Developmental Origins of Health and Disease

Barker et al proposed a correlation in the 1980s between low birth weight and increased rate of death by cardiovascular disease. Dr Barker’s team analysed records kept at Sheffield (1907-1925) and Hertfordshire (1911-1930) hospitals, looking at neonate weight, length and placental features. These children were then correlated with later death records to determine the outcome. It was found, by looking at records for 1586 men in Sheffield and 5654 men in Hertfordshire, that small for gestational age babies were approximately three times more likely to die of cardiovascular disease than normal and larger babies. Later developments have linked other metabolic disorders such as type 2 diabetes, high blood pressure and syndrome X to low birth weight. There have been further links to mental health disorders such as anxiety, depression and schizophrenia.

How does Intrauterine Growth Restriction (IUGR) occur?

The developmental origins of health and disease are thought to be associated with small for gestational age babies. This occurs as a result of intrauterine growth restriction (IUGR), also known as fetal growth restriction (FGR). IUGR arises when the baby does not receive enough nutrition via the placenta and consequently does not achieve its genetically determined growth potential. It is not fully understood what restricts the nutritional supply, but the placenta is widely believed to be a key factor in a number of cases. Defining IUGR can vary, but often the key measurements taken are head circumference, femur length and abdominal circumference. It is also possible to use the ponderal index (weight/length3) to help assess development. Should these measurements fall in the lowest percentiles, the baby is classed as small for gestational age. It is also important to take into account maternal and paternal body shape and history, for example, small parents will be more likely to have a genetically small baby.

The development of IUGR has many factors, some of which are still to be understood and identified. The action of glucocorticoids (cortisol) and the stimuli which increase their activity may be one such example linked to IUGR. These stimuli may include diet (where by certain foods inhibit 11βHSD2 in the placenta) and stress (which increases maternal production of glucocorticoids). Fetal glucocorticoid levels naturally increase towards the end of pregnancy and is believed to be one trigger of parturition. However early increases in glucocorticoids is thought to increase the risk of preterm birth and have developmental impacts on the fetus such as on lung surfactant production and brain structure.

Poor implantation has been linked to both IUGR and preeclampsia. Preeclampsia is a pathological condition that affects approximately 5% of pregnancies and typically arises during the second trimester of pregnancy. It is characterised by proteinuria, high blood pressure (>140/90), fluid retention and can result in seizures. Preeclampsia is a result of a systemic inflammatory response, the exact mechanisms of which are still unclear. However, the placenta has been implicated in the pathophysiology of preeclampsia. The only treatment currently available is emergency caesarean of the placenta and baby. Clearly, a medical advancement here would improve outcomes for mother and fetus. IUGR may or may not occur along side preeclampsia. Poor implantation may disrupt placental function, as failure to implant deeply enough into the decidua means the spiral arteries, supplying blood to the uterus, will not be remodelled sufficiently (Figure 1). Consequently an insufficient supply of blood flows into the intervillous space. Alternatively, blood could enter the placenta too early and expose the syncytiotrophoblast (maternal-fetal exchange barrier) to oxidative stress, or enter at too high a pressure which would also cause damage and disrupt function.

 

Figure 1. Spiral Artery Remodelling During Pregnancy



Certain genes of the mother will not be expressed in favour of the paternal genes and vice versa. This process is known as gene imprinting. Should the expressed gene be a mutant variant or imprinting was unsuccessful, IUGR could arise. One such gene is IGF-2, which is only expressed by the paternal allele, and has been identified as a key regulator of placental and fetal growth. IGF-2 is sensitive to a number of silencers and has also been identified as being reduced by glucocorticoids in later pregnancy. This could suggest that earlier exposure to glucocorticoids could reduce IGF-2. Therefore, errors in silencing IGF-2 could contribute to developmental problems.

The syncytiotrophoblast of the placenta (Figure 2) is the specialised transporting epithelia responsible for controlling solute transport between mother and fetus. This is facilitated by many specific transporters located on the microvillous and basement membranes. All these factors, imprinting, poor implantation, can accumulate and contribute to decreased expression of transporters, reducing the nutrients that can be made available to the developing fetus. The effect of this restricted in-take can affect the fetus in different ways depending on when, during the pregnancy, it arises. Currently we can only identify 'at-risk pregnancies' of developing IUGR babies or preeclampsia. This may be through uterine artery Doppler to determine the blood flow in the placenta. There has been some progress in utilising blood tests for certain pro and anti-angiogenic factors such as sFT1:PlGF ratio. Understanding the normal physiology of the syncytiotrophoblast is a vital step in the understanding of how it becomes disordered in pregnancy pathology and the potential for developing treatments.

Figure 2. Syncytiotrophoblast Layer of the Human Placenta



How does low birth weight increase the risk of adult life pathology?

We are still trying to understand the links between low birth weight and adult life pathology. Barker’s initial theory assessed how the way in which birth weight was distributed could predispose to different metabolic disorders. He also identified that it was particularly being small for the gestational age rather than preterm babies that predisposes to adult pathology. It is hypothesised that through restricting nutrients to the fetus, energy is diverted to the most vital organs such as brain and heart from organs which are not functional while in the womb, such as the kidneys.

Recent hypotheses have been investigated using models of IUGR. Schreuder (2007) looked at the nephron numbers of pups from IUGR pregnancies and found that they were significantly lower compared to the pups of normal pregnancies. Lower nephron numbers has been one of the highly supported hypotheses related to the development of 1˚ hypertension. Low nephron numbers is thought to lead to glomerular sclerosis which further exacerbates 1˚ hypertension.

A further hypothesis is the mismatch of pre and post natal environment. This includes the first three years of development. This is because our responses to environment remain plastic – able to adapt to change. It has been suggested that when the fetus is exposed to low nutrient supply in utero, it adapts to utilizing what it receives in the most energy efficient way. When this is mismatched with a nutrient-rich environment following birth, predisposition to metabolic disorders occurs.

There is also epigenetics to consider, where in utero conditions can affect gene imprinting. This can be through chemicals or nutrient levels altering the methylation of DNA bases, modification of histone tails and transcription factor activity. Understanding how our genes can be further controlled in utero may help reverse the damage IUGR causes to genetic imprinting. One in vitro study demonstrated that protein restriction resulted in hypomethylation of the glucocorticoid receptor and PPARγ (peroxisomal proliferator-activated receptor) promoter within mural hepatocytes. The increased expression of these genes can lead to cardiovascular disease and dyslipidaemia in later life. Lillycrop et al (2005) also identified that this epigenetic change could be reversed by supplementing the maternal diet with folic acid.

Studies such as that by Lillycrop et al (2005) highlight how it may be possible to improve the fetal outcome through supplemented diet. However, looking for ways in which to improve placental function and understanding the physiology of solute transport in healthy and abnormal pregnancies will be vital for treating IUGR and preeclampsia.

References

Avagliano L., Garò C.& Marconi A.M. 2012, 'Placental Amino Acids Transport In Intrauterine Growth Restriction', J Pregnancy, 2012, , p. 972562.

Barker D.J. 1993, 'The Intrauterine Origins Of Cardiovascular Disease', Acta Paediatr Suppl, 82 Suppl 391, , p. 93-9; discussion 100.

Benirschke k., Kaufmann P.& Baergen R. 2006, Pathology Of The Human Placenta, , 5th, Springer New York, . p. 1050.

Fowden A.L., Sibley C., Reik W. et al. 2006, 'Imprinted Genes, Placental Development And Fetal Growth', Horm Res, 65 Suppl 3, , pp. 50-58.

Harris L.K. 2010, 'Review: Trophoblast-Vascular Cell Interactions In Early Pregnancy: How To Remodel A Vessel.', Placenta, 31 Suppl, , p. S93-8.

Lillycrop K.A., Phillips E.S., Jackson A.A. et al. 2005, 'Dietary Protein Restriction Of Pregnant Rats Induces And Folic Acid Supplementation Prevents Epigenetic Modification Of Hepatic Gene Expression In The Offspring', J Nutr, 135, , pp. 1382-1386.

Lillycrop K.A. 2011, 'Effect Of Maternal Diet On The Epigenome: Implications For Human Metabolic Disease', Proc Nutr Soc, 70, , pp. 64-72.

Sharmin S., Guan H., Williams A.S. et al. 2012, 'Caffeine Reduces 11Β-Hydroxysteroid Dehydrogenase Type 2 Expression In Human Trophoblast Cells Through The Adenosine A(2B) Receptor', PLoS One, 7, , p. e38082.

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