The Effect of Parental Weight and Genetics on the Body Mass Index of Very Low Birth Weight Infants as They Reach School Age

Background: Prematurely born individuals are usually of low or normal weight in childhood; in adulthood, however, their probability of being overweight is twice that of persons born at full term. There is not yet any way to predict the weight development of premature babies.

Methods: A polygenic BMI score (BMI = body-mass index), calculated from the often very small individual effects of more than 2 million genetic variants, was recently described for adults. We studied the possible association of this score with the course of BMI in premature babies over time, from infancy up to the age of 10–14 years.

Results: 508 individuals were included in the study. At the age of 5–7 years, their mean body weight was 18.8 ± 3.3 kg. The difference between the highest and lowest deciles of the polygenic score was 3.3 kg. At age 10–14, the average body weight was 41.3 ± 11.3 kg, and the difference between the highest and lowest deciles had increased to 9.2 kg. In persons with birth weight under the 10th percentile (n = 68), the difference was 19.2 kg (30.9 kg vs. 50.1 kg). The polygenic BMI score was significantly associated with the BMI z-scores of the overall group and the subgroup of growth-retarded children.

Conclusion: Extreme values of a polygenic BMI score are strongly associated with the weight development of preterm infants as they develop into children aged 10–14. The large effect size implies that this score may aid in the counseling of prematurely born children and their parents.

Cite this as: Göpel W, Lüders C, Heinze K, Rausch TK, Fortmann I, Szymczak S, König IR, Herting E, Hanke K: The effect of parental weight and genetics on the body mass index of very low birth weight infants as they reach school age. Dtsch Arztebl Int 2025; 122: 65–70. DOI: 10.3238/arztebl.m2024.0253

Approximately 10% of children are born prematurely; prematurity is defined as a birth at a gestational age less than 37 weeks. In both prematurely born individuals and growth-retarded children with birth weights below the 10^th percentile of their respective gestational age (small for gestational age, SGA), the risk of becoming overweight or developing a metabolic syndrome-related condition is twice and twice to four times, respectively, that of children born at full term (1, 2). The reasons why prematurely born persons are at a greatly increased risk of metabolic syndrome-related conditions are not yet fully understood; however, an increased body mass index (BMI) appears to be a key risk factor (2). The parental BMI is known to have an effect on the weight of the child and can be easily determined (3, 4). However, the majority of prematurely born individuals and SGA children are underweight before puberty and usually become obese not earlier than age 14–19 (5). Since it is not yet possible to predict the long-term risk of obesity, it is recommended that all premature babies and SGA children initially receive a high-calorie diet after birth during their hospital stay to ensure adequate catch-up growth (6). So far no evidence is available on the question of when and especially in which preterm infants a high-calorie diet should be discontinued to prevent the development of obesity.

In 2019, a polygenic risk score for the human BMI was published which was calculated on the basis of more than two million genetic variants (7). Adults in the highest decile, i.e. the highest 10%, had a mean body weight of 85.3 kg and a mean BMI of 30 kg/m². These values were 13 kg (4.8 kg/m²) above the mean values for adults in the lowest decile, i.e. the lowest 10%, of the polygenic risk score (Box).The differences were particularly pronounced in the case of obesity with a BMI of over 40, which were found in only 0.2% of adults in the lowest decile, but in 5.6% of those in the highest decile of the score. The comparison of adults in the highest decile with those in the remaining 9 deciles showed a five-fold increased risk of bariatric surgery and a 72% increased risk of diabetes mellitus (7). The polygenic BMI risk score was associated with weight in children too. In newborns, the weight difference between the lowest and the highest decile was 60 g, in 8-year-olds it was 3.5 kg and in 18-year-olds it was 12.3 kg (7). Polygenic risk scores have not yet been adopted in routine clinical practice. However, first large clinical studies on the implementation of polygenic risk scores for ten common diseases, including obesity, in clinical practice are underway in the United States (8, 9).

Box

Polygenic risk score for BMI prediction

In this study, we tested the hypothesis that in individuals born preterm with a birth weight of less than 1500 g the polygenic BMI risk score is associated with weight development in childhood. Provided the effect size is sufficiently large, such a score could be used as an aid in counseling prematurely born children and their parents to help prevent the development of obesity in puberty.

Methods

Patients and study design

Premature babies born at a gestational age of less than 37 weeks + 0 days and with a birth weight of less than 1500 g were included in a multicenter cohort study (German Neonatal Network, GNN) during their hospital stay (eList). Preterm infants with a birth weight below the 10^th percentile of the respective gestational age were categorized as SGA preterm infants (10). Detailed information on participant selection and study design is provided in the eMethods section and in eFigure 1.

eFigure 1

Patient selection

Genotyping and calculation of the polygenic BMI risk score

DNA extraction, genotyping using a single nucleotide polymorphism (SNP) array (Affymetrix AXIOM or Illumina Global Screening Array) and imputation of additional polymorphisms in the GNN have already been described elsewhere (11). We used the BMI risk score describe by Khera et al. which includes 2 100 302 single-nucleotide polymorphisms (7, 12), of which 2 064 658 (98.3%) were available in the genotyping data of the GNN study and could be used for the calculation.

Statistical analysis

Associations of the polygenic BMI risk score decile with the BMI z-scores according to Kromeyer-Hauschild (13) measured at age 10–14 years were determined using linear regression for the overall group and for the following subgroups:

• SGA children
• Normal parental weight (BMI of both parents < 25)
• Parental obesity (BMI of father or mother > 30 kg/m²).

This resulted in four linear regression analyses, whereby the type-one error level according to Bonferroni was reduced from 0.05 to 0.0125 in order to achieve a global significance level of 0.05.

Results

A total of 23 652 premature babies with a birth weight of less than 1500 g were included in the GNN between 2009 and 2023. By April 2024, 13 150 of these children had already been genotyped using the SNP array. Of these, 12 628 (96%) had been discharged alive. The BMI risk score was not associated with in-hospital mortality. By April 2020, a total of 508 children had taken part in both the follow-up at 5 to 7 years and the follow-up at 10 to 14 years of age (including assessment of fat mass and grip strength) and thereby fulfilled the inclusion criteria.

The mean birth weight was 1002 ± 283 g. The mean gestational age at birth was 28.1 ± 2.3 weeks; it was slightly lower among premature babies with a higher BMI risk score. Other than that, no differences were found in the overall group with regard to the basic data or the weight gain achieved until discharge from hospital (Table 1).

Table 1

Basic data after birth

The mean age at the time of the follow-up examination at 5 to 7 years and at 10 to 14 years of age was 5.8 ± 0.4 years and 12.0 ± 1.2 years, respectively. The BMI z-score according to Kromeyer-Hauschild showed a strong correlation with the polygenic BMI risk score (+0.12 Z scores per additional decile of the polygenic BMI risk score; 95% confidence interval: [+0.08; +0.16] p = 7.1 × 10^–11). Likewise, all other weight variables, such body weight in kilogram, BMI and fat mass in kilogram, were highly associated with the polygenic BMI risk score, both at the follow-up examination at 5–7 years and at 10–14 years of age (Table 2). At the 5– to 7-years follow-up, the difference in mean weight between children of the first and tenth decile of the polygenic BMI risk score was 3.3 kg. At age 10 to 14, the difference between the two deciles had increased to 9.2 kg (+0.71 kg [+0.37; +1.04 kg] per additional decile of the polygenic BMI risk score). At age 5 to 7, the children of the highest decile of the polygenic BMI risk score were slightly taller, but this difference was no longer observed at the 10– to 14-years follow-up. The polygenic BMI risk score was not associated with grip strength (Table 2).

Table 2

Growth data by polygenic BMI risk score deciles

The weight development in the three subgroups (SGA, parents with BMI <25, at least one parent with BMI >30) from birth to age 10–14 years is summarized in Table 3. The most remarkable group were the SGA children. At birth, the mean weight of the 68 SGA children was 728 ± 319 g and there were no differences between the deciles of the polygenic BMI risk score. At the time of discharge from hospital, the preterm infants in the highest deciles of the polygenic BMI risk score had already gained slightly more weight, while the SGA preterm infants in the first decile of the polygenic BMI risk score were discharged with a weight that was about 300 g below the weight of the non-SGA preterm infants. This trend of very strong weight gain in the 10^th decile of the polygenic BMI risk score and low weight gain in the first decile was maintained throughout the follow-up period and led to a marked weight difference of 19.2 kg between the 1^st decile and 10^th decile at the follow-up examination after 10–14 years (+1.4 kg [+0.4; +2.3 kg] per additional decile of the polygenic BMI risk score).

Table 3

Weight development of prematurely born individuals of different subgroups by polygenic BMI risk score deciles

Maternal and paternal BMI values of 416 prematurely born individuals were available at the follow-up at 5 to 7 years of age. The mean maternal BMI was 25.3 ± 5.7 kg/m², the mean paternal BMI was 27.2 ± 4.2 kg/m². The polygenic BMI risk score was associated with child BMI z-scores, even when the parental BMI values were included in the linear regression analysis (eTable 1). As expected, the BMI of the parents was associated with a corresponding shift in the child‘s weight (eFigure 2, Table 3).

eFigure 2

Polygenic BMI risk score

eTable 1

Association of the polygenic BMI risk score and the parental BMI with the child BMI at the follow-up at 10 to 14 years of age

The analysis of the follow-up BMI z-scores of the prematurely born individuals based on the reference values by Kromeyer-Hauschildt, which are recommended in Germany, found mean z-scores of –0.7 ± 1.0 and –0.3 ± 1.2 for the overall group at age 5–7 and age 10–14, respectively. This means that the prematurely born individuals were underweight on average in both follow-up age groups, but approached the mean z-score of normal-weight children (which is 0). As a result, however, the proportion of overweight prematurely born individuals also increased. At age 5–7, only 0.8% of the children were obese and 2.4% overweight. At age 10–14, 69% of the children were of normal weight, 22% were underweight and 9% were overweight or obese. The distribution was particularly extreme in the extreme deciles of the polygenic BMI risk score in children who were born preterm and small for gestational age. All SGA preterm infants in the first decile of the polygenic BMI risk score were underweight at age 10–14 (the majority were severely underweight). In the 10th decile, 3 of 7 children were overweight or obese (Figure). For the endpoint “obesity at age 10–14“, the area under the curve (AUC) in the ROC diagram was 0.74 [0.61; 0.87] for the overall study population. In the subgroup of children for whom we had information on parental BMI available, the polygenic risk score achieved a higher AUC compared to the maternal and paternal BMI (eFigure 3). The sex of the children was not associated with the frequencies of underweight and obesity, both at the age 5–7 and age 10–14 follow-ups (eTable 2).

Figure

Association of the polygenic BMI risk score

eFigure 3

Receiver Operating Curve (ROC) for the endpoint “Obesity at age 10–14 years“

eTable 2

Weight categories of prematurely born individuals by sex

Discussion

The polygenic BMI risk score that we used in our analysis reflects part of the genetic predisposition to develop a high or low BMI in the overall population. The predictive power of the score in the overall population for the outcome “obesity” is moderate with an AUC of 0.64 (14). However, it has already been shown for specific populations at risk of obesity, for example children who survived cancer, that the score is predictive for the development of obesity in adulthood (AUC = 0.75) (12).

The data of our study revealed a significant association of the polygenic BMI risk score with the BMI of prematurely born individuals when they were 5–7 years old and 10–14 years old. Only 14 of the 508 (2.8%) prematurely born individuals were obese at the age of 10–14 years. The predictive power of the polygenic BMI risk score was in the clinically relevant range with an AUC of 0.74 in the overall group of prematurely born individuals and with an AUC of 0.78 already at age 10–14 years in the group of individuals born as SGA preterm babies. Given that obesity in preterm infants usually does not develop until puberty (5), it is to be expected that a large proportion of premature babies in the highest range of the score will be obese as adults.

Worldwide, about 13 million children are born prematurely and 23 million children are born small for gestational age every year (15). Since both being underweight and overweight have long-term negative effects on health (16, 17), the data from our analysis may have important implications for the counseling of preterm infants, SGA infants and their parents.

A long-term study from the UK evaluated the effect of breastfeeding (five months or longer) on the weight development of children with various genetic risks. The analyses were controlled for gestational age, maternal BMI, education, family income, and smoking. Newborns with high polygenic BMI risk scores, who had been breastfed for at least five months, had a significantly lower body weight as adults compared to non-breastfed children (18). According to our data, SGA preterm infants with a high polygenic BMI risk score and possibly also prematurely born children of obese parents can in particular benefit from breastfeeding counseling and the resulting success in breastfeeding.

According to recent data from the German Health Interview and Examination Survey for Children and Adolescents (KiGGS) study, the prevalence of overweight and obesity in children aged 3–6 years is 10.8% for girls and 7.3% for boys. In adolescents aged 11–13 years, the prevalence of overweight and obesity was 20% in girls and 21% in boys (19). In both age groups, overweight and obesity was considerably less common among the prematurely born individuals in our study (eTable 2). According to epidemiological data, many prematurely born individuals experience extreme weight gain during puberty and are at particularly high risk of cardiovascular disease as obese adults (20). We suspect that prematurely born individuals with a high polygenic BMI risk score are at extremely high risk of becoming obese during puberty. The costs of determining a polygenic BMI risk score are low. However, there is uncertainty as to whether the knowledge of an increased risk of obesity, combined with counseling on preventive measures such as exercise and a calorie-reduced diet, is enough to prompt a change in the behavior of the affected prematurely born individuals during puberty. Only a randomized trial could provide answers to this question..

High values of the polygenic risk score used in our study are associated with increased appetite in childhood. Yet, appetite explains only about 11% of the effect size of the polygenic score (21). Drugs such as semaglutide have a very strong appetite-reducing effect (22). However, only 25.4% of obese adolescents who were treated with semaglutide experienced a normalization of their body weight (23, 24). This shows how difficult it is to treat overt obesity in adolescents and highlights the great potential for prophylactic measures in prematurely born individuals, as only 14 children in the cohort we studied were obese at the 10– to 14-years follow-up.

As reported in numerous publications, intrauterine malnutrition in combination with postnatal overnutrition leads to overweight and a shortened lifespan, in both animals and humans (25). The current treatment of SGA preterm infants matches this constellation. However, the data of our study show that, besides intrauterine deficiency, the individual predisposition to a high or low body weight also has a decisive effect on weight development from infancy up to the age of 10–14 years. Furthermore, the results published here confirm recent reports on the impact of paternal BMI on the weight development of children (4).

The most important limitation of our study is the lack of data on the weight development after puberty. Additionally, there are currently still very few cases in the subgroups of SGA children and children of obese or normal-weight parents.

In summary, we were able to show that a polygenic BMI risk score developed in adulthood is strongly associated with the weight development of preterm infants as they develop into adolescents aged 10–14 years. In this age group, only 2.8% of the prematurely born individuals already suffer from overt obesity so that it would be possible to offer targeted preventive genetic counselling of prematurely born individuals and their parents, especially in SGA preterm infants. However, only prospective scientific studies can show whether the knowledge of a high genetic risk for obesity actually leads to a reduction in weight gain in predisposed prematurely born individuals during puberty.

Funding: German Federal Ministry of Education and Research (BMBF, Bundesministerium für Bildung und Forschung) (BMBF 01ER0805 und BMBF 01ER1501), German Research Foundation (DFG, Deutsche Forschungsgemeinschaft) (SFB 1665–515637292, Sexdiversity).

Acknowledgement: We would like to thank all parents and prematurely born children who made this study possible by participating in the GNN. We would also like to thank all physicians in the GNN network. A list of participating centers is provided in the supplement.

Conflict of interest statement

WG received reimbursement of travel expenses and payment of congress fees from GNPI.

The remaining authors declare no conflict of interest.

Manuscript received on 29 July 2024; revised version accepted on 16 December 2024

Translated from the original German by Ralf Thoene, M.D.

Corresponding author
Prof. Dr. Wolfgang Göpel

Universität Lübeck, UKSH, Klinik für Kinder- und Jugendmedizin

Ratzeburger Allee 160, 23538 Lübeck, Germany

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