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 [//www.methods.cochrane.org]. For systematic reviews, we used AMSTAR [//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 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 compared with 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 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.
LymphomaOne 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 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