https://orcid.org/0000-0002-5773-3665
Figures
Abstract
Background
Children conceived through infertility treatments may have altered birth outcomes and growth patterns compared to those conceived naturally. However, evidence on long-term growth trajectories, particularly distinguishing singletons and multiples, remains inconsistent. This study aimed to compare childhood growth trajectories from birth to 12 years of age between children conceived via infertility treatments and those conceived naturally, using a large national birth cohort.
Methods
We analyzed the follow-up data (6 months to 12 years of age) from the Taiwan Birth Cohort Study, an ongoing, nationwide, longitudinal study of children. Our final sample included 20,507 singletons (20,306 naturally conceived [NC], 104 via intrauterine insemination [IUI], 97 via in vitro fertilization [IVF]) and 950 multiples (670 NC, 68 IUI, 212 IVF). We used linear mixed models with random coefficient cubic splines for age to assess the growth trajectories for weight, height, and body mass index (BMI) by infertility treatment status and logistic regression to analyze risk of rapid weight gain, overweight, obesity, and underweight.
Results
Children conceived via IUI or IVF showed lower weight, height, and BMI in pooled analyses; however, these differences were largely attributable to the higher proportion of multiple births in the infertility treatment groups. After stratification by plurality, most differences were attenuated and not statistically significant, with the exception of slightly lower weight (−0.353 kg; p = 0.039) among IUI-conceived multiples. The risk of rapid weight gain (6 months–2 years) and underweight, overweight, or obesity (5.5–12 years) did not differ significantly by the conception mode after plurality was controlled.
Conclusions
After accounting for plurality, children conceived through infertility treatments showed similar growth trajectories to those conceived naturally. These findings are reassuring for families using infertility treatments and highlight the importance of minimizing multiple births in assisted reproduction to support optimal child growth and health outcomes.
Citation: Chang Y-S, Yu T, Wong T-J, Li C-Y (2026) Infertility treatment and the growth of children from birth to 12 years of age: A national cohort study. PLoS One 21(6): e0348091. https://doi.org/10.1371/journal.pone.0348091
Editor: Stefan Schlatt, University Hospital of Münster, GERMANY
Received: August 15, 2025; Accepted: April 12, 2026; Published: June 3, 2026
Copyright: © 2026 Chang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: No - some restrictions will apply; Access to the data is subject to ethical and legal restrictions imposed by the data custodian and relevant Institutional Review Boards, in accordance with Taiwan’s Personal Data Protection Act. As a result, the dataset cannot be publicly shared. Researchers interested in accessing the data may apply through the Health and Welfare Data Science Center (https://dep.mohw.gov.tw/DOS/cp-5119-59201-113.html). Access is granted upon review of a research proposal and documentation of ethics approval. Alternatively, access can be requested from the following Health and Welfare Data Science Center, Ministry of Health and Welfare (Taiwan) contacts: Mr. Cao Tel: +886-2-8590-6809 Email: sttony123@mohw.gov.tw Ms. Lin Tel: +886-2-8590-6812 Email: stlh@mohw.gov.tw Mr. Zheng Tel: +886-2-8590-6815 Email: stzxc3476@mohw.gov.tw.
Funding: This study is supported by National Science and Technology Council (113-2314-B-006 -065).
Competing interests: The authors declare that they have no competing interests.
Abbreviations: BMI, Body mass index; CI, Confidence interval; DOHaD, Developmental Origins of Health and Disease; FET, Frozen embryo transfer; ICSI, Intracytoplasmic sperm injection; IUI, Intrauterine insemination; IVF, In vitro fertilization; MAR, Medically assisted reproduction; NC, Natural conception; OR, Odds ratio; SD, Standard deviation; SDS, Standard deviation scores
Introduction
The Developmental Origins of Health and Disease (DOHaD) theory hypothesizes that early-life exposures influence health and disease risk later in life, with epigenetic changes potentially playing a key role in fetal programming mechanisms [1]. Low birth weight and preterm birth, both indicative of impaired intrauterine growth, along with rapid postnatal catch-up growth, are strong predictors of adverse cardiometabolic risk factors and chronic diseases in adulthood [2–4]. Therefore, understanding childhood growth trajectories is essential for assessing development and health across the life course.
Several studies have suggested that children conceived through medically assisted reproduction (MAR) have a shorter gestational age, lower birth weight, and a higher risk of being small for gestational age compared to those conceived naturally [5]. It has been hypothesized that these differences may result from factors such as ovarian stimulation, culture media, specific MAR procedures (e.g., intracytoplasmic sperm injection [ICSI] or frozen embryo transfer [FET]) [6–8], as well as the underlying causes of subfertility or infertility [9]. However, a systematic review by Bay et al. on the long-term growth of singletons found no significant differences in weight or height between children conceived through MAR and those conceived naturally [10].
In twin pregnancies, a recent systematic review by Marleen et al. found that MAR is associated with a higher risk of maternal complications but has a varied impact on perinatal outcomes compared to natural conception [11]. Furthermore, the association between MAR and growth patterns in twins remains unclear, with conflicting findings in the literature. For example, a Chinese cohort study of 26,818 twins reported no significant differences in growth from birth to 18 years between MAR-conceived and naturally conceived twins [12]. In contrast, a British cohort study of 13,528 twins suggested that MAR twins born after FET grew faster than those born after fresh embryo transfer or natural conception [13].
Given these inconsistencies, our study aimed to compare growth trajectories from birth to 12 years between children conceived via infertility treatments and those conceived naturally. We further stratified the analysis by singletons and multiples. This study was conducted using data from a long-term, population-based national birth cohort in Taiwan.
Methods
Study participants and design
The Taiwan Birth Cohort Study is an ongoing, nationwide, longitudinal study that recruited 21,648 children born in Taiwan in 2005. A two-stage stratified random sampling method was used to select a nationally representative sample. In the first stage, the study team selected 89 townships based on urbanization levels and total fertility rate. In the second stage, newborns were randomly selected from these townships using the probability proportional to size sampling method. Structured interviews were conducted with the primary caregivers, and baseline data were collected when the participants were 6 months old. Until 2009, follow-up surveys were conducted when the participants reached 1.5 years, 3 years, 5.5 years, 7 years, 8 years, 9 years, 12 years, and 13 years. More details can be found in previous publications [14,15].
Participant records were linked to the Birth Reporting Database, which provided information on plurality, birth weight, gestational age, and mode of delivery. The study cohort included 20,689 (95.6%) singletons and 959 (4.4%) multiples.
Infertility treatment and covariates
At baseline, primary caregivers reported the method of conception using a standardized questionnaire, which included the following categories: in vitro fertilization (IVF), intrauterine insemination (IUI), or natural conception (NC). Among the participants, 311 (1.4%) were conceived via IVF, 172 (0.8%) via IUI, and 21,159 (97.7%) via NC. Additional covariates included child sex, child age, birth defects, breastfeeding status, pre-pregnancy body mass index (BMI), parental nationality, parental education, family monthly income, and parental smoking status.
Anthropometric measurements
The Taiwanese government provides child preventive healthcare services, which include periodic health check-ups assessing growth and development. Healthcare providers conduct these assessments using standardized procedures. Primary caregivers were asked to record their child’s weight and length/height at the following ages: 1 month, 4 months, 6 months, 1 year, 1.5 years, 2 years, 2.5 years, 3 years, 4 years, 5 years, 5.5 years, 7 years, 8 years, 9.5 years, 12 years, and 13 years. For this study, we excluded measurements at 13 years of age. Weight was measured in kilograms (kg), and length/height in centimeters (cm). BMI was calculated as weight (kg) divided by height squared (m²).
Statistical analysis
Not all children had complete data at every time point, and some had missing weight or height measurements. We excluded 6 participants with missing infertility treatment data and 15 participants with missing BMI values at all time points, resulting in a sample of 21,627 participants. We used linear mixed models with random coefficient cubic splines for age that adjusted for sex and plurality to predict weight and height at each time point for every participant. Missing values for weight or height were imputed using these predicted values.
Weight gain since birth was calculated at four time points (6 months, 1 year, 1.5 years, and 2 years) by determining the difference between weight at each time point and birth weight. We computed the mean and standard deviation (SD) of weight gain at each time point among all singletons. Standard deviation scores (SDS) were calculated for each child, and those with a score above 0.67 were classified as experiencing rapid weight gain [16].
BMI values were standardized into z-scores using the World Health Organization (WHO) Child Growth Standards [17] and Growth Reference Data for children aged 5–19 years [18]. A child was classified as obese if their BMI z-score exceeded 2, overweight if their BMI z-score exceeded 1 and underweight if their BMI z-score was below −2 [19]. The risk of obesity, overweight, and underweight was assessed at 5.5 years, 7 years, 8 years, 9.5 years, and 12 years.
Our final analysis sample included 21,457 participants, each with at least one BMI record between 6 months and 12 years of age. Separate analyses were conducted for singletons and multiples (including twin and higher-order multiple births). We used linear mixed models with random coefficient cubic splines for age to estimate mean differences in weight, height, and BMI from 6 months to 12 years (model-implied differences averaged over time), according to infertility treatment type (IUI, IVF, and NC). Additionally, logistic regression was used to estimate odds ratios for rapid weight gain at various time points as well as the risk of underweight, overweight, and obesity at different time points. All analyses were adjusted for potential confounders, including child sex, birth defects, breastfeeding, pre-pregnancy BMI, parental age, parental nationality, parental education, family income, and parental smoking status. Missing covariate data (all < 1% missing) were imputed using the most common response. Data analyses were conducted using STATA 15 (College Station, TX: StataCorp LLC). Statistical commands used to fit linear mixed models with random coefficient cubic splines were provided in the S1 Text.
Ethical considerations
The Ethics Committees of the Health Promotion Administration, Ministry of Health and Welfare, Taiwan, approved the study protocol. All parents provided written informed consent before data collection. We accessed the data on June 1, 2024 and no authors had access to information that could identify individual participants.
Results
Characteristics of children
Infertility treatment was significantly more common among multiples (IUI: 7.2%; IVF: 22.3%) compared to singletons (IUI: 0.5%; IVF: 0.5%). On average, multiples had a shorter gestational age (35.6 weeks vs. 38.5 weeks) and lower birth weight (2,310 grams vs. 3,126 grams) than singletons. The baseline characteristics, stratified by plurality (singletons and multiples) and infertility treatment (NC, IUI, and IVF), are shown in Table 1.
Within both singleton and multiple births, infertility treatment (IUI or IVF) was associated with a higher proportion of male infants and a higher prevalence of birth defects compared with NC. Parents who conceived via infertility treatment were also older, had higher educational attainment and family income, and were more likely to be native-born. In addition, breastfeeding was more common among children conceived through infertility treatment, while maternal and paternal smoking rates were lower. Pre-pregnancy BMI was slightly higher in the infertility treatment groups.
Child growth at all assessment points
Among all children (singletons and multiples), infertility treatment (IUI or IVF) was associated with lower weight, shorter height, and lower BMI from 6 months to 12 years compared to the NC group (see Fig 1 and Table 2). These differences were largely driven by the higher proportion of multiples in the infertility treatment groups. After stratification by plurality, the differences in weight, height, and BMI were substantially attenuated, and most associations became statistically non-significant.
Among singletons, the adjusted mean differences in growth from 6 months to 12 years for children conceived via IUI compared with NC were −0.232 kg for weight (p = 0.067), −0.423 cm for height (p = 0.112), and −0.185 units for BMI (p = 0.149). Corresponding differences for IVF versus NC were −0.061 kg for weight (p = 0.647), −0.088 cm for height (p = 0.751), and 0.049 units for BMI (p = 0.713).
Among multiples, children conceived via IUI weighed significantly less than those conceived naturally (−0.353 kg, p = 0.039), while differences in height (−0.604 cm, p = 0.098) and BMI (−0.203 units, p = 0.279) were not statistically significant. No significant differences were observed among multiples conceived via IVF compared with NC for weight (−0.008 kg, p = 0.940), height (0.329 cm, p = 0.161), or BMI (−0.044 units, p = 0.717).
Prevalence of rapid weight gain from 6 months to 2 years
The prevalence of rapid weight gain from 6 months to 2 years, stratified by plurality and infertility treatment, is presented in Table 3. Overall, multiples had a higher risk of rapid weight gain compared to singletons (28.3% vs. 21.4% at 2 years). After stratifying by plurality, no significant differences were found in the risk of rapid weight gain between infertility treatment groups and the NC group. For example, at 2 years, the risk of rapid weight gain in the IUI group was slightly lower than in the NC group among singletons (adjusted odds ratio [aOR]: 0.685, p = 0.156; Table 4). Conversely, the IVF group had a slightly higher risk compared to the NC group (aOR: 1.250, p = 0.355). However, neither estimate was statistically significant.
Prevalence of underweight, overweight, and obesity from 5.5 to 12 years
The prevalence of underweight, overweight, and obesity from 5.5 to 12 years, stratified by plurality and infertility treatment, is presented in Table 3. Overall, multiples had a higher risk of underweight (4.1% vs. 3.4% at 12 years) and a lower risk of overweight (25.7% vs. 33.6%) and obesity (7.3% vs. 12.4%) compared to singletons at the same age. After stratifying by plurality, no significant differences were found in the risk of underweight, overweight, or obesity between infertility treatment groups and the NC group. Adjusted risks for different outcomes at various time points are provided in Table 5. For example, at 12 years, the risk of obesity in the IUI group was slightly lower than in the NC group among singletons (aOR: 0.643, p = 0.209), while the risk in the IVF group was slightly higher (aOR: 1.159, p = 0.644). However, neither estimate was statistically significant.
Discussion
We identified several key findings. First, although children conceived via IUI or IVF appeared to have lower weight, shorter height, and lower BMI than those conceived naturally when all children were analyzed together, these differences were primarily attributable to the higher proportion of multiple births in the IUI and IVF groups. Second, after stratifying by plurality, no significant differences in weight, height, or BMI were observed between the infertility treatment groups and the NC group. Among multiples, children in the IUI group might have slightly lower weight than those in the NC group. Third, the risks of rapid weight gain (6 months–2 years) and underweight, overweight, and obesity (5.5–12 years) did not significantly differ by infertility treatment status in either singletons or multiples. Overall, after accounting for plurality, we found no significant differences in growth trajectories between children conceived through infertility treatments and those conceived naturally.
The DOHaD hypothesis suggests that prenatal and perinatal exposure to environmental factors—such as undernutrition, stress, or environmental chemicals—can alter an individual’s phenotype and increase the risk of non-communicable diseases in adulthood [20]. Concerns have been raised that some MAR procedures may directly affect embryos, potentially impairing fetal and childhood growth. For example, IVF exposes gametes and embryos to various hormones, culture media, and in vitro manipulation techniques, including prolonged embryo culture, cryopreservation and thawing, prenatal genetic testing, and embryo biopsy [21]. Laboratory evidence indicates that these procedures can induce molecular changes, alter epigenetics and gene expression, and may influence placental and fetal development [22]. Therefore, monitoring the long-term health and growth of children conceived via infertility treatments is essential.
Most of our data showed that after accounting for plurality, infertility treatments were not significantly associated with childhood growth trajectories, suggesting that the higher rate of multiples, rather than the infertility treatments themselves, was the key factor related to impaired child growth. These findings demonstrate that the influence of MAR on long-term offspring growth is negligible if the rate of multiple births is controlled. Our findings also highlight the importance of minimizing multiple pregnancies in MAR. Singleton pregnancies result in better maternal and child outcomes than multiple pregnancies [23]. Therefore, most professional reproductive medicine societies, including those in Taiwan, advocate for elective single embryo transfer in IVF to reduce pregnancy risks associated with multiple births. As a result, the rate of multiples following IVF is declining globally [24,25].
In our analysis stratified by plurality, we found that multiples conceived via IUI had significantly lower weight than those conceived naturally. This finding aligns with research by Yeung et al., who observed that twins conceived via ovulation induction (with or without IUI) were smaller from birth to three years of age than naturally conceived twins [16]. Ovarian stimulation for IUI commonly involves clomiphene citrate, letrozole, or injectable gonadotropins, with gonadotropin use significantly increasing the risk of multiple gestation [26]. Ovarian hyperstimulation may lead to ovulation of immature oocytes or alter endometrial function due to exposure to high hormone levels (e.g., estradiol and progesterone), resulting in impaired placental function and restricted fetal growth [16]. Supporting this hypothesis, studies have shown that frozen embryo transfers—where endometrial preparation is more natural—carry a lower risk of small-for-gestational-age infants compared to fresh embryo transfers [27].
The major strengths of this study include its large, nationally representative cohort from Taiwan (n = 21,457), reducing selection bias. Participants were followed from 6 months of age, with repeated weight and height measurements enabling longitudinal analysis. Many previous studies lacked sufficient sample sizes or long-term follow-up, making our study a valuable addition to the literature. However, the numbers of children conceived via infertility treatment among singletons were relatively small. As a result, non-significant findings in singleton analyses should be interpreted with caution, as they do not necessarily indicate equivalence but may reflect limited statistical power and wide confidence intervals.
Study limitations should be considered. Infertility treatment status was self-reported rather than sourced from medical records, and child growth data were reported by caregivers rather than directly measured by healthcare professionals, introducing potential measurement errors, which might have biased the results towards the null. Additionally, children conceived by infertility treatments had shorter gestational ages and lower birth weights than naturally conceived children, even after stratifying by plurality (see Table 1). We did not adjust for these variables, as they are intermediate factors in the causal pathway. The observed lower weight in multiples conceived via IUI may partially reflect these differences.
Furthermore, although we adjusted for several sociodemographic and perinatal factors, information on maternal and paternal alcohol consumption and maternal nutrition during pregnancy was not available in the datasets accessed for this study and therefore could not be considered. In addition, breastfeeding was assessed only as a binary variable, as data on duration or exclusivity were not available. Finally, detailed information on the underlying etiology or pathophysiology of infertility among parents who underwent infertility treatment was not captured in the available data. These unmeasured factors may contribute to residual confounding and warrant further investigation in future studies with more detailed clinical and behavioral information.
Our findings contribute to the literature on long-term growth outcomes among children conceived through infertility treatments. Consistent with prior studies, we observed no clear evidence of differences in weight, height, or BMI after accounting for plurality, suggesting that infertility treatment itself is unlikely to have a clinically relevant impact on childhood growth. Instead, the higher prevalence of multiple births largely explains the differences observed in un-stratified analyses. This finding reassures couples undergoing infertility treatments. However, we lacked detailed MAR-related data, such as whether ICSI was used or whether embryo transfer was fresh or frozen. Future efforts should focus on establishing national MAR registries and birth cohort studies to assess the long-term effects of evolving MAR techniques on child growth and health outcomes. Importantly, our findings emphasize the need to minimize multiple births following MAR to optimize pregnancy and child health outcomes.
Supporting information
S1 Text. Supplementary Materials.
STATA commands used to fit linear mixed models.
https://doi.org/10.1371/journal.pone.0348091.s001
(DOCX)
Acknowledgments
This work was supported by the Health Promotion Administration, Ministry of Health and Welfare, Taiwan (MOHW114-HPA-H-113–112701). The content of this research may not represent the opinion of the Health Promotion Administration.
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