Association between maternal blood or cord blood metal concentrations and catch-up growth in children born small for gestational age: an analysis by the Japan environment and children's study.

BACKGROUND: Catch-up growth issues among children born small for gestational age (SGA) present a substantial public health challenge. Prenatal exposure to heavy metals can cause adverse effects on birth weight. However, comprehensive studies on the accurate assessment of individual blood concentrations of heavy metals and their effect on the failure to achieve catch-up growth remain unavailable. This study aimed to evaluate the effects of uterine exposure to toxic metals cadmium, lead, and mercury and essential trace metals manganese and selenium at low concentrations on the postnatal growth of children born SGA. METHODS: Data on newborn birth size and other factors were obtained from the medical record transcripts and self-administered questionnaires of participants in the Japan Environment and Children's Study. The blood concentrations of lead, cadmium, mercury, selenium, and manganese in pregnant women in their second or third trimester were determined by inductively coupled plasma mass spectrometry. These heavy metal concentrations were also assessed in pregnant women's cord blood. Furthermore, the relationship between each heavy metal and height measure/catch-up growth in SGA children aged 4 years was analyzed using linear and logistic regression methods. These models were adjusted for confounders. RESULTS: We studied 4683 mother-child pairings from 103,060 pregnancies included in the Japan Environment and Children's Study. Of these, 278 pairs were also analyzed using cord blood. At 3 and 4 years old, 10.7% and 9.0% of children who were born below the 10th percentile of body weight had height standard deviation scores (SDSs) below 2, respectively. Cord blood cadmium concentrations were associated with the inability to catch up in growth by 3 or 4 years old and the height SDS at 3 years old. In maternal blood, only manganese was positively associated with the height SDS of SGA children aged 2 years; however, it was not significantly associated with catch-up growth in these children. CONCLUSION: Cadmium exposure is associated with failed catch-up development in SGA children. These new findings could help identify children highly at risk of failing to catch up in growth, and could motivate the elimination of heavy metal (especially cadmium) pollution to improve SGA children's growth.

Within-individual relationships between mother-to-infant bonding and postpartum depressive symptoms: a longitudinal study.

BACKGROUND: Although the importance of the dynamic intra-individual relationship between mother-to-infant bonding and postpartum depressive symptoms has been widely recognized, the complex interplay between them is not well understood. Furthermore, the potential role of prenatal depressive symptoms and infant temperament in this relationship remains unclear. This study aims to examine the bidirectional influence of mother-to-infant bonding on postpartum depressive symptoms within individuals and to elucidate whether prenatal depressive symptoms and infant temperament would influence deviations from stable individual states. METHODS: Longitudinal data were collected from 433 women in early pregnancy. Of these, 360 participants completed the main questionnaires measuring impaired mother-to-infant bonding and postpartum depressive symptoms at least once during the postpartum period. Data were collected at early and late pregnancy and several postpartum time points: shortly after birth and at one, four, ten, and 18 months postpartum. We also assessed prenatal depressive symptoms and infant temperament. A random-intercept cross-lagged panel model was used. RESULTS: Within-individual variability in mother-to-infant bonding, especially anger and rejection, significantly predicted subsequent postpartum depressive symptoms. However, the inverse relationship was not significant. Additionally, prenatal depressive symptoms and difficult infant temperament were associated with greater within-individual variability in impaired mother-to-infant bonding and postpartum depressive symptoms. CONCLUSIONS: The present study demonstrated that the within-individual relationship between mother-to-infant bonding and postpartum depressive symptoms is likely non-bidirectional. The significance of the findings is underscored by the potential for interventions aimed at improving mother-to-infant bonding to alleviate postpartum depressive symptoms, suggesting avenues for future research and practice.

The Population-Attributable Fractions of Small-for-Gestational-Age Births: Results from the Japan Birth Cohort Consortium.

A fetal growth restriction is related to adverse child outcomes. We investigated risk ratios and population-attributable fractions (PAF) of small-for-gestational-age (SGA) infants in the Japanese population. Among 28,838 infants from five ongoing prospective birth cohort studies under the Japan Birth Cohort Consortium, two-stage individual-participant data meta-analyses were conducted to calculate risk ratios and PAFs for SGA in advanced maternal age, pre-pregnancy underweight, and smoking and alcohol consumption during pregnancy. Risk ratio was calculated using modified Poisson analyses with robust variance and PAF was calculated in each cohort, following common analyses protocols. Then, results from each cohort study were combined by meta-analyses using random-effects models to obtain the overall estimate for the Japanese population. In this meta-analysis, an increased risk (risk ratio, [95% confidence interval of SGA]) was significantly associated with pre-pregnancy underweight (1.72 [1.42-2.09]), gestational weight gain (1.95 [1.61-2.38]), and continued smoking during pregnancy (1.59 [1.01-2.50]). PAF of underweight, inadequate gestational weight gain, and continued smoking during pregnancy was 10.0% [4.6-15.1%], 31.4% [22.1-39.6%], and 3.2% [-4.8-10.5%], respectively. In conclusion, maternal weight status was a major contributor to SGA births in Japan. Improving maternal weight status should be prioritized to prevent fetal growth restriction.

Effect of nausea and vomiting during pregnancy on mother-to-infant bonding and the mediation effect of postpartum depression: the Japan Environment and Children's Study.

BACKGROUND: Mother-to-infant bonding (MIB) is critical for the health and well-being of the mother and child. Furthermore, MIB has been shown to boost the social-emotional development of infants, while also giving mothers a sense of happiness in raising their children. Nausea and vomiting during pregnancy (NVP) is a normal complication of pregnancy, occurring in approximately 50-90% of pregnant women in the early stages of pregnancy. Despite widespread knowledge of MIB and postpartum depression, little research attention has been given to the effects of NVP on MIB. This study aimed to investigate the relationship between NVP and MIB and the mediating effects of postpartum depression. METHODS: We analyzed the data of 88,424 infants and 87,658 mothers from the Japan Environment and Children's Study (JECS), which is a government-funded nationwide birth prospective cohort study. The Japanese version of the Mother-to-Infant Bonding Scale (MIBS-J) was used to assess MIB, and the Edinburgh Postpartum Depression Scale (EPDS) was utilized to assess postpartum depression. We divided participants into four groups according to a self-reported questionnaire assessing NVP (No NVP, Mild NVP, Moderate NVP, and Severe NVP). MIB disorder was defined as a MIBS-J score ≥ 5. Logistic analysis was performed to evaluate the effect of NVP on MIB disorder at one year after delivery. A mediation analysis was conducted to examine whether postpartum depression mediated the association between NVP and MIBS-J scores. RESULTS: The logistic regression analysis results revealed reduced risks of MIB disorder among mothers with Moderate NVP (adjusted OR 0.93; 95% confidence interval, 0.86-0.99) and Severe NVP (adjusted OR 0.81; 95% confidence interval, 0.74-0.89), compared to those with No NVP. The mediation analysis revealed that NVP positively correlated with MIBS-J score in the indirect effect via postpartum depression, while NVP (Mild NVP, Moderate NVP, and Severe NVP) negatively correlated with MIBS-J score in the direct effect. CONCLUSION: The risks of MIB disorder were reduced in the Moderate NVP and Severe NVP mothers, although NVP inhibited the development of MIB via postpartum depression. The development of effective interventions for postpartum depression is important to improve MIB among mothers with NVP.

Maternal antibiotic exposure and childhood allergies: The Japan Environment and Children's Study.

Background: The association of maternal antibiotic exposure during pregnancy with childhood allergic diseases remains unclear. Objective: We aimed to evaluate the association of maternal exposure to antibiotic use during pregnancy with childhood allergic diseases up to the age of 3 years by using data from a large Japanese birth cohort. Methods: We analyzed data on 78,678 pregnant women and their offspring aged 0 to 3 years. Prenatal antibiotic exposure was defined as the use of any antimicrobial agent during pregnancy. Information was collected from maternal interviews and medical record transcripts. The outcome variables in this study included preschool asthma, wheezing, food allergy, atopic dermatitis, eczema, allergic rhinoconjunctivitis, and any allergic disease. We used logistic regression analysis to evaluate the association of antibiotic exposure during pregnancy with childhood allergic diseases. Results: Among the participating mothers, 28.5% used antibiotics during pregnancy. Antibiotic exposure during pregnancy was associated with preschool asthma (adjusted odds ratio [aOR] = 1.12 [95% CI = 1.06-1.19]), wheezing (aOR = 1.11 [95% CI = 1.07-1.15]), allergic rhinoconjunctivitis (aOR = 1.10 [95% CI = 1.03-1.17]) and any allergic disease (aOR = 1.09 [95% CI = 1.05-1.14]) in offspring up to age 3 years. In contrast, maternal antibiotic use was not associated with food allergies, atopic dermatitis, or eczema. Additionally, the significant associations were not influenced by the timing of antibiotic exposure, sex of the infants, or maternal history of allergies. Conclusion: Maternal antibiotic exposure during pregnancy is associated with an increased risk of childhood respiratory allergies.

Prediction of gestational diabetes mellitus using machine learning from birth cohort data of the Japan Environment and Children's Study.

Recently, prediction of gestational diabetes mellitus (GDM) using artificial intelligence (AI) from medical records has been reported. We aimed to evaluate GDM-predictive AI-based models using birth cohort data with a wide range of information and to explore factors contributing to GDM development. This investigation was conducted as a part of the Japan Environment and Children's Study. In total, 82,698 pregnant mothers who provided data on lifestyle, anthropometry, and socioeconomic status before pregnancy and the first trimester were included in the study. We employed machine learning methods as AI algorithms, such as random forest (RF), gradient boosting decision tree (GBDT), and support vector machine (SVM), along with logistic regression (LR) as a reference. GBDT displayed the highest accuracy, followed by LR, RF, and SVM. Exploratory analysis of the JECS data revealed that health-related quality of life in early pregnancy and maternal birthweight, which were rarely reported to be associated with GDM, were found along with variables that were reported to be associated with GDM. The results of decision tree-based algorithms, such as GBDT, have shown high accuracy, interpretability, and superiority for predicting GDM using birth cohort data.

Screen Time and Developmental Performance Among Children at 1-3 Years of Age in the Japan Environment and Children's Study.

Importance: It is unclear whether increased television (TV) and DVD viewing in early childhood from age 1 year decreases development or whether poor development increases TV/DVD viewing. Objective: To investigate the directional association between TV/DVD screen time and performance on developmental screeners in children aged 1 to 3 years. Design, Setting, and Participants: This longitudinal cohort study analyzed data from 57 980 children and mothers from a national birth cohort, the Japan Environment and Children's Study. Data were collected in collaboration with 15 regional centers across Japan. The mothers were recruited between January 2011 and March 2014. Analyses using random intercept, cross-lagged panel models were performed for children aged 1, 2, and 3 years. Of 100 303 live births, children with missing developmental screening test scores and screen time data, those with congenital diseases or cerebral palsy, and those diagnosed with an autism spectrum disorder were excluded. Statistical analyses were conducted from October 2022 to July 2023. Exposures: TV and DVD screen time. Main Outcomes and Measures: Child development at ages 1, 2, and 3 years was assessed via the mother's or guardian's report using the Ages and Stages Questionnaire, third edition. Results: Of 57 980 included children, 29 418 (50.7%) were male, and the mean (SD) maternal age at delivery was 31.5 (4.9) years. A negative association between screen time and developmental scores was observed. Increased TV/DVD screen times at age 1 and 2 years were associated with lower developmental scores at age 2 and 3 years, respectively (2 years: ß = -0.05; 95% CI, -0.06 to -0.04; 3 years: ß = -0.08; 95% CI, -0.09 to -0.06). An obverse association was observed from the Ages and Stages Questionnaires, third edition, score in the communication domain at age 1 and 2 years to subsequent screen time (2 years: γ = -0.03; 95% CI, -0.04 to -0.02; 3 years: γ = -0.06; 95% CI, -0.07 to -0.04). Conclusions and Relevance: In this study, increased TV/DVD screen time from age 1 year negatively affected later development. To reduce the negative consequences of excessive media use, researchers and health care professionals should encourage family media management and recommend social support for parents who tend to rely on the media.

Spatiotemporal patterns of spontaneous movement in neonates are significantly linked to risk of autism spectrum disorders at 18 months old.

Infants make spontaneous movements from the prenatal period. Several studies indicate that an atypical pattern of body motion during infancy could be utilized as an early biomarker of autism spectrum disorders (ASD). However, to date, little is known about whether the body motion pattern in neonates is associated with ASD risk. The present study sought to clarify this point by examining, in a longitudinal design, the link between features of spontaneous movement at about two days after birth and ASD risk evaluated using the Modified Checklist for Autism in Toddlers by their caregivers at 18 months old. The body movement features were quantified by a recently developed markerless system of infant body motion analysis. Logistic regression analysis revealed that ASD risk at 18 months old is associated with the pattern of spontaneous movement at the neonatal stage. Further, logistic regression based on body movement features during sleep shows better performance in classifying high- and low-risk infants than during the awake state. These findings raise the possibility that early signs of ASD risk may emerge at a developmental stage far earlier than previously thought.

A Double-Blind, Randomized, Placebo-Controlled Trial of the Effect of 1-Kestose on Defecation Habits in Constipated Kindergarten Children: A Pilot Study.

Constipation is common in children and can significantly affect quality of life. Prebiotics are reportedly helpful for constipation in adults, but few studies have examined their use in young children. In this study, the effect of 1-kestose (kestose), which has excellent bifidobacterial growth properties, on constipation in kindergarten children (n = 11) was compared with that of maltose (n = 12) in a randomized, double-blind study. Three grams of kestose per day for 8 weeks did not affect stool properties, but significantly increased the number of defecations per week (Median; 3 → 4 times/week, p = 0.017, effect size = 0.53). A significant decrease in Intestinibacter, a trend toward increased bifidobacteria, and a trend toward decreased Clostridium sensu stricto were observed after kestose ingestion, while concentrations of short-chain fatty acids in stools were unchanged.

Vitamin D Receptor Mediates Attenuating Effect of Lithocholic Acid on Dextran Sulfate Sodium Induced Colitis in Mice.

Bile acids are major components of bile; they emulsify dietary lipids for efficient digestion and absorption and act as signaling molecules that activate nuclear and membrane receptors. The vitamin D receptor (VDR) is a receptor for the active form of vitamin D and lithocholic acid (LCA), a secondary bile acid produced by the intestinal microflora. Unlike other bile acids that enter the enterohepatic circulation, LCA is poorly absorbed in the intestine. Although vitamin D signaling regulates various physiological functions, including calcium metabolism and inflammation/immunity, LCA signaling remains largely unknown. In this study, we investigated the effect of the oral administration of LCA on colitis in a mouse model using dextran sulfate sodium (DSS). Oral LCA decreased the disease activity of colitis in the early phase, which is a phenotype associated with the suppression of histological injury, such as inflammatory cell infiltration and goblet cell loss. These protective effects of LCA were abolished in VDR-deleted mice. LCA decreased the expression of inflammatory cytokine genes, but this effect was at least partly observed in VDR-deleted mice. The pharmacological effect of LCA on colitis was not associated with hypercalcemia, an adverse effect induced by vitamin D compounds. Therefore, LCA suppresses DSS-induced intestinal injury in its action as a VDR ligand.

Association of Fatty Acid Desaturase 1 rs174547 Polymorphism with the Composition of Long-Chain Polyunsaturated Fatty Acids in Serum Glycerophospholipids during Pregnancy.

The increase in fetal requirements of long-chain polyunsaturated fatty acids (LCPUFAs) during pregnancy alters maternal fatty acid metabolism, and therefore, fatty acid desaturase (FADS) gene polymorphisms may change blood fatty acid composition or concentration differently during pregnancy. We investigated the relationship between a FADS1 single-nucleotide polymorphism (SNP) and maternal serum LCPUFA levels in Japanese pregnant women during the first and third trimesters and at delivery. Two hundred and fifty-three pregnant women were included, and fatty acid compositions of glycerophospholipids in serum (weight %) and the FADS1 SNP rs174547 (T/C) were analyzed. LCPUFAs, including arachidonic acid (ARA) and docosahexaenoic acid (DHA), significantly decreased from the first to the third trimester of pregnancy. Furthermore, DHA significantly decreased from the third trimester of pregnancy to delivery. At all gestational stages, linoleic acid (LA) and α-linolenic acid were significantly higher with the number of minor FADS1 SNP alleles, whereas γ-linolenic acid and ARA and the ARA/LA ratio were significantly lower. DHA was significantly lower with the number of minor FADS1 SNP alleles only in the third trimester and at delivery, suggesting that genotype effects become more obvious as pregnancy progresses.

[Elderly Advanced Breast Cancer Effectively Treated with Locoregional Therapy-A Case Report].

We report a case of advanced breast cancer in an elderly patient effectively treated with locoregional therapy. The patient was an 81-year-old woman who presented with an increasing right breast lump. The tumor was 55 mm in diameter, accompanied by fixation to pectoral muscle. A core needle biopsy for right breast tumor led to a diagnosis of mucinous carcinoma, positive for estrogen receptor(ER)and progesterone receptor(PgR), negative for HER2/neu. The Ki-67 positive cell index was 10%. A bone scintigraphy revealed multiple bone metastases, so, we confirmed the diagnosis as T4cN2aM1, Stage Ⅳ. She initiated endocrine therapy by letrozole. By changing the endocrine therapy to toremifene followed by fulvestrant, the therapy achieved a partial response. However, the size of the primary tumor increased accompanied by bleeding, and surgical resection of the right breast was performed for local control. The locoregional surgery was effective, improving the patient's quality of life. She was administered lapatinib as anti-HER2 therapy in addition to the endocrine therapy. Two years and 6 months after surgery, there has been no worsening of bone metastasis or appearance of visceral metastasis.

[Permissibility of Stoma Closure Surgery in Patients with Colorectal Cancer Who Underwent Primary Tumor Resection Including in Cancer-Bearing Conditions].

From 2006 to 2021, 27 patients who underwent stoma construction during colorectal cancer resection followed by stoma closure were grouped into 2 groups: Group A(7 patients with cancer)and Group B(20 patients without cancer). The male- to-female ratio were 6:1 for Group A and 13:7 for Group B. The average ages were 63.7 and 65.0 years, respectively. The ratios(Group A:Group B)of the causes for stoma construction were 5:13 for bowel obstruction due to colorectal cancer, 2:2 for abdominal wall invasion/dissemination and 0:5 for covering stoma. The causes of non-curative resection for Group A were peritoneal dissemination(4 patients), liver metastasis(1 patient), bladder infiltration(1 patient), and periaortic lymph node metastasis(1 patient). For Groups A and B, Hartmann surgery was performed in 4 and 10, colectomy and stoma construction in 3 and 5, and low anterior resection and covering stoma in 0 and 5 patients, respectively. The median time to stoma closure was 10 months for Group A and 6 months for Group B(p<0.05). There was no case of anastomotic leakage and 1 case of anastomotic stenosis(case not treated with anticancer drugs). No patient died of cancer within 1 year after stoma closure(median survival time after stoma closure was >26.0 months for Group A). Although stoma closure in patients with cancer was significantly delayed compared with patients without cancer, it was performed safely.

[Recurrent Breast Cancer with Bone Metastasis Effectively Treated with Abemaciclib plus Endocrine Therapy-A Case Report].

We report a case of recurrent breast cancer with bone metastasis in a premenopausal woman. A 46-year-old woman underwent mastectomy for right breast cancer 6 years ago. Histopathological diagnosis was invasive ductal carcinoma, T2N3aM0, stage ⅢC. She received adjuvant chemotherapy and irradiation followed by tamoxifen. Four and a half years after surgery, serum tumor marker levels elevated, and bone metastasis in the sacral region was revealed by PET-CT scan. After suppressing ovarian function with LH-RH agonist, we switched the endocrine therapy from tamoxifen to letrozole with a CDK4/6 inhibitor. Five months after starting administration of abemaciclib, the bone metastasis disappeared on PET-CT. The elevated tumor markers normalized and have continued to decrease. Abemaciclib combined with endocrine therapy was significantly effective as first-line treatment for premenopausal women with metastatic breast cancer.

Pretreatment Nutritional Status in Combination with Inflammation Affects Chemotherapy Interruption in Women with Ovarian, Fallopian Tube, and Peritoneal Cancer.

BACKGROUND: Discontinuing chemotherapy worsens cancer prognosis. This study aimed to investigate the relationship between nutritional status at the start of chemotherapy and chemotherapy discontinuation in patients with ovarian, fallopian tube, and primary peritoneal cancer. METHODS: This was a retrospective cohort study. One hundred and forty-six patients to whom weekly paclitaxel and carboplatin were administered as postoperative chemotherapy were included. Six courses in 21-day cycles were defined as complete treatment. As nutritional indicators, body mass index, weight change rate, serum albumin, total lymphocyte count, prognostic nutritional index, and C-reactive protein-to-albumin ratio (CAR) were compared between complete and incomplete treatment groups. Patients were divided into two groups according to CAR. The number of chemotherapy cycles was compared between these two groups. A Cox proportional hazard model was used for covariate adjustment. RESULTS: Several indicators differed between complete and incomplete treatment groups, and among the indicators, CAR had the highest discriminatory ability. The number of chemotherapy cycles was shorter in the high CAR group than in the low CAR group. A high CAR was associated with chemotherapy interruption even after adjusting for covariates. CONCLUSION: Based on CAR, nutritional status before chemotherapy is suggested to be associated with the risk of chemotherapy discontinuation.

Effect of Neonicotinoid Pesticides on Japanese Water Systems: Review with Focus on Reproductive Toxicity.

Neonicotinoid pesticides (NPs) are neurotoxic substances. They are highly effective as insecticides owing to their water solubility, permeability, and long-lasting activity. These molecules are structurally similar to nicotine and act as nicotinic acetylcholine receptor agonists. The administration of NPs to experimental animals reportedly causes neuromuscular and reproductive disorders. Moreover, recently reported problems caused by NPs include damage to land-dwelling creatures (such as mammals and birds), hydrobiology, and ecosystems. This review summarizes the recent reports on NP concentrations detected in river systems in several Japanese regions. These values were lower than the environmental standard values; however, seasonal variations were observed. Furthermore, reports on NP-induced testicular and ovarian toxicity were examined, revealing that the mechanism of injury is mainly driven by oxidative stress. The use of NPs is declining worldwide, except in Japan; therefore, continuous monitoring remains necessary.

Association between Media Use and Bedtime Delays in Young Children: An Adjunct Study of the Japan Environment and Children's Study.

Excessive screen media use has been reported to cause shorter sleep; however, the types of media environments that affect early childhood sleep are less known. This study examined the association of multiple media use, screen time for each device, and the purpose of smartphone and tablet use with delayed bedtime among 4-8-year-olds. Participants were recruited from the Japan Environment and Children's Study, a nationwide birth cohort study. Mothers of 1837 children reported screen media use and bedtime in a questionnaire. The association between delayed bedtimes (after 22:00 h) and media device use (smartphones, tablets, portable and console games, and TV/DVDs) was examined by logistic regression analysis. Children who used three or more devices besides TV/DVDs were more likely to have delayed bedtimes. Delayed bedtimes were associated with smartphone use, even with a 0.1-1 h/day screen time, and with prolonged screen time for tablets, portable games, and console games, but not for TV/DVDs. Gaming on smartphones and tablets was also associated with delayed bedtime. To ensure adequate sleep for young children, families must develop feasible measures to discourage children's use of multiple devices and prolonged device use, especially for games, and a social environment that supports such measures.

Individual and mixed metal maternal blood concentrations in relation to birth size: An analysis of the Japan Environment and Children's Study (JECS).

BACKGROUND: Growth restriction in the prenatal period is a significant public health concern. Metals can negatively affect birth size, and pregnant women may be exposed to metal mixtures. Comprehensive studies analyzing the effects of combined metal exposure with accurate individual blood metal concentrations are limited. The current study investigated the associations between maternal metal exposure and birth size in a large, nationwide Japanese cohort using individual and mixed model approaches. METHODS: Lead, cadmium, mercury, selenium, and manganese blood concentrations were measured in pregnant women in the Japan Environment and Children's Study (JECS). Measurements of infant birth size-including body weight, body length, and head and chest circumference-were collected. Linear and logistic regressions were used for birth size measurements and the odds of an infant being small in size for gestational age, respectively. Associations between combined metal mixtures and measurements at birth were evaluated using quantile g-computation and Bayesian kernel machine regression (BKMR). RESULTS: Of the 103,060 JECS pregnancies, 93,739 mother-infant pairs were analyzed. The linear regression models showed that lead, selenium, cadmium, and manganese-but not mercury-were associated with body weight. Cadmium was associated with length and chest circumference and mercury was associated with head circumference. Quantile g-computation revealed that manganese increased infant birth weight, length, head circumference, and chest circumference. Lead was the strongest negative factor for infant birth weight, length, head circumference, and chest circumference. The BKMR analysis revealed that the metals had an additive, rather than a synergistic effect. CONCLUSION: Metal exposure is associated with infant birth size, with lead and manganese playing a more significant role in Japan. The effects of prenatal combined metal exposure at low levels warrant public health attention.