Association Between Smoking and Hypertension in Pregnancy Among Japanese Women: A Meta-analysis of Birth Cohort Studies in the Japan Birth Cohort Consortium (JBiCC) and JECS.

BACKGROUND: Recent literature suggest the effect of maternal smoking on risk of hypertensive disorders in pregnancy (HDP) and preeclampsia may differ by ethnicity; however, studies on Asians are limited. METHODS: We investigated the association of maternal smoking with HDP and preeclampsia using a common analysis protocol to analyze the association in six birth cohorts participating in a Japanese consortium of birth cohorts (JBiCC). Results were compared with-published results from cohorts not included in this consortium, and, where possible, we produced a meta-analysis including these studies. RESULTS: Meta-analysis of four cohort studies including 28,219 participants produced an odds ratio (OR) of 1.24 (95% confidence interval [CI], 0.88-1.87) for the effect of smoking beyond early pregnancy compared to women who did not smoke during pregnancy. These results combined with those from the Japan Environment and Children's Study (JECS) yielded an OR of 1.19 (95% CI, 1.00-1.43, P = 0.056). Meta-analysis results for categories of smoking volume were insignificant, but when combined with JECS yielded an OR of 0.86 (95% CI, 0.65-1.12) for smoking 1-4 cigarettes, 1.25 (95% CI, 0.98-1.60) for smoking 5-9 cigarettes, and 1.27 (95% CI, 1.04-1.54) for smoking 10 or more cigarettes per day. All effects were insignificant for preeclampsia. CONCLUSION: Our results suggest that the protective effects of smoking longer and smoking more on HDP and preeclampsia repeatedly observed among Europeans and North Americans likely do not hold for the Japanese.

Gene-environment interactions related to maternal exposure to environmental and lifestyle-related chemicals during pregnancy and the resulting adverse fetal growth: a review.

BACKGROUND: There are only limited numbers of reviews on the association of maternal-child genetic polymorphisms and environmental and lifestyle-related chemical exposure during pregnancy with adverse fetal growth. Thus, this article aims to review: (1) the effect of associations between the above highlighted factors on adverse fetal growth and (2) recent birth cohort studies regarding environmental health risks. METHODS: Based on a search of the PubMed database through August 2021, 68 epidemiological studies on gene-environment interactions, focusing on the association between environmental and lifestyle-related chemical exposure and adverse fetal growth was identified. Moreover, we also reviewed recent worldwide birth cohort studies regarding environmental health risks. RESULTS: Thirty studies examined gene-smoking associations with adverse fetal growth. Sixteen maternal genes significantly modified the association between maternal smoking and adverse fetal growth. Two genes significantly related with this association were detected in infants. Moreover, the maternal genes that significantly interacted with maternal smoking during pregnancy were cytochrome P450 1A1 (CYP1A1), X-ray repair cross-complementing protein 3 (XRCC3), interleukin 6 (IL6), interleukin 1 beta (IL1B), human leukocyte antigen (HLA) DQ alpha 1 (HLA-DQA1), HLA DQ beta 1 (HLA-DQB1), and nicotinic acetylcholine receptor. Fetal genes that had significant interactions with maternal smoking during pregnancy were glutathione S-transferase theta 1 (GSTT1) and fat mass and obesity-associated protein (FTO). Thirty-eight studies examined the association between chemical exposures and adverse fetal growth. In 62 of the 68 epidemiological studies (91.2%), a significant association was found with adverse fetal growth. Across the studies, there was a wide variation in the analytical methods used, especially with respect to the genetic polymorphisms of interest, environmental and lifestyle-related chemicals examined, and the study design used to estimate the gene-environment interactions. It was also found that a consistently increasing number of European and worldwide large-scale birth cohort studies on environmental health risks have been conducted since approximately 1996. CONCLUSION: There is some evidence to suggest the importance of gene-environment interactions on adverse fetal growth. The current knowledge on gene-environment interactions will help guide future studies on the combined effects of maternal-child genetic polymorphisms and exposure to environmental and lifestyle-related chemicals during pregnancy.

Association of exposure to prenatal perfluoroalkyl substances and estrogen receptor 1 polymorphisms with the second to fourth digit ratio in school-aged children: The Hokkaido study.

Per- and Polyfluoroalkyl substances (PFAS) have endocrine-disrupting effects. The ratio of the lengths of the second and fourth digits (2D:4D) is a noninvasive retrospective index of prenatal exposure to sex hormones, and estrogen receptor 1 (ESR1) polymorphisms may contribute to 2D:4D determination. We investigated whether ESR1 polymorphisms modify the effects of prenatal PFAS exposure on 2D:4D. Participants (n = 1024) with complete data in a prospective birth cohort study (the Hokkaido Study) were included, and maternal plasma in the third trimester was used to examine PFAS concentrations. 2D:4D was determined from photocopies of palms of children using Vernier calipers. ESR1 polymorphisms (rs2234693, rs9340799, and rs2077647) were genotyped by TaqMan polymerase chain reaction. PFAS and 2D:4D association with ESR1 polymorphisms was assessed by multiple linear regression adjusted for potential confounding factors. A 10-fold increase in maternal perfluorooctanoic acid (PFOA) concentration was associated with a 1.54% [95% confidence interval (CI): 0.40, 2.68] increase in mean 2D:4D in children with an AA genotype at rs9340799 and a 2.24% (95% CI: 0.57, 3.92) increase in children with an AA genotype at rs2077647. A 10-fold increase in perfluorododecanoic acid (PFDoDA) was associated with a significant increase in 2D:4D in children with the AA genotype [rs9340799, 1.18% (95% CI: 0.02, 2.34); and rs2077647, 1.67% (95% CI: 0.05, 3.28)]. These associations were apparent among males. A significant gene-environment interaction between PFOA or PFDoDA and ESR1 polymorphism was detected. These findings suggest that ESR1 polymorphisms modify the effects of prenatal exposure to PFAS on sex differentiation.

Associations between maternal mono-(2-ethylhexyl) phthalate levels, nuclear receptor gene polymorphisms, and fatty acid levels in pregnant Japanese women in the Hokkaido study.

We assessed how the interaction between mono-(2-ethylhexyl) phthalate (MEHP) in maternal sera and the maternal genotypes associated with nuclear receptors affect fatty acid levels in a prospective birth cohort study of pregnant Japanese individuals (n = 437) recruited in Sapporo between 2002 and 2005. We analyzed MEHP and fatty acids using gas chromatography-mass spectrometry. Thirteen single nucleotide polymorphisms of peroxisome proliferator-activated receptor (PPAR) alpha, PPAR gamma (PPARG), PPARG coactivator 1A (PPARGC1A), PPAR delta, constitutive androstane receptor, liver X receptor (LXR) alpha, and LXR beta (LXRB) were analyzed using real-time PCR. Multiple linear regression models were used to confirm the influence of log10-transformed MEHP levels and maternal genotypes on log10-transformed fatty acid levels. When the effects of the interaction between MEHP levels and the maternal PPARGC1A (rs8192678) genotype on oleic acid levels were evaluated, the estimated changes (95 % confidence intervals) in oleic acid levels against MEHP levels, maternal PPARGC1A (rs8192678)-GA/AA genotype, and the interaction between them showed a mean reduction of 0.200 (0.079, 0.322), mean reduction of 0.141 (0.000, 0.283), and mean increase of 0.145 (0.010, 0.281), respectively, after adjusting for the perfluorooctanesulfonate level. The effects of the interaction between MEHP levels and maternal LXRB (rs2303044) genotype on linoleic acid levels was also significant (pint = 0.010). In conclusion, the interaction between MEHP and the maternal genotypes PPARGC1A (rs8192678) and LXRB (rs2303044) decreased fatty acid levels. Further, the interaction between MEHP and PPARGC1A (rs8192678) may have a greater effect on fatty acid levels than the interaction between PFOS and PPARGC1A.

Relationships between maternal perfluoroalkyl substance levels, polymorphisms of receptor genes, and adverse birth outcomes in the Hokkaido birth cohort study, Japan.

We assessed the associations between perfluorooctanesulfonate (PFOS) and perfluorooctanoate (PFOA) levels in third trimester maternal serum, the maternal genotypes of genes encoding nuclear receptors, and birth outcomes. We studied a prospective birth cohort of healthy pregnant Japanese women (n = 372) recruited in Sapporo between July 2002 and October 2005. We analyzed PFOS and PFOA levels using liquid chromatography-tandem mass spectrometry and analyzed 13 single nucleotide polymorphisms (SNPs) of proliferator-activated receptor alpha, gamma, gamma coactivator 1A, delta, constitutive androstane receptor, liver X receptor alpha, and beta (LXRB) using real-time polymerase reaction (PCR). We employed multiple linear regression models to establish the influences of log10-transformed PFOS and PFOA levels and maternal genotypes on birth size. In female infants, we identified interactions between PFOS levels, the maternal genotype of LXRB (rs1405655), and birth weight. The estimated mean changes in birth weight in response to PFOS levels, the maternal genotype LXRB (rs1405655)-TC/CC (compared to TT), and their interactions were -502.9 g (95 % confidence interval [CI] = -247.3, -758.5 g), -526.3 g (95 % CI = -200.7, -852.0 g), and 662.1 g (95 % CI = 221.0, 1,103.2 g; pint = 0.003), respectively. Interactions between PFOS levels and the maternal genotype of LXRB (rs1405655) also significantly affected birth chest circumference and the Ponderal index (pint = 0.037 and 0.005, respectively). Thus, interactions between PFOS levels and the maternal genotype of LXRB (rs1405655) affects birth sizes in female infants. We found that certain SNPs modify the effects of PFOS levels on birth size.

Associations among maternal perfluoroalkyl substance levels, fetal sex-hormone enzymatic gene polymorphisms, and fetal sex hormone levels in the Hokkaido study.

Prenatal sex hormones affect fetal growth; for example, prenatal exposure to low levels of androgen accelerates female puberty onset. We assessed the association of perfluoroalkyl substances (PFASs) in maternal sera and infant genotypes of genes encoding enzymes involved in sex steroid hormone biosynthesis on cord sera sex hormone levels in a prospective birth cohort study of healthy pregnant Japanese women (n = 224) recruited in Sapporo between July 2002 and October 2005. We analyzed PFAS and five sex hormone levels using liquid chromatography-tandem mass spectrometry. Cytochrome P450 (CYP) 17A1 (CYP17A1 rs743572), 19A1 (CYP19A1 rs10046, rs700519, and rs727479), 3ß-hydroxysteroid dehydrogenase type 1 (HSD3B1 rs6203), type 2 (HSD3B2 rs1819698, rs2854964, and rs4659175), 17ß-hydroxysteroid dehydrogenase type 1 (HSD17B1 rs605059, rs676387, and rs2676531), and type 3 (HSD17B3 rs4743709) were analyzed using real-time PCR. Multiple linear regression models were used to establish the influence of log10-transformed PFAS levels and infant genotypes on log10-transformed sex steroid hormone levels. When the interaction between perfluorooctanesulfonate (PFOS) levels and female infant genotype CYP17A1 (rs743572) on the androstenedione (A-dione) levels was considered, the estimated changes (95 % confidence intervals) in A-dione levels against PFOS levels, female infant genotype CYP17A1 (rs743572)-AG/GG, and interaction between them showed a mean increase of 0.445 (0.102, 0.787), mean increase of 0.392 (0.084, 0.707), and mean reduction of 0.579 (0.161, 0.997) (Pint = 0.007), respectively. Moreover, a female-specific interaction with testosterone levels was observed. A-dione and T levels showed positive main effects and negative interaction with PFOS levels and the female infant CYP17A1 genotype.

Associations among perfluorooctanesulfonic/perfluorooctanoic acid levels, nuclear receptor gene polymorphisms, and lipid levels in pregnant women in the Hokkaido study.

The effect of interactions between perfluorooctanesulfonic (PFOS)/perfluorooctanoic acid (PFOA) levels and nuclear receptor genotypes on fatty acid (FA) levels, including those of triglycerides, is not clear understood. Therefore, in the present study, we aimed to analyse the association of PFOS/PFOA levels and single-nucleotide polymorphisms (SNPs) in nuclear receptors with FA levels in pregnant women. We analysed 504 mothers in a birth cohort between 2002 and 2005 in Japan. Serum PFOS/PFOA and FA levels were measured using liquid chromatography-tandem mass spectrometry and gas chromatography-mass spectrometry. Maternal genotypes in PPARA (rs1800234; rs135561), PPARG (rs3856806), PPARGC1A (rs2970847; rs8192678), PPARD (rs1053049; rs2267668), CAR (rs2307424; rs2501873), LXRA (rs2279238) and LXRB (rs1405655; rs2303044; rs4802703) were analysed. When gene-environment interaction was considered, PFOS exposure (log10 scale) decreased palmitic, palmitoleic, and oleic acid levels (log10 scale), with the observed ß in the range of - 0.452 to - 0.244; PPARGC1A (rs8192678) and PPARD (rs1053049; rs2267668) genotypes decreased triglyceride, palmitic, palmitoleic, and oleic acid levels, with the observed ß in the range of - 0.266 to - 0.176. Interactions between PFOS exposure and SNPs were significant for palmitic acid (Pint = 0.004 to 0.017). In conclusion, the interactions between maternal PFOS levels and PPARGC1A or PPARD may modify maternal FA levels.

Haemodynamic benefit of bridging use of bosentan prior to pulmonary endarterectomy.

OBJECTIVES: Some patients present with excessive pulmonary hypertension (PH) prior to pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension (CTEPH). This study was performed to evaluate the clinical role of pretreatment before PEA in CTEPH patients. METHODS: A total of 370 patients with CTEPH undergoing first PEA between 2003 and 2017 were divided into those receiving pretreatment with bosentan (group B: n = 119) and those without targeted pretreatment for PH (group C: n = 251). After selecting patients given bosentan (2-8 months) and using propensity score matching, comparable patient cohorts (n = 23 each) were created from both groups. PEA was performed in the standard manner, and the median number of extracted segments was 14. RESULTS: There were no significant differences in perioperative demographic characteristics or 30-day mortality (overall 5.7%) between the groups before and after matching. In patients with preoperative pulmonary vascular resistance (PVR) ≥800 dynes s/cm5, a significantly larger decrease in PVR was found in group B (78%) compared to group C (68%) (P = 0.033). There was no significant difference in late survival between the groups after matching. The frequency of residual/persistent PH (mean pulmonary artery pressure >25 mmHg) was lower in group B than in group C, although the difference was not significant (22% vs 39%, respectively, P = 0.200). Advanced age and longer cardiopulmonary bypass time were independent predictors of both 30-day mortality and residual/persistent PH (odds ratio: age, 1.053, 1.013, cardiopulmonary bypass time, 1.065, 1.010, respectively). CONCLUSIONS: Preoperative treatment of CTEPH patients with bosentan for 2-8 months can improve post-PEA PVR without adverse clinical events in patients with a high preoperative PVR. A temporary bridging regime appears beneficial in selected patients prior to PEA.

Surgical Thoracoabdominal Aortic Aneurysm Repair in a Non-High-Volume Institution.

BACKGROUND: Surgical thoracoabdominal aortic aneurysm (TAAA) repair remains challenging. Apart from mortality, spinal cord injury (SCI) is a dreaded complication. We analyzed our experience to identify predictors for SCI in a nonhigh-volume institution. PATIENTS AND METHODS: All patients who underwent TAAA repair between February 1996 and November 2016 (n = 182) were enrolled. Most were male (n = 121; 66.4%), median age was 68 years (range: 21-84). Elective operations were performed in 153 instances (84.1%). Our approach to minimize SCI includes distal aortic perfusion, mild hypothermia, identification of the Adamkiewicz artery, and sequential aortic clamping. Cerebrospinal fluid drainage was introduced in 2001 and liberal use of selective visceral perfusion in 2006. RESULTS: Early mortality was 12.1%; it was 8.5% after elective procedures. Reduced left ventricular function, nonelective setting, older age, and longer bypass time were identified as independent predictors for mortality in multivariable logistic regression model. Permanent SCI was observed in nine patients (4.9%), of whom seven (3.8%) developed paraplegia. In a multivariable logistic regression model for paraplegia, peripheral arterial disease (PAD), Crawford type II repair, smaller body surface area, and era before 2001 were identified as independent predictors, whereas only PAD was significant for SCI. The incidence of paraplegia was 13.8% in extensive repair out of the first 91 cases, whereas it was improved up to 2.7% thereafter. CONCLUSION: Using an integrated approach, acceptable outcome of TAAA repair can be achieved, even in a nonhigh-volume center. PAD and extensive involvement of the aorta are strong independent predictors for spinal cord deficit after TAAA repair.

Association of exposure to prenatal phthalate esters and bisphenol A and polymorphisms in the ESR1 gene with the second to fourth digit ratio in school-aged children: Data from the Hokkaido study.

Phthalates and bisphenol A (BPA) are estrogenic endocrine disruptors. Polymorphisms in the gene encoding estrogen receptor 1 (ESR1) may contribute to the ratio of the lengths of the second and fourth digits (2D:4D), which is considered an index of prenatal exposure to sex hormones. Thus, we investigated whether ESR1 polymorphisms modify the effects of prenatal exposure to phthalates and BPA on 2D:4D in a birth cohort. Maternal serum in the first trimester was used to determine prenatal exposure to these compounds. Six hundred twenty-three children (7 years of age) provided mean 2D:4D from photocopies and were genotyped for single nucleotide polymorphisms in ESR1, particularly PvuII (T > C, dbSNP: rs2234693), XbaI (A > G, dbSNP: rs9340799), and rs2077647 (A > G). The associations among compound exposure, mean 2D:4D, and ESR1 polymorphisms were assessed by multiple linear regression adjusted for potential cofounding factors. Boys with the AG/GG genotype at rs2077647 in the group exposed to high levels of mono(2-ethylhexyl) phthalate (MEHP) or Σ Di(2-ethylhexyl) phthalate (DEHP) showed feminized 2D:4D compared with boys with the AA genotype at rs2077647 who had low exposure to MEHP or ΣDEHP (MEHP: increase in mean 2D:4D of 1.51%, 95% confidence interval [CI]: 0.40-2.63; ΣDEHP: increase in mean 2D:4D of 1.37%, 95% CI: 0.25-2.49). No significant differences were found among girls. There were no associations between mean 2D:4D and metabolites other than MEHP or BPA. These data suggest that ESR1 polymorphisms modify the effects of prenatal exposure to DEHP on mean 2D:4D among boys.

Dose-dependent associations between prenatal caffeine consumption and small for gestational age, preterm birth, and reduced birthweight in the Japan Environment and Children's Study.

BACKGROUND: Few previous studies have investigated the association between prenatal caffeine intake and birth size (small for gestational age [SGA], preterm birth, and birthweight Z-score) in Japan. OBJECTIVES: We examined the dose-dependency of this association (prenatal caffeine consumption and birth size) as part of the Japan Environment and Children's Study. METHODS: A prospective birth cohort included 94 876 fetuses in Japan. Participants were enrolled between January 2011 and March 2014. Adjusted multiple linear regression and Cox regression models were used to examine the association between prenatal caffeine levels and infant birth size. RESULTS: The median estimated caffeine consumption during pregnancy was 125.5 mg/day, as determined by self-administered questionnaires. There were 7252 SGA infants (7.6%) and 4281 preterm birth infants (4.5%). Compared with infants of mothers whose caffeine consumption during pregnancy was in the lowest quartile (4.2 to <86.4 mg/day), infants of mothers whose caffeine consumption was in the highest quartile 4 (205.5-5080.0 mg/day) were at an increased risk of SGA (relative risk [RR] 1.18, 95% confidence interval [CI] 1.10, 1.27), and at an increased risk of preterm birth at the second trimester of gestation (RR 1.94, 95% CI 1.12, 3.37), with a 0.32-day reduction in gestational age (95% CI -0.52, -0.12) and with a 0.07 reduction in birthweight Z-score observed (95% CI -0.09, -0.05). CONCLUSIONS: Prenatal caffeine consumption was associated with birth size. However, as the association between prenatal caffeine consumption and birth size was likely confounded by unpredicted potential factors, our confidence in the true causality of the association is moderate.

Association between maternal passive smoking and increased risk of delivering small-for-gestational-age infants at full-term using plasma cotinine levels from The Hokkaido Study: a prospective birth cohort.

OBJECTIVES: To investigate the association between plasma cotinine level measured at the 8th gestational month and the delivery of small-for-gestational-age (SGA) infants, using a highly sensitive ELISA method. DESIGN: Prospective birth cohort study from The Hokkaido Study on Environment and Children's Health. SETTING: Hokkaido, Japan. PARTICIPANTS: Our sample included 15 198 mother-infant pairs enrolled in 2003-2012. MAIN OUTCOME MEASURES: SGA, defined as a gestational age-specific weight Z-score below -2. RESULTS: The number of SGA infants was 192 (1.3%). The cotinine cut-off level that differentiated SGA infants from other infants was 3.03 ng/mL for both the total population and the full-term births subgroup (sensitivity 0.307; positive predictive value 2.3%). Compared with infants of mothers with a plasma cotinine level of <3.03 ng/mL, infants of mothers with a plasma cotinine level of ≥3.03 ng/mL showed an increased OR for SGA in the total population and the full-term infant group (2.02(95% CI 1.45 to 2.83) and 2.44(95% CI 1.73 to 3.44), respectively). CONCLUSION: A plasma cotinine level of ≥3.03 ng/mL, which included both passive and active smokers, was associated with an increased risk of SGA. This finding is of important relevance when educating pregnant women about avoiding prenatal passive and active smoking due to the adverse effects on their infants, even those born at full-term.

Association between ESR1 polymorphisms and second to fourth digit ratio in school-aged children in the Hokkaido Study.

The ratio of the lengths of the 2nd and 4th digits (2D:4D) is considered an index of prenatal exposure to androgen. Indeed, androgen receptors have been linked to digit length, but estrogen receptors are rarely investigated in this context. Thus, we investigated the association between estrogen receptor 1 (ESR1) genetic polymorphisms and 2D:4D in school-aged children. The 2D:4D ratios were determined using Vernier calipers from photocopies of palms provided by 1800 children aged 7 years who were enrolled in an ongoing prospective cohort study in Hokkaido, Japan. The children were genotyped using cord blood collected at birth for single nucleotide polymorphisms in ESR1, specifically PvuII (T > C, dbSNP: rs2234693), XbaI (A > G, dbSNP: rs9340799), and rs2077647 (A > G). The association between ESR1 polymorphisms and 2D:4D was assessed by multiple linear regression adjusted for potential cofounding factors. Boys with the GG genotype at rs9340799 had a significantly lower 2D:4D in the right hand than boys with the AA/AG genotype (-0.96% lower, 95% confidence interval: -1.68 to -0.24). However, this association was detected only in boys born to non-smoking mothers. No significant differences were found between rs9340799 polymorphisms and 2D:4D among girls. There was also no link between 2D:4D and polymorphisms at rs2234693 and rs2077647. These data suggest that rs9340799 polymorphisms in ESR1 may contribute to digit length and 2D:4D.

Aortic annulus does not dilate over time after aortic root remodeling with or without annuloplasty.

OBJECTIVE: The lack of annular stabilization is the drawback of aortic root remodeling, and recently the addition of annuloplasty has been proposed. Limited data, however, exist on late annular size after remodeling. We studied annular size over time. METHODS: In 241 patients (53 ± 16 years) annular size was determined preoperatively (T0), before discharge (T1), and at least 2 years after remodeling (T2, 54 ± 27 months) with (n = 52) or without external suture annuloplasty. Seventeen patients had Marfan syndrome (7%), 100 a bicuspid valve (41%), and 22 acute dissection (9%). Mean graft size was 25.2 ± 1.3 mm, and annuloplasty size 24.3 ± 1.4 mm. RESULTS: Annular size was significantly reduced after repair and remained stable over time (T0: 27.4 ± 3.0 mm, T1: 24.2 ± 2.5 mm, T2: 24.2 ± 2.6 mm). After propensity-score matching (n = 33 each), baseline annular size was similar (with annuloplasty vs without: 28.7 ± 4.1 mm vs 27.8 ± 2.8 mm). Annular reduction was less effective without annuloplasty (23.9 ± 2.0 mm vs 25.6 ± 2.2 mm, P < .01); size was identical at follow-up (23.8 ± 2.2 mm vs 25.1 ± 2.5 mm, P = .03). After matching, freedom from annular size increase >10% at 4 years was 93 ± 5% without annuloplasty and 91 ± 9% with annuloplasty (P = .92). A linear mixed-effects model identified no significant effect of annuloplasty on annulus diameter change at T2 (P = .48). Era after 2004, Marfan syndrome, and smaller annulus diameter at discharge were the independent predictors for late annular expansion. CONCLUSIONS: Aortic annulus rarely dilates over time after remodeling. In the case of annular dilatation, annuloplasty normalizes annular size and may prevent further dilatation by enhancing cusp coaptation. Even without annuloplasty, the aortic annulus becomes smaller compared with preoperative dimensions when aortic valve remains competent.

Gender-specific association of exposure to non-dioxin-like polychlorinated biphenyls during pregnancy with methylation levels of H19 and long interspersed nuclear element-1 in cord blood in the Hokkaido study.

BACKGROUND: Associations between prenatal exposure to polychlorinated biphenyls (PCBs) and reduced birth-size, and between DNA methylation of insulin-like growth factor-2 (IGF-2), H19 locus, and long interspersed nuclear element-1 (LINE-1) and reduced birth-size are well established. To date, however, studies on the associations between prenatal exposure to PCBs and alterations in methylation of IGF-2, H19, and LINE-1 are lacking. Thus, in this study, we examined these associations with infant-gender stratification. METHODS: We performed a prospective birth cohort study using the Sapporo cohort from the previously described Hokkaido Birth Cohort Study on Environment and Children's Health conducted between 2002 and 2005 in Japan. In the final 169 study participants included in this study, we measured the concentrations of various non-dioxin-like PCBs in maternal blood during pregnancy using high-resolution gas chromatography/high-resolution mass spectrometry. IGF-2, H19 and LINE-1 methylation levels in cord blood were measured using the bisulfite pyrosequencing methods Finally, we assessed the associations between prenatal exposure to various PCBs and the gene methylation levels using multiple regression models stratified by infant gender. RESULTS: We observed a 0.017 (95% confidence interval [CI]: 0.003-0.031) increase in the log10-transformed H19 methylation levels (%) in cord blood for each ten-fold increase in the levels of decachlorinated biphenyls (decaCBs) in maternal blood among all infants. Similarly, a 0.005 (95% CI: 0.000-0.010) increase in the log10-transformed LINE-1 methylation levels (%) in cord blood was associated with each ten-fold increase in heptachlorinated biphenyls (heptaCBs) in maternal blood among all infants. In particular, we observed a dose-dependent association of the decaCB levels in maternal blood with the H19 methylation levels among female infants (P value for trend=0.040); likewise a dose-dependent association of heptaCB levels was observed with LINE-1 methylation levels among female infants (P value for trend=0.015). Moreover, these associations were only observed among infants of primiparous women. CONCLUSION: Our results suggest that the dose-dependent association between prenatal exposure to specific non-dioxin-like PCBs and increases in the H19 and LINE-1 methylation levels in cord blood might be more predominant in females than in males.

Modification of adverse health effects of maternal active and passive smoking by genetic susceptibility: Dose-dependent association of plasma cotinine with infant birth size among Japanese women-The Hokkaido Study.

OBJECTIVES: We aimed to assess the individual dose-response effects of eight maternal polymorphisms encoding polycyclic aromatic hydrocarbon-metabolizing and DNA-repair genes on prenatal cotinine levels according to infant birth size. METHODS: In total, 3263 Japanese pregnant women were assigned to five groups based on plasma cotinine levels during the 8th month of pregnancy, as measured using ELISA (cut-offs: 0.21, 0.55, 11.48, and 101.67ng/mL). Analyses were performed using multiple linear regression. RESULTS: Birth weight reduction showed a dose-dependent relationship with prenatal cotinine levels (P for trend<0.001). When considering the specific aromatic hydrocarbon receptor (AHR) (G>A, Arg554Lys; db SNP ID: rs2066853) and X-ray cross-complementing gene 1 (XRCC1) (C>T, Arg194Trp, rs1799782) genotypes, a larger birth weight reduction was noted among infants born to mothers with the highest cotinine level. CONCLUSION: Infants born to women with specific AHR and XRCC1 genotypes may have higher genetic risks for birth weight reduction.

Association of prenatal passive smoking and metabolic gene polymorphisms with child growth from birth to 3years of age in the Hokkaido Birth Cohort Study on Environment and Children's Health.

Although the effects of prenatal passive smoking on birth weight have been reported, the effects of metabolic gene polymorphisms on passive smoking have not been studied. Therefore, we investigated the effects of maternal passive smoking and metabolic gene polymorphisms on child growth up to 3years of age using cotinine as a biomarker. We included 1356 Japanese participants in a prospective cohort between 2003 and 2007 (cotinine levels at the third trimester≤0.21ng/mL and 0.22 to 11.48ng/mL for non-passive and passive smokers, respectively), and measured child outcomes such as weight, length, head circumference, and Kaup index. Additionally, we analyzed cytochrome P450 1A1 (CYP1A1), epoxide hydrolase 1 (EPHX1), and two N-acetyltransferase 2 (NAT2) genotypes using real-time polymerase chain reaction methods. Associations were investigated using multiple regression models. Kaup index gain from birth up to 3years of age was significantly smaller in children born to passive smokers than in those born to non-passive smokers (-0.34kg/m2; 95% confidence interval: -0.67, -0.01). Maternal CYP1A1 genotype was not associated with prenatal passive smoking and Kaup index gain, but was significantly associated with prenatal passive smoking and head circumference gain from birth up to 3years of age (-0.75cm; 95% confidence interval: -1.39, -0.12). Thus, this study suggests that prenatal passive smoking may have potent effects on postnatal growth from birth up to 3years of age. Moreover, children with maternal CYP1A1 genotype may be more susceptible to the effects of prenatal passive smoking.

Interaction between maternal caffeine intake during pregnancy and CYP1A2 C164A polymorphism affects infant birth size in the Hokkaido study.

BackgroundCaffeine, 1,3,7-trimethylxanthine, is widely consumed by women of reproductive age. Although caffeine has been proposed to inhibit fetal growth, previous studies on the effects of caffeine on infant birth size have yielded inconsistent findings. This inconsistency may result from failure to account for individual differences in caffeine metabolism related to polymorphisms in the gene for CYP1A2, the major caffeine-metabolizing enzyme.MethodsFive hundred fourteen Japanese women participated in a prospective cohort study in Sapporo, Japan, from 2002 to 2005, and 476 mother-child pairs were included for final analysis.ResultsCaffeine intake was not significantly associated with mean infant birth size. When caffeine intake and CYP1A2 C164A genotype were considered together, women with the AA genotype and caffeine intake of ≥300 mg per day had a mean reduction in infant birth head circumference of 0.8 cm relative to the reference group after adjusting for confounding factors. In a subgroup analysis, only nonsmokers with the AA genotype and caffeine intake of ≥300 mg per day had infants with decreased birth weight (mean reduction, 277 g) and birth head circumference (mean reduction, 1.0 cm).ConclusionNonsmokers who rapidly metabolize caffeine may be at increased risk for having infants with decreased birth size when consuming ≥300 mg of caffeine per day.

Overview of Longitudinal Survey of Newborns in the 21st Century: Factors Affecting Infant Growth.

There are two major nationwide birth cohort studies in Japan, namely, the Longitudinal Survey of Newborns in the 21st Century conducted by the Ministry of Health, Labor and Welfare (MHLW) and the Japan Environment and Children's Study (JECS) conducted by the Ministry of Environment. The former was a longitudinal questionnaire survey focusing on environmental and socioeconomic factors for descriptive epidemiology conducted every year since 2001 by mail. The latter was based on 15 unit centers nationwide with environmental measurements and collection of biological samples for environmental risk evaluation. Both are prospective birth cohort studies whose findings will be expected as the basis for establishing health policies. The data obtained in the former study can be used for research with permission from MHLW. To date, there have been more than ten published studies using those data. We have reviewed these studies and introduced our preliminary findings on factors affecting infant growth. Employment before delivery, educational background of parents, household income, and smoking habit of both parents have been suggested to affect infant growth. We will analyze the associations between socioeconomic factors and infant growth trajectory to elucidate the most adequate intervention for children.