts: A Prospective Cohort Study From the Japan Environment and Children's Study.

OBJECTIVE: This study examined psychological status trajectories of mothers of infants with nonsyndromic orofacial clefts in Japan. DESIGN: Prospective cohort study. SETTING: Data from the Japan Environment and Children's Study. PARTICIPANTS: Infants with a nonsyndromic cleft (N = 148) including cleft lip and palate (CLP; n = 72), cleft lip (CL; n = 46), and cleft palate (CP; n = 30). The control group included unaffected infants (N = 84 454). MAIN OUTCOME MEASURES: At 15 weeks and 27 weeks of pregnancy and 12 months after birth, the Kessler Psychological Distress Scale (clinical cutoff ≥5) was used. At 1 month and 6 months after birth, the Edinburgh Postnatal Depression Scale (clinical cutoff ≥9) was used. RESULTS: Prenatal diagnosis rates were unavailable. Mothers of infants with CLP had higher psychological distress than controls at 27 weeks of pregnancy (prevalence ratio [PR] = 1.36, 95% CI: 1.06-1.74) and postnatal depression at 1 month after birth (PR = 2.21, 95% CI: 1.53-3.19). Mothers of infants with CP showed heightened psychological distress at 27 weeks of pregnancy (PR = 1.62, 95% CI: 1.21-2.17) and postnatal depression 6 months after birth (PR = 1.86, 95% CI: 1.01-3.43). There was no significant association between CL and maternal psychological status. At 12 months after birth, no differences in distress were found between mothers of infants with a cleft and controls. CONCLUSIONS: Mothers of infants with orofacial clefts may need psychosocial support, particularly during pregnancy and the first year after birth.

Association Between Maternal Serum Folate Concentrations in the First Trimester and the Risk of Birth Defects: The Hokkaido Study of Environment and Children's Health.

BACKGROUND: Low red blood cell folate concentrations during early pregnancy might cause neural tube defects. However, the association between folate concentrations and birth defects of other neural crest cell-derived organs remains unknown. We investigated the associations between birth defects and first-trimester serum folate concentrations in a birth-cohort study in Japan. METHODS: In total, 14,896 women who were prior to 13 weeks of gestation were enrolled from 2003 through 2012. Birth defect information was obtained from medical records and questionnaires. The association between folate levels in the first trimester and birth defects categorized as ICD-10 cord defects and neural crest cell-derived organ defects was examined. The crude and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) per log-transformed folate concentration were calculated using logistic regression. RESULTS: Blood samples were obtained at a mean of 10.8 weeks of gestation. Median serum folate level was 16.5 (interquartile range, 13.4-21.5) nmol/L, and the deficiency level (less than 6.8 nmol/L) was 0.7%. There were 358 infants with birth defects. The adjusted odds ratio for any birth defect, ventricular septal defects, and cleft lip was 0.99 (95% CI, 0.74-1.32), 0.63 (95% CI, 0.30-1.33), and 4.10 (95% CI, 0.96-17.58), respectively. There were no significant associations between first-trimester maternal serum folate and the risk of birth defects. CONCLUSIONS: We were unable to demonstrate a relationship between maternal serum folate in the first trimester and birth defects. Potential confounding factors may have influenced our results.

Short- and Long-Term Outcomes of Extremely Preterm Infants in Japan According to Outborn/Inborn Birth Status.

OBJECTIVES: Outborn (born outside tertiary centers) infants, especially extremely preterm infants, are at an increased risk of mortality and morbidity in comparison to inborn (born in tertiary centers) infants. Extremely preterm infants require not only skilled neonatal healthcare providers but also highly specialized equipment and environment surroundings. Maternal transport at an appropriate timing must be done to avoid the delivery of extremely preterm infants in a facility without the necessary capabilities. Cases of unexpected deliveries at birth centers or level I maternity hospitals need to be attended emergently. We compared the differences in short- and long-term outcomes between outborn and inborn infants to improve our regional perinatal system. DESIGN: Retrospective cohort study. SETTING: Neonatal Research Network of Japan database. PATIENTS: Extremely preterm infants (gestational age between 22 + 0 and 27 + 6 wk) in the Neonatal Research Network of Japan database between 2003 and 2011. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 12,164 extremely preterm infants, who were divided into outborn (n = 785, 6.5%) and inborn (n = 11,379, 93.5%) groups, were analyzed. Significant differences were observed in demographic and clinical factors between the two groups. Outborn infants had higher short-term odds of severe intraventricular hemorrhage (adjusted odds ratio, 1.49; 95% CI, 1.11-2.00; p < 0.01), necrotizing enterocolitis (adjusted odds ratio, 1.49; 95% CI, 1.11-2.00; p < 0.01), and focal intestinal perforation (adjusted odds ratio, 1.58; 95% CI, 1.09-2.30; p = 0.02). There were no significant differences in long-term outcomes between the two groups, except in the rate of cognitive impairment (adjusted odds ratio, 1.49; 95% CI, 1.01-2.20; p = 0.04). CONCLUSIONS: The frequency of severe intraventricular hemorrhage, necrotizing enterocolitis or focal intestinal perforation, and cognitive impairment was significantly higher in outborn infants. Thus, outborn/inborn birth status may play a role in short- and long-term outcomes of extremely preterm infants. However, more data and evaluation of improvement in the current perinatal environment are needed.

Comparison of human papillomavirus genotyping and cytology triage, COMPACT Study: Design, methods and baseline results in 14 642 women.

Although cytology-based screening programs have significantly reduced mortality and morbidity from cervical cancer, the global consensus is that primary human papillomavirus (HPV) testing for cervical screening increases detection of high-grade cervical intraepithelial neoplasia (CIN) and invasive cancer. However, the optimal triage strategy for HPV-positive women to avoid over-referral to colposcopy may be setting specific. As Japan requires data that have been generated domestically to modify screening guidelines, we conducted a 3-year prospective study, COMparison of HPV genotyping And Cytology Triage (COMPACT), to evaluate the potential role of HPV16/18 partial genotyping and cytology for primary HPV screening. In total, 14 642 women aged 20 to 69 years undergoing routine screening at 3 centers in Hokkaido were enrolled. Conventional cytology and HPV testing were carried out. Women with abnormal cytology or HPV16/18 positivity underwent colposcopy. Those with 12 other high-risk (hr) HPV types underwent repeat cytology after 6 months. Primary study endpoints were detection of high-grade cervical disease defined as CIN2/CIN3 or greater as determined by consensus pathology. Prevalence of cytological abnormalities was 2.4%. hrHPV, HPV 16, and HPV 18 were detected in 4.6%, 0.9%, and 0.3% of women, respectively. HPV16/18 were detected in all (8/8) invasive cervical cancers and in all (2/2) adenocarcinomas in situ. Both cytological abnormalities and hrHPV positivity declined with increasing age. This is the first Japanese study to investigate the role of partial genotyping and cytology in an HPV-based screening program. Results should help policy-makers develop guidelines for future cervical screening programs and management of cervical abnormalities based on HPV genotype.

Abnormal Expression of PICT-1 and Its Codon 389 Polymorphism Is a Risk Factor for Human Endometrial Cancer.

OBJECTIVE: The protein interacting with carboxyl terminus-1 (PICT-1) gene has been implicated as a tumor suppressor gene, and its alterations have been reported in several cancers. This study investigated the association of PICT-1 alterations with endometrial carcinogenesis. METHODS: We analyzed the entire coding region of the PICT-1 gene using polymerase chain reaction-single-strand conformation polymorphism and DNA sequencing to examine PICT-1 mutations in endometrial cancer. Western blotting and immunohistochemical staining were performed to analyze the protein expression and cellular localization of PICT-1 in endometrial cancer cell lines and patient samples. RESULTS: The codon 389 polymorphism of PICT-1 increased the risk of endometrial cancer. Interestingly, 2 of 13 endometrial cancers somatically acquired this mutation compared to normal counterparts. Immunohistochemical staining revealed lower levels of PICT-1 in samples from atypical endometrial hyperplasia and endometrial cancer tissues compared to normal endometrial tissues (p < 0.01). This decrease in PICT-1 expression was significantly correlated with histological grade and lymph node metastasis (p < 0.05). CONCLUSIONS: The findings of this study suggest that disruption of PICT-1 protein expression and codon 389 polymorphism can contribute to the pathogenesis or neoplastic progression of endometrial cancer.

Prevalence and Risk of Birth Defects Observed in a Prospective Cohort Study: The Hokkaido Study on Environment and Children's Health.

BACKGROUND: Prevalence rates of all anomalies classified as birth defects, including those identified before the 22nd gestational week, are limited in published reports, including those from the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR). In our birth cohort study, we collected the data for all birth defects after 12 weeks of gestation. METHODS: Subjects in this study comprised 19,244 pregnant women who visited one of 37 associated hospitals in the Hokkaido Prefecture from 2003 through 2012, and completed follow-up. All birth defects after 12 weeks of gestation, including 55 marker anomalies associated with environmental chemical exposures, were recorded. We examined parental risk factors for birth defects and the association between birth defects and risk of growth retardation. RESULTS: Prevalence of all birth defects was 18.9/1,000 births. The proportion of patients with birth defects delivered between 12 and 21 weeks of gestation was approximately one-tenth of all patients with birth defects. Among those with congenital malformation of the nerve system, 39% were delivered before 22 weeks of gestation. All patients with anencephaly and encephalocele were delivered before 22 weeks of gestation. We observed different patterns of parental risk factors between birth defect cases included in ISBDSR and cases not included. Cases included in ISBDSR were associated with an increased risk of preterm birth. Cases not included in ISBDSR were associated with an increased risk of being small for gestational age at term. CONCLUSIONS: Data from our study complemented the data from ICBDSR. We recommend that birth defects not included in ICBDSR also be analyzed to elucidate the etiology of birth defects.

The protein interacting with carboxyl terminus-1 codon 389 polymorphism impairs protein interacting with carboxyl terminus-1 function and is a risk factor for uterine cervical cancer.

PICT-1 is a nucleolar protein with various tumor suppressor functions. Recently, PICT-1 expression was reported to be dramatically reduced in several cancers. To investigate the role of PICT-1 in uterine cervical carcinogenesis, we examined its gene mutations, protein expression, cellular localization, and effect on p53 stabilization. PCR-SSCP analysis of the entire coding region of PICT-1 showed that a polymorphism at codon 389 may increase the risk of uterine cervical cancers, and also identified a novel missense mutation. Expression of wild-type PICT-1 inhibited the degradation of p53 in the presence or absence of HPV 18 E6 viral protein in vitro, while the expression of codon 389 polymorphic PICT-1 had a diminished inhibitory effect on p53 degradation. Moreover, we observed that PICT-1 degradation was induced both independently and cooperatively by E6 and E7 proteins from high-risk HPVs, but only marginal degradation was observed with proteins from low-risk HPV. Immunohistochemical staining of tumor samples revealed that lower levels of PICT-1 were observed in samples from CIN III and cervical cancer tissues, compared to normal cervical epithelium and CIN I, II tissues (P < 0.05). The reduction of PICT-1 may therefore be an early event in uterine cervical tumorigenesis. Our results indicated that PICT-1 counteracts HPV-induced p53 degradation and that aberrant PICT-1 function may contribute towards inactivating p53. Therefore, PICT-1 may play a critical role during the pathogenesis of uterine cervical cancers.

An atypical case of SPG56/CYP2U1-related spastic paraplegia presenting with delayed myelination.

Hereditary spastic paraplegia (HSP) is a neurological disorder characterized by a progressive spasticity and muscle weakness of the lower limbs. It is divided into two subtypes, uncomplicated and complicated forms. Biallelic mutations in the cytochrome P450 2U1 gene (CYP2U1) are associated with spastic paraplegia type 56 (SPG56), manifesting both uncomplicated and complicated HSP. Accompanying clinical features include intellectual disability, dystonia, cerebellar ataxia, subclinical peripheral neuropathy, visual impairment, as well as abnormalities in brain magnetic resonance imaging. As a rare clinical feature, delayed myelination has previously been reported in only two patients with CYP2U1 mutations. Here, we report a patient with SPG56 with novel compound heterozygous mutations in CYP2U1 which were identified by whole exome sequencing. Our patient exhibited complex features together with delayed myelination, broadening the phenotypic spectrum of SPG56, and implying that CYP2U1 should be screened in HSP with delayed myelination.

Liver dysfunction in women with pregnancy-induced antithrombin deficiency.

AIM: The aim of this study was to determine whether women with pregnancy-induced antithrombin deficiency (PIATD) had higher risk of liver dysfunction in the absence of thrombocytopenia. METHODS: We carried out a retrospective observational study at five centers in all 129 women with incidentally found PIATD among 5249 maternities and 129 control women without PIATD matched for number of fetuses and gestational week at delivery. PIATD was diagnosed in women with antenatal antithrombin (AT) activities of ≤75% followed by a further decrease to ≤65% peripartum. Liver dysfunction was defined as serum aspartate aminotransferase >  45 IU/L concomitant with lactate dehydrogenase >  400 IU/L. Thrombocytopenia was defined as platelet count < 120 × 109 /L. RESULTS: Thrombocytopenia (22% [28/129] vs 5.4% [7/129], P =  0.0001) and liver dysfunction (16% [20/129] vs 0.0% [0/129], P =  0.0000) occurred significantly more often in PIATD than in control women. Of the 20 women with liver dysfunction, 15 (75%) had PIATD, but not thrombocytopenia. Thus, even in the absence of thrombocytopenia, liver dysfunction occurred significantly more often in PIATD than in control women (15% [15/101] vs 0.0% [0/122], respectively, P =  0.0000). The relative risk (95% confidence interval) of liver dysfunction was 28.6 (1.64-500) for women with AT activity of 60-65% and 52.4 (3.17-865) for women with AT activity of <60%, compared to women with AT activity ≥66%. CONCLUSION: PIATD can occur in the absence of thrombocytopenia and PIATD women had higher risk of liver dysfunction even in the absence of thrombocytopenia.

Human male infertility and its genetic causes.

Background: Infertility affects about 15% of couples who wish to have children and half of these cases are associated with male factors. Genetic causes of azoospermia include chromosomal abnormalities, Y chromosome microdeletions, and specific mutations/deletions of several Y chromosome genes. Many researchers have analyzed genes in the AZF region on the Y chromosome; however, in 2003 the SYCP3 gene on chromosome 12 (12q23) was identified as causing azoospermia by meiotic arrest through a point mutation. Methods: We mainly describe the SYCP3 and PLK4 genes that we have studied in our laboratory, and add comments on other genes associated with human male infertility. Results: Up to now, The 17 genes causing male infertility by their mutation have been reported in human. Conclusions: Infertility caused by nonobstructive azoospermia (NOA) is very important in the field of assisted reproductive technology. Even with the aid of chromosomal analysis, ultrasonography of the testis, and detailed endocrinology, only MD-TESE can confirm the presence of immature spermatozoa in the testes. We strongly hope that these studies help clinics avoid ineffective MD-TESE procedures.

Predictors of folate status among pregnant Japanese women: the Hokkaido Study on Environment and Children's Health, 2002-2012.

The International Clearinghouse for Birth Defects, Surveillance and Research reports a rise in the prevalence rate of spina bifida in Japan. We determined first-trimester folate status of Hokkaido women and identified potential predictors. Participants were 15 266 pregnant women of the Hokkaido Study on Environment and Children's Health Cohort. Data were extracted from self-reported questionnaires and biochemical assay results. Demographic determinants of low folate status were younger maternal age (adjusted OR (AOR) 1·48; 95 % CI 1·32, 1·66), lower educational level (AOR 1·27; 95 % CI 1·17, 1·39) and lower annual income (AOR 1·11; 95 % CI 1·01, 1·22). Plasma cotinine concentrations of 1·19-65·21 nmol/l increased the risk of low folate status (AOR 1·20; 95 % CI 1·10, 1·31) and concentrations >65·21 nmol/l further increased the risk (AOR 1·91; 95 % CI 1·70, 2·14). The most favourable predictor was use of folic acid (FA) supplements (AOR 0·19; 95 % CI 0·17, 0·22). Certain socio-demographic factors influence folate status among pregnant Japanese women. Modifiable negative and positive predictors were active and passive tobacco smoking and use of FA supplements. Avoiding both active and passive tobacco smoking and using FA supplements could improve the folate status of Japanese women.

Male infertility and its genetic causes.

AIM: Infertility is a serious social problem in advanced nations, with male factor infertility accounting for approximately half of all cases of infertility. Here, we aim to discuss our laboratory results in the context of recent literature on critical genes residing on the Y chromosome or autosomes that play important roles in human spermatogenesis. METHODS: The PubMed database was systematically searched using the following keywords: 'genetics of male factor infertility'; 'male infertility genes', 'genetics of spermatogenesis' to retrieve information for this review. RESULTS: Striking progress has recently been made in the elucidation of mechanisms of spermatogenesis using knockout mouse models. This information has, in many cases, not been directly translatable to humans. Nevertheless, mutations in several critical genes have been shown to cause male infertility. We discuss here the contribution to male factor infertility of a number of genes identified in the azoospermia factor (AZF) region on the Y chromosome, as well as the autosomally located genes: SYKP3, KLHL10, AURKC and SPATA16. CONCLUSIONS: Non-obstructive azoospermia is the most severe form of azoospermia. However, the presence of spermatozoa can only be confirmed through procedures, which may prove to be unnecessary. Elucidation of the genes underlying male factor infertility, and thereby a better understanding of the mechanisms that cause it, will result in more tailored, evidence-based decisions in treatment of patients.

Clinicopathologic risk factors for recurrence of ovarian endometrioma following laparoscopic cystectomy.

OBJECTIVE: To identify epidemiologic risk factors and investigate whether the characteristics of removed ovarian tissue during surgery influence the recurrence of endometriomas. DESIGN: Retrospective cohort study. SETTING: Medical university hospital. POPULATION: 248 women with endometriomas. METHODS: All women who had a minimum of 2 years of follow-up after the laparoscopic excision of endometriomas were analysed retrospectively. Specimens were analysed histologically. MAIN OUTCOME MEASURES: Sixteen epidemiologic variables were analysed as possible risk factors for recurrence. The association between the characteristics of removed ovarian tissue (the thickness of the cyst wall, the thickness of ovarian tissue, and the morphological features) and endometrioma recurrence was investigated. RESULTS: The cumulative incidence of endometriomas reached 42% at 60 months after surgery. We identified only a younger age at surgery as a risk factor, and postoperative pregnancy as a preventive factor. There were no differences in the mean thickness of the cyst wall and the removed ovarian tissue between patients with and without recurrence. No statistically significant associations were found between the morphologic characteristics of removed cyst wall, ovarian tissue, graded on a semi-quantitative basis, and recurrence. CONCLUSIONS: These results suggest that the rate of endometrioma recurrence had a significant relation to patient age and postoperative pregnancy; however, there was no association between the histological characteristics of the excised tissue and recurrence.

First-trimester serum folate levels and subsequent risk of abortion and preterm birth among Japanese women with singleton pregnancies.

OBJECTIVES: To determine whether a low serum folate level during the first trimester predicts subsequent late abortion, preterm birth, or fetal growth restriction (FGR). STUDY DESIGN: A prospective cohort study involving 5,075 women whose serum folate levels were measured during the first trimester. The participants were informed of their serum folate levels. RESULTS: The pregnancy duration, birthweight, rate of late abortion/preterm birth, and the rate of FGR did not differ significantly among the four groups classified according to folate status. The mean serum folate levels did not differ among quartiles classified according to the gestational week at the time of delivery. Nineteen of the 20 women with folate deficiency gave birth at term to infants with a birthweight of 3.132 ± 321 g; only one infant had FGR. CONCLUSION: Low serum folate levels during the first trimester were not associated with the risk of late abortion, preterm birth, or FGR.

High doses of intravenous immunoglobulin stimulate regulatory T cell and suppress natural killer cell in women with recurrent pregnancy loss.

The aim was to evaluate whether natural killer (NK) cells and regulatory T (Treg) cells were involved in mechanisms underlying beneficial effects of a high dose of intravenous immunoglobulin (IVIG) on recurrent pregnancy losses (RPL) of unexplained etiology. In a double-blind, randomized, placebo-controlled trial of IVIG (400 mg/kg, for 5 days in 4-6 weeks of gestation) in women with RPL, blood samples were collected pre-infusion, one week after infusion (1 w), and eight weeks of gestation/when miscarried (8 w). Levels of NK and Treg cells in peripheral blood were compared between women with IVIG (n = 50) and placebo (n = 49), and between women with IVIG who gave live birth (n = 29) and those who had miscarriage with normal chromosome (n = 12). Effector Treg cell percentages in IVIG group at 1 w (mean 1.43 % vs. 1.03 %) and at 8 w (1.91 % vs. 1.18 %) were higher than those in placebo group (p < 0.01). Total Treg cell percentages in IVIG group at 1 w (4.75 % vs. 4.08 %) and at 8 w (5.55 % vs. 4.47 %) were higher than those in placebo group (p < 0.05). In women with live birth, total Treg cell percentages increased at 8 w (5.52 %, p < 0.001) compared with pre-infusion (4.54 %) and 1 w (4.47 %), while NK cell activity decreased at 1 w (20.18 %, p < 0.001) compared with pre-infusion (26.59 %). IVIG increased Treg cell percentages and suppressed NK cell activity very early in pregnancy, and these were associated with subsequent live birth. Stimulation of Treg cells and suppression of NK cell activity very early in pregnancy may be a mechanism of pharmacological effects of high dose IVIG.

Effects of maternal 5,10-methylenetetrahydrofolate reductase C677T and A1298C Polymorphisms and tobacco smoking on infant birth weight in a Japanese population.

BACKGROUND: Intracellular folate hemostasis depends on the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene. Because 5,10-MTHFR 677TT homozygosity and tobacco smoking are associated with low folate status, we tested the hypothesis that smoking in mothers with 5,10-MTHFR C677T or A1298C polymorphisms would be independently associated with lower birth weight among their offspring. METHODS: We assessed 1784 native Japanese mother-child pairs drawn from the ongoing birth cohort of The Hokkaido Study on Environment and Children's Health. Data (demographic information, hospital birth records, and biological specimens) were extracted from recruitments that took place during the period from February 2003 to March 2006. Maternal serum folate were assayed by chemiluminescent immunoassay, and genotyping of 5,10-MTHFR C677T/A1298C polymorphisms was done using a TaqMan allelic discrimination assay. RESULTS: The prevalence of folate deficiency (<6.8 nmol/L) was 0.3%. The 5,10-MTHFR 677CT genotype was independently associated with an increase of 36.40 g (95% CI: 2.60 to 70.30, P = 0.035) in mean infant birth weight and an increase of 90.70 g (95% CI: 6.00 to 175.50, P = 0.036) among male infants of nonsmokers. Female infants of 677TT homozygous passive smokers were 99.00 g (95% CI: -190.26 to -7.56, P = 0.034) lighter. The birth weight of the offspring of smokers with 5,10-MTHFR 1298AA homozygosity was lower by 107.00 g (95% CI: -180.00 to -33.90, P = 0.004). CONCLUSIONS: The results suggest that, in this population, maternal 5,10-MTHFR C677T polymorphism, but not the 5,10-MTHFR A1298C variant, is independently associated with improvement in infant birth weight, especially among nonsmokers. However, 5,10-MTHFR 1298AA might be associated with folate impairment and could interact with tobacco smoke to further decrease birth weight.