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. Author manuscript; available in PMC: 2026 Jan 30.
Published in final edited form as: Reprod Biomed Online. 2025 Jan 30;51(1):104846. doi: 10.1016/j.rbmo.2025.104846

Fertility treatment and cardio-metabolic risk factors in middle childhood

Edwina Yeung a, Tzu-Chun Lin b, Diane L Putnick a, Pauline Mendola c
PMCID: PMC12229779  NIHMSID: NIHMS2053116  PMID: 40441930

Abstract

Research question:

Is growth or blood pressure altered among children conceived by fertility treatment compared with children conceived without use of treatment?

Design:

The Upstate KIDS birth cohort originally oversampled for infants conceived by fertility treatment including by in vitro fertilization or intracytoplasmic sperm injection (IVF/ICSI) and by ovulation induction and/or intrauterine insemination (OI/IUI). Between 6-9 years of age, 1658 families completed annual questionnaires including children’s weight, height and blood pressure as reported from pediatric visits. Age and sex specific z-scores of weight, height and body mass index (BMI) were calculated. Mixed effects models were applied to assess differences for children conceived by any fertility treatment (n=541) and by IVF/ICSI (n=258) and OI/IUI (n=283) separately relative to children conceived without treatment (n=968), adjusting for sociodemographic and other factors.

Results:

Children conceived by any fertility treatment did not differ in anthropometry or blood pressure compared to children not conceived by treatment. Children conceived by OI/IUI were slightly smaller than children conceived without treatment in both weight-for-age (−0.19; 95%CI: −0.35; −0.03) and height-for-age (−0.27; 95%CI: −0.47; −0.08) z-scores. Lower systolic blood pressure was also observed but not after accounting for height. Children conceived by IVF/ICSI were similar in weight, height, BMI, and blood pressure but had slightly larger waist circumference (0.54 cm; 95%CI: 0.12, 0.94).

Conclusions:

Children conceived by OI/IUI were slightly smaller in middle childhood than children not conceived by treatment but remained in the normal range of growth. Overall, these findings point to reassuring growth and blood pressure levels for children conceived by fertility treatments.

Keywords: in vitro fertilization, intracytoplasmic sperm injection, ovulation induction, childhood, blood pressure, body mass index

Introduction

Fertility treatment has been increasingly used worldwide as couples delay childbearing owing to economic and other factors (Mills et al. 2011). Hence, assisted reproductive technologies (ART), defined by the Centers for Disease Control (CDC) as fertility treatments whereby eggs or embryos are handled outside the body (Sunderam et al. 2022), has gained acceptability and steadily risen in use. Nearly all ART procedures are in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). According to 2019 estimates from the European Society of Human Reproduction and Embryology (ESHRE), 3% of births overall were reported being conceived by IVF/ICSI, with country specific rates ranging from 0.6% in Ukraine to 8.9% in Spain.(European et al. 2023) In 2019, the estimated proportion of births from IVF/ICSI in the United states was 2.1%.(Sunderam et al. 2021)

There were initial concerns over whether children born by IVF grow differently, due to overgrowth syndromes in ruminants (Sinclair et al. 2000). Some attention was also drawn to concerns over cardio-metabolic health consequences, particularly with observations of higher blood pressure.(Yeung and Druschel 2013) The perinatal outcomes from large population studies continue to point to lower birth weight and earlier gestational age of newborns conceived by IVF/ICSI among singletons (Pinborg et al. 2013) as well as twins (Marleen et al. 2024). These perinatal outcomes have, in turn, been associated with increased cardiovascular disease risk across different populations (Crump 2020; Huxley, Shiell, and Law 2000).

Less attention has been focused on children conceived by ovulation induction without embryo culture despite potential of pregnancy exposures to supraphysiological levels of hormones having adverse consequences (Pereira et al. 2017). In fact, the evidence from perinatal research linking exposure to lower birthweight (Ganer Herman et al. 2024) hints at potential for higher risks of obesity or elevated blood pressure long term. Fewer studies have also been conducted in both singletons and twins, despite a substantial number of twins being born after OI and IVF/ICSI.

Therefore, we aimed to evaluate the anthropometry and blood pressure of children between 6-9 years of age in association with mode of conception. We hypothesized that differences would be observed by fertility treatment exposure in total or by IVF/ICSI or OI/IUI separately.

Materials and methods

Study Design and Population

The Upstate KIDS Study was designed to prospectively follow a cohort of newborns from New York State to determine whether conception using fertility treatment would impact long-term health.(Buck Louis et al. 2014) This population-based birth cohort utilized vital records to identify a population-based sample of families, oversampling on babies conceived by fertility treatment between 2008 and 2010. Families with singletons indicated as conceived using fertility treatment of any type were recruited approximately 2-4 months after delivery.(Buck Louis et al. 2014) For every singleton conceived by treatment recruited, three singletons who were not conceived by treatment were also recruited, frequency matched on seven perinatal regions of birth within New York State.(Buck Louis et al. 2014) Communications with families were directed to primary caregivers who were almost exclusively mothers, so we use the term mothers to refer to our respondents in the following text. Mothers of all twins and higher order multiples were also invited to participate regardless of mode of conception. The study enrolled 5,034 mothers with their 6,171 newborns.(Buck Louis et al. 2014) Details on the first phase of follow-up until 2014 when the children were 3 years old can be found elsewhere.(Yeung et al. 2016) A second phase of follow-up began in 2015 with invitation to mothers of 5529 children to complete an annual survey over three years (children aged 6-9).(Yeung et al. 2022) This follow-up excluded triplets and quadruplets (n=134), withdrawals (n=486) and lost to follow-up (n=22).(Yeung et al. 2022) For this analysis, we included 1,658 children (1,352 singletons and one twin (n=306) from each family) with outcome information reported on any of the school-aged surveys.

The New York State Department of Health and the University of Albany Institutional Review Board (IRB) (#15E-122) approved the study and served as the IRB designated by the National Institutes of Health under a reliance agreement. Mothers provided written informed consent.

Fertility treatment ascertainment

Mothers completed a baseline questionnaire at approximately 4 months postpartum which included an item asking them to select all medical services or medications used to assist them with conceiving. By design, about a third of the cohort was conceived by any type of fertility treatment, and among them, about half were conceived by ART and half by non-ART types of treatments (Yeung et al. 2016). ART was defined as use of IVF, ICSI, assisted hatching, frozen embryo transfer, gamete intrafallopian transfer, zygote intrafallopian transfer, with or without the use of donor eggs or embryos.(Yeung et al. 2016) High sensitivity (93%) and specificity (99%) were found for maternal report of ART use compared to ART use identified by linkage with the Society for Assisted Reproductive Technology Clinic Outcome Reporting System.(Buck Louis et al. 2015) In the current analysis, only IVF/ICSI were used among those undergoing ART procedures. Ovulation induction (OI) was defined as indication of using oral or injectable medications (e.g., Clomid® or gonadotropins) with or without intrauterine insemination (IUI) to conceive.(Buck Louis et al. 2014) The current sample of children conceived by OI/IUI included 16 children conceived with IUI without an indication of any method of ovulation stimulation.

Cardio-metabolic outcomes

Mothers received a child health journal in 2016 which included items for recording height, weight, blood pressure and other health conditions from pediatric visits. With the aid of this journal, the information was then solicited from parents in subsequent surveys. Three annual questionnaires were completed between 2016-2019 for children when they were around 6-9 years of age. These questionnaires asked mothers to report weight, height and blood pressure measured from well child visits along with dates of visits to calculate the age at these visits. They also included separate questions for in-home measurements of weight, height and waist circumference at the time of the questionnaire. Families were mailed a measuring tape and instructions on how to measure waist to the nearest quarter inch at the natural waistline. Parent-measured height, weight, and waist circumference have been found to be reliable (Barrios et al. 2016; Chai et al. 2019). Waist circumference was found to be highly related to experimenter measured circumference (ICC=0.97), even when using a home-printed tape measure (Chai et al. 2019). Body mass index (BMI) was calculated from the weight and height measures. Children’s age and sex specific z-scores for weight, height and BMI were derived using the CDC growth charts.(Kuczmarski et al. 2002) We defined overweight as BMI over the 85th percentile using the well child visit measures.

Covariates

Maternal race/ethnicity, education, marital status, smoking status and pre-pregnancy BMI (derived from pre-pregnancy weight and height) were reported by mothers on the baseline questionnaire. Maternal age and insurance status at delivery and children’s plurality, sex, birthweight, and gestational age came from vital records.

Statistical analysis

Baseline characteristics by mode of conception were compared by t-test for continuous variables or chi-square tests for categorical variables. Repeated outcome measures were modeled using mixed effects models to estimate mean differences (95% CIs) in anthropometry and blood pressure measures by mode of conception. First, all children conceived by any fertility treatment were compared against children conceived without use of any treatment. Secondly, we compared children conceived by IVF/ICSI, and then by OI/IUI separately, versus children conceived without any fertility treatment. Unadjusted models were run along with models adjusting for maternal age at delivery, education, race/ethnicity, insurance, child sex, plurality (twin or not) and smoking during pregnancy. We additionally adjusted for pre-pregnancy BMI in models evaluating anthropometry outcomes. Due to low levels of missing covariate data (<5%), complete case analysis was used. We previously found that twins catch up in size by middle childhood.(Gleason et al. 2023) Hence, our primary analysis did not stratify by plurality. Nevertheless, due to our previous finding of slight differences in size in the OI/IUI among twins (Yeung et al. 2016), models were also run stratified by plurality along with formal tests for interaction. The same covariates were adjusted for in generalized linear mixed models with quadrature approximation method for estimating odds ratios for overweight. To evaluate the impact of losses to follow-up, we also conducted weighted analyses applying inverse probability weights for attrition. Application of inverse probability weights is an approach many longitudinal cohorts take to assess the impact of attrition. (Howe et al., 2016) The probability of item specific response to any of the three annual questionnaires was modeled using logistic regression with fertility treatment, maternal age, maternal education, maternal race, private insurance, child sex, pregnancy smoking, pre-pregnancy BMI, and plurality as variables based on baseline information from the full cohort (n=4989). We modeled three sets of inverse probability weights corresponding to responses for anthropometry information from well child visits, for blood pressure information from well child visits and for parental measured anthropometry. The main analyses between fertility treatment and cardio-metabolic outcomes were then re-run weighted by these inverse probabilities which essentially counted those whose characteristics were most like those who did not respond more highly by giving them greater weights (to represent those who had left the study). All statistical analyses were conducted using SAS version 9.4 (SAS Institute Inc).

Results

Table 1 shows that children conceived by fertility treatment were more likely to come from households with higher socioeconomic status (i.e., higher education, private insurance, married/living as married) and less likely to have reported smoking during pregnancy. Some of these differences were also apparent even comparing the OI/IUI with the IVF/ICSI groups (i.e., maternal age, advanced degree, pre-pregnancy BMI, and plurality).

Table 1.

Descriptive characteristics of participants by mode of conception among 7-9 year old children in Upstate KIDS

Overall No fertility Treatment Any fertility Treatment OI/IUI IVF/ICSI
N (%) or mean (SD)* 1658 (100.00) 1073 (64.72) 585 (35.28) 306 (18.46) 279 (16.83)
Maternal age (years) ab 31.33 (5.87) 29.65 (5.57) 34.41 (5.12) 32.60 (4.59) 36.40 (4.93)
Maternal race/ethnicity
Non-Hispanic White 1419 (85.59) 908 (84.62) 511 (87.35) 276 (90.20) 235 (84.23)
Non-Hispanic Black 43 (2.59) 32 (2.98) 11 (1.88) 4 (1.31) 7 (2.51)
Non-Hispanic Asian 59 (3.56) 37 (3.45) 22 (3.76) 8 (2.61) 14 (5.02)
Hispanic 101 (6.09) 65 (6.06) 36 (6.15) 15 (4.90) 21 (7.53)
Mixed race or ethnicity / Other 36 (2.17) 31 (2.89) 5 (0.85) 3 (0.98) 2 (0.72)
Maternal education ab
Less than high school 48 (2.90) 45 (4.20) 3 (0.51) 3 (0.98) 0 (0.00)
HS or GED equivalent 154 (9.30) 137 (12.79) 17 (2.91) 12 (3.92) 5 (1.79)
Some college 418 (25.24) 313 (29.23) 105 (17.95) 66 (21.57) 39 (13.98)
College 421 (25.42) 251 (23.44) 170 (29.06) 87 (28.43) 83 (29.75)
Advanced degree 615 (37.14) 325 (30.35) 290 (49.57) 138 (45.10) 152 (54.48)
Private Insurance a 1378 (83.16) 815 (76.03) 563 (96.24) 290 (94.77) 273 (97.85)
Married/Living as married a 1483 (91.88) 942 (90.40) 541 (94.58) 286 (95.02) 255 (94.10)
Smoked during pregnancy a 163 (9.84) 143 (13.34) 20 (3.42) 13 (4.25) 7 (2.52)
Prepregnancy BMI (kg/m2) b 26.74 (6.95) 26.67 (7.03) 26.88 (6.78) 27.88 (7.37) 25.78 (5.89)
Plurality ab
Singleton 1352 (81.54) 913 (85.09) 439 (75.04) 243 (79.41) 196 (70.25)
Twin 306 (18.46) 160 (14.91) 146 (24.96) 63 (20.59) 83 (29.75)
Child sex as male 870 (52.47) 580 (54.05) 290 (49.57) 150 (49.02) 140 (50.18)
Birthweight (grams) a 3228 (697) 3278 (661) 3138 (751) 3187 (743) 3085 (757)
Gestational age (weeks) a 38.2 (2.4) 38.4 (2.3) 37.9 (2.7) 38.1 (2.7) 37.6 (2.7)
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*

Sample size of 1,658 includes those who have outcome information (parent measured or doctor visit measure) reported on any of the follow-up surveys.

a

P<0.05 for comparisons between no infertility treatment and any treatment

b

P<0.05 for comparisons between OI/IUI and IVF/ICSI

Missing data: maternal education (n=2), private insurance (n=1), married/living as married (n=44), smoking (n=2), prepregnancy BMI (n=1).

Children conceived by any fertility treatment did not differ from those not conceived by treatment in anthropometry whether as measured by parents or as reported from well child visits between 6-9 years of age (Table 2). Similarly, no significant differences were seen in blood pressure. If anything, there was a tendency to have lower rather than higher systolic blood pressure. After stratifying by plurality, singletons conceived by any fertility treatment had slightly lower weight and systolic blood pressure (−1.54 mmHg; 95% CI: −2.92, −0.15). No differences were observed among twins, although confidence intervals were much wider owing to the smaller sample size of twins. A significant p-value of interaction by plurality was detected for weight (p=0.018) but not systolic blood pressure (p=0.39).

Table 2.

Conception by any fertility treatment and mean differences (95% confidence interval) in anthropometry and blood pressure compared to children conceived without treatment at 7-9 years in Upstate KIDS

All children n (tx vs. no tx) Unadjusted p Adjusted* p
Pediatric visit measure
Height z-score 1306 (478 vs. 828) −0.10 (−0.25, 0.05) 0.19 −0.11 (−0.27, 0.06) 0.20
Weight z-score 1373 (496 vs. 877) −0.11 (−0.24, 0.02) 0.09 −0.05 (−0.18, 0.09) 0.50
BMI z-score 1283 (471 vs. 812) −0.06 (−0.20, 0.08) 0.42 0.01 (−0.14, 0.16) 0.92
SBP** 839 (340 vs. 499) −1.17 (−2.39, 0.05) 0.06 −1.22 (−2.49, 0.05) 0.06
DBP** 835 (341 vs. 494) −0.96 (−2.09, 0.17) 0.10 −0.65 (−1.85, 0.56) 0.29
Parent measure
Height z-score 1509 (541 vs. 968) −0.03 (−0.15, 0.09) 0.63 −0.09 (−0.22, 0.04) 0.19
Weight z-score 1491 (543 vs. 948) −0.10 (−0.22, 0.03) 0.12 −0.08 (−0.21, 0.05) 0.21
BMI z-score 1363 (509 vs. 854) −0.02 (−0.18, 0.15) 0.85 0.02 (−0.13, 0.17) 0.77
Waist circumference 1469 (526 vs. 943) −0.04 (−0.34, 0.26) 0.81 0.10 (−0.20, 0.40) 0.52
Singletons n (tx vs. no tx) Unadjusted p Adjusted* p
Pediatric visit measure
Height z-score 1080 (367 vs. 713) −0.08 (−0.25, 0.09) 0.36 −0.14 (−0.32, 0.05) 0.15
Weight z-score 1130 (376 vs. 754) −0.11 (−0.25, 0.04) 0.14 −0.09 (−0.24, 0.06) 0.25
BMI z-score 1058 (360 vs. 698) −0.06 (−0.21, 0.09) 0.45 −0.03 (−0.19, 0.14) 0.74
SBP** 694 (256 vs. 438) −1.32 (−2.65, 0.02) 0.05 −1.54 (−2.92, −0.15) 0.03
DBP** 689 (256 vs. 433) −1.20 (−2.45, 0.05) 0.06 −1.02 (−2.34, 0.29) 0.13
Parent measure
Height z-score 1225 (405 vs. 820) −0.04 (−0.18, 0.10) 0.61 −0.11 (−0.26, 0.04) 0.14
Weight z-score*** 1217 (409 vs. 808) −0.14 (−0.28, −0.0007) 0.05 −0.15 (−0.30, −0.01) 0.04
BMI z-score 1107 (382 vs. 725) −0.04 (−0.23, 0.14) 0.65 −0.03 (−0.20, 0.13) 0.69
Waist circumference 1199 (398 vs. 801) −0.05 (−0.39, 0.29) 0.76 0.03 (−0.32, 0.37) 0.88
Twins n (tx vs. no tx) Unadjusted p Adjusted* p
Pediatric visit measure
Height z-score 226 (111 vs. 115) −0.09 (−0.40, 0.23) 0.60 0.04 (−0.28, 0.36) 0.81
Weight z-score 243 (120 vs. 123) 0.03 (−0.28, 0.33) 0.86 0.20 (−0.08, 0.49) 0.16
BMI z-score 225 (111 vs. 114) 0.10 (−0.27, 0.48) 0.58 0.18 (−0.16, 0.51) 0.30
SBP** 145 (84 vs. 61) 0.23 (−2.95, 3.40) 0.89 0.91 (−2.16, 3.98) 0.56
DBP** 146 (85 vs. 61) 0.69 (−2.07, 3.44) 0.62 1.43 (−1.34, 4.19) 0.31
Parent measure
Height z-score 284 (136 vs. 148) 0.09 (−0.17, 0.36) 0.48 0.06 (−0.22, 0.35) 0.67
Weight z-score*** 274 (134 vs. 140) 0.21 (−0.08, 0.49) 0.15 0.20 (−0.08, 0.47) 0.16
BMI z-score 256 (127 vs. 129) 0.20 (−0.11, 0.51) 0.21 0.17 (−0.13, 0.48) 0.27
Waist circumference 270 (128 vs. 142) 0.22 (−0.42, 0.86) 0.51 0.31 (−0.24, 0.86) 0.27
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Abbreviations: BMI, body mass index; DBP, diastolic blood pressure; SBP, systolic blood pressure; tx, fertility treatment

*

Adjusted for maternal age, education, race/ethnicity, private insurance, child sex, plurality, maternal smoking, pre-pregnancy BMI

**

Adjusted models for SBP and DBP are minimally adjusted without pre-pregnancy BMI

***

Significant p-value of interaction for differences in association between twins and singletons (p-interaction=0.018)

After breaking down the treatment type further, it seems these differences in weight and blood pressure were driven by the group of children conceived by OI/IUI (rather than IVF/ICSI). The children conceived by OI/IUI were somewhat smaller in weight and shorter in height and had lower systolic blood pressure (SBP −1.55 mmHg; 95%CI: −3.02, −0.07) (Table 3) than children conceived without any treatment. Additionally adjusting for height to account for their slightly shorter stature, attenuated this SBP difference (−0.86 mmHg; 95%CI: −2.53, 0.82). After stratifying by plurality, the singletons conceived by OI/IUI were smaller and shorter than singletons not conceived with fertility treatment. By the well child visit measures, the mean difference in weight z-score was −0.24 (95%CI: −0.42, −0.07) and in height z-score of −0.26 (95%CI: −0.48, −0.05). In keeping with these observations, the odds for overweight among singletons was also lower among those conceived by OI/IUI (adjusted odds ratio: 0.45; 95% CI 0.22, 0.90; Supplemental Table 1). However, after examining the mean anthropometric z-scores across the surveys, it became apparent that the children conceived by OI/IUI were not growing atypically but rather that the comparison group of children not conceived by any fertility treatment were slightly larger than the 50th percentile (i.e., the median) of the general population in US according to the CDC growth reference (Supplemental Figure 1). In other words, the OI/IUI children averaged around zero in z-scores (as designated by the dashed reference line) while the other two groups averaged slightly higher z-scores. Nevertheless, noting the children conceived by OI/IUI were smaller, we also adjusted for paternal body size as a potential confounding variable, but there were no substantive differences from the main results which had adjusted for maternal pre-pregnancy BMI (data not shown).

Table 3.

Conception by OI/IUI and mean differences (95% confidence interval) in anthropometry and blood pressure compared to children conceived without treatment at 7-9 years in Upstate KIDS

All children n (OI/IUI vs no tx) Unadjusted p Adjusted* p
Pediatric visit measure
Height z-score 1069 (241 vs. 828) −0.28 (−0.47, −0.08) 0.01 −0.27 (−0.47, −0.08) 0.01
Weight z-score 1130 (253 vs. 877) −0.22 (−0.38, −0.05) 0.01 −0.19 (−0.35, −0.03) 0.02
BMI z-score 1050 (238 vs. 812) −0.07 (−0.25, 0.10) 0.41 −0.08 (−0.26, 0.09) 0.36
SBP** 662 (163 vs. 499) −1.55 (−3.05, −0.05) 0.04 −1.55 (−3.02, −0.07) 0.04
DBP** 657 (163 vs. 494) −0.88 (−2.29, 0.54) 0.23 −0.64 (−2.07, 0.80) 0.39
Parent measure
Height z-score 1251 (283 vs. 968) −0.15 (−0.31, −0.0005) 0.05 −0.21 (−0.36, −0.05) 0.01
Weight z-score 1225 (277 vs. 948) −0.19 (−0.34, −0.04) 0.01 −0.20 (−0.35, −0.04) 0.01
BMI z-score 1115 (261 vs. 854) −0.06 (−0.24, 0.13) 0.56 −0.07 (−0.25, 0.10) 0.41
Waist circumference 1218 (275 vs. 943) −0.23 (−0.59, 0.13) 0.21 −0.22 (−0.56, 0.12) 0.20
Singletons n (OI/IUI vs no tx) Unadjusted p Adjusted* p
Pediatric visit measure
Height z-score 911 (198 vs. 713) −0.25 (−0.46, −0.03) 0.03 −0.26 (−0.48, −0.05) 0.02
Weight z-score 960 (206 vs. 754) −0.24 (−0.41, −0.06) 0.01 −0.24 (−0.42, −0.07) 0.01
BMI z-score*** 893 (195 vs. 698) −0.14 (−0.33, 0.04) 0.13 −0.15 (−0.34, 0.04) 0.12
SBP** 566 (128 vs. 438) −1.85 (−3.47, −0.23) 0.03 −1.81 (−3.40, −0.22) 0.03
DBP** 561 (128 vs. 433) −1.30 (−2.88, 0.28) 0.11 −1.01 (−2.59, 0.57) 0.21
Parent measure
Height z-score 1044 (224 vs. 820) −0.13 (−0.30, 0.04) 0.12 −0.18 (−0.36, −0.01) 0.04
Weight z-score 1028 (220 vs. 808) −0.25 (−0.41, −0.08) 0.004 −0.26 (−0.42, −0.09) 0.002
BMI z-score 931 (206 vs. 725) −0.14 (−0.35, 0.06) 0.18 −0.15 (−0.34, 0.04) 0.13
Waist circumference 1022 (221 vs. 801) −0.25 (−0.65, 0.15) 0.23 −0.27 (−0.66, 0.11) 0.16
Twins n (OI/IUI vs no tx) Unadjusted p Adjusted* p
Pediatric visit measure
Height z-score 158 (43 vs. 115) −0.41 (−0.84, 0.02) 0.06 −0.25 (−0.66, 0.15) 0.22
Weight z-score 170 (47 vs. 123) −0.03 (−0.43, 0.38) 0.89 0.03 (−0.33, 0.40) 0.85
BMI z-score*** 157 (43 vs. 114) 0.32 (−0.17, 0.80) 0.20 0.21 (−0.21, 0.62) 0.32
SBP** 96 (35 vs. 61) 0.49 (−3.45, 4.44) 0.81 1.17 (−2.86, 5.20) 0.57
DBP** 96 (35 vs. 61) 1.46 (−1.84, 4.75) 0.38 2.45 (−0.90, 5.79) 0.15
Parent measure
Height z-score 207 (59 vs. 148) −0.18 (−0.52, 0.16) 0.31 −0.24 (−0.59, 0.11) 0.18
Weight z-score 197 (57 vs. 140) 0.15 (−0.23, 0.53) 0.45 0.03 (−0.33, 0.38) 0.89
BMI z-score 184 (55 vs. 129) 0.34 (−0.05, 0.73) 0.09 0.23 (−0.14, 0.60) 0.23
Waist circumference 196 (54 vs. 142) −0.04 (−0.83, 0.75) 0.93 −0.14 (−0.82, 0.53) 0.68
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Abbreviations: BMI, body mass index; DBP, diastolic blood pressure; SBP, systolic blood pressure; tx, fertility treatment

*

Adjusted for maternal age, education, race/ethnicity, private insurance, child sex, plurality, maternal smoking, pre-pregnancy BMI

**

Adjusted models for SBP and DBP are minimally adjusted without pre-pregnancy BMI

***

Significant p-value of interaction for differences in association between twins and singletons (p-interaction=0.035

Turning to the children conceived by IVF/ICSI (Table 4), no differences in any cardio-metabolic outcomes were observed except for larger waist circumference, which only became significant after adjustment for covariates which included maternal pre-pregnancy BMI (0.53 inches; 95%CI: 0.12, 0.94). Increased waist circumference was observed among both the singletons and twins conceived by IVF/ICSI. Higher weight z-scores were also observed among twins conceived by IVF/ICSI compared to twins conceived without any treatment.

Table 4.

Conception by IVF/ICSI and mean differences (95% confidence interval) in anthropometry and blood pressure compared to children conceived without treatment at 7-9 years in Upstate KIDS

All children n (IVF/ICSI vs. no tx) Unadjusted p Adjusted* p
Pediatric visit measure
Height z-score 1065 (237 vs. 828) 0.07 (−0.11, 0.26) 0.42 0.13 (−0.08, 0.34) 0.23
Weight z-score 1120 (243 vs. 877) −0.01 (−0.18, 0.16) 0.91 0.15 (−0.02, 0.33) 0.09
BMI z-score 1045 (233 vs. 812) −0.04 (−0.23, 0.14) 0.64 0.16 (−0.04, 0.35) 0.11
SBP** 676 (177 vs. 499) −0.81 (−2.36, 0.74) 0.30 −0.78 (−2.49, 0.92) 0.37
DBP** 672 (178 vs. 494) −1.04 (−2.44, 0.36) 0.14 −0.63 (−2.16, 0.90) 0.42
Parent measure
Height z-score 1226 (258 vs. 968) 0.10 (−0.06, 0.26) 0.20 0.05 (−0.13, 0.23) 0.57
Weight z-score 1214 (266 vs. 948) −0.002 (−0.16, 0.16) 0.98 0.09 (−0.08, 0.26) 0.32
BMI z-score 1102 (248 vs. 854) 0.03 (−0.18, 0.23) 0.80 0.11 (−0.07, 0.30) 0.23
Waist circumference 1194 (251 vs. 943) 0.17 (−0.22, 0.57) 0.39 0.53 (0.12, 0.94) 0.01
Singletons n (IVF/ICSI vs. no tx) Unadjusted p Adjusted* p
Pediatric visit measure
Height z-score 882 (169 vs. 713) 0.11 (−0.10, 0.33) 0.29 0.07 (−0.16, 0.31) 0.54
Weight z-score 924 (170 vs. 754) 0.04 (−0.15, 0.24) 0.65 0.14 (−0.06, 0.35) 0.17
BMI z-score 863 (165 vs. 698) 0.04 (−0.16, 0.24) 0.71 0.18 (−0.04, 0.40) 0.10
SBP** 566 (128 vs. 438) −0.75 (−2.51, 1.01) 0.40 −1.12 (−3.10, 0.85) 0.27
DBP** 561 (128 vs. 433) −1.10 (−2.66, 0.46) 0.17 −1.00 (−2.69, 0.69) 0.24
Parent measure
Height z-score 1001 (181 vs. 820) 0.08 (−0.11, 0.27) 0.39 −0.01 (−0.22, 0.20) 0.92
Weight z-score 997 (189 vs. 808) −0.01 (−0.20, 0.17) 0.89 0.001 (−0.20, 0.20) 0.99
BMI z-score 901 (176 vs. 725) 0.07 (−0.15, 0.30) 0.53 0.15 (−0.07, 0.37) 0.19
Waist circumference 978 (177 vs. 801) 0.19 (−0.28, 0.66) 0.43 0.50 (0.01, 1.00) 0.05
Twins n (IVF/ICSI vs. no tx) Unadjusted p Adjusted* p
Pediatric visit measure
Height z-score 183 (68 vs. 115) 0.11 (−0.25, 0.47) 0.55 0.26 (−0.12, 0.64) 0.18
Weight z-score 196 (73 vs. 123) 0.06 (−0.29, 0.41) 0.73 0.34 (0.002, 0.68) 0.05
BMI z-score 182 (68 vs. 114) −0.02 (−0.44, 0.40) 0.91 0.18 (−0.20, 0.57) 0.36
SBP** 110 (49 vs. 61) 0.03 (−3.51, 3.58) 0.98 0.78 (−2.54, 4.10) 0.64
DBP** 111 (50 vs. 61) 0.15 (−3.08, 3.38) 0.93 0.69 (−2.62, 4.00) 0.68
Parent measure
Height z-score 225 (77 vs. 148) 0.29 (−0.01, 0.60) 0.06 0.27 (−0.06, 0.61) 0.11
Weight z-score 217 (77 vs. 140) 0.25 (−0.07, 0.57) 0.13 0.34 (0.02, 0.65) 0.04
BMI z-score 201 (72 vs. 129) 0.09 (−0.27, 0.46) 0.61 0.13 (−0.24, 0.49) 0.50
Waist circumference 216 (74 vs. 142) 0.40 (−0.37, 1.16) 0.31 0.67 (−0.02, 1.36) 0.06
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Abbreviations: BMI, body mass index; DBP, diastolic blood pressure; IVF/ICSI, in vitro fertilization / intracytoplasmic sperm injection; SBP, systolic blood pressure; tx, fertility treatment

*

Adjusted for maternal age, education, race/ethnicity, private insurance, child sex, plurality, maternal smoking, pre-pregnancy BMI

**

Adjusted models for SBP and DBP are minimally adjusted without pre-pregnancy BMI

Results were similar in sensitivity analysis applying inverse probability weights to account for lost to follow-up (Supplemental Table 2).

Discussion

Findings add to the reassuring evidence that children conceived by IVF/ICSI generally do not grow differently or have elevated blood pressure compared to their peers in middle childhood. While children conceived by OI/IUI weighed less and were shorter in height than children not conceived by treatment, the differences were slight (translating to about half an inch in height and less than 2 pounds in weight). Moreover, the average z-scores in the comparison group of children not conceived by any treatment were slightly higher than the national average indicating that the OI/IUI group was actually similar to the median US reference population. Thus, taken together, no clinically concerning differences were observed between children conceived by any type of fertility treatment when compared against those not conceived by treatment.

Our findings for IVF/ICSI align with many other studies. In 2017, a meta-analysis observed no differences in BMI (−0.04; 95%CI: −0.28, 0.20) after pooling data from offspring as young as 2 to as old as 22 years of age (Guo et al. 2017). While this meta-analysis found higher blood pressure largely stemming from studies of children born before 2000 (Guo et al. 2017), meta-analyses of publicly available data are limited in ability to control for what covariates were adjusted in models. The Assisted Reproductive Technology and Future Health (ART-Health) Cohort Collaboration pooled together results from multiple prospective cohort studies with information on ART conception with specified adjustment models. They have examined both offspring blood pressure (Elhakeem et al. 2023) and anthropometry (Elhakeem et al. 2022). They found no differences in systolic (−0.06 standardized mean difference; −0.17, 0.06) or diastolic blood pressure (−0.03; −0.10, 0.05) from nearly 36,000 children (of which 654 were conceived by IVF/ICSI) (Elhakeem et al. 2023). The ART-HEALTH consortium had a much larger sample size for evaluating BMI differences in early age as more cohorts has this information. They found that children conceived by IVF/ICSI(n =3337) compared to children not conceived by any treatment (n=107,750) had slightly lower BMI through middle childhood (6-9 years) (−0.06 kg/m2; −0.12, −0.01) (Elhakeem et al. 2022). At this same age group, they observed that height (−0.07 cm; −0.11, −0.13) and weight (−0.07 kg; −0.10, −0.04) were also slightly lower (Elhakeem et al. 2022). They also observed smaller waist circumference (−0.15 cm; −0.25, −0.05) in a subgroup with this information. As they had such a large sample size, they were able to also evaluate the impact of frozen embryo transfer (FET) which did not alter their findings on anthropometry. We add to their study, results from a cohort from the United States, where practices such as single embryo transfer can greatly differ. Taken together, the body of evidence is reassuring that there are no differences in BMI or blood pressure in middle childhood. Nevertheless, the technology continues to advance and a few recent studies of contemporary cohorts had contrary findings of higher childrhood blood pressure following IVF/ICSI conception (Catford et al. 2022; Cui et al. 2021).

Very few studies have focused on children conceived by other types of fertility treatment outside of IVF/ICSI, making it difficult to compare the current OI/IUI findings. Blood pressure findings among the few studies with information have generally been null (Pontesilli et al. 2015; Yeung et al. 2022). One study randomized treatment and found controlled ovarian hyperstimulation with intrauterine insemination (COH-IUI) compared to natural cycle IVF had no association with blood pressure at 4-7 years (Mintjens et al. 2019). Our own study with clinical measures of blood pressure in a subgroup of the children from Upstate KIDS, also found no associations with conception by OI/IUI compared to no treatment (Yeung et al. 2022). As for being of smaller size, the inconsistency between our previous findings among twins and our current findings among singletons may be due to the period of BMI rebound which occurs between 4-6 years of age. However, we also acknowledge that the loss to follow-up contributed to uncertainty, with a smaller group of twins available at the longer-term follow-up. We tried to evaluate potential bias using inverse probability weighting and did not find a difference in our results. Moreover, in our first examination in younger age, we recognized that the comparison group not conceived by any treatment also had higher than average anthropometry versus the general population in sex and adjusted mean z-scores. As such, similar to the current analysis, a difference indicating smaller size was actually due to the twins conceived by OI/IUI being more similar to the general population based on the World Health Organization reference. Here, we used the CDC reference for our examination in keeping with the recommendations for this age group (6-9 years).(Grummer-Strawn et al. 2010) Lastly, some caution should be taken as many statistical tests were performed, and with 9 outcome measures, a very conservating Bonferroni correction would mean a p-value of 0.006 is a more appropriate cut-off and only one comparison (i.e., OI/IUI and weight) reached this threshold.

Importantly, we did not observe a difference when all types of treatments were combined as a single exposure group, which suggests that parental infertility on its own is not associated with differences. Some studies which investigated a subfertile group for comparison, suggested that it is subfertility or its indicators, rather than the treatment techniques, that impact child growth. For instance, another study from ART-HEALTH found increased BMI and slight differences in blood pressure of children born from subfertile compared to fertile parents using reported time to pregnancy (TTP) information from four cohorts (Hernaez et al. 2024). Due to the smaller sample with TTP information, this finding of higher BMI was a little incongruous with IVF/ICSI being associated with lower BMI in the aforementioned larger study (Elhakeem et al. 2022). Nevertheless, previously, at clinic visits we also found no differences in growth and blood pressure by fertility treatment taken altogether (Mintjens et al. 2019). While we have not directly looked at subfertility based on time to pregnancy as an exposure in the current paper, we have previously examined more direct infertility indications, specifically with respect to polycystic ovarian syndrome (PCOS) as an exposure, as it has a clear biological mechanism and associations with long-term cardio-metabolic risk. However, we also not did not find differences in early growth (Bell et al. 2018) or blood pressure (Polinski et al. 2024) in children conceived by mothers with PCOS compared to those not.

Strengths and Limitations

In addition to leveraging on detailed individual-level data such as pre-pregnancy BMI and socioeconomic status to account for confounding, strengths of this study include capturing OI/IUI and twins. Many studies did not include twins, even though they are more likely to occur in the context of not just IVF/ICSI but also OI/IUI. Our study adds to the literature that the twins also did not have differential cardio-metabolic risk in middle childhood. Nevertheless, the study experienced loss to follow-up, in similar fashion to many longitudinal pediatric cohorts. We also note that pediatric blood pressure was reported more often for children conceived by treatment than not; which may be due to socioeconomic disparities in who gets pediatric hypertension screening (Goulding et al. 2023; Shapiro et al. 2012). Nevertheless, the robustness of the associations was demonstrated in our supplementary analysis using inverse probability weights to account for the questionnaire non-response. Relying on parental report might have increased non-differential errors as anthropometric and blood pressure measures were not uniformly conducted by research staff but measured by different individuals. Blood pressure could also differ by measurement device. However, the device and individual measurement differences should be random with respect to who was conceived by fertility treatment. The cohort was predominantly non-Hispanic white which may not be representative of all families seeking fertility treatment.

Conclusions

In conclusion, our findings reinforce the developing consensus that conception using IVF/ICSI or other fertility treatment techniques is not associated with differences in harmful overgrowth or elevated blood pressure. As the use of these treatment techniques continue to grow, this information is vital as couples are not only seeking to have children, but to have some assurance that those children conceived with assistive treatments will have healthy lives.

Supplementary Material

1

Highlights.

  • No adverse blood pressure or size differences observed after conception by IVF/ICSI

  • Conception by OI/IUI associated with slightly smaller size and lower blood pressure

  • OI/IUI group was closer to national average than comparison group in middle childhood

  • Reassuring evidence of the physical health of children conceived by fertility treatment

Key Message.

Our findings reinforce the developing consensus that children conceived using IVF/ICSI or ovulation induction grow physically similarly as children not conceived by treatment. Given the continuing rise in use of these treatments worldwide, the information is important to clinicians and couples alike to better understand long-term risks, or lack thereof.

Acknowledgements:

The authors thank the Upstate KIDS participants and staff for their important contributions. The authors also thank all the members of SART for providing clinical information to the SART Clinic Outcome Reporting System database for use by patients and researchers.

Funding Source:

Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD; contracts #HHSN275201200005C, #HHSN267200700019C, #HHSN275201400013C, #HHSN275201300026I/27500004, #HHSN275201300023I/27500017).

Biography

Edwina Yeung, PhD is a Senior Investigator in the Epidemiology Branch at the Eunice Kennedy Shriver National Institute of Child Health and Human Development at NIH. She is a perinatal and pediatric epidemiologist researching on the developmental origins of health and disease and has published over 160 peer-reviewed manuscripts.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Disclosures: None to declare.

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