SeriesBiological and pathological mechanisms leading to the birth of a small vulnerable newborn
Introduction
Embedded in the UN's Sustainable Development Goals is a roadmap to break the cycle of poverty and disadvantage perpetuated by poor health in childhood and adolescence giving rise to vulnerable pregnancy and infancy. In this Series, we examine the vulnerability conferred by small size at birth resulting from growth restriction or preterm birth. We cover the prevalence, causes, consequences, and possible routes to prevention, either by accelerating existing strategies or considering new approaches.1, 2, 3, 4 Approximately a quarter of infants worldwide are born either preterm, small-for-gestational-age (SGA), or both.2 40% of global neonatal mortality occurs in preterm infants and 28% occurs in infants who are SGA born at term.2
Despite global attention and targets set for reducing the prevalence of the small vulnerable newborn, there has been little change in the past 10 years.2 The slow progress can be attributed in part to gaps in our common understanding of the mechanisms controlling fetal growth and gestational duration. Multiple, often interacting risk factors contribute to poor health in women both before and during pregnancy (panel 1). However, connecting risk factors to the biological processes leading to preterm birth and growth restriction remains a challenge. For some of the most prevalent risk factors, the relationship with causal mechanisms could be indirect. For example, maternal iron deficiency anaemia is the largest global population-attributable risk factor for spontaneous preterm and SGA births;43, 44 however, iron supplementation (which reduces maternal anaemia by 70%) has not reduced the prevalence of these outcomes in most contexts.45 A similar conundrum is the global prevalence of bacterial vaginosis and its association with spontaneous preterm birth; 25 years of trials with antibiotics during pregnancy show that treatment can reduce the prevalence of bacterial vaginosis but not the risk of spontaneous preterm birth.46, 47
Within the Series, this article reviews the pathway to the birth of a healthy thriving newborn to provide a framework to describe factors that can affect this pathway. Knowledge of these mechanisms is incomplete; however, new information is constantly emerging, often from disciplines outside of mammalian reproduction and development. Novel concepts emerging from randomised controlled trials, animal models, observational studies, and laboratory work that recapitulate mechanisms in vitro have enabled connections to be made with biological mechanisms to explain why some strategies for prevention are effective and some require new approaches. This paper will show that considering preterm birth and growth restriction together is useful because many risk factors can contribute to both, albeit via different pathways. Context-specific, targeted, and even personalised intervention strategies to prevent preterm and SGA births are possible and will probably bring improved health to the next generation.
Section snippets
Born at the right size but how?
Factors influencing the growth and development of the fetus change during the course of pregnancy. The first crucial period begins around the time of conception and ends at implantation. At this stage, the embryo can sense the concentrations of nutrients in the surrounding fluids and calibrate metabolic processes to compensate for over-abundance in the case of maternal obesity or paucity in the case of undernutrition.48 The subsequent adaptations in embryonic gene expression and regulation can
Born at the right time
Pregnancy is maintained by progesterone-mediated suppression of the processes of labour and by an impenetrable cervix (figure 2). Progesterone inhibits the production of components involved in receiving signals to prepare the uterus for labour, such as the oestrogen and oxytocin receptors. In most mammals, plasma progesterone concentrations decrease towards the end of pregnancy. By contrast, levels remain high throughout human pregnancy, even during labour. Activation of labour systems is
Good nutrition supports more than just growth
The effect of maternal nutrition before and during pregnancy is now understood to extend well beyond birth and childhood into the life courses of future generations.48, 73 Physiological changes in pregnancy enable women to meet the increased demand for energy, nutrients, and oxygen to supply to the growing fetus (panel 2). However, women who begin a pregnancy before having reached their own biological growth potential due to chronic undernourishment, young age, or both, are at increased risk of
Infectious threats to the fetus
Microbial infections in pregnant women are major contributors to preterm birth, growth restriction, stillbirth, and infection in newborns. Screening for and treating infections in pregnant women has well established positive effects and there is a need for wider coverage for syphilis, chlamydia, gonorrhoea, HIV, and malaria. However, even in parts of the world where the prevalence of these infections is low, the majority of spontaneous preterm birth—that is, preterm birth preceded by labour or
Cervical shortening and preterm birth
When a woman's cervix shortens in the course of pregnancy, there is an increased risk of preterm birth. The reason why cervical shortening occurs in some women is not known, but it is associated with the premature expression of proteins involved in the recruitment of monocytes and neutrophils, which could lead to the premature destruction of collagen and loss of integrity.113 As a key hormone responsible for maintaining pregnancy, progesterone might be able to disrupt this process. Progesterone
Pre-eclampsia, fetal growth restriction, and preterm birth
Impediments to implantation and early placental development result in miscarriage. However, minor issues often remain silent until around mid-gestation when the fetus overtakes the placenta in size. At this time, minor inadequacies in placental size, patterning, or maternal blood supply can result in an inability to meet the requirements for the growth and development of the fetus. For reasons that are not completely understood, one of the most common signs that there are supply-and-demand
Changing social and environmental contexts
Some subgroups of pregnant women, such as smokers, primigravidae, secundigravidae, teenagers, and women with low BMI (<18·5 kg/m2), tend to respond more favourably to nutrient supplementation or preventive treatment of infections, reducing the risk of delivering small and vulnerable newborns. However, this response does not justify the exclusive use of these interventions strategies to reduce the prevalence of small vulnerable newborns. Increased antenatal contacts afford opportunities to
What can be done? The foreground and the horizon
Knowledge of the mechanisms that lead to the birth of a small vulnerable newborn continues to grow as well as our understanding of how to intervene to reduce or prevent this outcome. In the short term, increasing the quantity and quality of antenatal contacts with health-care providers affords the opportunity to monitor and support physical (weight gain, fetal growth, and prevention and treatment of pregnancy complications) and psychological (mental health, agency) wellbeing. Reductions in
Declaration of interests
PA reports a grant from the Children's Investment Fund Foundation in support of the preparation of this manuscript (grant number 2004-04635). ALD is an unpaid Scientific Trustee of Tommy's Charity. CPD reports grant support from WHO, the US Agency for International Development, and National Institutes of Health (NIH; P30 DK040561); royalties from UpToDate; and grant support on behalf of his institution from Takeda and the American Society for Nutrition in work unrelated to this paper. UR
References (150)
- et al.
Maternal anemia and risk of adverse birth and health outcomes in low- and middle-income countries: systematic review and meta-analysis
Am J Clin Nutr
(2016) - et al.
Short maternal stature increases risk of small-for-gestational-age and preterm births in low- and middle-income countries: individual participant data meta-analysis and population attributable fraction
J Nutr
(2015) - et al.
Burden, pathology, and costs of malaria in pregnancy: new developments for an old problem
Lancet Infect Dis
(2018) - et al.
Asymptomatic bacterial vaginosis and intermediate flora as risk factors for adverse pregnancy outcome
Best Pract Res Clin Obstet Gynaecol
(2007) - et al.
Gestational diabetes mellitus and lesser degrees of pregnancy hyperglycemia: association with increased risk of spontaneous preterm birth
Obstet Gynecol
(2003) - et al.
Association of maternal thyroid function with birthweight: a systematic review and individual-participant data meta-analysis
Lancet Diabetes Endocrinol
(2020) - et al.
A systematic review and meta-analysis of prospective studies on the association between maternal cigarette smoking and preterm delivery
Am J Obstet Gynecol
(2000) - et al.
Effects of cocaine use during pregnancy on low birthweight and preterm birth: systematic review and metaanalyses
Am J Obstet Gynecol
(2011) - et al.
Early clindamycin for bacterial vaginosis in pregnancy (PREMEVA): a multicentre, double-blind, randomised controlled trial
Lancet
(2018) - et al.
Origins of lifetime health around the time of conception: causes and consequences
Lancet
(2018)
Carbohydrate and lipid metabolism in pregnancy: normal compared with gestational diabetes mellitus
Am J Clin Nutr
Adipokines in gestational diabetes
Lancet Diabetes Endocrinol
Comparative newborn anthropometric data in symmetric versus asymmetric intrauterine growth retardation
Am J Obstet Gynecol
Cervical leukocytes and spontaneous preterm birth
J Reprod Immunol
Endocrinology of human parturition
Ann Endocrinol (Paris)
The International Federation of Gynecology and Obstetrics (FIGO) recommendations on adolescent, preconception, and maternal nutrition: “Think Nutrition First”
Int J Gynaecol Obstet
Respiratory function in singleton and twin pregnancy
BJOG
Suppression of cytotoxic T-lymphocyte activity during human pregnancy
J Reprod Immunol
Modifiers of the effect of maternal multiple micronutrient supplementation on stillbirth, birth outcomes, and infant mortality: a meta-analysis of individual patient data from 17 randomised trials in low-income and middle-income countries
Lancet Glob Health
Maternal height and the risk of preterm birth and low birth weight: a systematic review and meta-analyses
J Obstet Gynaecol Can
Maternal blood mitochondrial DNA content during normal and intrauterine growth restricted (IUGR) pregnancy
Am J Obstet Gynecol
Oxidative stress
Best Pract Res Clin Obstet Gynaecol
Compartmental analyses of plasma n-3 essential fatty acids among male and female smokers and nonsmokers
J Lipid Res
The effect of omega-3 supplementation on pregnancy outcomes by smoking status
Am J Obstet Gynecol
Small vulnerable newborns—big potential for impact
Lancet
Small babies, big risks: global estimates of prevalence and mortality for vulnerable newborns to accelerate change and improve counting
Lancet
Evidence-based antenatal interventions to reduce the incidence of small vulnerable newborns and their associated poor outcomes
Lancet
The ethical imperative to prevent small and vulnerable newborns and stillbirths: essential and urgent country actions to improve the global response
Lancet
Zinc supplementation for improving pregnancy and infant outcome
Cochrane Database Syst Rev
Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems
Cochrane Database Syst Rev
Maternal underweight and the risk of preterm birth and low birth weight: a systematic review and meta-analyses
Int J Epidemiol
Gestational weight gain across continents and ethnicity: systematic review and meta-analysis of maternal and infant outcomes in more than one million women
BMC Med
Association between maternal HIV infection and low birth weight and prematurity: a meta-analysis of cohort studies
BMC Pregnancy Childbirth
Reported estimates of adverse pregnancy outcomes among women with and without syphilis: a systematic review and meta-analysis
PLoS One
Chlamydia trachomatis and adverse pregnancy outcomes: meta-analysis of patients with and without infection
Matern Child Health J
Adverse pregnancy and neonatal outcomes associated with Neisseria gonorrhoeae: systematic review and meta-analysis
Sex Transm Infect
Urinary tract infections in pregnancy
Clin Microbiol Infect
Trichomonas vaginalis associated with low birth weight and preterm delivery
Sex Transm Dis
Preterm birth associated with group b streptococcus maternal colonization worldwide: systematic review and meta-analyses
Clin Infect Dis
The associations of parity and maternal age with small-for-gestational-age, preterm, and neonatal and infant mortality: a meta-analysis
BMC Public Health
The associations of birth intervals with small-for-gestational-age, preterm, and neonatal and infant mortality: a meta-analysis
BMC Public Health
The distribution of clinical phenotypes of preterm birth syndrome: implications for prevention
JAMA Pediatr
Placental and clinical characteristics of term small-for-gestational-age neonates: a case-control study
Pediatr Dev Pathol
The length of the cervix and the risk of spontaneous premature delivery
N Engl J Med
Obstetric complications in women with congenital uterine anomalies according to the 2013 European Society of Human Reproduction and Embryology and the European Society for Gynaecological Endoscopy Classification: a systematic review and meta-analysis
Obstet Gynecol
Endometriosis and adenomyosis are associated with increased risk of preterm delivery and a small-for-gestational-age child: a systematic review and meta-analysis
Acta Obstet Gynecol Scand
Maternal and perinatal outcomes of twin pregnancy in 23 low- and middle-income countries
PLoS One
Associations of unintended pregnancy with maternal and infant health outcomes: a systematic review and meta-analysis
JAMA
Intimate partner violence during pregnancy and the risk for adverse infant outcomes: a systematic review and meta-analysis
BJOG
Socioeconomic inequalities and adverse pregnancy outcomes in the UK and Republic of Ireland: a systematic review and meta-analysis
BMJ Open
Cited by (12)
Accelerating the progress of low birthweight reduction
2024, The LancetInfections and Acute Kidney Injury: A Global Perspective
2024, Seminars in NephrologySmall vulnerable newborns—big potential for impact
2023, The LancetGrowth patterns of preterm and small for gestational age children during the first 10 years of life
2024, Frontiers in Nutrition
- *
Members listed at the end of the paper