Introduction

Hypertension (HTN) is a common disorder that affects 25–35% of adults worldwide [1]. Although several treatments have been developed, the control of HTN remains insufficient [2]. Recently, the global prevalence of chronic kidney disease (CKD) has been determined to be 13.4% and is rising [3, 4]. Furthermore, CKD is the fourth fastest increasing cause of death globally [5]. Both CKD and HTN are strong risk factors for cardiovascular disease and end-stage renal disease (ESRD), with ESRD having a particularly great economic impact on social systems due to the high cost of renal replacement therapy [6]. Preemptive medical treatment is a strategy for managing these disorders [7], and the developmental origins of health and disease (DOHAD) concept has been recognized as a potential source of clues for preventing these diseases [8].

Low birth weight (LBW) is regarded as an indicator of intrauterine growth restriction (IUGR) and/or preterm birth (<37 weeks gestation). LBW is believed to be an antecedent of chronic noncommunicable diseases (NCDs) and a potential contributor to HTN and CKD in adults. The prevalence of LBW is high in developing countries and is increasing in most developed countries [9, 10], making it a global public health problem associated with mortality and morbidity in infants and adults. However, the actual influence of the increasing trend in LBW prevalence on renal function and blood pressure (BP) is currently unknown. In this review, we examine the recent evidence for the effects of LBW on renal function/BP and discuss the impact of the increasing prevalence of LBW on the incidence of CKD/HTN.

LBW prevalence

LBW, defined as a birth weight ≤2500 g, is attributed to IUGR (small for gestational age) or preterm birth (birth before 37 weeks of pregnancy) and has a prevalence of ~10–15% in developing countries [10]. In addition, the prevalence of LBW in most countries belonging to the Organization for Economic Cooperation and Development has been increasing since 1990. On average, in these countries, LBW births have a prevalence of 6.5% among live births [11]. The reasons for the global increase in LBW prevalence include increases in the number of multiple pregnancies (probably due to reproductive medicine improvements), maternal prepregnancy factors (e.g., older ages at parturition and undernutrition), and increased smoking by young women [12]. Increases in the numbers of LBW infants, as a proportion of total live births, are also high in East Asia, including in Japan and Korea [11]. In Japan, the prevalence of LBW has been increasing since the 1980s, and the current prevalence is high (9.4%), even when compared with the average for countries in the Organization for Economic Cooperation and Development (6.5%) [11]. In Japan, strict body weight management during pregnancy had been recommended for a long time, and a large percentage of young women remain underweight [13]. In Korea, the proportion of LBW births has increased along with the proportion of underweight young women [14]. Recently, ~25% of young women in Japan and ~15% of young women in Korea are underweight (BMI <18.5), compared with ~2% of young women in the USA. Therefore, as seen in developing countries, malnutrition in young women might contribute to the increasing prevalence of LBW births. This upward trend in the numbers of LBW births has raised concern about the potential influence of LBW on NCD development [15].

Impacts of increased LBWs on renal function

The actual effect of declining average birth weight on NCD development remains unknown. To investigate the relationship between the upward trend in LBW prevalence and renal function, we conducted an annual cross-sectional study over an 18-year period (1998–2015), which included 3737 male adolescents who did not manifest age-related CKD [16]. We found that both renal function and birth weight have decreased since 1998 in these apparently healthy adolescents. Although metabolic parameters, such as serum glucose and total cholesterol, were not associated with reduced renal function, a significant association between stage 2 CKD and LBW was found. To the best of our knowledge, this was the first study to demonstrate an actual association between the trend of LBW and renal function. We also reported a significant increase in the prevalence of proteinuria in the same study of adolescent males [16]. According to a national survey, the prevalence of proteinuria in high school students in Japan has gradually increased in conjunction with decreasing birth weights since the 2000s (Fig. 1) [13, 17].

Fig. 1
figure 1

Association of the protein-positive urine rate with the average birth weight. A national survey in Japan demonstrates that the rate of protein-positive urine samples obtained during school medical examinations is rising, in conjunction with decreasing birth weights

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DOHAD

The DOHAD concept suggests that undesirable environmental conditions, such as maternal malnutrition and smoking during the perinatal period, influence the susceptibility to NCDs during adulthood. For several decades, epidemiological studies have pointed to an association between insults occurring in utero and during infancy with NCD risk. In the 1970s, individuals who had been exposed as fetuses to the Dutch winter famine during World War II were reported to frequently manifest lifestyle-related diseases, such as adulthood obesity [18, 19], implying the potential contribution of malnutrition during pregnancy to the future onset of disease. In the 1980s, Barker et al. reported a geographic relationship between high cardiovascular mortality and high infant mortality in England and Wales, where social conditions were poor and death rates have been consistently elevated [20]. They also found that LBW individuals have higher incidences of ischemic heart disease, HTN, and insulin resistance [21]. Based on these findings, the same authors also proposed that adulthood NCDs may originate from fetal malnutrition, the so-called “fetal origins of adult disease (FOAD) theory” [22]. In the 1990s, animal experiments documented the phenotype of fetal programming of NCDs. Entering this century, investigations into the possible underlying mechanisms of FOAD progressed, with the FOAD hypothesis developing into the broader concept of DOHAD [23]. The DOHAD concept suggests that the period from the early embryonic stage through childhood is important for determining NCD susceptibility later in life.

CKD and the DOHAD concept

The main causes of CKD include diabetes, HTN, and glomerulonephritis, while aging also contributes to its development [24]. LBW has also been identified as a potential risk factor for CKD. Reduced renal function, evaluated using the estimated glomerular filtration rate (eGFR), has been documented in adolescents who were LBW babies [25], and their renal function likely declines with advancing age [24]. Furthermore, in young adulthood, LBW individuals have been found to have decreased renal function, as assessed using creatinine clearance (the odds ratio [OR] for low–normal creatinine clearance (<100 ml/min) in young adults who were LBW babies was 1.66, with a 95% confidence interval [CI] of 1.16–2.37) [26]. In later life, meta-analyses further demonstrated a significant relationship between LBW and the onset of CKD, defined as albuminuria, reduced eGFR (<60 ml/min/1.73 m2 or <10th centile for age/sex), or ESRD (OR, 1.73; 95% CI, 1.44–2.08) [27]. A recent meta-analysis found that LBW contributes to a 70% increased risk of CKD in adulthood; the risk was especially high among Asian and Australian populations (reduced eGFR (<60 ml/min/1.73 m2): OR, 2.68; 95% CI, 1.73–4.15; albuminuria: OR, 2.28; 95% CI, 1.17–4.43) [28]. For every 1 kg increase in birth weight, the eGFR (calculated using creatinine and cystatin-based formulas) increased by 2.13 ml/min/1.73 m2 (95% CI, 0.69–3.58) [29].

Preterm birth, regardless of birth weight, is also a risk factor for the development of CKD in mid-adulthood; preterm individuals have a twofold higher risk of CKD than do individuals born at full term [30]. Pathological assessments showed that LBW and preterm birth are also risk factors for the development of secondary focal segmental glomerulosclerosis (FSGS) [31, 32]. The glomerulomegaly, focal and segmental matrix expansion, and podocytopenia seen in these patients might contribute to the progression of proteinuria and FSGS [31]. As also shown for diabetic kidney disease [33], individuals with LBW are prone to various primary and secondary renal diseases [32, 34, 35]. Together, these data indicate that LBW is associated with an increased susceptibility to renal disease that can, in turn, contribute to CKD progression.

HTN and the DOHAD concept

As in reports regarding CKD, LBW is also associated with high BP in later life. Specifically, LBW was significantly associated with a 30% increased risk of HTN compared with term infants with normal birth weights (OR, 1.30; 95% CI, 1.16–1.46) [36]. Furthermore, a significant inverse correlation between BP and birth weight was observed; for every 1 kg increase in birth weight, systolic BP was reduced by 1.36 mmHg (95% CI, −1.62 to −1.09), and diastolic BP was reduced by 0.33 mmHg (95% CI, −0.54 to −0.13) [36]. In a study involving twins, the twin with the lower birth weight manifested a more rapid increase in systolic BP during infancy [37], indicating that prenatal environmental factors determine susceptibility to high BP, regardless of genotype. In addition, African–Americans often demonstrate higher BPs than White Americans, and IUGR can explain the racial predisposition to high BP. Birth weights are often lower in Black infants than in White infants, and BPs are typically higher in Black adolescents than in White adolescents, indicating that intrauterine growth may play an important role in the Black/White difference in BPs [38]. Preterm birth, regardless of birth weight, is also a risk factor for HTN development. Individuals born preterm are more likely to have higher BPs (on average, 2.5 mmHg higher) than individuals born at term [39]. Furthermore, individuals born preterm remain smaller than their full-term counterparts; however, any postnatal catch-up growth augments the risk of elevated BP [40]; therefore, the perinatal period plays an important role in regulating BP in later life. In our 18-year study, we did not observe increased BPs in adolescents with LBWs, nor was there a significant upward trend in BP values [16, 41]. Accordingly, the association between LBW and the development of HTN in adolescence is inconsistent among several reports [16, 41,42,43]. Young adults who had very LBWs (VLBWs; birth weight <1500 g) showed increased BPs compared with others born at term [44]. Young adults with VLBWs demonstrated 24-h systolic BPs that were 2.4 mmHg higher (95% CI, 0.2–4.6) after adjusting for sex, age, and body mass index (BMI) than for those born with normal birth weights [45]. Even among those born with VLBWs, the apparent increase in mean BP is small; therefore, the increased BPs are only evident in later adulthood, as confirmed by epidemiological studies [46]. Individuals with LBWs are vulnerable to obesity, and BMI is likely a potential contributor to increased BP, especially in children and adolescents.

DOHAD mechanisms

Although several potential mechanisms for DOHAD have been suggested, there are likely two main mechanisms. One is that immature organ development may be induced by gestational stress, which leads to structural changes and impaired functioning of the affected organ. For example, LBW is a risk factor for diabetes in adults, and reduced islet cell mass and β cell numbers have been reported in LBW infants [47]. Another possible mechanism is epigenetic modification. Below, we summarize the possible mechanisms for disturbances in renal function and BP in LBW individuals.

Low nephron numbers

A low number of nephrons is a major, known factor that determines the development of CKD and HTN (reviewed in [48]). Nephron numbers decrease linearly as individuals age, at least until the age of 70 years [49]. LBW due to IUGR and/or preterm birth affects renal function by causing a reduction in the number of functional nephrons, as suggested by Brenner et al. [50, 51]. The fetal period is a critical period for nephron formation (nephron endowment), and nephron formation continues until 36 weeks gestation; additional nephrons do not develop thereafter [52]. An analysis of autopsies performed on IUGR infants showed a linear increase in the number of glomeruli as the birth weight rose to 3000 g, after which the number stabilized [53]. In preterm infants, nephrogenesis continues after birth, but preterm infants have fewer functional nephrons [54]. The reduction in the number of glomeruli observed in IUGR/preterm births decreases the surface area available for filtration, and the development of glomerular hyperfiltration could eventually cause proteinuria and glomerular sclerosis. In turn, increases in proteinuria and glomerular sclerosis may lead to further glomerular hyperfiltration. Ethnic groups that are prone to renal disease, including aboriginal Australians, have low nephron numbers and large glomeruli and are at an increased risk of developing ESRD [55]. Overall, nephron numbers vary widely between ethnic groups, with Japanese people having a particularly low number of nephrons, probably due to their short stature, compared with other ethnicities [56]. Furthermore, the low nephron numbers seen in Asians may account for their high incidence of ESRD [6].

The total GFR is the product of the total nephron number and the single-nephron GFR. Since the single-nephron GFR is stable in healthy adults, the decreasing number of nephrons that has been associated with aging is believed to lead to a decreasing total GFR [49]. According to the glomerular hyperfiltration theory, the single-nephron GFR is likely to be higher in LBW individuals. Indeed, we and others have demonstrated that adolescents born with LBWs have lower eGFRs than adolescents born with normal birth weights [16, 25]. These results do not necessarily indicate that the single-nephron GFR is increased to compensate for the low nephron numbers in such individuals. The significance of the single-nephron GFR on LBW-related kidney disease could be more evident after secondary insults, such as obesity and HTN, which also cause deterioration of glomerular hyperfiltration. Brenner et al. proposed that low nephron numbers may reduce renal salt excretion because of the reduced filtration surface area, increasing an individual’s susceptibility to high BP in the setting of high sodium intake. In fact, LBW individuals do manifest increased salt sensitivity [57], which results from shifting pressure natriuresis curves and the maintenance of high BP.

Cardiovascular development

IUGR and preterm birth affect proper vascular development and result in vascular structure and function alterations. During microvascular development, the reduced density of arterioles/capillaries and the narrowing of arterioles, both observed in individuals with LBW, lead to increased peripheral vascular resistance that can contribute to increased BP [58, 59]. Macrovascular development is also affected by LBW. The production of elastin, an extracellular matrix protein, is largely restricted before birth and is also reduced in LBW individuals; reduced elastin production leads to aortic stiffness and high BP [60]. These vascular structural alterations affect the functioning of the vascular system, including a contribution to the endothelial dysfunction observed in adults born with LBW [61, 62]. In addition to the effect on BP, insufficient vascular development may affect renal function [63]. LBW mice, the development of which is induced through prenatal caloric and protein restriction, manifest low renal vascular densities and endothelial dysfunction, which contribute to declines in renal blood flow and GFR [64]. Impaired cardiovascular structure and function have also been reported in cases of severe, acute malnutrition during childhood [65]. Such individuals manifest increased peripheral vascular resistance at ~30 years of age, suggesting that they will be hypertensive later in life [65].

Epigenetic modifications

Epigenetic modifications (i.e., altered gene expression without DNA sequence changes) have been suggested as potential molecular mechanisms of DOHAD [66]. For example, promoter hypomethylation is associated with transcriptional permissiveness that results in increased target gene expression. Among survivors of the Dutch winter famine, malnutrition (maternal intake of 400–800 calories/day during pregnancy) has been associated with an increased risk of NCD development once the affected fetuses reached adulthood [19]. Fetal exposure to famine led to hypomethylation of insulin-like growth factor 2, which might influence growth and development [67], and altered the methylation status of several other genes [68]. Hypomethylation of the angiotensin-converting enzyme gene promoter [69] and the Ang II receptor type 1 receptor in the adrenals [70] was reported in protein-restricted animal models to lead to HTN, as suggested by the DOHAD concept. The role of epigenetic mechanisms in the development of CKD remains under investigation [71]; some studies have reported the participation of the epigenome in the development of CKD induced by LBW. Recently, Wanner et al. demonstrated that DNA methyltransferases are abundant during nephrogenesis and that DNA methyltransferase 1 deficiency induces global DNA hypomethylation in kidney progenitor cells and upregulates genes such as germline genes, leading to reduced differentiation of the nephrons [72]. These changes reduce nephron numbers and lead to renal hypoplasia at birth, indicating the role of DNA methylation in renal development, especially as related to IUGR [72].

Other factors

LBW is also associated with sympathetic nerve activation, which may explain BP increases [73, 74]; experimental data have shown that sympathetic nerve activity is increased in a rat model with IUGR [75]. Gene expression changes in components of the renin–angiotensin system and in renal sodium transporters have also been considered to increase BP in this model (reviewed in [76]). Recently, the gut microbiota has been associated with NCDs, and gut microbiota alterations are believed to contribute to BP regulation through changes in the composition of the gut microbiota and/or its metabolites, such as short-chain fatty acids and trimethylamine N-oxide (reviewed in [77]). For example, short-chain fatty acids were shown to stimulate renin secretion and regulate BP through the Olfr78 and Gpr41 receptors [78]. Furthermore, transgenerational inheritance of high BP has been suggested to be related to the gut microbiota [77]. Some studies have also demonstrated that the gut microbiota is altered in pregnant hypertensive patients [79]; this implies that the gut microbiota acquired from an individual’s mother might contribute to HTN. However, some LBW infants are delivered by cesarean section and may avoid exposure to the maternal gut microbiota. Thus, the role of early colonization on NCD development has not been clearly elucidated. The strain composition of the gut microflora remains stable for several years [80], suggesting that the gut microbiota acquired during the fetal period may affect susceptibility to HTN/CKD when the individual reaches adulthood.

Sex impact on CKD in the DOHAD concept

Previous studies investigating sex differences have revealed that females have significantly lower nephron numbers than males (794,493 ± 248,725 vs. 941,023 ± 337,705), suggesting an increased risk of CKD in females based on a reduced renal endowment [81]. However, one meta-analysis showed that renal functioning declines faster among males than among females, despite females having a lower nephron number [82]. Theoretically, a protective effect of estrogen in females and higher risk lifestyles among males might explain the faster renal functioning decline in males [83]. To date, some reports demonstrate that the potential association between birth weight and CKD is weak in women [84]. To determine sex differences in CKD susceptibility due to birth weight, we evaluated the annual cross-sectional data from 2417 Japanese adolescents (1736 males and 681 females), 15–16 years old, over an 8-year period (2007–2014) [41]. We noted that birth weights and eGFRs of the study subjects decreased over the course of our study; LBW was significantly associated with renal dysfunction in both male and female adolescents. The incidence of stage 2 CKD was significantly related to LBW (males: OR, 1.73; 95% CI, 1.06–2.80; females: OR, 3.29; 95% CI, 1.25–8.02), although the accuracy may have been lost when determining the higher GFR because we used an equation to estimate GFR for Japanese adolescents with CKD [16, 85]. These results indicate that LBW individuals of either sex may be vulnerable to CKD in later life.

We also considered the effects of secondary insults, such as catch-up growth and later obesity, on the occurrence of HTN/CKD. In developing countries, a high LBW prevalence and subsequent obesity, due to poor nutrition, synergistically contribute to NCD development [10]. In Japan, the prevalence of obesity is increasing among men but not women [86]. In fact, the mean body weight of young Japanese women is low, despite the global trend toward obesity. In view of the recent increases in LBW prevalence and subsequent obesity later in life, we speculate that the incidence of CKD in men might also increase, as previously suggested [87]. The high percentage of underweight women, the pregnancy-related increase in BP, and the deterioration of renal function (discussed below) indicate the need for a longitudinal study to evaluate the effects of LBW on renal function and BP.

Pregnancy and the DOHAD concept

Pregnancy unmasks a vulnerable female to LBW-related diseases. Western diets, lack of exercise, and aging are factors that exacerbate LBW-related NCDs; however, pregnancy is another of these factors for reproductive-age women. During the early stages of pregnancy, women manifest small BP decreases due to reduced peripheral vascular tone. As pregnancy progresses, BP normalizes, and blood volume is expanded with an increased GFR [88]. This hypervolemic state further exacerbates HTN and proteinuria, especially in individuals with poor reserves, such as those with low nephron numbers or vascular remodeling. Interestingly, there is a significant correlation between a pregnant woman’s own birth weight and the hypertensive disorders of pregnancy/renal dysfunction that she may experience. According to a previous study, the ORs for the development of HTN in a female born following IUGR or born preterm were 1.8 (95% CI, 1.1–2.8) and 1.5 (95% CI, 0.96–2.5), respectively [89]. LBW and preterm birth were significantly related to an increased risk of preeclampsia (birth weight <2041 g: OR for preeclampsia, 2.19 (95% CI, 0.91–5.25); prematurity: OR, 1.39 (95% CI, 1.01–1.93)) [90]. In addition, females with previous preeclampsia have higher risks of developing ESRD and HTN than females without it [91]. Therefore, LBW females who experience pregnancy-related complications require long-term follow-up to prevent CKD and HTN.

Transgenerational effects of DOHAD

Adverse environmental conditions in utero or during infancy affect not only a parent’s susceptibility to NCDs but also that of their offspring [67, 92, 93]. According to observational studies involving survivors of the Dutch winter famine, malnutrition during pregnancy has life-long effects on the health of affected fetuses that reach across generations [67]. Two possible mechanisms for the transgenerational effects of DOHAD have been suggested (reviewed in [94]). First, as shown in a previous paragraph, LBW females have an increased risk for hypertensive disorders during pregnancy. These disorders can also retard the fetal growth of their offspring, resulting in another generation of LBW children [95]. Second, undesirable uterine conditions also affect epigenetics by inducing permanent gene expression changes in germ cells. Several animal experiments have revealed that malnutrition during pregnancy contributes to increased BPs in the offspring once they reach adulthood [94, 96]. In humans, supporting evidence for the transgenerational effects of DOHAD has also been reported. The risk of preeclampsia and gestational HTN is increased in individuals born with LBW, and these hypertensive disorders are associated with the next generation of offspring having LBWs and an increased risk of HTN in later life [97]. Systolic BP values are higher in the offspring of mothers who experienced hypertensive disorders of pregnancy than in the offspring of mothers without such disorders (gestational HTN: 2.06 mmHg; 95% CI, 1.28–2.84; preeclampsia: 1.12 mmHg; 95% CI, 0.89–3.12). These hypertensive disorders are associated with changes in cord blood DNA methylation patterns in the offspring, which may contribute to HTN onset in the offspring [98]. In Japan, birth weights have been decreasing since the 1980s, and LBW females have now reached reproductive ages. Thus, close attention should be paid to the health conditions of both the mothers and their offspring. The concept of DOHAD impacting the onset of HTN/CKD is summarized in Fig. 2.

Fig. 2
figure 2

The impact of life-course insults on HTN/CKD occurrence as related to the concept of DOHAD. LBW is an indicator of undesirable perinatal environmental conditions and predisposes to the occurrence of HTN/CKD. Secondary insults such as obesity and pregnancy add to the risk during the life course. HDP hypertensive disorder of pregnancy, LBW low birth weight, CKD chronic kidney disease, HTN hypertension

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Management of CKD and HTN relative to DOHAD

The effective treatment of CKD and HTN in adults remains insufficient to combat the global increases in the prevalence of these diseases, making the early recognition of risk factors and developing prevention strategies especially important. The management of CKD and HTN within the DOHAD concept was reviewed by the Low Birth Weight and Nephron Number Working Group [99]. They determined that medical histories should include birth weights for patients of all ages to screen for high-risk (LBW) patients [100]. In particular, individuals born prematurely and/or with VLBWs are vulnerable to acute kidney injury due to nephrotoxic agents with the presence of incomplete nephrogenesis. Indeed, acute kidney injuries occur in 40% of such individuals during infancy [101], and these injuries are potential risk factors for subsequent CKD development [102]. Therefore, medical histories should also include information regarding neonatal acute kidney injury.

Prenatal calorie restriction, followed by postnatal overfeeding, also contributes to an increased NCD risk [103, 104]. This association between IUGR and subsequent “catch-up” (glucose- and fat-enriched) diets and NCDs was demonstrated in animal models [105]. Furthermore, accelerated kidney cell senescence, following catch-up growth, was observed in LBW rats [106]. A meta-analysis demonstrated that young adults who were born preterm have higher (~3 mmHg) systolic BPs than individuals born at term [107]. As BP is known to track with age [108], these small differences between preterm and term individuals are likely to increase with age. Young adults with prehypertension already have an increased risk of developing cardiovascular disease [109]; therefore, early treatment involving lifestyle modifications and/or antihypertensive medication could theoretically prevent the onset of HTN and CKD [107].

Treatment with renin–angiotensin blockade

The activity of the renin–angiotensin II-aldosterone system is high in individuals with LBW-related renal complications and HTN. In LBW rat pups, the intrarenal renin–angiotensin system is upregulated by four weeks of age, unlike in control animals [110]. This upregulation leads to increased efferent arteriolar resistance and glomerular HTN. Pathological assessments have also shown that VLBW, LBW, and premature birth are risk factors for secondary FSGS [31, 32], for which blocking of the renin–angiotensin system may reduce proteinuria and retard renal injury. Indeed, a case report has shown that treatment with an angiotensin-converting enzyme inhibitor effectively ameliorates proteinuria and HTN in patients born extremely prematurely [111]. In addition, patients with both autosomal dominant polycystic kidney disease and LBW benefit more from the use of drugs that block the renin–angiotensin system compared with the use of beta-blockers or diuretics, as these drugs postpone the onset of ESRD by 4.3 years [112]. Therefore, the use of angiotensin-blocking agents in patients with LBW-related renal complications may be reasonable.

Conclusion

The prevention and treatment of various age-related NCDs are becoming crucial issues as the number of elderly people increases, especially in Japan. Preemptive medical treatments comprise a potential effective strategy for combatting NCDs because they intervene before disease onset to actively prevent the disease. The relevance of the DOHAD concept has been recognized because of its impact on our understanding of HTN/CKD development, particularly in view of the increasing prevalence of LBW births worldwide. In Japan, the mean annual eGFR has decreased and the incidence of proteinuria has increased over the last two decades, and these changes are significantly associated with the increased number of Japanese adolescents who were LBW babies [16, 41]. These results indicate that adolescents who had LBWs are prone to HTN and CKD during their later lives. Considering the risk of HTN/CKD onset, establishing a screening and follow-up program for managing individuals who were born with LBWs and their offspring is needed.