Biological mechanisms for nutritional regulation of maternal health and fetal development

This review paper highlights mechanisms for nutritional regulation of maternal health and fetal development. Malnutrition (nutrient deficiencies or obesity) in pregnant women adversely affects their health by causing or exacerbating a plethora of problems, such as anaemia, maternal haemorrhage, insulin resistance, and hypertensive disorders (e.g. pre-eclampsia/eclampsia). Maternal malnutrition during gestation also impairs embryonic and fetal growth and development, resulting in deleterious outcomes, including intrauterine growth restriction (IUGR), low birthweight, preterm birth, and birth defects (e.g. neural tube defects and iodine deficiency disorders). IUGR and preterm birth contribute to high rates of neonatal morbidity and mortality. Major common mechanisms responsible for malnutrition-induced IUGR and preterm birth include: (i) abnormal growth and development of the placenta; (ii) impaired placental transfer of nutrients from mother to fetus; (iii) endocrine disorders; and (iv) disturbances in normal metabolic processes. Activation of a series of physiological responses leading to premature and sustained contraction of the uterine myometrium also results in preterm birth. Recent epidemiologic studies have suggested a link between IUGR and chronic metabolic disease in children and adults, and the effects of IUGR may be carried forward to subsequent generations through epigenetics. While advanced medical therapies, which are generally unavailable in low-income countries, are required to support preterm and IUGR infants, optimal nutrition during pregnancy may help ameliorate many of these problems. Future studies are necessary to develop effective nutritional interventions to enhance fetal growth and development and alleviate the burden of maternal morbidity and mortality in low- and middle-income countries.     

Iron status during pregnancy: setting the stage for mother and infant

Supplementation with iron is generally recommended during pregnancy to meet the iron needs of both mother and fetus. When detected early in pregnancy, iron deficiency anemia (IDA) is associated with a > 2-fold increase in the risk of preterm delivery. Maternal anemia when diagnosed before midpregnancy is also associated with an increased risk of preterm birth. Results of recent randomized clinical trials in the United States and in Nepal that involved early supplementation with iron showed some reduction in risk of low birth weight or preterm low birth weight, but not preterm delivery. During the 3rd trimester, maternal anemia usually is not associated with increased risk of adverse pregnancy outcomes and may be an indicator of an expanded maternal plasma volume. High levels of hemoglobin, hematocrit, and ferritin are associated with an increased risk of fetal growth restriction, preterm delivery, and preeclampsia. While iron supplementation increases maternal iron status and stores, factors that underlie adverse pregnancy outcome are considered to result in this association, not iron supplements. On the other hand, iron supplements and increased iron stores have recently been linked to maternal complications (eg, gestational diabetes) and increased oxidative stress during pregnancy. Consequently, while iron supplementation may improve pregnancy outcome when the mother is iron deficient it is also possible that prophylactic supplementation may increase risk when the mother does not have iron deficiency or IDA. Anemia and IDA are not synonymous, even among low-income minority women in their reproductive years.     

Pregnancy disorders that lead to delivery before the 28th week of gestation: an epidemiologic approach to classification

Epidemiologists have grouped the multiple disorders that lead to preterm delivery before the 28th week of gestation in a variety of ways. The authors sought to identify characteristics that would help guide how to classify disorders that lead to such preterm delivery. They enrolled 1,006 women who delivered a liveborn singleton infant of less than 28 weeks' gestation at 14 centers in the United States between 2002 and 2004. Each delivery was classified by presentation: preterm labor (40%), prelabor premature rupture of membranes (23%), preeclampsia (18%), placental abruption (11%), cervical incompetence (5%), and fetal indication/intrauterine growth restriction (3%). Using factor analysis (eigenvalue = 1.73) to compare characteristics identified by standardized interview, chart review, placental histology, and placental microbiology among the presentation groups, the authors found 2 broad patterns. One pattern, characterized by histologic chorioamnionitis and placental microbe recovery, was associated with preterm labor, prelabor premature rupture of membranes, placental abruption, and cervical insufficiency. The other, characterized by a paucity of organisms and inflammation but the presence of histologic features of dysfunctional placentation, was associated with preeclampsia and fetal indication/intrauterine growth restriction. Disorders leading to preterm delivery may be separated into two groups: those associated with intrauterine inflammation and those associated with aberrations of placentation.     

Micronutrients and reproductive health issues: an international perspective

Micronutrients may have a role in enhancing reproductive health of women living in the developing world. Two illustrative micronutrients, zinc and vitamin A, have received some attention in this regard. Numerous animal experiments and observational studies suggest the potential role of zinc deficiency in labor and delivery-related complications such as premature rupture of membrane, placental abruption, preterm labor and inefficient uterine contraction. These associations have not been confirmed in supplementation studies. Zinc does not appear to be a limiting factor in intrauterine growth in the developing world, contrary to some evidence of its suggested benefit among women residing in industrialized countries. One study in Nepal found that maternal vitamin A or beta-carotene supplementation reduces pregnancy-related mortality but not infant mortality. These findings are corroborated by observations of the significantly higher risk of mortality among night-blind women compared to non-night-blind women long after the termination of pregnancy and the resolution of night blindness. Maternal multiple micronutrient supplementation needs more careful evaluation before its use in large-scale programs. Two recent trials indicated that a prenatal multiple micronutrient supplement provides no added advantage over iron and folate in reducing outcomes such as low birth weight and probably no survival benefit. Data are also suggestive that adding zinc may negate the beneficial effect of iron and folic acid on birth weight. Research is needed to further our understanding of nutrient-nutrient interactions.     

Jail incarceration and birth outcomes

This study examined the relationships between jail incarceration during pregnancy and infant birth weight, preterm birth, and fetal growth restriction. We used multivariate regression analyses to compare outcomes for 496 births to women who were in jail for part of pregnancy with 4,960 Medicaid-funded births as matched community controls. After adjusting for potential confounding variables, the relationship between jail incarceration and birth outcomes was modified by maternal age. Relative to controls, women incarcerated during pregnancy had progressively higher odds of low birth weight and preterm birth through age 39 years; conversely, jail detainees older than 39 years were less likely than controls to experience low birth weight or preterm birth. For women in jail at all ages, postrelease maternity case management was associated with decreased odds of low birth weight, whereas prenatal care was associated with decreased odds of preterm birth. Local jails are important sites for public health intervention. Efforts to ensure that all pregnant women released from jail have access to enhanced prenatal health services may improve perinatal outcomes for this group of particularly vulnerable women and infants.     

The impact of short interpregnancy intervals on pregnancy outcomes in a low-income population.

OBJECTIVES: The objective of this study was to determine whether the length of the interval between pregnancies was associated with either preterm birth or intrauterine growth retardation in a low-income, largely Black population. METHODS: The study population consisted of 4400 women who had received prenatal care in county clinics and had two consecutive singleton births between 1980 and 1990. RESULTS: Interpregnancy intervals were positively associated with age and negatively associated with the trimester in which care was initiated in the second pregnancy. Whites had shorter intervals than non-Whites. The percentage of preterm births increased as the length of the interpregnancy interval decreased, but only for women who had not had a previous preterm birth. The association between interval and preterm birth was maintained when other factors associated with preterm birth were controlled. There was no significant relationship between intrauterine growth retardation and interpregnancy interval. CONCLUSIONS: Women, particularly those who are poor and young, should be advised of the potential harm to their infants of short interpregnancy intervals.     

The Impact of Migration on Pregnancy Outcomes Among Mexican-Origin Women

To examine the association between individual-level and state-level migration status in the United States (US) and the risk of preterm and low birth weight infants among Mexican-origin women. We performed secondary analysis of the 2003 US birth certificate data for 641,474 infants born to Mexican-origin Latina women. The dependent variables were prematurity and low birth weight. The primary independent variables were individual- (maternal) and state-level migration status. Logistic regression analysis estimated the relationship between maternal and state-level migration status, maternal and infant factors, and the risk of prematurity and low birth weight. Women who were born in Mexico had less education and use of prenatal care than US-born, Mexican-origin women but also fewer preterm or low birth weight infants. After adjusting for maternal and infant characteristics, women who were born and resided in Mexico at delivery were 37–64 % less likely to deliver preterm or low birth weight infants, and women who were born in Mexico and resided in the US had a 20–21 % lower risk as compared to women who were born and resided in the same US state. Women who delivered in states with a higher proportion of Mexican-origin mothers were slightly more likely to deliver a preterm infant and slightly less likely to give birth to a low birth weight infant. These findings support the perinatal advantage of Mexican-born women and provide evidence that both individual- as well as state-level migration factors influence perinatal outcomes.     

Racial Disparity in Infant and Maternal Mortality: Confluence of Infection,and Microvascular Dysfunction

OBJECTIVES: Racial disparities in infant and maternal mortality have been attributed to the unique stresses faced by Black women in the United States, but the underlying pathophysiological pathways are poorly understood. This paper reviews the literature related to potential causes of racial disparities in infant and maternal mortality. METHODS: A review of the literature from 1966 to 2003 was conducted using a series of searches of Medline, obstetrical journals, and bibliographies. The review focused on potential contributing pathophysiological factors to infant and maternal mortality. RESULTS: Racial disparities in neonatal mortality largely result from excess rates of preterm birth, fetal growth restriction, and neonatal sepsis while racial disparities in maternal mortality reflect greater prevalence and/or severity of cardiovascular/preeclamptic complications, hemorrhage, and infection among African American women. A large body of epidemiological, placental, and pathophysiological evidence suggests that racial disparities in these disparate outcomes result from two distinct, but potentially converging, pathways: infection and vascular. Racial disparities in intrauterine infection and microvascular dysfunction during pregnancy may result from a constellation of environmental and intergenerational risk factors including psychosocial stress, douching, bottle-feeding, lead exposure, diet, intrauterine growth, and genes. CONCLUSIONS: Disparities in infant and maternal mortality appear to reflect a confluence of infections and microvascular dysfunction during pregnancy among African American women. Interventions that target these conditions offer promise for reducing racial disparities in these critical outcomes.     

Does evidence of inflammation on Papanicolaou smears of pregnant women predict preterm labor and delivery?

BACKGROUND: Preterm delivery is the most common cause of neonatal morbidity and mortality in the United States. There is evidence that cervicovaginal infection could predispose to preterm labor. This study explored a possible association of evidence of inflammation on an otherwise normal Papanicolaou smear obtained during pregnancy with subsequent preterm labor and preterm delivery. METHODS: Using a retrospective matched cohort design, we studied women who gave birth to live singleton infants at the University of Missouri Hospital and Clinics during a 21-month period. Papanicolaou smears were obtained from 1 to 8 months before delivery and were interpreted in the same cytopathology laboratory. Data pertaining to outcome variables and potential confounding variables were collected from hospital charts. RESULTS: Incidence rates were 14.4 percent for labor < 37 weeks' gestation (preterm labor), 12.3 percent for hospitalization for preterm labor, 9.9 percent for delivery < 37 weeks (preterm delivery), 2.6 percent for delivery < 34 weeks, and 7.5 percent for birth weight < 2500 g. On univariate and multivariate analyses, there were no significant differences in any outcome between the 293 women with inflammation and the 284 women without inflammation on Papanicolaou smear. Results were unchanged when the analysis was limited to the 412 women who received no antibiotics during pregnancy. Among the 38 women with a history of preterm labor or preterm delivery, those with cervical inflammation had a higher rate of preterm labor than those without inflammation. CONCLUSIONS: In the sample as a whole, there was little evidence that findings of inflammation on Papanicolaou smear constituted a risk factor for preterm labor or preterm delivery. The data suggest that inflammation could be associated with an increased risk in a subgroup of women at higher risk by virtue of their obstetric history.     

A cohort study found that white blood cell count and endocrine markers predicted preterm birth in symptomatic women

OBJECTIVE: This cohort study investigated potential clinical and biochemical predictors of subsequent preterm birth in women presenting with threatened preterm labor. STUDY DESIGN AND SETTING: Subjects were 218 pregnant women admitted to hospital with a diagnosis of threatened preterm labor at 22-36 weeks gestation. Exclusion criteria were multiple pregnancy, fetal anomalies, diabetes mellitus, abruptio placenta, preeclampsia, intrauterine growth restriction, cervical dilatation > 4 cm, and clinical signs of infection. Analyses used logistic regression. RESULTS: The presence of ruptured membranes was the best predictor of birth within 48 hours. Other important predictors were maternal white blood cell count at 22-27 weeks gestation and maternal adrenocorticotropin and corticotropin-releasing hormone concentrations at 28-36 weeks gestation. CONCLUSION: Subclinical infection may be an important etiologic factor in preterm births of gestational age < 28 weeks. For those at > or = 28 weeks gestation, the findings support the etiologic role of activation of the fetal and/or maternal hypothalamic pituitary adrenal axis leading to preterm birth.     

Severe acute malnutrition in very low birth weight preterm infants

Malnutrition in preterm low birth weight infants has adverse long-term metabolic, growth, and neurodevelopmental effects. In the past 3 decades, parenteral nutrition, enriched preterm formula, and fortification of human milk have been used to alleviate these adverse effects. Unfortified human breast milk does not provide sufficient nutrients for the growth and development of preterm infants at the volumes recommended; however, it is usually the only source of nutrition available for such infants in low-resource countries. Many newborns, including very low birth weight infants, are surviving in these countries because of concerted efforts to achieve the fourth millennium development goal. These efforts have not addressed the nutrition needs of sick preterm very low birth weight infants. The authors report 3 cases of severe acute malnutrition in very low birth weight newborns and suggest possible interventions.     

The need for maternal zinc supplementation in developing countries: an unresolved issue

Maternal zinc deficiency during pregnancy has been related to adverse pregnancy outcomes. Most studies in which pregnant women have been supplemented with zinc to examine effects on pregnancy outcome have been carried out in industrialized countries and the results have been inconclusive. This review discusses preliminary findings of eight randomized, controlled intervention trials performed recently in less-developed countries. It is based on evidence presented by investigators and discussed during a workshop held in Wageningen, The Netherlands in June 2001. Preliminary findings from these studies indicate maternal zinc supplementation has a beneficial effect on neonatal immune status, early neonatal morbidity and infant infections. With respect to labor and delivery complications, gestational age at birth, maternal zinc status and health and fetal neurobehavioral development, evidence is conflicting and more research is required. Data currently available do not support the hypothesis that maternal zinc supplementation promotes intrauterine growth. Thus despite the emerging evidence for a positive effect of zinc on some outcomes of pregnancy, the workshop concluded that the full results of studies carried out need to be known and that more research is required to determine the benefits of large-scale introduction of zinc supplementation of pregnant women in less-developed countries.     

Weight of all births and infant mortality.

Birth weight is the most important determinant of perinatal and infant mortality. The lowest mortality rates in the first week of life are recorded among newborn infants weighing 3500 g or more and the proportion of such infants may be regarded as a measure of optimality of the birth population. There is an inverse relationship between the proportion of heavy newborn infants in a country and its infant mortality rate. In both these respects Iceland, Norway, and Sweden have better experience than England and Wales, Denmark, and the United States of America. The effects of parity, maternal age, social class, and smoking are considered, but it appears that there are still factors that inhibit the intrauterine growth potential of American, British, and Danish fetuses. Elective delivery, use of diuretics, and restriction of diet in pregnancy have shifted the birth distribution to the left and this may have more than counterbalanced the possible beneficial effects. These other factors may adversely affect birthweight distribution in North America and Europe to such an extent as to limit or even damage the favourable position already achieved in health and social development as measured by fetal survival.     

Body Composition of Infants Born with Intrauterine Growth Restriction: A Systematic Review and Meta-Analysis

Intrauterine growth restriction (IUGR) may predispose metabolic diseases in later life. Changes in fat-free mass (FFM) and fat mass (FM) may explain this metabolic risk. This review studied the effect of IUGR on body composition in early infancy. Five databases and included studies from all countries published from 2000 until August 2021 were searched. Participants were IUGR or small-for-gestational age (SGA) infants, and the primary outcomes were FFM and FM. Eighteen studies met the inclusion criteria, of which seven were included in the meta-analysis of primary outcomes. Overall, intrauterine growth-restricted and SGA infants were lighter and shorter than normal intrauterine growth and appropriate-for-gestational age infants, respectively, from birth to the latest follow up. They had lower FFM [mean difference −429.19 (p = 0.02)] and FM [mean difference −282.9 (p < 0.001)]. The issue of whether lower FFM and FM as reasons for future metabolic risk in IUGR infants is intriguing which could be explored in further research with longer follow-up. This review, the first of its kind can be useful for developing nutrition targeted interventions for IUGR infants in future.     

Infant growth patterns in the slums of Dhaka in relation to birth weight, intrauterine growth retardation, and prematurity

BACKGROUND: Relations between size and maturity at birth and infant growth have been studied inadequately in Bangladesh, where the incidence of low birth weight is high and most infants are breast-fed. OBJECTIVE: This study was conducted to describe infant growth patterns and their relations to birth weight, intrauterine growth retardation, and prematurity. DESIGN: A total of 1654 infants born in selected low-socioeconomic areas of Dhaka, Bangladesh, were enrolled at birth. Weight and length were measured at birth and at 1, 3, 6, 9, and 12 mo of age. RESULTS: The infants' mean birth weight was 2516 g, with 46.4% weighing <2500 g; 70% were small for gestational age (SGA) and 17% were premature. Among the SGA infants, 63% had adequate ponderal indexes. The mean weight of the study infants closely tracked the -2 SD curve of the World Health Organization pooled breast-fed sample. Weight differences by birth weight, SGA, or preterm categories were retained throughout infancy. Mean z scores based on the pooled breast-fed sample were -2.38, -1. 72, and -2.34 at birth, 3 mo, and 12 mo. Correlation analysis showed greater plasticity of growth in the first 3 mo of life than later in the first year. CONCLUSIONS: Infant growth rates were similar to those observed among breast-fed infants in developed countries. Most study infants experienced chronic intrauterine undernourishment. Catch-up growth was limited and weight at 12 mo was largely a function of weight at birth. Improvement of birth weight is likely to lead to significant gains in infant nutritional status in this population, although interventions in the first 3 mo are also likely to be beneficial.     

Preterm singleton births--United States, 1989-1996

Preterm birth (birth at <37 completed weeks of gestation) is the second leading cause of neonatal mortality in the United States. Preterm birthrates differ by race; in 1996, black infants were 1.8 times more likely than white infants to be preterm. From 1989 through 1996, the overall rate of preterm birth (per 1000 live-born infants) increased 4%, and the rate of multiple births (e.g., twins, triplets, or other higher-order births) increased 19%. Multiple births are associated with preterm birth; trends in preterm births independent of the influence of multiple births have not been fully explored. To characterize race- and ethnicity-specific trends in preterm birth independent of multiple births, data from U.S. birth certificates for 1989-1996 were analyzed for singleton births only. This report summarizes the results of this analysis and indicates that although singleton preterm birthrates are stable overall, substantial changes in rates occurred in some racial/ethnic subgroups.     

Invited commentary: disaggregating preterm birth to determine etiology

Identifying the causes of preterm birth has been problematic, in part because of heterogeneous pathways leading to the same event, early delivery. If a risk factor affects only a subset of cases, then studies that address the aggregate outcome will generate diluted measures of association. McElrath et al. (Am J Epidemiol. 2008;168(9):980-989) examined an array of potential influences on very early preterm birth (<28 weeks' gestation) and divided cases on the basis of proximal causes. Through factor analysis, they found empirical support for dividing preterm cases into 2 groups: intrauterine inflammation (preterm labor, preterm membrane rupture, placental abruption, and cervical insufficiency) and abnormal placentation (preeclampsia and intrauterine growth restriction). Replication of this classification in less extreme preterm births is needed, requiring large numbers of preterm births that have been characterized in detail. Nonetheless, this division is worthy of study by using previously collected data to determine whether, in fact, stronger associations are found for these subsets than for preterm birth in the aggregate. Ultimately, the test of the approach is in improving our understanding of etiology, ideally generating stronger, more consistent associations with preterm birth subsets than have been found for preterm birth in the aggregate.     

Predictors of Preterm Births and Low Birthweight in an Inner-City Hospital in Sub-Saharan Africa

Adverse birth outcomes remain significant contributors to perinatal mortality as well as developmental disabilities worldwide but limited evidence exists in sub-Saharan Africa based on a conceptual framework incorporating neighborhood context. This study therefore set out to determine the prevalence and risk factors for preterm births and low birthweight in an urban setting from this region. A cross-sectional study of all live births from May 2005 to December 2007 in an inner-city maternity hospital in Lagos, Nigeria. Factors predictive of preterm births and low birthweight were determined by unconditional multivariable logistic regression within a conceptual framework for adverse birth outcomes. Population attributable risk (PAR%) for each factor was also determined. Of the 4,314 newborns enrolled, 859 (19.9%) were preterm and 440 (10.2%) were low birthweight. One-third of mothers received no antenatal care while about 6% had HIV and another 6% had a history of hypertensive disorders. About 43% of the low birthweight infants were born full term. Maternal predictors of preterm delivery and/or low birthweight were marital status, occupation, residential accommodation with shared sanitation facilities, lack of antenatal care, absence of previous cesarean section, hypertensive disorders and antepartum hemorrhage. Gender and intrauterine growth restriction (IUGR) were also predictive of low birthweight. IUGR (PAR = 48.74%) and lack of prior cesarean section (PAR = 41.99%) were the leading contributors to preterm birth and/or low birthweight. The burden of preterm and low birthweight deliveries in this setting is associated with modifiable individual and neighborhood-level risk factors that warrant community-oriented public health interventions.     

Interpregnancy interval and risk of preterm labor

In 1977-1980, over 12,000 pregnant women being followed at the Boston Hospital for Women were interviewed and had their medical records reviewed. The effect of interpregnancy interval on the risk of preterm labor was estimated in 4,467 of these women whose previous pregnancy had resulted in a full-term live birth. The rate of preterm birth after the spontaneous onset of labor in this cohort was 3.8 percent. While the possibility of an increased risk of preterm labor for interpregnancy intervals of 3 months or less cannot be definitely excluded (adjusted odds ratio = 2.0, 95 percent confidence interval 0.7-5.4), no relation was found between other interpregnancy intervals and the risk of preterm labor. Earlier work from this same cohort showed a strong negative association between interpregnancy interval and small-for-gestational-age birth. Combining this with the results from the present study reinforces the importance of differentiating low birth weight due to preterm birth from that due to intrauterine growth retardation.