Design and other methodological considerations for the construction of human fetal and neonatal size and growth charts

This paper discusses the features of study design and methodological considerations for constructing reference centile charts for attained size, growth, and velocity charts with a focus on human growth charts used during pregnancy. Recent systematic reviews of pregnancy dating, fetal size, and newborn size charts showed that many studies aimed at constructing charts are still conducted poorly. Important design features such as inclusion and exclusion criteria, ultrasound quality control measures, sample size determination, anthropometric evaluation, gestational age estimation, assessment of outliers, and chart presentation are seldom well addressed, considered, or reported. Many of these charts are in clinical use today and directly affect the identification of at-risk newborns that require treatment and nutritional strategies. This paper therefore reiterates some of the concepts previously identified as important for growth studies, focusing on considerations and concepts related to study design, sample size, and methodological considerations with an aim of obtaining valid reference or standard centile charts. We discuss some of the key issues and provide more details and practical examples based on our experiences from the INTERGROWTH-21^st Project. We discuss the statistical methodology and analyses for cross-sectional studies and longitudinal studies in a separate article in this issue.     

Obstetrical volume and early neonatal mortality in preterm infants

Objective Regionalised perinatal care with antenatal transfer of high risk pregnancies to Level III centres is beneficial. However, levels of care are usually not linked to caseload requirements, which remain a point for discussion. We aimed to investigate the impact of annual delivery volume on early neonatal mortality among very preterm births. Methods All neonates with gestational age 24–30 weeks, born 1991–1999 in Lower Saxony were included into this population-based cohort study (n = 5,083). Large units were defined as caring for more than 1,000 deliveries/year, large NICUs as those with at least 36 annual very low birthweight (<1,500 g, VLBW) admissions. Main outcome criterion was mortality until day 7. Adjusted Odds Ratios (adj. OR) and 95% confidence intervals (CI) were calculated based on generalised estimating equation models, accounting for correlation of individuals within units. Results Within the first week of life, 20.6% of all neonates deceased; 10.2% were stillbirths, 3.7% died in the delivery unit, and 6.7% in the NICU. The crude OR for early neonatal mortality after having been delivered in a small delivery unit (excluding stillbirths) was 1.36 (95%CI 1.04–1.78; adj. OR 1.16 (0.82–1.63)). It increased to 1.96 (1.54–2.48; adj. OR 1.21 (0.86–1.70)) after the inclusion of stillbirths. Conclusion This study has shown a slight, but non-significant association between obstetrical volume and early neonatal mortality. In future studies the impact of caseload on outcome may become more evident when referring to high-risk patients instead of to the overall number of deliveries.     

新生儿危重病例评分和第三代小儿死亡危险评分预测危重新生儿死亡风险比较

目的 比较第三代小儿死亡危险评分(pediatric risk of mortality III score, PRISM III)和新生儿危重病例评分(neonatal critical illness score, NCIS)在预测危重新生儿死亡风险方面的优越性, 探讨更适合我国NICU应用的评分系统。方法 对2013年1-6月入住新疆石河子大学第一附属医院新生儿重症监护室(neonatal intensive care unit, NICU)的135例患儿同时采用NCIS和PRISM III两种评分系统进行评分, 根据评分将入组病例分为极危重、危重、非危重3组, 分别对各组病死率进行比较, 并描绘受试者工作特征曲线(receiver operating characteristic curve, ROC), 比较ROC曲线下面积(area under the ROC curve, AUC), 以观察两种评分系统在预测危重新生儿死亡风险的优越性。结果 NCIS评分与PRISM III评分非危重组、危重组与极危重组组间病死率比较, 差异均有统计学意义(P＜0.05);两种评分对应组组间比较, 差异均无统计学意义(P＞0.05);AUC:NCIS评分0.900, PRISM III评分0.909。结论 NCIS评分与PRISM III评分均能准确预测新生儿死亡风险, PRISM III评分在我国完全适用。     

Fetal growth and childhood cholesterol levels in the United States

Research has linked fetal environment to subsequent adult disease. This study examines the extent to which infants born small-for-gestational age (SGA) were at risk for high cholesterol levels in early childhood (ages 4-6 years). Data were obtained from 1727 children aged 4-6 years who participated in the cross-sectional third US National Health and Nutrition Examination Survey and had both birth certificates and blood cholesterol information. The odds of having moderately elevated (170-199 mg/dL) or high (> or =200 mg/dL) serum total cholesterol after being born SGA were determined after controlling for sex, race/ethnicity, education of household head, saturated fat intake, parental history of high cholesterol and overweight status. Approximately 11% of participants were SGA. Proportions of children with moderately elevated and high cholesterol levels were approximately 28 and 8%, respectively. SGA children were almost twice as likely (odds ratio 1.97, 95% confidence interval [0.8, 4.8]) to have high cholesterol vs. low cholesterol than non-SGA children, although the result was not statistically significant. Multiple linear regression demonstrated a similar inverse, non-significant relationship between gestation-adjusted birthweight and cholesterol (beta = -2.3, P = 0.33). These data indicate a possible association between reduced fetal growth, represented by birthweight adjusted for gestational age, and increased cholesterol levels in early childhood.     

Lower early neonatal mortality among singletons in transnational marriage families: Taiwan Birth Registry

The nativity composition of the Taiwan population has changed substantially since 1980, which resulted in one in six children being born to foreign-born mothers in 2004. The purpose of this study was to compare the early neonatal mortality rates among babies of foreign-born and Taiwan-born mothers. Data was obtained from the Taiwan Birth Registry Database in 2004 by the Bureau of Health Promotion, Department of Health, Taiwan. Multivariate analysis was used to examine the influence of the different maternal nationalities on early neonatal mortality after adjusting for important maternal and infant variables. Infants born to foreign-born mothers had a lower early neonatal mortality rate (5.6 per thousand) compared to those born to Taiwan-born mothers (9.4 per thousand). Even after adjusting for important maternal and infant variables, newborns of foreign-born mothers still had a lower risk of early neonatal death compared to newborns of Taiwan-born mothers (odds ratio = 0.68, 95% CI = 0.57-0.80). Foreign-born status may serve as an important index of differentiation in early neonatal mortality among the current Taiwan population. Selection, economic and non-economic aspects may explain the paradox of favorable early neonatal mortality outcomes.     

Lower mortality but higher neonatal morbidity over a decade in very preterm infants

Better perinatal care has led to better survival of very preterm children, but may or may not have increased the number of children with cerebral and pulmonary morbidity. We therefore investigated the relationship between changes in perinatal care during one decade, and short-term outcome in very preterm infants. Perinatal risk factors and their effects on 28-day and in-hospital mortality, and on intraventricular haemorrhage and bronchopulmonary dysplasia (BPD) in survivors, were compared in two surveys of very preterm singleton infants in the Netherlands. Between 1983 and 1993, 28-day mortality decreased from 52.1% to 31.8% in infants of 25-27 weeks' gestation and from 15.2% to 11.3% in infants of 28-31 weeks' gestation. The incidence of intraventricular haemorrhage in survivors did not change (44.4% and 43.3% in infants of 25-27 weeks' gestation, and 29.0% and 24.0% in infants of 28-31 weeks' gestation). The incidence of BPD in survivors increased from 40.3% to 60.0% in infants of 25-27 weeks' gestation and remained similar in infants of 28-31 weeks' gestation (8.5% and 9.8% respectively). In multivariable analysis, higher mortality was associated with congenital malformation, low gestational age, low birthweight, no administration of steroids before birth, low Apgar scores and intraventricular haemorrhage, in 1983 as well in 1993, and with male gender in 1993. The effect of maternal age on mortality diminished significantly between 1983 and 1993. Intraventricular haemorrhage in surviving children was associated with low gestational age and artificial ventilation, both in 1983 and in 1993. The effect of artificial ventilation on the incidence of intraventricular haemorrhage diminished significantly between 1983 and 1993. BPD was associated with low gestational age and artificial ventilation, both in 1983 and in 1993, and with low birthweight and caesarean section in 1993. We conclude that the better survival of very preterm infants, especially of those of 25-27 weeks' gestation, has been accompanied by a similar incidence (and thus with an increased absolute number) of children with intraventricular haemorrhage and by an increased incidence of children with BPD.     

Early neonatal mortality, low birth weight and related factors in Japan

Objectives The author conducted an ecological study to examine prefectural differences in ENMR and the related factors in Japan, using two new indicators; birth weight (BW) adjusted ENMR and expected ENMR by BW distribution. Method Correlate analysis of data from national vital statistics and some indicators of medical care services among 47 prefectures edited by the Ministry of Health and Welfare, Japan were conducted. BW-adjusted ENMR and expected ENMR by BW, as well as other indicators, were prepared for statistical analysis. Result Crude and BW-adjusted ENMRs were significantly correlated with ENMRs for low birth weight (LBW) and very low birth weight (VLBW) early neonates (p<0.01). The number of Obstetrics and Gynecology (OB/GYN) physicians was negatively correlated with BW adjusted ENMR. Conclusion Crude and BW-adjusted ENMRs were affected mainly by LBW and VLBW early neonate specific ENMR, but not by the rate of LBW. The variation of ENMR among prefectures in Japan is attributable to the number of OB/GYN physicians. The present findings suggest that emphasis should be laid upon enhancement of regional perinatal care systems.     

Local economic growth and infant mortality

We estimate the effect of local economic growth on infant mortality. We use geo-referenced data for non-migrating mothers from 46 developing countries and a total of 128 DHS survey rounds and combine it with nighttime luminosity data at a granular level. Using mother fixed effects we show that an increase in local economic activity significantly reduces the probability that the same mother loses a child before its first birthday.     

Low birthweight and mortality: the tendency to repeat low birthweight and its association with early neonatal and infant morbidity and mortality

Previous studies have demonstrated the tendency to repeat gestational age and birthweight in successive pregnancies and that this tendency is associated with infant survival. Thus, newborn outcome and survival is less favourable if the gestational age and size departs from this maternal tendency. This paper aims to study diseases or conditions that might be associated with this effect. Data were provided through a linkage between three Danish health registries: the Danish Fertility Database, the National Hospital Registry, and the Registry for Preventive Medicine. Such linkage was possible due to the use of unique ID-person numbers. The study included all 8219 second-order low-birthweight (LBW) singleton Danish births, 1980-94, of whom 7811 were liveborn. It was also required that the mother's first delivery took place during that period. The analysis considered 7803 of these births; eight were excluded due to insufficient information. Of the second-order LBW children, 26% had an elder sibling who was also LBW. Early neonatal mortality of a 'non-repeat' LBW birth was 1.3 times higher than 'repeat' LBW births [53.8 vs. 41.2 per 1000; RR 1.31; 95% CI 1.03, 1.65], as was infant mortality [78.4 vs. 60.8 per 1000; RR 1.30; 95% CI 1.06, 1.56]. Also, proportionately more LBW repeat births had Apgar scores of >or=7 after 1 and 5 min. Overall, repeat second-order LBW babies weighed 68 g more than non-repeat LBW babies (P < 0.001). At term, the weight difference was 160 g higher among repeat LBW births (P < 0.001). The mean number of hospitalisations during the first year of life was lower among repeat than non-repeat LBW babies (2.30 vs. 2.46, P < 0.001), while the mean duration of stay was 23.71 vs. 23.97 days (P > 0.05). Newborn immaturity was the most common diagnosis for hospitalisation, and infections the second most common. There were no differences between repeat and non-repeat LBW births in the proportion with each diagnosis. Apart from the differences in birthweight, we were unable to explain the improved survival for repeat compared with non-repeat LBW babies. Except for differences in Apgar scores, we observed no differences in morbidity based on registered hospitalisations during infancy.     

Aetiology of stillbirths and neonatal deaths in rural Ghana: implications for health programming in developing countries

In developing countries many stillbirths and neonatal deaths occur at home and cause of death is not recorded by national health information systems. A community-level verbal autopsy tool was used to obtain data on the aetiology of stillbirths and neonatal deaths in rural Ghana. Objectives were to describe the timing and distribution of causes of stillbirths and neonatal deaths according to site of death (health facility or home). Data were collected from 1 January 2003 to 30 June 2004; 20 317 deliveries, 696 stillbirths and 623 neonatal deaths occurred over that time.
Most deaths occurred in the antepartum period (28 weeks gestation to the onset of labour) (33.0%). However, the highest risk periods were during labour and delivery (intrapartum period) and the first day of life. Infections were a major cause of death in the antepartum (10.1%) and neonatal (40.3%) periods. The most important cause of intrapartum death was obstetric complications (59.3%). There were significantly fewer neonatal deaths resulting from birth asphyxia in the home than in the health facilities and more deaths from infection. Only 59 (20.7%) mothers of neonates who died at home reported that they sought care from an appropriate health care provider (doctor, nurse or health facility) during their baby's illness. The results from this study highlight the importance of studying community-level data in developing countries and the high risk of intrapartum stillbirths and infectious diseases in the rural African mother and neonate. Community-level interventions are urgently needed, especially interventions that reduce intrapartum deaths and infection rates in the mother and infant.     

孕妇血清唾液酸与正常新生儿的体格生长

目的 研究孕妇不同妊娠期的血清唾液酸含量、脐血清唾液酸含量、唾液酸胎盘转运率与新生儿体格生长的关系。 方法 采取前瞻性队列研究的方法,从妊早、中、晚期至分娩时,分析孕期血清唾液酸水平与子代出生体重、身长、头围和Kaup指数的关系。结果 妊早、中、晚期孕妇不同血清唾液酸含量的新生儿出生体重、出生身长、出生头围及Kaup指数差异均无统计学意义(P>0.05);不同脐血清唾液酸和唾液酸胎盘转运率的新生儿出生体格差异亦无统计学意义(P>0.05)。 结论妊娠期的唾液酸含量、新生儿脐唾液酸含量和唾液酸胎盘运转率对新生儿出生体格生长无显著影响,唾液酸不会对婴儿造成肥胖的影响,唾液酸胎盘转运率只是反映唾液酸通过胎盘的一个度量,可以衡量胎儿当时生长发育的营养需求。     

新生儿窒息126例临床分析

目的：通过对126例窒息新生儿临床分析,探讨其影响因素及其并发症,为制定新生儿窒息的预防和处理提供科学依据。方法选取2012年1月至2014年12月安康市妇幼保健院产科出生的126例新生儿窒息住院患儿的临床资料进行回顾性分析。结果连续3年新生儿窒息发生率差异均无统计学意义（χ2值分别为0．21、0．23、0．90,均P＞0．05）;新生儿窒息发生围产因素主要为胎儿宫内窘迫、低出生体重儿、羊水污染、早产、胎膜早破,所占比例分别为31．75％、29．36％、22．22％、22．22％、21．43％;新生儿窒息并发症主要包括吸入性肺炎、新生儿缺氧缺血性脑病（ HIE）、黄疸、颅内出血、低钠血症、低钙血症、心肌损害、消化道出血,分别占86．51％、77．77％、68．25％、53．97％、45．24％、31．75％、30．95％、11．11％。结论新生儿窒息关键在于预防,加强产前监测,及时了解有无胎儿宫内窘迫的发生,监测有异常者及时采取有效措施,加强产儿科合作,分娩时实施新法新生儿复苏,在窒息新生儿处理上清理呼吸道是关键,在复苏后处理上早期要维持内环境稳定,减少脑损害及心肌损害。     

Relationship between dietary folate intakes,maternal plasma total homocysteine and B-vitamins during pregnancy and fetal growth in Japan

Background Adequate folate status in pregnancy is important for satisfactory pregnancy outcome. Aim of the Study The objective of the present study was to evaluate folate status in healthy pregnant women by assessing dietary folate intakes and measuring changes in folate-related biomarkers including plasma tHcy, serum vitamin B₁₂ (B₁₂), and serum and RBC folate concentrations in each trimester and to examine their relation to fetal growth. Methods From 94 pregnant women, 3-day-dietary records were obtained and blood was collected for plasma total homocysteine (tHcy), serum B₁₂, and serum and red-blood cell (RBC) folate measurements. Infant anthropometric measurements were made immediately after birth. Results Average folate intake was less than 300 μg/day with a mean energy intake of about 1800 kcal. Mean serum and RBC folate concentrations declined significantly during gestation (p < 0.05). Mean serum B₁₂ also significantly decreased (p < 0.01), whereas plasma tHcy increased from 5.1 in the first trimester to 5.9 μmol/l in the third trimester (p < 0.01). Multiple regression analyses, after controlling for maternal age, parity and pre-pregnancy body-mass index indicated that a 1.0 μmol/l increase in plasma tHcy in the third trimester corresponded to a 151 g decrease in birth weight (p < 0.01). Neither B₁₂ nor folate concentrations in all three trimesters showed any significant associations with birthweight. Plasma pyridoxal-5′-phosphate concentrations were markedly low, and were consistent with low intake of vitamin B₆ in our population. Conclusion Our data suggest that higher plasma tHcy in the third trimester is a predictor of lower birth weight. In general, the dietary intake of B-vitamins and energy may be inadequate in our population, suggesting intervention is necessary.     

Trends in stillbirths, early and late neonatal mortality in rural Bangladesh: the role of public health interventions

Trends were examined in a cohort study of stillbirths and early and late neonatal deaths in Matlab, a rural area of Bangladesh between 1975 and 2002, using routinely collected demographic surveillance data. Main outcome measures were stillbirths per 1000 births, early neonatal deaths per 1000 livebirths, and late neonatal deaths per 1000 children surviving after 1 week. We performed a logistic regression examining trends over time and between two areas in the three outcome measures, controlling for the effects of parental education, religion, time, geography, parity, maternal age and birth spacing. There was a marked decline in stillbirths, early and late neonatal mortality over time in both areas, though the pace of decline was somewhat faster in the ICDDR,B (International Centre for Diarrhoeal Disease Research, Bangladesh) service area. Stillbirths declined by 24% overall in the ICDDR,B service area (crude OR comparing 1996-2002 with 1975-81: 0.76 [95% CI 0.68, 0.84]), compared with 15% in the Government service area (crude OR comparing 1996-2002 with 1975-81: 0.85 [0.76, 0.94]). The overall reduction in early and late neonatal mortality comparing the same periods was 39% and 73%, respectively, in the ICDDR,B area, compared with 30% and 63%, respectively, in the Government service area. Adjusting for socio-economic or demographic factors did not substantially alter the time or area differentials. The dramatic decline in neonatal mortality was, in large part, due to a fall in deaths from neonatal tetanus. The pace of decline was faster in the area receiving intense maternal and child health and family planning interventions, but stillbirths, early and late neonatal deaths also declined in the area not receiving such intense attention, suggesting that factors outside the formal health sector play an important role.     

Diagnostic accuracy of verbal autopsies in ascertaining the causes of stillbirths and neonatal deaths in rural Ghana

This study evaluated the diagnostic accuracy of a verbal autopsy (VA) tool in ascertaining the causes of stillbirths and neonatal deaths in rural Ghana and was nested within a community-based maternal vitamin A supplementation trial (ObaapaVitA trial). All stillbirths and neonatal deaths between 1 January 2003 and 30 June 2004 were prospectively included. Community VAs were carried out within 6 months of death and were classified with a primary cause of death by three experienced paediatricans. The reference standard diagnosis was obtained by the study paediatrician in 4 district hospitals in the study area.
There were 20 317 deliveries, 661 stillbirths and 590 neonatal deaths with a VA diagnosis in the study population. A total of 311 stillbirths and 191 neonatal deaths had both a VA and a hospital reference standard diagnosis. The VA performed poorly for stillbirth diagnoses such as congenital abnormalities and maternal haemorrhage. Accuracy was higher for intrapartum obstetric complications and antepartum maternal disease. For neonatal deaths, sensitivity was >60% for all major causes; specificity was 76% for birth asphyxia but >85% for prematurity and infection. Overall, VA diagnostic accuracy was higher than expected in this rural African setting. Our classification system was based on the expected public health importance of the individual causes of death, differing implications for intervention and the ability to distinguish between the individual causes in low-resource settings. We believe this system was easier to use than traditional approaches and resulted in high precision and accuracy. However, further simplifications are needed to allow use of the World Health Organisation VA in routine child health programmes. The diagnostic accuracy of the VA tool should also be assessed in other regions and in multicentre studies.     

Nutritional Control of Fetal Growth

Maternal micronutrient nutrition is an important determinant of size and body composition of the fetus. Maternal iron, iodine, calcium, folate, vitamin A, and vitamin C nutrition all influence offspring size. The Pune Maternal Nutrition Study was designed to study the relationship between maternal nutrition and fetal growth, size at birth, and postnatal growth. Maternal circulating folate and vitamin C concentrations predicted larger offspring size, while higher ferritin levels predicted smaller-sized babies. Subclinical vitamin B₁₂ deficiency is common in India, especially in vegetarians, and children born to mothers with the lowest vitamin B₁₂ but the highest folate status were the most adipose and the most insulin resistant. Furthermore, the relationship between maternal nutrition, fetal growth, and risk of type 2 diabetes and coronary heart disease appears to be much more complex than the simplistic postulates of the "fetal origins" hypothesis.     

Adverse perinatal and neonatal outcomes and their determinants in rural Vietnam 1999-2005

Population-based estimations of perinatal and neonatal outcomes are sparse in Vietnam. There are no previously published data on small for gestational age (SGA) infants. A rural population in northern Vietnam was investigated from 1999 to 2005 (n=5521). Based on the birthweight distributions within the population under study, reference curves for intrauterine growth for Vietnamese infants were constructed and the prevalence and distribution of SGA was calculated for each sex. Neonatal mortality was estimated as 11.6 per 1000 live births and the perinatal mortality as 25.0 per 1000 births during the study period. The mean birthweight was 3112 g and the prevalence of low birthweight was 5.0%. The overall prevalence of SGA was 6.4%. SGA increased with gestational age and was 2.2%, 4.5% and 27.1% for preterm, term and post-term infants, respectively. Risk factors for SGA were post-term birth: adjusted odds ratio (AOR) 7.75 [95% CI 6.02, 9.98], mothers in farming occupations AOR 1.72 [95% CI 1.21, 2.45] and female infant AOR 1.61 [95% CI 1.27, 2.03]. There was a pronounced decrease in neonatal mortality after 33 weeks of gestation. Suggested interventions are improved prenatal identification of SGA infants by ultrasound investigation for fetal growth among infants who do not follow their expected clinical growth curve at the antenatal clinic. Other suggestions include allocating a higher proportion of preterm deliveries to health facilities with surgical capacity and neonatal care.     

"Development" is not essential to reduce infant mortality rate in India: experience from the Ballabgarh project

BACKGROUND: India aims to reduce the infant mortality rate (IMR) to below 60 per 1000 live births by 2000. IMR is higher in northern India as compared with south Indian states like Kerala. Any further reduction in IMR needs identification of new strategies. The Ballabgarh project with an IMR of 36 in 1997 can help identify such strategies. OBJECTIVE: To see the trend in reduction of neonatal mortality rate (NNMR) and IMR at the Ballabgarh project, compare it with Kerala and rural India's trend and look at the causes of neonatal and infant mortality. DESIGN: The Comprehensive Rural Health Services Project, Ballabgarh, run by the All India Institute of Medical Sciences, covered an estimated population of 70,079 in 1997. The health care delivery system is on the national pattern. All the deaths are identified during the house visits by the male workers. The cause of death is ascertained by the health assistant based on the symptomatology at the time of death. RESULTS: The trends in reduction of IMR for Ballabgarh, Kerala and rural India are roughly parallel with the IMR of Ballabgarh lying somewhere in between the two. However, the NNMR of Ballabgarh (10.6 in 1996) was comparable to Kerala's NNMR (10.9 in 1992). The proportion of infant deaths occurring during the neonatal period had fallen from 50% in the early seventies to 30% during 1996-97. In 1992-1994, 33.8% of all neonatal deaths were attributable to low birth weight and 37.3% to infective causes. Acute respiratory infection and diarrhoea continue to be the chief cause of postneonatal mortality. CONCLUSION: It is possible to bring down neonatal mortality before postneonatal mortality. The Kerala model, which focuses on social development, may not apply to northern India for sociocultural reasons.     

IGF系统与胎儿生长发育

胎儿几乎所有组织中都能合成及分泌胰岛素样生长因子。胰岛素样生长因子以自分泌和旁分泌机制与靶细胞表面特异受体结合 ,在局部组织发挥生理作用 ,加强机体同化作用。其对胎儿是必需的 ,在胎儿组织器官生长发育和成熟中起重要作用。母体及胎盘胰岛素样生长因子水平也影响胎儿的生长。基因重组多肽类生长因子已用于产科临床治疗一些相关病症     

Manganese and birth outcome

Manganese is an essential mineral nutrient needed for proper fetal development and other important aspects of metabolism. However, manganese excess can have a potent neurotoxicity effect, especially in infants. Little is known about the effects of manganese deficiency or excess on the developing human fetus. The findings of two recent studies indicate that lower maternal blood manganese is associated with fetal intrauterine growth retardation (IUGR) and lower birth weight. In light of the importance of IUGR and birth weight on neonatal morbidity and mortality, additional basic studies of maternal and fetal manganese physiology are needed, as well as more epidemiologic studies in different populations of the association of manganese exposure and birth outcome.