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Abstract

The idea of intrauterine or fetal factors being the cause of several prevalent noninfectious diseases in adults has recently gained the status of an axiom. One of the most thoroughly studied predictors is birth weight (BW). Although many published studies point at relations between BW and later adult morbidity or mortality, much less attention is paid to associations between baby BW and maternal morbidity. Available data suggest a sort of dichotomy in these relationships. Thus, cardiovascular risk is higher in mothers of babies with a reduced BW, while cancer risk, mainly of the breast and some other hormone-dependent cancers, is often higher among mothers of babies with a large BW (newborn macrosomia). This review addresses possible causes and endocrine mechanisms of this topic and suggests a ‘particular’ and ‘general’ solution for arising controversy. Emphasis is placed on a probable competition between chronic diseases (mainly, between female hormone-related cancer and cardiovascular pathology) within the concept of multiple causes of death. These associations should be remembered while studying the relation between offspring BW and maternal predisposition to hormone-associated cancers and other noncommunicable diseases.

Keywords

birth weight cardiovascular diseases hormone-related cancer macrosomia maternal morbidity/mortality

Although many chronic diseases including cardiovascular disorders and cancer are more common in older adults, their causal factors often occur during the earlier stages of ontogenesis. Therefore, deviations in the physical parameters of newborns are often viewed as the first signs of apparent or, more often, occult pathology of both the child and mother [1]. The importance of these factors to the child is partly reflected by popular concepts such as thrifty genotype, thrifty phenotype, developmental plasticity, compensatory or ‘catch-up’ growth and fetal programming [2 –9]. The ‘fetal, or developmental, origin of adult diseases’ is currently in the focus of attention [3,10 –12]. Its significance is confirmed by multiple published studies often based on integral indices, such as birth weight (BW) at term. The occasionally published critique of these views does not compromise the general idea of human noncommunicable diseases as a complex condition originating, at least partly, from in utero factors [13,14].

However, some of the critical arguments are quite convincing, leading to the “causal inference in this domain remains a serious challenge” and “the reported associations may be biased rather than causal” conclusions [15]. In a comment to a large Danish publication regarding U-shaped rather than linear association of BW, with later adult mortality owing to circulatory diseases and other causes [16], Basso pointed, that “we should be cautious to not focus excessively on fetal growth,” while speaking of adult outcomes [17]. In another commentary to the same paper Lawlor added that, “This area of research needs to move away from simply describing the association of BW with disease/health outcomes. Instead, we must aim to understand whether there are modifiable risk factors during the developmental period that are importantly causally related to later disease outcomes” [18]. Therefore, the discussed subject should be reviewed in all its complexity, taking in account the mechanisms and possible factors leading to the development of chronic noninfectious conditions, such as cardiovascular diseases (CVDs) and hormone-associated cancers.

Meanwhile, the ‘birth weight is forever’ concept is still popular [17], not only because BW is an important indicator of both biological traits and socioeconomic circumstances [19], but also because of its apparent relationship with distant manifestations of human pathological conditions, although its exact machinery is not yet clear [1,20]. Moreover, as the attention of ‘developmental origin of chronic noncommunicable diseases’ proponents is traditionally focused on low BW (LBW) babies, they mostly overlook the opposite side of the weight spectrum. However, recent trends suggest that high BW (HBW; more than 4000 g at birth) babies are becoming more prevalent than LBW babies [21,101]; hence, the HBW group is beginning to attract more attention.

This review is based on long-term experience of studying chronic disease-related aspects of HBW [20,22]. After a brief discussion of BW relation to later adult pathological conditions, the article will mainly concentrate on the other side of the problem: the association of babies’ BW with the morbidity of their parents, particularly their mothers. Finally, possible causes of opposite associations of newborn macrosomy with maternal morbidity rate due to hormone-associated cancer and CVDs will be discussed.

BW & liability for adult conditions including cancer & CVDs

During the late 1980s, when the first papers describing relations between BW and adult diseases were published [3,13,23 –25], the total number of relevant publications exceeded several hundred. The main discussion points included the relationship between BW and subsequent all-cause mortality, diabetes prevalence (with more emphasis placed on glucose intolerance and insulin resistance than metabolic syndrome and obesity) and most of all, morbidity and mortality due to cardiovascular conditions and cancer. Although the connections between cancer and developmental issues in the beginning ‘were in the shadow’, the later studies highlighted this subject's importance [13]. Since our review is focused mainly on few quite specific aspects of the matter, the mentioned topic is illustrated by two recently published meta-analyses, chosen among many available sources [26,27].

One meta-analysis is based on data presented in 22 publications on the associations between BW and adult all-cause mortality due to CVDs, and cancer [27]. The analysis only included studies of the relationship between hazard ratios (HRs) and 95% CIs per BW increase measured in kilograms. BW associations with all-cause mortality were established based on ten studies (12,995 deaths among women and 23,839 deaths among men), CVD mortality association analysis included nine studies (2796 cardiovascular deaths in women and 8570 in men), while BW and cancer-related mortality association was assessed using data from five studies (4208 cancer deaths in women and 4176 in men). The observations revealed a decrease of all-cause death risk with an increase in BW (HR: 0.93 for females and HR: 0.95 for male population). Higher all-cause mortality was discovered in a population with a relatively LBW (i.e., less than 3000 g; sex-adjusted HR: 1.11), while there was no evidence of an association between HBW (more than 4000 g) and all-cause mortality changes when compared to the reference group of 3000–4000 g (HR: 1.02). Meta-analysis of cardiovascular mortality showed a reduction of risk per kg increase in BW in both women and men (HR: 0.88). On the contrary, a higher BW in men was positively associated with cancer mortality (HR: 1.13 per BW kg), while in women there was no strong evidence of such a connection (HR: 1.04) [27]. Although these results pointed at the possible gender-based differences in cancer morbidity, it should be noted that the analysis performed by Risnes et al. did not include the connection between BW and breast cancer incidence in females, reviewed in detail later [27].

Indeed, in the other meta-analysis, the authors focused on adult breast cancer incidence and birth parameter relationships, including weight (kg), length (cm), head circumference (cm), and ponderal index (defined as weight [kg]/height [m³]). The data on over 22,000 females with breast cancer and 604,854 noncases from 32 epidemiological studies was analyzed [26]. The analysis was restricted to singletons divided into several BW groups of <2500, 2500–2999, 3000–3499, 3500–3999 and >4000 g. A 0.5-kg increase in BW was associated with a statistically significant increase of breast cancer risk in studies based on birth records (pooled relative risk: 1.06; p = 0.002). Higher breast cancer risk was also associated with increased newborn length values (17% higher in women with newborn length of more than 51 cm) and birth head circumference (11% higher in women with birth head circumference of more than 35 cm), while it had no connection to ponderal index value (relative risk: 1.01). The association with BW became insignificant after adjustment for birth length and head circumference, while the association with birth length persisted after adjustment for BW and head circumference. These findings were consistent with positive associations at both pre- and post-menopausal ages, and did not appear to be confounded or modified by known breast cancer risk factors. As a whole, these facts gave evidence of the independent role of newborn macrosomy in breast cancer development [26]. Assuming causality, the authors came to the conclusion of a possible connection between high birth parameter (i.e., a BW more than 3.5 kg) values and approximately 5% of all breast cancer cases in developed countries, in contrast to previously stated inverse associations between BW and adult all-cause mortality, especially due to circulatory diseases [16,27].

Associations between BW and other adult cancers were addressed in several studies. In a cohort of more than 200,000 women and men, born between 1936 and 1975, a total of 12,540 primary invasive cancers were diagnosed during 6,975,553 person-years of follow-up. Analyses of site-specific cancers showed a positive linear association between most cancers (e.g., liver and kidney cancer, among others) and BW increase, although for testicular cancer this association was inverse, while pancreas and bladder cancer demonstrated a U-shaped connection. For breast cancer, relative risk was 1.07 in the group with BW >4500 g compared with 3000–3499 g in the reference group [28]. The results of this [28] and another study [29], while suggestive of a general trend toward a positive association between BW increase and adult cancer risk, pointed out some site-specific features compatible with differences between tissue targets, as well as between involved mediating factors, such as gender. Some of these factors are discussed in the following sections.

Opposite associations of HBW with maternal morbidity owing to cancer & CVDs

The aforementioned patterns are partly true not only for adults with a history of HBW, but also for their parents. Data on CVD and cancer incidence in both mothers and fathers are summarized in Tables 1 & 2 [20,30 –44]. The choice of these pathological conditions is apparent: by the end of the 20th century, seven out of ten deaths in the total world population were caused by noninfectious chronic conditions, mostly CVDs and cancer [102]. Therefore, the fact (described in detail later) of a de facto opposite relationship between anthropometric values of the babies at birth and CVD/cancer morbidity of their parents, especially mothers, is extremely important from a medical and biological point of view.

Table 1.

Relationships between cardiovascular mortality/morbidity in parents and babies’ birth weight.

Study (year)	Subjects & methods	Main findings	Conclusions	Ref.
Davey Smith et al. (1997)	A study of all-cause and CVD mortality incorporating 794 married couples in the Renfrew district of Scotland (UK) during a 15-year follow-up period	Total mortality was inversely related to offspring BW in both mothers (RR: 1.82 for a 1-kg decrease of BW) and fathers (RR: 1.35). The inverse associations of CVDs were stronger in mothers (2.00), than in fathers (1.52)	The strength of association was greater, than would have been expected by the degree of concordance of BWs across generations	[30]
Smith et al. (2005)	Data from the Swedish Medical Birth Register on 783,814 children born between 1973 and 1980 analyzed together with death records of their parents (783,340 mothers and 768,583 fathers)	For associations with BW, adjusted HRs were all-cause mortality: 0.84 (mothers) and 0.92 (fathers); and cardiovascular mortality: 0.75 and 0.92, respectively	Offspring BW was inversely associated with CVDs and all-cause mortality in parents, the association was weaker in fathers, than in mothers	[31]
Lawlor et al. (2003)	Multiple linear regression was used to assess the association between offspring BW and intima–media thickness, an indicator of preclinical atherosclerosis, in 268 women and 418 men aged 56–75 years	Intima–media thickness was inversely associated with offspring BW in both women and men	The data are consistent with the association between offspring BW and coronary heart disease that has been seen in both sexes	[32]
Li et al. (2010)	Data on 1,400,383 parents were linked to the Asian (Taiwanese) Death Registry and then used to calculate the adjusted HRs of mortalities in relation to BW of offspring	For 1-SD-higher offspring BW, a reduced adjusted HR (0.89) for CVD mortality was noted in mothers, and a small inverse association was also revealed in fathers (HR: 0.97)	The fathers of LBW infants showed a weaker association with CVD mortality, consistent with findings from several previous studies	[33]
Davey Smith et al. (2007)	Prospective observational study (which included 12,086 mothers and 6936 fathers from the British 1958 birth cohort) and meta-analysis	The adjusted HR of CVD mortality for a 1-SD increase in offspring BW was 0.87 and 0.94 in mothers and fathers, respectively. In a meta-analysis, the respective values were 0.75 and 0.93	The inverse association between BW and CVD mortality is stronger in mothers; providing support for a role of specific maternal factors	[34]

BW: Birth weight; CVD: Cardiovascular disease; HR: Hazard ratio; LBW: Low birth weight; RR: Relative risk; SD: Standard deviation.

Table 2.

Relationships between cancer mortality/morbidity in mothers and weight at birth of their babies.

Study (year)	Subjects & methods	Main findings	Conclusions	Ref.
Berstein (1988)	Data on offspring BW in 1035 female cancer patients and 421 healthy women were collected. Only singleton births at 40 ± 1 weeks of gestation were considered	A significant increase in the proportion of women with HBW babies (≥4000 g) was found among colorectal, cervical, EC, ovarian, gastric, BC and skin melanoma patients. The increase was more pronounced in patients aged>50 years. The prevalence of overt diabetes in cancer patients having or not having HBW babies was not different	HBW is an early marker of events contributing to the development of a number of tumors in mothers	[20]
Olsen and Storm (1998)	BWs of 5213, 557 and 173 infants born to women who later developed BC, ovarian cancer and EC, respectively, were compared with four-times as many infants born to women without cancer	The only significant finding was a higher proportion HBW infants (>4000 g) in the EC group	HBW as an indirect indication of elevated estrogen levels during pregnancy is valid only in females with EC	[35]
Wohlfahrt and Melbye (1999)	BW was studied in 9495 BC cases among 998,499 females aged 13–48 years at entry. Follow-up duration was 12.8 person-years. Only the latest birth was taken into account	HBW babies (≥3.75–4 kg) compared with LBW babies (<3.0 kg) are associated with a higher BC risk (OR: 1.1) in their mothers. The highest OR (1.2) was found during the first 5 years after birth and especially with tumor size>2 cm and BW >3.75 kg (OR: 1.4)	Large babies are a significant marker of BC risk in women	[36]
Davey Smith et al. (2000)	Data on birth outcomes were recorded in 3706 women who in 1954–1963 gave birth to singletons. HRs relating birth length, ponderal index (weight/height³) and BW to mortality were calculated	BC (contrary to smoking-related cancer) mortality was positively associated with ponderal index of offspring	Maternal factors that affect intrauterine growth seem to produce important influences on long-term mortality risk in women	[37]
Mogren et al. (2001)	Data on 40,951 women and the outcomes of their deliveries between 1955 and 1995 were obtained from birth registries and linked to a cancer registry	There were no associations between low (<2500 g) or high (>4000 g) offspring BW and cervical cancer, EC, ovarian cancer and BC in mothers (1360 cases)	HBW might indicate a higher or longer exposure to estrogens, but no such associations were demonstrated	[38]
Innes and Byers (2004)	Characteristics of the first pregnancy were compared with subsequent BC risk in 2522 BC patients aged 22–55 years (average age: ~40 years) and 10,052 primiparous controls without BC	Very low (<1500 g) and very high (>4500 g) BW in babies were associated with a trend toward lower BC risk in mothers	Little evidence for an effect of infant BW on cancer risk was found	[39]
Cnattingius et al. (2005)	Among 314,019 women in the Swedish Birth Register, a cohort of 2216 cases with singleton births developed BC during follow-up from 1982–1989 to 2001, and 2100 of them (95%) were diagnosed before the age of 50 years	A HBW (>4000 g) in two successive births was associated with an increased risk of BC before, but not after adjusting for placental weight. Women who delivered an infant with a BW >4500 g had a higher incidence rate of BC than women who delivered infants with a lower BW (p = 0.008 if age-adjusted and p = 0.71 if fully adjusted)	The weight of the placenta seems more important than BW for associations with BC, although the amount of blood in the placenta influences placental weight and needs to be taken into account	[40]
Smith et al. (2005)	See respective description in Table 1	Offspring BW is inversely associated with smoking-related (lung) cancer mortality in both mothers and fathers (HR for a 1-SD increase in BW is 0.68 and 0.86, respectively)	The inverse associations of offspring BW with lung cancer mortality in mothers are expected, given the known effects of smoking on fetal growth and development	[31]
Davey Smith et al. (2007)	See respective description in Table 1	HR in mothers per 1 SD increase in offspring BW is 0.97 for all cancers, 1.08 for BC, 0.89 for smoking-related cancer, and 1.0 for nonsmoking-related cancer; BW distribution: lowest quintile <2890 g and highest quintile >3680 g	The authors mainly addressed BW associations with CVD-related mortality in parents and did not make conclusions concerning cancer	[34]
Mucci et al. (2007)	Study sample included 1.1 million Swedish women who delivered singleton births. During 12.6 million person-years, 1017 epithelial ovarian cancers developed. Mean age at diagnosis was 43 years	Women giving birth to small-for-gestational-age babies (<2500 g) had a reduced ovarian cancer risk (adjusted HR: 0.7) vs the reference group (BW 3000–3499 g; HR: 1.0) or the group with BW >3500 (HR: 1.07)	The effect discovered highlights a potential role of fetal growth in predicting a mother's future risk	[41]
Paltiel et al. (2008)	The association between offspring BW and leukemia risk in the parents was assessed. Study population comprised 39,336 mothers and 38,031 fathers from the Jerusalem Perinatal Study database	Leukemia developed in 57 mothers and 132 fathers. BW ≥4500 g was associated with a 3.4-fold risk of leukemia in mothers, but not fathers; for the subgroup with BWs >4000 g, HR was 1.31	Mothers of very HBW babies may be at increased risk of leukemia compared with mothers whose infants are not as heavy	[42]
Li et al. (2010)	See respective description in Table 1	Practically no association was found between offspring BW and mortality from all and smoking-related neoplasms (HR for 1-SD-higher BW is 1.00 and 0.99 in mothers, and 1.00 and 0.96 in fathers)	Cancer-related issues were not discussed in this study, which was concerned mostly with CVD	[33]
Nechuta et al. (2010)	Women aged <50 years were linked through Michigan Cancer Registry and Michigan birth records (1978–2004). BC cases (n = 7591) were matched to controls (n = 28,382) for maternal birth year and race	Compared with mothers of infants with a BW between 2500 and 3499 g, OR for BC risk was 0.80 in the <1500 g group, 0.73 for 1500–1999 g and 1.08 for >3500 g. Having a small-for-gestational-age infant at a last birth at age ≥30 years modestly reduced risk (OR: 0.82)	There is limited evidence for an overall association between fetal growth and maternal BC risk	[43]
Bukowski et al. (2012)	A prospective study that included 410 females from the Framingham cohort. During follow-up with a 14-year median, 31 women (7.6%) were diagnosed with BC. The effect of the first infant's BW on BC incidence was evaluated	BW (mean ± SE) of the offspring of all females was 3304 ± 29 g. Women who gave birth to large infants (BW in the top quintile) had a higher BC risk (HR: 2.5; p = 0.012). The difference was more evident in the females older than 55 years	Women who give birth to babies with HBWs are at increased BC risk irrespective of the women's own weight at birth	[44]

BC: Breast cancer; BW: Birth weight; CVD: Cardiovascular disease; EC: Endometrial cancer; HBW: High birth weight; HR: Hazard ratio; LBW: Low birth weight; OR: Odds ratio; SD: Standard deviation; SE: Standard error.

The data presented in Table 1 suggests that the negative correlation between babies’ BW and cardiovascular pathology incidence in their parents is a prevailing trend, more evident in mothers than in fathers. However, some studies show a U-shaped relationship between these factors – that is, cardiovascular and, what is more important, overall mortality may be increased among parents having LBW as well as HBW babies [45]. This makes the temptation of seeing ‘how it is with cancer’ still stronger. Table 2 summarizes in chronological order most of the available data on the latter subject.

These data are not clearly uniform, yet nine out of 14 studies report a positive correlation between cancer incidence in mothers and BW or other anthropometric values of their offspring. Several of the research groups also included fathers of the babies in the study, and in these cases no correlations were found. The variability of certain results in the population of mothers may be caused by differences in data input (e.g., in different publications the data could date back to the first or subsequent births). The studies also use different end points, such as cancer site or potential role of environmental factors (smoking-related vs smoking-unrelated cancers). The data on tumor localization seems most important, as among the nine studies showing evidence of BW and cancer incidence, positive correlations of most of the tumors were hormone-associated (breast cancer in eight studies, endometrial and ovarian cancer in two studies) with only one study mentioning hormone-independent cancer (leukemia) [42]. In some cases, the breast cancer morbidity association with baby BW was more evident in women older than 50 years [20,44]. This may drive one to conclude that the limited evidence for an overall connection between fetal growth and maternal breast cancer risk described in some of the papers may be explained, at least partly, by restriction of the study population to women younger than 50 years [43]. Such age-dependent differences in breast cancer incidence between mothers of babies with high BW can be most likely be attributed to disparities in the hormonal and metabolic background of pre- and post-menopausal breast cancer [20,36,44].

On the whole, the available data suggest that there is a positive correlation between cancers in mothers (predominantly breast cancer) and large BW in their babies. While this correlation contradicts the data on cardiovascular mortality in mothers ( Table 1 ), there are several potential reasons for this controversy, discussed in detail in the next section.

Newborn macrosomy & cancer/cardiovascular morbidity: the endocrine & other mechanisms of dichotomy

The child's own life

The biological mechanisms connecting prenatal factors with adult diseases are still poorly understood [10,15,16,31,32]. Attempts to find causes for the inverse relationship between newborn BW and subsequent cardiovascular mortality in their adult life are based on intrauterine undernutrition, developmental plasticity and compensatory growth concepts [3,11,23]. In particular, potential roles of the key factors (e.g., neuroendocrine, immunological, inflammatory, oxidative and DNA-damaging) involved in chronic diseases are considered. Environmental factors, apart from nutritional ones, are gaining more recognition [12]. In addition, more attention has recently been given to the genetic and epigenetic factors influencing mortality trends among women with a history of LBW [31,34,46], as well as to the genetics of BW itself [47,48]. There have also been attempts to find a common base for impaired insulin-mediated growth of the fetus and insulin resistance in adulthood [49].

The prevalence of CVDs among the causes of death in adult women with LBW history compared with cancer deaths warrants the search for some additional explanations [13,27,50,51]. In particular, the increased risk of breast cancer in women with HBW may be influenced by the number and properties of stem cells during the intrauterine period, this factor relates to mammographic density in later life, the effects of excess estrogen levels on stem cells or the shift in the MAPK/estrogen receptor-α ratio in the mammary gland tissue [13,52 –56]. However, these factors cannot be the cause of the positive association between BW and adult cancer mortality in men [27]. On the other hand, taking into consideration other hormone-like and growth factors (including IGF-1), epigenetic and genetic variations, ethnic differences, role of secular trend (acceleration) and some other assumptions, this research field looks increasingly important for understanding the relations between intrauterine factors and adult cancer morbidity [26,51 –55,57,58].

Diseases in mothers

The aforementioned trends may partly refer to the relationship between BW in babies and mortality caused by the main noninfectious conditions in their parents, mainly mothers. Clearly, the degree of parental (mothers and fathers) involvement in intrauterine life of their children is different. Therefore, the effect of birth characteristics on newborns and each of the two parents cannot be the same (see [27] and data presented in Tables 1 & 2). Indeed, the phenomenon sometimes mentioned with regard to associations between baby BW and parental morbidity/mortality is the intergenerational correlation of BW and intrauterine programming across generations [59,60]. This correlation is not always confirmed [44,61] and, when confirmed, it is relevant mainly to mothers. However, other mother-specific factors may also play a prominent role, especially regarding cancer [34]. They include hormonal and metabolic factors, influencing both mothers and fetuses during pregnancy, which may also be evident in other (pregravidal and postpartum) periods of mothers’ lives due to associations with lipid and carbohydrate metabolism, steroidogenesis, thyroid function and autoimmunity (Figure 1) [20,22]. For example, significantly higher placental weights were observed among mothers with low thyroid-stimulating hormone and high levels of free T₄ or high thyroid-stimulating hormone and low levels of free T₄ during the first trimester of pregnancy, as well as among autoantibodies to thyroid peroxidase-positive mothers [62], while thyroid autoimmunity itself is considered as a factor predisposing to breast cancer [63].

Figure 1.

Health perspectives of high birth weight female babies and their mothers.

Some additional factors may be as specific, while having a distinct nature. In particular, giving birth to children who are small for their gestational age is associated with decreased placenta-derived angiogenic growth factors levels in maternal circulation and, thus, decreased angiogenesis and coronary circulation repair later resulting in ischemic heart disease [61]. This can also relate to cancers (including mammary cancer) as higher levels of angiogenic factors may stimulate tumor initiation or promotion in mothers of macrosomic children (the assumption could be checked experimentally).

Four decades ago, as we initiated our studies of HBW in babies as an early marker of hormone-associated cancer risk for their mothers [20,22,64], we were motivated by the concept of maternal hyperglycemia leading to fetal hyperglycemia and, consequently, to insulin hypersecretion in fetuses [65]. This complex cause–effect relationship may lead to a fetal weight increase due to increased fat accumulation [65] and metabolic predisposition to cancer, which was termed ‘cancrophilia’ [66,67]. We hypothesized that a history of giving birth to macrosomic baby (>4000 g) may be, at least partly, associated in female cancer patients with latent carbohydrate metabolism disturbances, since there was no evident increase in overt diabetes rate observed for cancer patients, including patients with breast or endometrial cancer, in comparison to female cancer patients, who had not delivered a large baby [20].

The significance of glucose intolerance as a stimulating factor for both macrosomy of newborns and predisposition of their mothers to cancer can hardly be denied, especially owing to the well-known association between diabetes and certain types of cancer [68]. However, considering the U-shaped (rather than the linear) relationship between weight at birth and diabetes-related maternal mortality [69], we later started looking for other explanations for dichotomy (here, the opposite type of correlation) between mother cancer and CVDs risks in relation to baby BW. Clearly, this controversy contradicted the belief, that insulin resistance, metabolic syndrome, glucose intolerance and body mass excess are common causal factors for the main noninfectious conditions (i.e., CVDs) and, at least, some cancers (breast, endometrial and colorectal) [70 –72].

This dilemma may have a ‘particular’ and a ‘general’ solution. The particular solution concerns, for example, the potential role of excessive of estrogenic stimulation during the birth of HBW babies. Of note, although estriol is believed to be the main pregnancy-associated estrogen, the amount of more biologically active estradiol produced during pregnancy is also high, reaching 10,000 pg/ml by week 33 [73]. This may leave behind long-term ‘imprints’ manifested as initiation and promotion of occult breast tumors in mothers [40,44] and, also, as decreased maternal CVD risk [74].

The general solution may be reduced to the following reasoning [75]. In cases with multiple death causes (when the main cause is supplemented by additional ones with possible influence on lethal outcome [76]), ischemic heart disease as the main death cause is most often associated with diabetes mellitus and atherosclerosis, whereas cancers, including hormone-associated ones, are much more rare as comorbidity, located, in particular in females, behind stroke, asthma, tuberculosis and Alzheimer's disease [77]. The inverse relationship between mortality rates related to cancer and CVDs may be explained by gradual changes in morbidity structure and, more importantly, by competition and interaction between different diseases [78]. Thus, although the incidence of the main noncommunicable conditions increases with age, the rate of increase and disease combinations may have individual variations [75]. Since one of the crucial and integral intrauterine development markers, BW, has a positive correlation with cancer incidence (mainly breast and endometrial cancer) and a negative correlation with ischemic heart disease and hypertension in mothers, it mostly illustrates the general trend [77,78]. This general trend may be modified by endocrine-related ontogenetic features characteristic of separate individuals [5,10,12,20,64], and also by factors associated with heredity, ethnicity and different environmental effects [28,34,48,79]. However, speaking of breast cancer, one should note the fact that, as in many hormone-associated cancers, the pathogenesis of breast cancer concerns hormonal mechanisms, but also pathways based on DNA damage [80 –82]. Nevertheless, as the genotoxic damage often needs hormonal backing to cause cancer (and it is, in particular, evident in patients with genetic predisposition to malignant growth [83,84]), this factor should be acknowledged as a legitimate additional answer to the question on how offspring macrosomy at birth can be predominantly related to maternal inclination for tumor development in hormone-dependent tissues; at the same time, the role of DNA damage in the initiation and progression of CVDs remains highly debated [85].

Conclusion

The concept of intrauterine or fetal origins of prevalent adult noninfectious conditions has recently gained the status of an axiom. This idea was strongly influenced by the discovery of a relationship between BW and subsequent ‘medical events’ in adult life [24,27,30]. There is also an association between a baby's BW and morbidity/mortality rates of their mothers due to cardiovascular conditions and some types of cancer (mostly hormone-associated). Moreover, these associations are different, are even the opposite [20,36,37,44,61]. These may have a distinct hormonal and metabolic background starting rather early (the initiation time may vary) and influencing both child and mother (Figure 1).

Thus, what conclusions can we draw from the abovementioned facts, taking into consideration the topic of this report? The founder of the currently accepted approach to the ‘fetal origin of adult disease’ and his coauthors have long believed that measures promoting pre- and post-natal growth are able to decrease mortality from ischemic heart disease [23]. As this approach was mostly focused on small newborns, it somewhat missed potential cancer-related threats associated with increased BW, revealed by other authors [15,17,86,87] and the authors of this article [22,88]. As time passed the approach gradually tended to become more balanced [12,57].

Therefore, while assuming the existence of associations between fetal development and later chronic noninfectious diseases emerging both in babies reaching adulthood and, as was expressly pointed in this article, in their mothers, we should have two objectives in mind. The first is achieving an optimal weight at birth (approximately 3400 g at 40 weeks in Caucasians [1]). The second is working out a reasonable approach to prevent hormone-associated cancers (mainly, breast and endometrial cancer) in mothers of macrosomic babies and cardiovascular conditions in women whose newborn babies are on the contrary often relatively small [12,18,20,52,53]. The question of whether such preventive measures are to be taken during pregnancy or in other periods has already been discussed (see, for example, [20,89,90]), although this is yet to be studied in full.

Future perspective

The peculiar point in babies’ BW association with distant/delayed pathological conditions is its relation to both baby's adult life and his or her mother's health.

In either case, those concerned in this specific area of women's health have to face, at present and in the future, not only biomedical, but ethical problems as well.

Since body weight at birth is, in a sense, recognized as a resultant and starting parameter, we should expect the prevalence of two research lines in the near future. The first will be focused, as one may foresee, on the identification of the most effective markers, mainly molecular and genetic ones, of HBW association with real cancer risk in mothers and causes of these associations. The second line will apparently be centered on finding the period of a mother's life when preventive interventions against potentially adverse events, possibly associated with high body weight of newborn babies, are most optimal and reasonable. The same is true for mothers in the opposite (LBW/CVDs) situation, while the change in trend in markers and preventive measures will obviously be needed.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Executive summary

Background

Many chronic diseases (e.g., cardiovascular diseases and cancer) are more common in older adults, but their causal factors often occur at earlier stages of ontogenesis.

One of the most thoroughly studied predictors in this area is birth weight (BW), which is considered an integral parameter for the evaluation of fetus–mother relations. Lately, a great deal of attention has been focused on groups of newborns with low and high BW.

BW & liability to adult conditions including cancer & cardiovascular disease

Although there are many studies highlighting the relationship between BW and later adult morbidity or mortality, much less attention is paid to associations between baby BW and maternal morbidity.

The opposing relationship between HBW, cancer & cardiovascular disease occurrence in mothers

The available data suggest a sort of dichotomy in these relationships. Thus, cardiovascular risk is higher in mothers of babies with low BWs, while cancer risk, mainly of the breast and some other hormone-dependent cancers, is often higher among mothers of babies with high BWs (newborn macrosomia).

This controversy contradicts the belief that insulin resistance, metabolic syndrome, glucose intolerance and body mass excess are common causal factors of the main noninfectious conditions (i.e., cardiovascular disease) and, at least, some cancers (breast, endometrial and colorectal).

Newborn macrosomy & cancer/cardiovascular morbidity: the endocrine & other mechanisms of dichotomy

While explaining this dilemma, the emphasis can be made on ‘particular’ (mother-specific) and more ‘general’ factors, namely on a probable competition between chronic diseases (first of all, between hormone-related cancer and cardiovascular conditions) in view of the multiple causes of death concept.

The general trend may be modified by endocrine-related ontogenetic features characteristic for separate individuals, and also by factors associated with heredity, ethnicity and different environmental effects.

References

Papers of special note have been highlighted as:.

of interest

of considerable interest

Hytten

Leitch

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High Bab Birth Weight Andof Hormone-Associated Cancer in Mothers: The Cancer–Cardiovascular Disease Dichotomy and its Possible Causes

Abstract

Keywords

BW & liability for adult conditions including cancer & CVDs

Opposite associations of HBW with maternal morbidity owing to cancer & CVDs

Newborn macrosomy & cancer/cardiovascular morbidity: the endocrine & other mechanisms of dichotomy

The child's own life

Diseases in mothers

Conclusion

Future perspective

Financial & competing interests disclosure

References