Barkers Hypothesis

Critical review of the foetal origin of disease hypothesis

Louise Usher

David Barker CBE, born 1938, was a physician and epidemiologist. 

Prior to his death in August 2013 saw him argue the next generation do not have to suffer from diseases such as heart disease and diabetes. Rather that the diseases are not mandated by the human genome.  As such diseases were not in existence 100 years ago to the levels of the turn of the millennium, Barker hypothesised we could prevent them should we have the will to do so. 

During Barkers position in 1984 was director of Medical Research Council Environmental Epidemiology Unit (now renamed MRC Lifecourse epidemiology unit), he began to observe maps of the UK. Each county in 1910 and 1920 showed mortality rates of neonatal and post-natal correlated to 60 and 70 years later a higher death rate from coronary heart disease. 

Barker began at this stage to suggest an adverse environment within the uterus may mean chronic disease later in life. (Hanson., 2015)

2006 saw him awarded a CBE for his work. (Pincock., 2013)

Barkers hypothesis proposed in 1990 that low birth weight, premature birth and intra uterine growth retardation have a causal relationship to the origins of non-insulin dependent diabetes, hypertension and coronary heart disease in middle age.  A historical cohort study saw the hypothesis as it was derived. Significantly, an association of hypertension and coronary heart disease in middle age and low birth weight, along with premature birth was ascertained as an association. (Hanson., 2015)

Socio-economic status has a bearing on the support of the hypothesis.  Evidence from low income counties sees low birth weight and intrauterine growth retardation highly prevalent and therefore could not support this study for fear of skewed results.  In conjunction, hypertension and coronary heart disease are less prevalent by a significant number than in higher income countries. (Barker., 1986)

Barker presents the evidence within his book Fetal and infant Origins of Adult Disease (1992)  

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Universally it is known and accepted a malnourished mother will give birth to low birthweight babies (Hales et al., 2001).  As the babies mature into children often they are further undernourished (Rayhan and Khan., 2006).

The cycle of poor nutrition leads to cognitive and health issues. Hence maternal malnutrition needs to be prevented (Paneth and Susser., 1995).

The prevalence of adult onset hypertension and type 2 diabetes mellitus have been linked to a slow rate of growth in years 2-3 of childhood (Rosenbloom et al., 1999).

Seemingly there is much evidence to support Barker in his hypothesis.  However, he does not explore further into the possible other causes, for example, should a mother carry a bigger baby due to gestational diabetes, could this be a preventative for the future of the child? Possibilities are endless yet not explored currently under the hypothesis. What might make the fetus a larger born child that might have a preventative effect on the later life of the adult?  Of course, the reverse may be true. Would something to cause a lower birth weight baby cause them to be more prone to chronic disease later in life?

The Thrifty phenotype hypothesis

Hales and Barker studied the associations of increased risk of impaired glucose tolerance and the metabolic syndrome in 2001 in the Thrifty phenotype hypothesis.

Epidemiological findings are concurrent across ethnic group and populations (Hales and Barker., 2001).  Validity of these findings is therefore widely accepted as a general rule.  Debating the extent of the underlying causes posed the question of the mechanisms of causal agents.  Was this genetic or environmental? 

Rarely, genetic causes of insulin secretion are found in association with poor fetal growth yet as insulin is a major fetal growth hormone this is a difficult position to prove.  While changes in glucose metabolism may be linked to genetic polymorphisms yet this will be less conclusive than the association with lower birth weights.  Every human characteristic may possibly be suggesting within Hales and Barkers paper that type 2 diabetes mellitus resides within a mix of both genetic and environmental.  Leaving the question if a genetically disposed fetus might overcome the risk factors slightly should the environmental situation be more favorable.

This hypothesis proposes that indeed environmental factors are a dominant cause of type 2 diabetes mellitus.  Other influences have a part to play of course.  Maternal and placental factors may lead to poor fetal nutrition

(Muthayya, S., 2009) which gives rise to the under development of pancreatic beta cell mass (Garofano et al., 1998).  The islets of Langerhans vasculature may be compromised in these fetus’ according to Nielsen et al (1999), which will contribute as a key element to later life type 2 diabetes mellitus.

Should an individual continue to be poorly nourished as they grow, therefore remaining thin, the insulin secretion functional capability and capacity would not be a detrimental factor.  

Typically, within these findings, Barker and Hales concluded that fetal malnutrition led to insulin resistance.

Glucose intolerance would be triggered by obesity.  Calories imbalanced as the individual had a lower calorie expenditure, higher calorie intake and therefore gained weight.  Genes were accepted within this paper to play a part in type 2 diabetes mellitus development yet was encouraged to consider fetal growth and development.

Below, figure 1 shows 64-year-old men given a ratio for risk of development of impaired glucose tolerance or type 2 diabetes.  Figure 2 shows metabolic syndrome. However, an age is not stated so the tables are difficult to compare with the differing types of diagnoses.

Figure 3 gives a clear indication of the pathway Hales and Barker were considering for the development of the metabolic syndrome within the Thrifty phenotype.

Conclusions stated within this paper ascertained the genetic versus environmental factors were conclusive towards determining growth and development of type 2 diabetes mellitus and metabolic syndrome.  Within the conclusion Hales and Barker mention the use of identical twins with the respect to conclusively showing the importance of fetal environment.  However, this does not state in what way. Could future work lead a study considering twins of equal nutritional status in utero and yet contrasting environment to discover the development of type 2 diabetes or metabolic syndrome in later life? Hales and Barker finalized with a statement that this is a stage to consider their finding as a useful framework for further study.

Syndrome X

1993 saw Barker et al conducting studies to question the prevalence of syndrome x in lower birthweight babies, shown in table 2. Syndrome X being the development of Type 2 Diabetes mellitus, hypertension and hyperlipidaemia.  The 407 British men from Hertfordshire were born between 1920 and 1930. 

Later on, studies were performed to test the theory of correlation between lower birth weight and the incidence of Syndrome X. In the town of Preston, UK, health visitors recorded the weight of the males babies mentioned above. Between birth and one year old, details of weights were accurately kept. As 64-year-old men, revisited, these subjects who were of a birth weight of 6.5lbs or less showed a significant 22% had been diagnosed with syndrome X.  Subjects with birthweights of more than 9.5lbs showed a ten times lower risk factor.

The second study also carried out in Preston was both sexes. Between 1935 and 1943 (including the war years which may have a bearing on nutritional status of the mothers), (Winter, JM, 1983). 266 subjects were also measured and the results comparable of the original findings of Barker and Hales, (1993).

Confounding variables such as smoking, alcohol consumption and socio-economic status was an independent factor.

Those diagnosed later in life with syndrome x had small head circumferences noted and eruption of teeth was later as seen in table 1. Barker and Hales stated confidentially that syndrome x and type 2 diabetes have originated from the less favorable conditions in utero.

Interestingly, hypertension in adults rose by a mean of 15mmHg in systolic pressure as placental weight read less than 1lb as measured in table 3. Those with greater placental weight of 1.5lb saw a fall by 11mmHg of mean systolic pressure.

Highest blood pressures were recorded in small babies who were born alongside a larger placenta. The adaptation of circulation may contribute to this finding.  Barker and Hales (1993), state that hypertension may be dependent on improving health and nutrition of mothers.  However, with little evidence except the facts of measuring and assessing later in life this seems a broad statement of a fact.

Could those children catch up?

Pampanini et al, (2017) very recently carried a study on pregnant rats. Assessing of intrauterine growth restriction (day 19 of gestation) would affect the developments of the gonads in the fetal rats.  Uterine artery ligation was performed on the postnatal rat testis. Several offspring were killed at day 5, 20 and 40 after birth.  At this time, one gonad was preserved within liquid nitrogen, processed for RNA and steroid extraction. The other, formalin fixed for histology.

Hormones testosterone, serum gonadotrophins and estradiol were measured.  The control group had shown the growth restricted rats had 30 genes dysregulated.

By 40 days post partum, the weights of the testis were beginning to catch up in comparison to those at days 5 and 20.

Harper et al (2015), explored the effect of food restriction in mice during early pregnancy. The mice were subject to a 50% restriction of calorie intake from day 1.5 to 11.5 of pregnancy. While placental weights were reduced, little effect continued into adulthood.  Liver gene expression and reduction in adipose tissue (in males only) was demonstrated.  Irreversible effects on the placenta into adulthood was doubted. By day 18 global gene expression was non-remarkable compared to the control group. This study saw the conclusion that alterations in the placenta caused by restricting nutrients (it remains unclear which nutrients) early on within pregnancy may in fact be reversible.

Bonel et al (2010), blindly tested the apparent diffusion co-efficient (ADC) of the placenta in the paper Diffusion-weighted MR imaging of the placenta in fetuses with placental insufficiency. If the fetus birthweight was predicted to be in the 10^th percentile or less, placental insufficiency was diagnosed.  Interestingly, when a Doppler of the umbilical artery was performed, abnormal findings were recorded.  Conclusion of the results showed an accuracy of 99% that placental dysfunction associated with growth restriction is associated with restricted diffusion and reduced ADC.  Early markers used ADC as an indication of pregnancy complications such as intra uterine growth retardation.  Yet still, no causal factor was examined as to the placental dysfunction.

Barker stated in his research Fetal Origins of coronary heart disease (CHD), (1995), active research needed to continue.  Blood pressure, insulin response to glucose, cholesterol metabolism, blood coagulation and hormonal setting are beginning to show something within the underlying causal factors relating back to fetal undernutrition.  What specific type of nutrition, we do not know.  Also is this purely due to calorific restrictions of more specific to nutrition intake and possibly bio availability from mother to fetus? During mid to late gestation, fetal growth seems to go some way to programming CHD later in life. Once again, placental size comes into discussion within this paper.  Relation of birth size to placenta affects the outcome of later diseases.  Yet within this paper, quality of placenta is not assessed

Toxic exposures?

Rogers, (2006) reviewed Barkers Hypothesis more recently in 2006. While this paper is now dated, at the time Rogers stated new discoveries were suggestive of the ability of toxic exposures to also impact fetal development. Post-natal and during the intrauterine period, metabolic programming may be affected due to sensitivity to endogenous and exogenous influences. Animal studies he looked at showed low protein and high fat and high carbohydrate diets linked to adverse metabolic profiles.

Later still, Thomas (2012), began to look deeper into Barkers hypothesis as he subjected individuals to an activity questionnaire.  Those with a greater activity level showed a lower propensity for type 2 diabetes. This gives questionability to wondering if there could be a reversal of type 2 diabetes and perhaps other chronic diseases which may have been prevalent in this cohort yet with prior knowledge and adjustment to lifestyle, could this effect be reversed and prevented from development. 

Dutch famine

During the Dutch famine (Roseboom,. 2006) in 1944-1945 some mothers were limited to a low calorific diet of 400-1000 kcal/day.  Within the mothers who were pregnant and their fetus’ endured famine early on in its development were born with an atherogenic lipid profile and higher body mass index. 

Those who were mid to late pregnancy while enduring the famine were more likely to be impaired with relation to reduced glucose tolerance.

What causes such differences? This is something we currently do not know.

However, it is proven (Ong and Loos, 2006.,) rapid weight gain should not be promoted in small birth weight babies as this can have a central obesity and insulin resistant effect on health over time (Ibanez et al, 2006). Ibanez et al state the importance of understanding the underlying predisposition of adversity could aid preventative interventions.

Is this evidence conclusive?

Many scientific papers have looked at many numbers of people and aiming to prove or disprove Barkers hypothesis.  Yet most seem to draw a similar conclusion.  Fetal development and low birth weights seems to link to a higher prevalence of cardiovascular disease, hypertension, diabetes type 2 (non-insulin dependent), hyperinsulinemia and hyperlipidemia.  With even stronger evidence showing large placenta linked to low birth weight may be more suggestive.

Body composition has not been broken down within the newborn babies to ascertain if there may be an influential factor within the make-up of the body at this early stage. Could adipose tissue perhaps be a higher percentage within malnourished fetal growth? If so, might this give a casual factor to type 2 diabetes mellitus, CHD and hypertension? Current studies show these chronic diseases contribute to atherosclerosis, (Luehmann et al., 2017) leading to a further prevalence of disease and fatality.  Could body composition be influenced by maternal diet in the fetus and early child?  Studies might be conducted with a simple test of when a child holds its head up, suggesting early development of muscular system, (Bri and Sabatier, 1986.)  Watching these children into later life may be another opportunity for further work.  Many studies leading this research forward is of the utmost importance as Barker began to scratch the surface of something revealing. Most studies in relation to this have agreed with the hypothesis of development of chronic disease linked to lower birth weight babies.  However passionate Barker appeared in relation to this research, was he perhaps also bias? Hoping to find something deeper than he already had discovered does give way to a bias although with many other respected scientists confirming Barkers hypothesis goes some way to realising his claims.

Most of Barkers early evidence was correlational.  Potential confounders were not addressed.  Smoking cessation, alcohol, mothers nutritional status all were not adjusted for.  How the baby was fed from birth was not considered as a factor while evidence shows (Bonel et al, 2010.) the benefits of breastfeeding over other means. During breastfeeding, should the mother be exposed to toxins, eat well, sleep well and keep stress low?  Any of these factors may contribute to the child and their body composition as well as nutritional status.

What are the latent effects of such a hypothesis? How would the mother benefit from being forced to eat a healthy diet while pregnant, would she comply, and would she suffer psychological stress which may be passed on to the baby? (Lsarais et al, 2006).

To conclude

Li et al, (2017) have begun to go further into Barkers Hypothesis recently. Questioning the chances of other factors becoming influential within this study.

We know that a developing female embryo will begin to lay down the foundations for her own daughter within the ovaries as she starts very early in the embryonic stages (Laraia et al, 2006.)  Therefore, it could be suggested that the maternal mother in pregnancy may not only affect her daughters health but that of a future grandchild.

Changes in current food culture needs inspiration for change. Health at a population level must become a priority as we head into the future as disease must turn into a lower incidence. 

As a species, the health of our nation is currently being compromised worldwide.   The effects of what todays expectant mother subjects her baby to during pregnancy can quite clearly be seen to have an impact on their long term health. Carrying a daughter will mean many years of damage will be done which seemingly is very hard to undo. Over such a long period of time, the nation will become sicker which puts a financial pressure on the economy as we aim to try and fix these diseases and keep the public healthful.

Barker clearly highlighted an amazing and conclusive subject. Yet without further work and of course education to the mothers for them to see the levels of which they are able to influence the future of the health of the nation, the chances of change are very limited.  While this sounds bleak, developed countries are becoming more aware of choices of lifestyle affecting them in their day to day lives.

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