Elsevier

The Lancet

Volume 391, Issue 10132, 5–11 May 2018, Pages 1842-1852
The Lancet

Series
Origins of lifetime health around the time of conception: causes and consequences

https://doi.org/10.1016/S0140-6736(18)30312-XGet rights and content

Summary

Parental environmental factors, including diet, body composition, metabolism, and stress, affect the health and chronic disease risk of people throughout their lives, as captured in the Developmental Origins of Health and Disease concept. Research across the epidemiological, clinical, and basic science fields has identified the period around conception as being crucial for the processes mediating parental influences on the health of the next generation. During this time, from the maturation of gametes through to early embryonic development, parental lifestyle can adversely influence long-term risks of offspring cardiovascular, metabolic, immune, and neurological morbidities, often termed developmental programming. We review periconceptional induction of disease risk from four broad exposures: maternal overnutrition and obesity; maternal undernutrition; related paternal factors; and the use of assisted reproductive treatment. Studies in both humans and animal models have demonstrated the underlying biological mechanisms, including epigenetic, cellular, physiological, and metabolic processes. We also present a meta-analysis of mouse paternal and maternal protein undernutrition that suggests distinct parental periconceptional contributions to postnatal outcomes. We propose that the evidence for periconceptional effects on lifetime health is now so compelling that it calls for new guidance on parental preparation for pregnancy, beginning before conception, to protect the health of offspring.

Introduction

The notion that maternal physiology, body composition, diet, and lifestyle during pregnancy have profound and enduring effects on the long-term health of the offspring, and disease risk into adulthood, has received strong evidential support across the epidemiological, medical, and basic science fields.1, 2, 3 Thus, the Developmental Origins of Health and Disease concept has emerged,3 suggesting that poor developmental experience can increase the risk of non-communicable diseases in later life, including cardiovascular and metabolic comorbidities (such as hypertension, obesity, and type 2 diabetes), atopic conditions, cancer, and neurological impairment. Research into the concept has focused on the time during pregnancy when the conceptus is most vulnerable to adverse influences, thereby informing targeted protection and possible intervention. Increasing evidence points to the importance of the time around conception, known as the periconceptional period.

This Series paper focuses on four broad periconceptional environmental exposures shown to adversely affect humans and animal models (figure 1), and discusses mechanistic causes and consequences. We also report a meta-analysis on the relative contributions of maternal and paternal factors on long-term periconceptional influences, in an established low protein diet model of parental undernutrition.

Section snippets

Periconceptional developmental conditioning

The periconceptional period has been variously defined, but for the Developmental Origins of Health and Disease concept the key events broadly cover the completion of meiotic maturation of oocytes, differentiation of spermatozoa, fertilisation, and resumption of mitotic cell cycles in the zygote, marking the transition from the parental to the embryonic genome,4 and the onset of morphogenesis up to implantation.5 This process represents a period of a few weeks, depending on the mammalian

Periconceptional developmental conditioning through maternal overnutrition and obesity

The global rise in maternal obesity is associated with reduced female fertility and heightened risk of obesity in the offspring.2 The adverse effects of high maternal body-mass index (BMI) on the offspring could reflect elevated maternal glucose and insulin concentrations, which drive fetal growth and adiposity (resulting in increased birth and childhood weight), but might also include shared life-style factors within families.8 Impaired metabolism in offspring might also be associated with

Human studies

Poor nutrition in utero and low birthweight remain highly prevalent in low-income and middle-income countries, and are associated with increased risks of chronic diseases in later life across diverse human populations, particularly if followed by accelerated weight gain during infancy.1, 3 Similar human cardiometabolic and neurological consequences arise from maternal exposure to famine, for example, the Dutch Hunger Winter of 1944–45. In human studies it is difficult to pinpoint gestational

Paternal origin of periconceptional developmental programming

Although the connection between a mother's diet and the long-term health of her offspring has been studied in detail, understanding of how a father's diet impacts his offspring remains limited. However, links are emerging between paternal lifestyle, sperm quality, and impaired offspring health.11 Here, both direct (sperm quality, epigenetic status, DNA integrity) and indirect (seminal fluid composition) paternal mechanisms have been identified; in mice these mechanisms have been shown to affect

Defining the parental contribution to periconceptional developmental effects

Shared maternal and paternal dietary and lifestyle influences could potentially combine for greater impact on periconceptional development. However, most research models to date are uniparental in design, and the combined effects of both parents are unknown. Whether the impact of poor paternal diet on offspring development and wellbeing is of equivalent importance to that of poor maternal diet is also unknown. We did a meta-analysis of our mouse maternal and paternal LPD diet models, using

Periconceptional developmental programming and assisted reproductive treatment

Direct evidence for human periconceptional effects comes from assisted reproductive treatments, during which mature gametes, and the preimplantation embryo, are exposed to precisely timed in-vitro manipulations. Several million, apparently healthy, children have now been born worldwide using assisted reproductive treatments, but relatively little is known about the possible impact of the technology-associated exposures during conception and very early development on their health status during

Diversity and commonality in periconceptional effects

The evidence reviewed previously suggests that periconceptional experience can induce lifelong changes in phenotype, affecting disease risk. Beyond these nutritional and assisted reproductive treatment conditions, studies in rodents show broad examples of periconceptional effects, such as from maternal stress.88 Moreover, maternal alcohol consumption exclusively around conception induced metabolic dysfunction in rat adult offspring with evidence of epigenetic disturbance.89 Maternal systemic

Conclusion

We propose that there is sufficient evidence from human and animal research showing that the periconceptional period is a key window during which poor maternal and paternal physiology, body composition, metabolism, and diet can induce increased risk of chronic disease in offspring—a lifetime legacy and major driver of health burden in the 21st century. The evidence that similar consequences can result from assisted reproductive treatment practices sharpens the focus on this window.

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