Background
Current World Health organization (WHO) statistics have reported Cardiovascular Disease (CVD) to be the leading cause of mortality worldwide with an estimation of 17.9 million deaths each year [
1]. In the United Arab Emirates (UAE), the burden of CVD is no different, where a recent report estimates that 40% of total deaths are linked to CVD [
2]. The aetiology of heart disease is complex and multifactorial [
3], however there are various factors that have been implicated in increasing disease risk. Lifestyle risk factors include smoking, physical inactivity, obesity (with strong emphasis on central/visceral adiposity) and alcohol intake [
4]. These behavioral risk factors are often manifested into one or more of the following: high blood pressure (BP), insulin resistance, diabetes, increased blood lipids, and even kidney dysfunction [
5,
6].
Hypertension is a highly prevalent condition that affects up to 1.13 billion adults all over the world and is highly incriminated in increased risk of CVD amongst other chronic conditions [
7]. Normal readings of both systolic blood pressure (SBP) and diastolic blood pressure (DBP) are essential to optimal functioning of all vital organs. However, studies have demonstrated that SBP is possibly more significant as an independent predictor of risk for stroke, heart failure and other coronary events [
8]. Numerous factors contribute to the development of hypertension, including intrauterine growth restriction (IUGR), which has been linked to high BP in adulthood. This could be attributed to the effect that restricted growth has on the number of nephrons an individual develops, a number that is set at birth [
5,
9]. Mounting evidence has found that retarded growth in utero is significantly associated with a reduction in nephron number, which in turn is a risk factor for the development of hypertension. Animal studies have shown that rats subjected to growth retardation by restricting maternal protein intake presented with a nephron deficit in comparison to the control group [
10]. Therefore, low birth weight for gestational age can be used as a marker to link intrauterine growth and the effect maternal investment potentially had on the offspring’s capacity for maintaining metabolic homeostasis [
5]. A multitude of studies have demonstrated the significant links between low birth weight and elevated BP in adults [
5,
11,
12]. In 2020, Aye et al. [
13], reported that maternal hypertension was associated with ‘both prenatal and postnatal differences in cardiac development, with right ventricular changes proportional to the severity of the pregnancy disorder’. Yet, long term effect and relationship to CVD is still not fully explored as more work is needed to determine if these changes persist into adulthood and whether they impact the physical, respiratory, and cardiac functions [
13].
Adiposity-related health consequences are well known and documented, and high adiposity levels have been linked to numerous chronic diseases including CVD [
14]. Body Mass Index (BMI) continues to be used as a marker for obesity levels and disease risk, however it is just as important to take into account body fat distribution due to the fact that excess central adiposity is detrimental to health and is highly correlated with a host of metabolic diseases including increased CVD risk [
14]. Because precise measurement of central fat is expensive and requires radiological imaging, waist circumference is accepted and often used as a surrogate marker instead [
15]. Evidence suggests that the intrauterine environment as well as the early infancy period could be responsible for shaping body composition in later life, where several studies have found an inverse association between birth weight and greater BMI as well as higher abdominal obesity levels (larger waist circumference) [
16‐
18]. A cohort study of indigenous Australians found that those with the highest CVD risk were both in the highest waist circumference quartile group and of low birth weight [
19]. Boscaini & Pellanda [
20] revealed that high birth weight individuals had higher BMI and waist circumference. This implies that the relationship is much more complex and our understanding of it needs further exploration [
21]. Sex is another factor added to the birth weight and adiposity association. Rockenbach et al. [
22] examined sex-specific relationship of birth weight with measures of adiposity. Results in men showed that low birth weight was linked with lower adiposity while low birth weight in females showed greater adiposity [
22].
The risk factors explored above are only able to predict disease risk up to a limited point. So far, the lifestyle model has only been successful in partly explaining CVD risk by exploring lifestyle interactions with underlying genetic influences [
23]. Other theories were developed in an attempt to explain the complex nature of heart disease aetiology to help understand how prenatal period influences can bridge the gap in our understanding of both CVD aetiology [
24] and prenatal associations with chronic disease susceptibility [
25].
Hales and Barker [
26], in accordance with earlier observations by Forsdahl [
27], proposed one of the earliest models explaining this link. They found that CVD mortality rates were recorded to be highest in areas of poverty that were exposed to later prosperity. If later affluence and nutritional overabundance in childhood and adulthood was not experienced, the risk did not appear to be increased [
27]. This implied that energy insufficiency in-utero could affect the ability to manage nutritional affluence (excessive intake of energy) later on in life [
5]. They suggested that CVD and other chronic diseases are ‘programmed’ during critical windows in fetal life and even into early infancy. This hypothesis was termed ‘fetal origins of adult disease’ [
28]. Research has found that suboptimal nutrition in-utero, particularly halfway through the gestational period, increases CVD risk in adulthood by “the programming of blood pressure, cholesterol metabolism, blood coagulation, and hormonal settings” [
24]. Specifically, arteriosclerotic heart disease was linked to an increase in serum cholesterol levels in those who grew up in least affluent households and were exposed to a high fat diet [
27].
Although past studies have shown that biological programming in prenatal life as a response to nutritional affluence or lack of is an important factor to consider, it is important to also take into account how lifestyle measures later on in life affect the degree of disease manifestation. To address this issue, Wells et al. [
5] went on to propose a ‘capacity-load’ model for risk of disease. This builds on the original ‘thrifty phenotype’ hypothesis by Hales and Barker [
26] and incorporates two different variables: metabolic capacity and metabolic load. The former refers to the ability to maintain homeostasis throughout adulthood and stems from prenatal growth (birth weight and gestational age). The latter is defined as various stresses that strain cardio-metabolic function, such as obesity, smoking, sedentary lifestyle and inflammation.
During critical windows in gestation, “epigenetic processes are thought to alter gene expression in the fetus based on maternal environmental cues” [
29] in order to best prepare the fetus for the extra uterine environment. A ‘mismatch’ in the predicted environment due to exposure to nutritional affluence post birth is proposed to increase disease risk. Therefore, the phenotype developed during those windows of under nutrition in order to aid in survival, results in lower ability to tolerate metabolic load later on in life [
30]. In this context, diminished metabolic capacity becomes an issue only when metabolic load is intensified [
30]. This explains why individuals who are not exposed to nutritional affluence after birth do not appear to have heightened metabolic risk even if exposed to malnutrition in the uterine environment [
5]. It also explains why those born with a lower birth weight (lower metabolic capacity) and become large (high metabolic load) exhibit higher risk of CVD [
5,
31,
32]. Wells et al. [
5] also suggested that life-history theory could explain why individuals have varying ranges of load and capacity. This theory proposes that individuals must allocate their energy resources in a way that maximizes fitness. They can either invest in characteristics that “affect the age-schedule of mortality; or in traits that affect the age-schedule of fertility” [
33]. For example, investing in reproductive fitness (higher adiposity stores) could reduce investment in growth. This theory could be used to justify why energy allocation during periods of nutritional insufficiency during the life course is directed towards reproductive functions instead of maintenance ones [
34]. According to this evolutionary theory, individuals who were recipients of diminished maternal investment (restricted nutritional environment in utero proxied by lower birth weight and shorter gestational period) can be said to have a fast-paced life-history strategy [
5]. This translates to earlier maturation in the form of earlier menarche as well as a shorter stature. This is suggested to lead to a reduced metabolic capacity, and a high metabolic load that increases CVD risk. So, lower maternal investment
faster pace of life history
lower adult height, higher energy stores for reproduction and lower metabolic health. In other words, low birth
weight earlier maturation + shorter height
later increased adiposity. The opposite holds true for those receiving high maternal investment and optimal nutrition in fetal life [
5]. In 2018, Wells proposed the relative partitioning concept of maternal investment between fetal life and infancy. This analytical framework suggests that low fetal weight gain diminishes the energy needed for growth and maintenance, and if continued, growth postnatally will continue to be constrained. This leads to earlier menarche and reproductive maturation, small adult size, elevated fat stores. ‘Through the partitioning described above, the combination of short adult stature and high fatness favour the same trade-offs emerging in the next generation’ [
35]. Bleil et al. [
36] reported that younger menarcheal age was related to greater CVD risk. A study conducted in the UK found that less than optimal maternal investment led to faster life histories which were marked by earlier menarcheal age, shorter stature and higher adult adiposity levels [
5]. Another study of Indian girls, who moved to Sweden, found that those with the most stunted growth had earlier menarche as well [
37]. Maternal investment is defined as a combination of two elements: maternal resources at conception (proxied by her size and nutritional status) and the resources provided by her to offspring though pregnancy and then lactation, stemming from her nutritional intake [
31]. For the purpose of this study, birth weight SDS, computed from birth weight and gestational age, is used as a marker to reflect degree of maternal investment; this being consistent with earlier studies [
5].
Low birth weight, which is an indicator of poor fetal growth and low maternal investment, has been found to result in lower fat free mass (FFM) in adulthood [
38‐
40]. This could partly explain why lower birth weight is linked to an increased risk of CVD, since a lower muscle mass could lead to impaired glucose regulation [
38]. This is due to the fact that muscles play a critical role in the homeostasis of blood sugar, as 70–90% of the glucose is taken up by the muscles [
41] making the muscles ‘the primary tissue contributing to whole-body insulin-mediated glucose disposal’ [
42]. Therefore, lower FFM could lead to development of insulin resistance, which is an impairment that contributes heavily to CVD development in adulthood [
38]. Different theories have been proposed in an attempt to explain the link between prenatal life factors and occurrence of CVD. However, further studies still need to be carried out in order to establish whether early malnutrition in-utero negatively influences metabolic competence and organ physiology [
31].
Aim of study
To the best of our knowledge, this study is the first one of its kind in the UAE. It investigates how maternal investment shapes the life history pace of the offspring. This will offer us a chance to study the extent that maternal investment influences life history pace and generates the trade-off between maturation/adiposity versus growth/homeostatic maintenance. It then looks at whether this trade-off increases risk of CVD in adulthood.
Hypotheses
In healthy women from the UAE, based on the interpretations of the life history theoretical framework, we hypothesized that:
a)
Those who were on the receiving end of poor maternal investment (characterized by lower birth weight standard deviation score (SDS)) during the fetal period would develop earlier maturation (proxied by earlier age of menarche).
b)
Lower maternal investment, coupled with an earlier maturational timing (proxied by earlier age of menarche), would then lead to reduced growth (proxied by shorter height, and leg length).
c)
Lower maternal investment, coupled with an earlier maturational timing (proxied by lower birth weight SDS and earlier age at menarche), would then lead to elevated CVD risk (proxied by greater waist circumference, higher fat mass index (FMI) and lower fat free mass index (FFMI).
d)
Reduction in metabolic capacity (proxied by low birth weight) in addition to a high metabolic load (proxied by elevated adult adiposity and lower FFMI) would lead to higher risk of CVD (proxied by elevated BP).
Discussion
This study was set out to test the hypothesis that maternal investment in utero would shape the life history pace of the offspring. An accelerated life history pace (assessed by earlier menarcheal age) would cause the individual to prioritize reproduction overgrowth and homeostatic maintenance. In other words, the individual develops higher energy stores for reproductive purposes, and present with reduced growth and increased risk for chronic disease through poorer BP regulation, lower FFMI and higher central adiposity. In a sample of 94 young Emirati women (17–27 years), our results showed that birth weight SDS was positively and significantly associated with both height and leg length, while age at menarche did not show the same relationship. Body fat was inversely associated with menarcheal age, but not waist circumference (p > 0.05). Birth weight SDS was positively and significantly associated with waist circumference, FMI, and FFMI. All indices of adult adiposity (FMI and waist circumference) and FFMI were positively and significantly associated with SBP. Regarding DBP, the relationship was negatively and significantly associated with FFMI only.
Our data showed an inverse yet not significant association between birth weight and age at menarche, this did not reach significance; a finding which does not align with findings of some other studies [
5,
37,
54]. An explanation given to this is that those born with lower birth weights present with higher amounts of adrenal concentrations in circulation, which results in earlier attainment of menarche [
55]. However, these findings remain inconsistent across studies, as the opposite association has been demonstrated as well; that those born larger experience earlier menarche [
56]. An alternative explanation offered for this phenomenon is that both elevated insulin-like growth factor-1 and leptin levels associated with a higher birth weight could trigger earlier menarche [
55,
56]. Lack of observed significance in our study could also be attributed to failure in incorporating other factors that could affect age at menarche such as length at birth and postnatal growth rate. The suggested theoretical framework is not upheld in this population, which provokes further research into the specific environments and circumstances in which the relationship between birth weight and age at menarche is established.
A study in the Philippines concluded that menarcheal age was not significantly associated with birth weight alone, however ‘girls who were relatively long and thin at birth attained menarche approximately 6 months earlier than did girls who were short and light’ [
57]. Recent research by Wells et al., in 2019, presented a theoretical model derived from life history theory where the researchers hypothesized that with lower maternal investment, early offspring reproduction was favored, body immune function was elevated, and risk-prone behaviors were increased. Results showed that daughters with early first reproduction had ‘growth trajectory favoring weight gain at the expense of linear growth’ [
58]. This indicates that more markers need to considered, other than just early menarche, before deriving definitive conclusions about indicators of fast life history strategy.
Moreover, our findings support the hypothesis stating that lower maternal investment (lower birth weight) is linked to reduction in growth (proxied by height and leg length). This finding is consistent with earlier studies that reported the effect of birth weight on adult height [
5,
59]. This is an important conclusion as adult height has been demonstrated to be inversely and significantly linked to mortality due to coronary heart disease [
59]. Lower leg length measurements, in specific, may relate to higher risk of fatness, coronary heart disease and diabetes [
45]. Independent of any other indicator, in our analysis, for every 1 cm increase in leg length, waist circumference increased by 1.01 cm (
p = 0.005). Leg length was not significantly predictive of FFMI, FMI, SBP, and DBP. Additionally, those born small for gestational age and achieving shorter height were found to be associated with elevated sympathetic nerve activity [
60]. This is suggested to be the link connecting maternal investment (birth weight), adult height and risk of hypertension and CVD [
61]; not excluding the aforementioned function of nutrition and its effect on prenatal and postnatal growth.
In our analysis, lower birth weight was not linked to elevated adult adiposity levels, in fact the data showed the opposite association: the higher the birth weight, the higher the adult central adiposity (waist circumference). On the other hand, an earlier menarche was found to be associated with higher adult adiposity markers when adjusted for age. Our results are consistent with other findings reported in the meta-analysis conducted by Prentice and Viner in 2013 [
62]. However, it is unclear whether earlier menarche is due to 1) fast postnatal catch-up growth following retarded intrauterine growth in the presence of nutritional affluence (associated with higher adult adiposity), or 2) low birth weight induced an increase in body fat in later life, or 3) both [
61]. It is well documented that body composition changes with age, where fat mass increases and muscle mass decreases [
63]. Hence, age was accounted for in the adiposity regression models (waist circumference and FMI). The analysis showed that age inclusion did not affect the results. This could be explained by the fact that our age group is young, hence no major shifts in body composition is seen at this stage of life [
64]. Knowing the physical activity level could have given a better interpretation to the findings of both fat mass and fat free mass.
Clinical and experimental studies revealed that IUGR is associated with a significantly higher incidence of metabolic, renal and CVD in adult life where ‘IUGR directly cause cardiovascular alterations independent of pre-existing metabolic disease’ [
65]. It has been proposed that early growth restriction in the womb due to lower maternal investment has been linked to higher rates of CVD risk by altering homeostatic capacity for blood pressure regulation [
66], as well as increasing insulinemia [
67]. Falkner stated that SBP is lowered by 1–2 mmHg with every kg increase in birth weight [
68]. Contrary to the latter and other findings [
5,
69], in this study, birth weight was not found to be indicative of adult blood pressure homeostasis as none of the models showed a significant relationship. Worth noting that, in all the SBP models, for every 1 unit increase in the BW SDS predicted an increase of 1.1 to 1.3 mmHg in SBP. As for the DBP, there was a general drop with increases in birth weight.
However, indices of adult adiposity were found to be positively and highly significantly linked to SBP. This stresses the importance of ‘metabolic load’ and post-natal environmental stressors on the development of disease rather than just birth weight. It is also important to note that while some studies have supported the link between birth weight and increased blood pressure, these findings were inconsistent. A study looking into the association between intrauterine growth and obesity suggested that it could be more useful to assess weight at birth “relative to genetic potential, indicated by the size of the parents or by the individuals body height” [
21]. This is due to the evidence that support the theory that failure to reach growth potential has a higher association with blood pressure than solely birth weight [
32]. Therefore, models that include post-natal growth and take into account parental genetics would be important to gain a better understanding of links to blood pressure regulation.
Waist circumference was found to be positively associated with birth weight SDS. This indicates that higher birth size equates to higher adult central adiposity. Some studies had found inverse associations between birth weight and abdominal obesity in adulthood than not [
16‐
18].
Size at birth was also significantly and positively associated with FFMI. To explain why those who are born smaller end up with less adult fat free tissue mass, it has been suggested that suboptimal nutrition in prenatal period would restrict insulin secretions by causing hypoglycemia and so an upsurge in protein breakdown and a reduction in protein accretion [
38]. Another pathway through which poor intrauterine conditions could affect FFM in adulthood is by lowering circulating levels of insulin-like growth factor 1, which in turn could affect intrauterine muscle growth [
38]. Kuh et al. [
70] added that the number of muscle fibers established at birth is related to birth weight. So, low FFM in those born smaller reduces metabolic capacity in adulthood and therefore increases disease risk especially in those who are subjected to an affluent environment [
31].
It is important to note that although this type of study may offer us a chance to explore the links between maternal influences in prenatal period and adult disease risk, the issue remains much more multifaceted and there exist numerous limitations that make interpretation more complex. It is difficult to determine whether the heightened risk was due to lack of maternal investment and not attributable to other influences.
There were several limitations to the study. First, our study was cross-sectional, hence the inability to make causal relationship between early life events and their effect on later life outcomes [
71]. Second, a relatively small sample size using a convenient sampling strategy was recruited, therefore impacting the generalizability of our results. Third, self-reporting was used to obtain participant information such as birth weight, gestational age, age at menarche, and breastfeeding duration. Our inability to verify this information by any other means such as hospital records meant that there is a possibility of recall bias due to memory limitations, which potentially threatens the internal validity of the study [
72]. Also, recall might bias the mean measurements, reducing the variance and therefore probably masking relationships between variables. Fourth, there are many confounding factors that we did not account for and could have affected the study outcomes in terms of weight and body composition changes later in life or prenatal development, including postnatal circumstances such as dietary intake, physical activity levels and stress [
5,
21]; maternal smoking habits [
21,
73], and maternal blood pressure [
13]. Finally, although socioeconomic data [
74] was not collected, the UAE is a high-income country [
75], and public universities are tuition-free for UAE nationals. Hence, it is safe to generalize that the sample population’s socioeconomic status would be representative of that of the national population. Overall, we consider this study relatively preliminary and encourage replication.
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