Which contributing factor in large for gestational age LGA infants accounts for the greatest number of cases?

Introduction

The association between preterm birth (PTB), low birth weight (LBW), and small for gestational age (SGA) and neonatal and long-term outcomes is well-described and suggests higher risks for cardiovascular diseases, diabetes, hypertension, and stroke later in life according to the Barker hypothesis (1). Less attention has been paid to high birthweight children and children born large for gestational age (LGA), particularly the long-term outcomes. The prevalence of high birthweight and LGA babies is increasing (2, 3), in parallel with the worldwide rise in obesity, also among women of childbearing age (3). In assisted reproduction, several studies have shown that children born after transfer of frozen/thawed embryos (FET) have a lower risk of preterm birth, low birth weight, and SGA compared with singletons born after fresh transfer but also a higher risk of being born with a high birth weight and LGA (4–6). Due to high success rates, FET of vitrified/warmed blastocysts has increased dramatically in recent years, including the “freeze all” technique where all available embryos of good quality are cryopreserved for later use in a natural or programmed cycle (7–11). The perinatal outcomes for babies of high birth weight and being LGA are mainly associated with difficulties at delivery such as asphyxia, shoulder dystocia, hypoglycemia, respiratory problems, cesarean section, and obstetric injuries (12, 13). For long-term outcomes, an association has been found between high birth weight and child malignancies, breast cancer, psychiatric disorders, and cardiometabolic diseases (14–19).

The aim of this systematic review and meta-analysis is to summarize the present knowledge on long-term outcomes for children born with a high birth weight or being LGA.

Methods

We searched PubMed, Scopus, and Web of Science databases up to January 2021. Exposures were large for gestational age and high birth weight. Long-term morbidity outcomes studied were cancer, metabolic disease, cardiovascular disease, and psychiatric disorders. Cancer was focused on breast cancer, child malignancies in the central nervous system (CNS), hematological malignancies, and Wilm's tumor. Metabolic diseases were focused on diabetes type 1 and type 2. Cardiovascular disease was focused on hypertension and other cardiovascular disorders. Psychiatric disorders were focused on schizophrenia/psychosis and cognitive disorders. Some of these outcomes, when appropriate, were used for meta-analysis.

Systematic Search for Evidence

The terms used in the searches are listed below:

LGA[tiab] OR large for gestational age[tiab] OR large-for-gestational age[tiab] OR HBW[tiab] OR high birth weight*[tiab] OR higher birth weight*[tiab] OR highest birth weight*[tiab] OR high birthweight*[tiab] OR higher birthweight*[tiab] OR highest birthweight*[tiab] OR macrosomia[tiab]. Because of large heterogenecity in the nomenclature of diseases and to avoid missing any important morbidity, we decided not to include any specific disease or morbidity terms in the search.

We also manually searched reference lists of identified articles for additional references. Guidelines for meta-analysis and systematic reviews (SR) of observational studies were followed (20). The literature search was performed by two researchers (Å.M. and C.B.) and one librarian. Screening of abstracts and of full papers for inclusion was done by pairs of reviewers. Differences of opinion in the team were solved by discussion until consensus was achieved.

The last literature search was performed January 14, 2021.

Inclusion and Exclusion of Studies

Original studies published in English or Scandinavian languages were included. In the case of double publication, the latest study was included. Studies with a control group were included. Studies published only as abstracts and case reports were excluded.

Definitions

High birth weight was defined by each author but usually ≥4,000 or ≥4,500 or occasionally >5 g. LGA was defined by each author.

Appraisal of Certainty of Evidence

The methodological quality of original studies, in terms of risk of bias, was assessed by pairs of reviewers by the tool Robins-I (http://www.methods.cochrane.org). For systematic reviews, we used AMSTAR (http://www.amstar.ca). For certainty of evidence, we used the GRADE system (21). The systematic review followed PRISMA guidelines (22).

Data Synthesis

Outcomes are given in odds ratio (OR), adjusted odds ratio (AOR), hazard ratio (HR), adjusted hazard ratio (AHR), relative risk (RR), adjusted relative risk (ARR), incidence rate ratio (IRR), adjusted incidence rate ratio (AIRR), standardized incidence ratio (SIR), or random-effects odds ratio (REOR) with 95% CIs. Meta-analyses were performed despite significant heterogeneity in reference groups and despite the fact that outcomes were given in AOR, ARR, or ROR. However, studies reporting estimates as HR, AHR, AIRR, and SIR were not mixed with the RR- and OR-based outcomes. The HR- and IR-based outcomes were also too few to be included in a separate meta-analysis. A random-effects meta-analysis using the Der Simonian and Laird method, with the estimate of heterogeneity being taken from the Mantel–Haenszel model, was used in the analysis (command metan in Stata 15).

Results

The search strategy identified a total of 11,767 abstracts, of which 173 were selected for inclusion in the systematic review and 63 for inclusion in quantitative synthesis (meta-analysis) (Figure 1). No papers, particularly focusing in children with high birth weight born after FET, were identified.

FIGURE 1

Among the studies included were 19 meta-analyses, 73 cohort studies, 74 case–control studies, and seven cross-sectional studies (tables, characteristics of included studies and excluded studies, with reasons for exclusion, are presented in Supplementary Tables 1.1–1.4, 2.1–2.4).

A quality assessment of the cohort, case–control, and cross-sectional studies included is presented in Supplementary Tables 3.1–3.4 and for systematic reviews in Supplementary Table 4. Of the selected cohort, case–control, and cross-sectional studies, 28 articles had low, 79 had moderate, 47 had serious, and two had critical risk of bias. Of the systematic reviews, 10 were of high, five of medium, and four were of low quality. Summary of findings (SoF) is presented in Supplementary Table 5.

Malignancies

Outcomes are listed in Table 1.1.

TABLE 1.1

Table 1.1. LGA and high birth weight and long-term outcomes—malignancies.

Breast Cancer

Three SR/meta-analyses (23–25), 10 cohort studies (26–35), and nine case–control studies (14, 36–43) investigated the association between high birth weight and the risk of breast cancer. The three SR, one of high and two of low quality, reported an increase of breast cancer per 500 g increase in birth weight [RR 1.02 (95% CI 1.01–1.03)] (25) and if birth weight was >4,000 g [RR 1.23 (95% CI 1.13–1.24) and RR 1.15 (1.09–1.21)] (23, 24). Among the 10 cohort studies, five out of nine studies with low to moderate risk of bias (27–29, 31–35, 39), found an association between high birth weight and later development of breast cancer. Three out of four case–control studies with low to moderate risk of bias also found an association (37, 40, 42). When only evaluating studies with low risk of bias (32, 33, 40, 42), three studies found an association. Our meta-analysis including 15 original studies showed a pooled AOR of 1.24 (95% 1.11–1.39) for development of breast cancer, when comparing birth weight >4,000 or >4,500 g vs. birth weight of <4,000 g (Figure 2).

FIGURE 2

Figure 2. Forest plot describing the association between high birth weight and breast cancer.

Conclusion: High birth weight is probably associated with a moderate increase in breast cancer, moderate certainty of evidence (GRADE ⊕⊕⊕O).

CNS Tumors

Four SR/meta-analyses, three cohort studies, 14 case–control studies, and one cross-sectional study reported on the association between high birth weight and CNS tumors. Two SRs, of medium and high quality, found an association between birth weight >4,000 g and astrocytoma [OR 1.38 (95% CI 1.07–1.79) and REOR 1.60 (95% CI 1.23–2.09)] and medulloblastoma [OR 1.27 (95% CI 1.02–1.60) and REOR 1.31(95% CI 1.08–1.58)] compared with <4,000 g (44, 45). A meta-analysis of medium quality (46) found for neuroblastoma, an OR of 1.19 (95% CI 1.04–1.36) for birth weight >4,000 g compared with <4,000 g. The SR/meta-analysis (high quality) by Georgakis and co-workers in 2017 (47) reporting on all CNS tumors, found an OR of 1.14 (95% CI 1.08–1.20) for high birth weight and an OR of 1.12 (95% CI 1.03–1.22) for LGA. Two cohort studies, both with low risk of bias, found an association between high birth weight and CNS tumors (48, 49), while one cohort study, with low risk of bias, found no association between LGA and CNS tumors (50). Nine out of 14 case–control studies had moderate risk of bias, where three studies (45, 51, 52) found an association between birth weight >4,000 g and CNS tumors, while six case–control studies, with moderate risk of bias, and one cross-sectional study (53) found no association.

Our meta-analysis, including 15 original studies, showed a pooled AOR of 1.15 (95% CI 1.05–1.27) for development of CNS tumors, when comparing birth weight >4,000 or >4,500 g vs. birth weight of <4,000 g (Figure 3). For LGA vs. AGA, the corresponding figure was AOR 1.09 (95% CI 0.95–1.23) (Figure 4).

FIGURE 3

Figure 3. Forest plot describing the association between high birth weight and CNS tumors.

FIGURE 4

Figure 4. Forest plot describing the association between LGA and CNS tumor.

Conclusion: High birth weight is probably associated with a slight increase of CNS tumors, moderate certainty of evidence (GRADE ⊕⊕⊕O).

Hematological Malignancies

Two systematic reviews (54, 55), four cohort studies (34, 56–58) and 17 case–control studies (51, 52, 59–73) investigated the association between high birth weight and leukemia, one cohort study (74), and two case–control studies (16, 75) reported on lymphoma and five case–control studies (76–80) had investigated the impact of high birth weight on both leukemia and lymphoma.

Leukemia

Both SR, of high and low quality, respectively, reported an association between birth weight >4,000 g and leukemia [OR 1.25 (95% CI 1.17–1.37) and AOR 1.35 (95% CI 1.24–1.48)] (54, 55). Two out of three cohort studies (56–58), all with low risk of bias, found an association between birth weight >4,000 g and acute lymphatic leukemia (ALL) (56, 58) and between LGA and ALL (56). Fourteen of the 22 case–control studies investigating the association between high birth weight and leukemia had a low to moderate risk of bias, and of these, 10 showed an increased risk if birth weight ≥4,000 or ≥4,500 g. The results from 22 original studies reporting on leukemia and high birth weight were pooled in a meta-analysis showing an AOR of 1.29 (95% CI 1.20–1.39) (Figure 5) and for LGA an AOR of 1.45 (95% CI 1.10–1.91) (Figure 6).

FIGURE 5

Figure 5. Forest plot describing the association between high birth weight and leukemia.

FIGURE 6

Figure 6. Forest plot describing the association between LGA and leukemia.

Lymphoma

One cohort and seven case–control studies reported on lymphoma. The cohort study by Petridou et al. (74) (low risk of bias) reported an increased risk for non-Hodgkin lymphoma when the child was born LGA while no significant increased risk was found for high birth weight. Two case–control studies with moderate risk of bias (16, 78), comparing >4,000 g as exposure to the reference <4,000 g, reported an association between high birth weight and Hodgkin/non-Hodgkin lymphoma. One case–control study, with moderate risk of bias reported an association between LGA and risk of Burkitt's lymphoma but no increased risk for other lymphomas (75).

Conclusion: High birth weight is probably associated with a moderate increase in leukemia, moderate certainty of evidence (GRADE ⊕⊕⊕O). LGA may be associated with a moderate increase in non-Hodgkin lymphoma, low certainty of evidence (GRADE ⊕⊕OO).

Wilm's Tumor

One SR (81), two cohort studies (82, 83), and 12 case–control studies (51, 78, 80, 84–92) reported on Wilm's tumor in childhood. The SR being of medium quality reported an increased risk for Wilm's tumor if birth weight >4,000 g as well as for LGA [OR 1.36 (95% CI 1.12–1.64) and OR 1.51 (95% CI 1.25–1.83)] (81).

One out of two cohort studies with low-moderate risk of bias (82, 83) showed an association between high birth weight and Wilm's tumor (82). Five out of eight case–control studies, being of low to moderate risk of bias showed an increased risk of Wilm's tumor if birth weight >4,000 g or if LGA. Our meta-analysis including 11 original studies showed a pooled AOR of 1.68 (95% CI 1.38–2.06) for Wilm's tumor, when comparing birth weight >4,000 g vs. birth weight of <4,000 g (Figure 7). For LGA vs. AGA, the corresponding figure was AOR 1.77 (95% CI 1.31–2.39) (Figure 8).

FIGURE 7

Figure 7. Forest plot describing the association between high birth weight and Wilm's tumor.

FIGURE 8

Figure 8. Forest plot describing the association between LGA and Wilm's tumor.

Conclusion: High birth weight and/or LGA is probably associated with a moderate increase in Wilm's tumor, moderate certainty of evidence (GRADE ⊕⊕⊕O).

Psychiatric Disorders

Outcomes are listed in Table 1.2a.

TABLE 1.2A

Table 1.2a. LGA, high birth weight, and long-term outcomes—psychiatric disorders.

Schizophrenia

Four out of six cohort studies, with low to moderate risk of bias, found an association between high birth weight and/or LGA and schizophrenia (17, 93–95). All studies but one (17) included both males and females and were adjusted by sex. High birth weight also increased the risk of schizophrenia considerably in families with parental psychosis (94, 96). However, two studies found no association in adjusted models (96, 97).

Depression

Two cohort studies, one with low and one with moderate risk of bias reported on depression. In these studies, women born with high birth weight had increased risk for new-onset depression (98) and current depression (98, 99). In men, no association was found (99).

Psychiatric Disorders in General

According to a recent systematic review and meta-analysis, high birth weight >4,000 g was a protective factor for different types of psychotic disorders (OR 0.86, 95% CI 0.80–0.92) (100). In our search, we found three cohort studies investigating the association between several mental or psychotic disorders and high birth weight with contradictory results. According to two Finnish studies, no general increased risk of any mental disorder (substance use, psychotic, mood, anxiety, personality disorders, suicides, suicide attempts) or any primary psychotic disorder was observed in individuals born LGA (95, 101). However, Van Lieshout et al. (102) reported higher odds of some psychiatric disorders [oppositional defiant disorder, conduct disorder, attention deficit hyperactivity disorder (ADHD)] in 12–17-year-old children born macrosomic (102). Participants exposed to macrosomia and socioeconomic disadvantage were more susceptible to major depressive disorders, and generalized anxiety disorders, compared with those with higher socioeconomic status (102).

Conclusion: High birth weight and/or LGA may be associated with a moderate increase in schizophrenia and an increase in depression, low certainty of evidence (GRADE ⊕⊕OO).

It is uncertain whether high birth weight is associated with psychiatric disorders in general, very low certainty of evidence (GRADE ⊕OOO).

Cognitive Function

Outcomes are listed in Table 1.2b.

TABLE 1.2B

Table 1.2b. LGA, high birth weight, and long-term outcomes—cognitive performance.

Autism

One case–control study with moderate risk of bias reported no association of LGA with autism or Asperger syndrome (103). Two cohort studies with moderate risk of bias reported a slightly increased risk for autism in children born LGA (104, 105).

Behavioral Problems

Four cohort studies reported results on associations between high birth weight/LGA and behavior/attention problems among children and adolescents aged 6–16 years, of which three reported an association between LGA and behavioral problems (106–108).

In a study with low risk of bias, a higher risk for externalizing behaviors (inattention, hyperactivity/impulsivity, aggression, delinquency) was found in high birthweight children (106). In another study with moderate risk of bias, an association between birth weight and social problems was observed in babies at the higher end of the birth weight distribution (107). In contrast, one study (109) found that high birthweight children had no increased risk of attention problems. In a study from Japan, the relation between LGA and neurodevelopment was U-shaped, with mild LGA having the lowest risk and severe LGA (>3 SD) was associated with higher risk of unfavorable behavioral development (110), while another study found no association (111).

Cognitive Development

In five cohort studies with low or moderate risk of bias, high birth weight was associated with high cognitive ability (112–115) and 7-year math score (116).

Intellectual Performance

Eight cohort studies investigated the association between high birth weight and intellectual performance, seven with moderate and one with serious risk of bias. Five of these studies consisted of a study population of Nordic conscripts (117–121), one was a large cohort study of children born in Western Australia (104) and one study was from the USA (122). In five studies, no clear association was found between high birth weight and intellectual performance, risk of intellectual disability, or low IQ score (104, 117–119, 121). However, in one study the crude mean IQ score was 1.2 points lower for those with the extreme birth weight (≥5,000 g) (120). The major part of the apparent association between high birth weight and low IQ score was caused by confounding family factors (120). Of note, the risk for subnormal intellectual performance was dependent on a BMI at young adulthood BMI >30 OR 1.86 (1.58–2.19) (119). In the recently published study from the USA, a slightly decreased risk of poor academic performance was noticed for LGA children (122). In addition, one study from UK Biobank, the middle birth weight category showed better performance for hearing, vision, reaction time, and IQ than the highest category (123).

Conclusion: High birth weight and/or LGA may be associated with a slight increase in autism and behavioral problems, low certainty of evidence (GRADE ⊕⊕OO). High birth weight may be positively associated with cognitive ability, low certainty of evidence (GRADE ⊕⊕OO). No association was found between high birth weight and/or LGA and intellectual performance, moderate certainty of evidence (GRADE ⊕⊕⊕O).

Cardiovascular Health

Outcomes are listed in Table 1.3. Two SR/meta-analyses of high quality, one on hypertension and blood pressure (19) and one on coronary heart disease (CHD) (124), were included, together with 27 original articles.

TABLE 1.3

Table 1.3. LGA and high birth weight and long-term outcomes—cardio-vascular diseases.

Blood Pressure and Hypertension

The SR and meta-analysis by Zhang et al. (19), including 31 studies on the association between high birth weight or LGA and blood pressure or hypertension, showed that high birth weight in younger children (6–12 years) was associated with a higher systolic and diastolic blood pressure, while in older adults (41–60 years) the reverse association was found. The same pattern was seen for the relative risk of hypertension. The authors describe the phenomenon as a “catch-down” effect in the elevation of blood pressure that is observed in subjects with high birth weight as they grow older (19). Hence, older individuals with high birth weight are less likely to develop hypertension than those with normal birth weight (19).

Fourteen original studies (125–138), not included in the review by Zhang et al. (19) were found. Four studies, all with serious risk of bias, showed an inverse relation between high birth weight/LGA and blood pressure, but the mean age of the individuals included in the studies varied tremendously ranging from 6–9 to >50 years of age. Six studies, four with serious and two with moderate risk of bias, showed no association between high birth weight/LGA and blood pressure/hypertension. The two studies with moderate risk of bias included individuals with age ranging from 6–18 years (126) to 33–65 years (129). Finally, four studies, one with moderate risk of bias and three with serious risk of bias, showed that high birth weight/LGA was positively associated with high blood pressure/hypertension. The study with moderate risk of bias included individuals with age 12–15 years (130).

Conclusion: There may be an association between high birth weight and hypertension in childhood, low certainty of evidence (GRADE ⊕⊕OO).

There may be an inverse association between high birth weight and hypertension in adulthood, low certainty of evidence (GRADE ⊕⊕OO).

Coronary Heart Disease

One SR of high quality including 27 articles on birth weight and CHD in adults was identified (124). A meta-analysis based on six prospective cohort studies on CHD exploring the risk of CHD in high birthweight children found no difference in the risk of CHD in children with high birth weight [OR 0.89 (95% CI 0.79–1.01)] (124). Furthermore, the meta-analysis showed that a 1-kg increase in birth weight is associated with a lower risk of CHD [OR 0.83 (95% CI 0.80–0.86)].

Only one original study (139) from the USA was identified which was not included in the SR.

Conclusion: There is probably no difference in the risk of CHD in men and women born with high birth weight compared with adults born with normal birth weight, moderate certainty of evidence (GRADE ⊕⊕⊕O).

Atrial Fibrillation and Other Cardiovascular Outcomes

Two studies with serious (140) and moderate risk of bias (141) explored the association between high birth weight and atrial fibrillation in adulthood and found no association.

Two studies found higher thickness of the radial artery intima (142) and the carotid artery intima (143) in adults of high birth weight or LGA while other cardiovascular risk factors and arterial function did not differ. In a Finnish study with moderate risk of bias, men with higher birth weight had a higher risk of poor cardiac autonomic function while the same association was not seen in women (144). Finally, higher BW z-scores were associated with small differences in diastolic function in adolescence in a study with moderate risk of bias (145).

Conclusion: It is uncertain if there is an association between high birth weight or LGA and altered cardiovascular function in adulthood, very low certainty of evidence (GRADE ⊕OOO).

Diabetes

Outcomes are listed in Table 1.4.

TABLE 1.4

Table 1.4. LGA and high birth weight and long-term outcomes—type 1 and type 2 diabetes.

Type 1 Diabetes

Two SR and meta-analyses (18, 146) (moderate and low quality), six cohort studies (147–152), and 14 case–control studies (153–166) reported on the association between high birth weight or LGA and type 1 diabetes. Both SR/meta-analyses reported an association between high birth weight and childhood-onset type 1 diabetes [AOR of 1.43 (95% CI 1.11–1.85) and AOR 1.11 (95% CI 1.03–1.20)] (18, 146).

Of the 20 original studies, four were assessed being of low, six of moderate, and the rest of critical or serious risk of bias.

Our meta-analysis, including 13 studies, found a pooled OR of 1.15 (95% CI 1.05–1.26) for type 1 diabetes when comparing birth weight >4,000 g with <4,000 g (Figure 9). For LGA vs. AGA, the OR was 1.1 (95% CI 1.03–1.21) (Figure 10). All but one study (163) included children below 18 years of age. Two of the eight studies not included in the meta-analysis had moderate risks of bias and these studies found no significant association between high birth weight and type 1 diabetes. Other studies not included in the meta-analysis were of serious or critical risk of bias.

FIGURE 9

Figure 9. Forest plot describing the association between high birth weight and Diabetes type 1.

FIGURE 10

Figure 10. Forest plot describing the association between LGA and Diabetes type 1.

Conclusion: High birth weight and/or LGA is probably associated with a slight increase in type 1 diabetes, moderate certainty of evidence (GRADE ⊕⊕⊕O).

Type 2 Diabetes

Four SR investigated the association between birth weight/high birth weight and type 2 diabetes (167–170). Three of these SR were considered being of high quality (168–170). The literature search identified few additional studies (171, 172). The SR by (168, 170) only included adults while the SR by (167, 169) also included children; however, only in a few studies. The SR by Knop et al. (169) reported a slight increase in type 2 diabetes if birth weight is above 4,500 g, OR 1.19 (95% CI 1.04–1.36), while the SR by Zhao et al. (170) found no increase, OR 1.11 (95% CI 1.00–1.24) for birth weight above 4,000 g. The SR by Knop et al. (169) pointed out the J-shaped association with a higher risk, particularly at low and to a less extent at high birth weight.

Conclusion: High birth weight may be associated with a slight increase in type 2 diabetes, low certainty of evidence (GRADE ⊕⊕ OO).

Discussion

In this systematic review and meta-analysis, we have summarized the evidence for an association between high birth weight and/or LGA and some severe long-term outcomes for the children (Supplementary Table 5). The outcomes included are malignancies in childhood and breast cancer, cardiovascular diseases, psychiatric disorders, and diabetes type 1 and 2. To clarify if such associations exist and if so, the magnitude of these associations is of high importance for children born after spontaneous conception in view of the dramatic increase in obesity among women of childbearing age and the associated rise in high birth weight babies. In ART, these findings are important due to the increase in frozen/thawed cycles in ART and the recent findings of higher risks of high birth weight and LGA in offspring from FET cycles.

The systematic literature search identified a huge number of articles which were scrutinized and 173 of these publications were selected for this review.

The choice of the selected types of malignancies was based on the number of publications. Thus, our SR does not include all types of malignancies, but the ones where most publications were identified. The metabolic part was limited to diabetes type 1 and 2. Cardiovascular and psychiatric diseases were selected due to being common in the population and having a high impact on human health.

Malignancies

We found a small to moderately increased risk for all types of malignancies studied, with estimates of OR between 1.19 and 1.69. The most pronounced association was found for Wilm's tumor. The biological mechanism linking fetal growth and cancer is largely unknown (51). The observation in children with overgrowth disorders, such as Beckwith–Wiedemann syndrome (BWS), supports a theory that the number, size, and proliferative potential of muscle stem cells (173) which correlate with birth weight are involved. These cells are particularly susceptible to oncogenic mutations and thus a faster growing fetus may involve an increased cancer risk. BWS children, characterized by increased fetal growth, are prone to a wide range of cancers, including Wilm's tumor and leukemia (174). BWS is caused by overexpression of insulin-like factor 2 (IGF-2) gene. Furthermore, several cancers in adults are associated with increased levels of IGFs. Since IGF levels also are increased in heavy babies without these syndromes, there may be a more general association between levels of IGF in newborns and risk of childhood cancer (175). Further support for the IGF-1 theory comes from a study on children with congenital IGF-1 deficiency who seems to be protected against the risk of developing cancer (176). Other suggested mechanisms include exposure of fast-growing babies to elevated levels of estrogen in utero and/or epigenetic mechanisms, both associated with fetal birth weight and cancer risk (177).

Psychiatric Disorders

Four out of six cohort studies on high birth weight and/or LGA and schizophrenia reported an increased risk of developing schizophrenia in the offspring while no association was found in two studies in adjusted models. All these studies were performed in the Nordic countries and the limit for being born with high birth weight varied being >4,000 and >4,500 g. The mechanisms underlying the association between high birth weight and schizophrenia are unclear. It has been suggested that potential fetal exposure to gestational diabetes may play a role, as an association between maternal diabetes and schizophrenia among offspring has been found (94, 178). Furthermore, gestational diabetes may lead to macrosomic babies, who are at increased risk of delivery complications such as shoulder dystocia and asphyxia which also, per se, may increase a risk to later psychiatric problems (12, 94). Interestingly, in a study using self-report questionnaires, high birth weight increased the risk for depression only in women (99).

Interestingly, a recent systematic review suggested that high birth weight was protective of psychotic disorders in general (100). It was, however, unclear which studies were included in this review and no quality assessment was presented.

In many studies, several types of psychiatric disturbances were investigated and even combined. This may explain the contradictory results concerning high birth weight/LGA and psychiatric disorders. Environmental and socioeconomic status probably play an important role in a person's susceptibility for a psychiatric disease making those with higher socioeconomic status less vulnerable (102).

There might be an association between high birth weight/LGA and negative behaviors in adolescence. The reasons for this connection are largely unknown. Family and genetic factors certainly are important in the tendency of developing behavior problems, but the neurobiological mechanisms underlying interactions to high birth weight are unclear (106). Due to delivery complications, the macrosomic infants have an increased risk of birth trauma and asphyxia (12, 176). Such adverse perinatal outcomes are, per se, associated with later behavioral problems (179).

Most of the studies about intellectual performance and high birth weight have been carried out on male conscripts generally excluding women and part of the most vulnerable men. A reassuring notice was that no association was found between high birth weight/LGA and risk of intellectual disability, or low IQ score. However, according to Lundgren et al. (119) high BMI in adulthood had a negative effect on IQ level.

Cognitive performance was positively related to high birth weight at least up to the birth weight of 4,200 g (113). This association is thought to be mediated by optimal prenatal factors and healthy nutrition both pre- and postnatally. Such findings related to mental development emphasize the importance of maternal care during pregnancy (113).

Cardiovascular Diseases

Based on the current evidence, there may be an age-related association between high birth weight/LGA and high blood pressure in childhood while the opposite is found in adulthood. For CHD or cardiovascular function in adults, there was no obvious association with high birth weight or LGA. In the study by Wang et al. (124) the focus was on the relation between birth weight and CHD over the full birth weight range from low to high birth weight, and they found a consistent inverse relation between birth weight and CHD.

In general, individuals with high birth weight are taller and heavier later in life than subjects with normal birth weight (180). However, their metabolic health seems to be better later in life as they have less adipose tissue than lean mass (181).

Contradictory to the findings of a lower risk of CHD in children born with high birth weight, babies are more likely to be born large-for-gestational age in mothers with diabetes, increasing the risk of diabetes and CHD later in the children's life (18). High birth weight could be a result of gestational diabetes in the mother thus, hypothetically, high birth weight may be a potential risk factor of CHD in the offspring (182, 183).

Type 1 Diabetes

In our meta-analysis, high birth weight was associated with a slightly higher risk of type 1 diabetes in line with previous meta-analyses (18, 146).

The mechanism between high birth weight and type 1 diabetes seems unknown. It may be other factors besides the birth weight per se that are responsible for this association. Gestational diabetes and maternal overweight during pregnancy are risk factors for increased birth weight (184, 185). It has been suggested that maternal and/or fetal hyperglycemia also may predispose to an increased susceptibility of the overstimulated fetal pancreatic beta cells to processes causing type 1 diabetes (186, 187). Furthermore, a rapid postnatal growth during the first year of life also seem to be associated with a later risk of developing type 1 diabetes (18). Other triggering factors of the genetic predisposition may also be related to the association between high birth weight and type 1 diabetes (188).

Type 2 Diabetes

For type 2 diabetes, recently performed meta-analyses of high quality found some divergent results. Knop et al. (169) identified a small but significant increase in risk of type 2 diabetes at birth weight above 4,500 g while the meta-analysis by Zhao et al. (170), could not identify any increased risk; however, the estimate was of borderline significance. The biological mechanism behind such an association, if it exists, is a matter of debate. According to the fetal programming hypothesis, also small changes in organ maturation during the fetal period might result in altered growth and disordered endocrine function in adulthood (169).

Strengths and Limitations

The major strength of this systematic review is the comprehensive literature search, identifying a considerable number of relevant articles. The ability to present meta-analyses, either of high quality and recently published or new meta-analyses performed for the purpose of this SR, makes interpretation of the summarized literature easier to capture. The main limitation is that all data are based on observational studies, both cohort studies being of higher quality but also case–control studies with their inborn risk of selection bias. Our conclusions are, however, based mainly on meta-analyses and/or on studies with low risk of bias.

In conclusion, this systematic review and meta-analysis, investigating high birth weight and LGA as risk factors for adverse outcome in offspring, found elevated risks for certain malignancies in childhood, breast cancer, several psychiatric disorders, hypertension in childhood, although not in adulthood, and type 1 and type 2 diabetes. Although these risks represent serious health effects, both in childhood and in adulthood, the size of these effects seems moderate. The results are important for the overall implications of increasing birth weight and will contribute to the ongoing discussion of the pros and cons of fresh or frozen embryo transfer cycles in ART.

Data Availability Statement

The original contributions presented in the study are included in the article/Supplementary Materials, further inquiries can be directed to the corresponding author.

Author Contributions

ÅM, HL, AL, NO, AP, LR, VS-A, and CB contributed to conception and design of the study. ÅM and CB search databases. Screening of abstracts and of full papers for inclusion was done by pairs of reviewers by ÅM, HL, AL, NO, AP, LR, VS-A, and CB. MP performed the statistical analysis. ÅM, HL, AL, NO, AP, LR, VS-A, MP, and CB wrote sections of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.

Funding

This work was supported in part by grants from the Swedish state under the agreement between the Swedish government and the county councils the ALF-agreement (ALFGBG-70940), the Hjalmar Svensson's foundation, and the Research Council of Norway through its Centres of Excellence funding scheme, Project Number 262700.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

We thank Gedeon Richter for providing travel, accommodation, and working facilities to the Nordic Collaboration Group. Furthermore, we thank librarian Helen Sjöblom for excellent help with literature search.

Supplementary Material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fped.2021.675775/full#supplementary-material

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