Elsevier

The Lancet

Volume 401, Issue 10389, 20–26 May 2023, Pages 1720-1732
The Lancet

Series
Biological and pathological mechanisms leading to the birth of a small vulnerable newborn

https://doi.org/10.1016/S0140-6736(23)00573-1Get rights and content

Summary

The pathway to a thriving newborn begins before conception and continues in utero with a healthy placenta and the right balance of nutrients and growth factors that are timed and sequenced alongside hormonal suppression of labour until a mature infant is ready for birth. Optimal nutrition that includes adequate quantities of quality protein, energy, essential fats, and an extensive range of vitamins and minerals not only supports fetal growth but could also prevent preterm birth by supporting the immune system and alleviating oxidative stress. Infection, illness, undernourishment, and harmful environmental exposures can alter this trajectory leading to an infant who is too small due to either poor growth during pregnancy or preterm birth. Systemic inflammation suppresses fetal growth by interfering with growth hormone and its regulation of insulin-like growth factors. Evidence supports the prevention and treatment of several maternal infections during pregnancy to improve newborn health. However, microbes, such as Ureaplasma species, which are able to ascend the cervix and cause membrane rupture and chorioamnionitis, require new strategies for detection and treatment. The surge in fetal cortisol late in pregnancy is essential to parturition at the right time, but acute or chronically high maternal cortisol levels caused by psychological or physical stress could also trigger labour onset prematurely. In every pathway to the small vulnerable newborn, there is a possibility to modify the course of pregnancy by supporting improved nutrition, protection against infection, holistic maternal wellness, and healthy environments.

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

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