Lower Respiratory Tract Infections and Orofacial Clefts: A Prospective Cohort Study From the Japan Environment and Children's Study.

BACKGROUND: Lower respiratory tract infections (LRTIs) are a cause of inpatient and outpatient care among children. Although orofacial clefts seem to be associated with LRTIs, epidemiological studies are scarce on this topic. This study aimed to examine whether infants with orofacial clefts were associated with LRTIs. METHODS: This prospective cohort study used data from the Japan Environment and Children's Study, for which baseline recruitment was conducted during 2011-2014. This study included 81,535 participants. The number of infants with cleft lip and palate (CLP), cleft lip (CL), and cleft palate only (CP) was 67, 49, and 36, respectively. We defined history of LRTIs until 12 months' age reported by their mothers as the dependent variable. Accumulated breastfeeding duration was used as a potential mediator. RESULTS: The incidence proportion of LRTIs among the control group was 6.0%. The incidence proportion among infants with CLP, CL, and CP were 11.9%, 14.3%, and 5.6%, respectively. After adjusting for covariates, compared with the control group, infants with CLP and CL were associated with risk of LRTIs (incidence risk ratio [IRR] of CLP, 2.38; 95% confidence interval [CI], 1.30-4.36 and IRR of CL, 2.73; 95% CI, 1.40-5.33), but not ones with CP (IRR 1.08; 95% CI, 0.28-4.15). Accumulated breastfeeding duration decreased the IRR of CLP only (IRR of CLP, 2.16; 95% CI, 1.19-3.93). CONCLUSION: Infants with orofacial clefts aged 1 year have a potentially high incidence proportion of LRTIs. Accumulated breastfeeding duration might mediate the associations of CLP.

Importance of real-time measurement of sperm head morphology in intracytoplasmic sperm injection.

Intracytoplasmic sperm injection (ICSI) is an important technique in male infertility treatment. Currently, sperm selection for ICSI in human assisted reproductive technology (ART) is subjective, based on a visual assessment by the operator. Therefore, it is desirable to develop methods that can objectively provide an accurate assessment of the shape and size of sperm heads that use low-magnification microscopy available in most standard fertility clinics. Recent studies have shown a correlation between sperm head size and shape and chromosomal abnormalities, and fertilization rate, and various attempts have been made to establish automated computer-based measurement of the sperm head itself. For example, a dictionary-learning technique and a deep-learning-based method have both been developed. Recently, an automatic algorithm was reported that detects sperm head malformations in real time for selection of the best sperm for ICSI. These data suggest that a real-time sperm selection system for use in ICSI is necessary. Moreover, these systems should incorporate inverted microscopes (×400-600 magnification) but not the fluorescence microscopy techniques often used for a dictionary-learning technique and a deep-learning-based method. These advances are expected to improve future success rates of ARTs. In this review, we summarize recent reports on the assessment of sperm head shape, size, and acrosome status in relation to fertility, and propose further improvements that can be made to the ARTs used in infertility treatments.

Parental educational level and childhood wheezing and asthma: A prospective cohort study from the Japan Environment and Children's Study.

BACKGROUND: The influence of mothers' and fathers' educational levels in separate evaluations of asthma has not been fully investigated. This study aims to examine the associations of the mother's and fathers' educational levels with childhood wheeze and asthma adjusting for crude and pre-and post-natal modifiable risk factors. 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. The mother's and father's educational levels were surveyed by a questionnaire during the pregnancy, and childhood wheezing and doctor-diagnosed asthma were estimated using a 3-year questionnaire. Multilevel logistic regression analysis was performed to evaluate the association between the mother's and father's educational levels and childhood wheezing and asthma, adjusted for pre-and post-natal factors. RESULTS: A total of 69,607 pairs of parents and their single infants were analyzed. We found 17.3% of children had wheezing and 7.7% had asthma. In crude analyses, lower educational level of parents was associated with an increased risk of childhood wheezing and asthma. After full adjustment, a lower educational level of mothers was associated with an increased risk of childhood asthma (junior high school (reference: high school); odds ratio (OR): 1.17, 95% CI, 1.01-1.36), and higher educational level, especially the mother's, was associated with an increased risk of childhood wheezing (technical junior college, technical/vocational college, or associate degree (ECD3); OR: 1.12, 95% CI, 1.06-1.18, bachelor's degree, or postgraduate degree; OR: 1.10, 95% CI, 1.03-1.18), and asthma (ECD3; OR: 1.13, 95% CI, 1.04-1.21). CONCLUSIONS: Parents' lower educational level was a crude risk factor for childhood wheezing and asthma. However, an increased risk of wheezing due to mothers' higher educational level was found after adjusting for pre-and post-natal factors.

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.

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.

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.

Factors correlating with serum birch pollen IgE status in pregnant women in Hokkaido, Japan: The Japan Environment and Children's Study (JECS).

BACKGROUND: Birch pollen allergy affects pregnant women, and such allergy may affect the development of allergic diseases in their children. Using nationwide birth cohort data, this study aimed to investigate the prevalence of birch pollen IgE positivity and to identify correlating factors in pregnant women in Hokkaido, Japan, a high-latitude island. METHODS: Participants included 6856 pregnant women. Participants responded to questionnaires regarding lifestyle factors and history of allergies. Data regarding parity, height, and pre-pregnancy weight were collected from medical records. Blood samples were obtained from participants during the first trimester of pregnancy, and serum allergen-specific IgE titers were determined. RESULTS: The serum of 30.2% participants was positive for birch pollen IgE (≥0.35 UA/mL). Such positivity significantly correlated with a history of other allergic diseases, particularly food allergy and allergic rhinitis/hay fever. In multivariate logistic regression analysis, pre-pregnancy high body mass index (BMI ≥ 25) significantly correlated with birch pollen IgE positivity [odds ratio (OR), 1.24; 95% CI, 1.05-1.47; reference BMI, 18.5-24.9] and higher income (≥10 million yen per year; OR,0.55; 95% CI, 0.37-0.81; reference, household income < 2 million yen per year), and second quintile level physical activity (OR,0.75; 95% CI, 0.63-0.88; reference, the first quintile of physical activity) had significant protective effects. CONCLUSIONS: Birch pollen IgE positivity in pregnant women was positively associated with food allergy, allergic rhinitis, pre-pregnant high BMI, and was negatively associated with light exercise and high household income in Hokkaido. TRIAL REGISTRATION: UMIN000030786.

The relationship between prenatal psychological stress and placental abruption in Japan, The Japan Environment and Children's Study (JECS).

BACKGROUND: Prenatal psychological stress may increase the risk of placental abruption (PA). This study aimed to clarify the effects of psychological distress during pregnancy and exposure to stressful life events in the year before or during pregnancy on the occurrence of PA in Japanese women. METHODS: Using a nationwide prospective birth cohort study, we obtained data from 103,099 women between January 2011 and March 2014. Information on exposure to 14 stressful life events and psychological distress (Kessler 6 scale) was collected using a self-administered questionnaire during pregnancy. Clinical diagnoses of PA were obtained from medical records. A total of 80,799 women with singleton births were analyzed using logistic regression models that adjusted for possible confounders. RESULTS: PA was diagnosed in 335 (0.4%) women. There was no significant difference in the Kessler 6 score during pregnancy between the PA group and non-PA group. Exposure to the death of a child in the year before or during pregnancy was significantly associated with PA in multigravid women (adjusted odds ratio [aOR] 3.57; 95% confidence interval [CI] 1.50-8.34). A spouse's loss of employment was significantly associated with PA in parous women (aOR 3.25; 95% CI 1.40-7.56). CONCLUSIONS: This study identified the possible effects of exposure to the death of a child on PA occurrence that adjusted for important confounding factors.

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.

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.

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.

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.

Single-nucleotide polymorphisms in the human RAD21L gene may be a genetic risk factor for Japanese patients with azoospermia caused by meiotic arrest and Sertoli cell-only syndrome.

Genetic mechanisms are implicated in some cases of male infertility. Recently, it was demonstrated that male mice lacking the gene for RAD21L exhibited azoospermia caused by meiotic arrest. Mouse RAD21L is a functionally relevant meiotic α-kleisin that is essential for male fertility. Therefore, we hypothesized that RAD21L mutations or polymorphisms may be associated with male infertility, especially azoospermia secondary to meiotic arrest. To determine if RAD21L defects are associated with azoospermia in groups of patients with meiotic arrest, we performed direct sequencing of the RAD21L coding regions in 38 Japanese patients with meiotic arrest and in 200 normal controls. Three coding single-nucleotide polymorphisms (SNP1-SNP3) were detected in the meiotic arrest patient group. Sertoli cell-only syndrome is considered a common cause of non-obstructive azoospermia. For comparison, the RAD21L coding regions in which SNP1-SNP3 were detected were sequenced in 140 patients with Sertoli cell-only syndrome. Statistical analyses were used to compare the two groups of patients with the control group. Genotype and allele frequencies of SNP2 and SNP3 were notably higher in the two patient groups compared with the control group (Bonferroni adjusted p value <0.016). These results suggest a critical role for RAD21L in human spermatogenesis.

The Association between Prenatal Yoga and the Administration of Ritodrine Hydrochloride during Pregnancy: An Adjunct Study of the Japan Environment and Children's Study.

INTRODUCTION: While the beneficial effects of prenatal yoga have been reported in recent years, little is known about its effectiveness in pregnant Japanese women. Despite several adverse effects, ritodrine hydrochloride is frequently prescribed to suppress preterm labor in Japan, and its usage may therefore indicate cases of preterm labor. This study aimed to clarify the association between prenatal yoga and ritodrine hydrochloride use during pregnancy. METHODS: An observational study was conducted as an adjunct study by the Hokkaido unit of the Japan Environment and Children's Study. Information on prenatal yoga practice was collected using a self-questionnaire between March 21, 2012, and July 7, 2015, targeting women who had recently delivered. Ritodrine hydrochloride use was identified from medical records. A total of 2,692 women were analyzed using logistic regression models that adjusted for possible confounders. RESULTS: There were 567 (21.1%) women who practiced prenatal yoga, which was associated with a lower risk of ritodrine hydrochloride use (adjusted odds ratio [OR] 0.77; 95% CI 0.61-0.98). This was especially evident in women with a total practice duration that exceeded 900 minutes throughout their pregnancy (adjusted OR 0.54; 95% CI 0.38-0.76). A sensitivity analysis that excluded patients with threatened abortion during the study period produced similar results. CONCLUSIONS: Prenatal yoga was associated with a lower risk of ritodrine hydrochloride use, particularly in women with more than 900 minutes of practice time over the course of their pregnancy. Prenatal yoga may be a beneficial option for pregnant women in the selection of alternative therapies.

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.