Increased blood pressure and impaired endothelial function after accelerated growth in IVF/ICSI children
Authors: Zandstra H , van Montfoort A P A , Dumoulin J C M , Zimmermann L J I , Touwslager R N H 
Published: November 2019

Abstract

STUDY QUESTION
What is the effect of growth velocity (height and weight) in early infancy on metabolic end-points and endothelial function in children born after ART?

SUMMARY ANSWER
Neonatal, infant and childhood growth is positively related to blood pressure in 9-year-old IVF/ICSI offspring, while growth in childhood was negatively associated with endothelial function.

WHAT IS KNOWN ALREADY
Offspring of pregnancies conceived after ART are at risk for later cardiometabolic risk factors. It is well established that early growth is related to numerous later cardiometabolic risk factors such as high blood pressure. This concept is known as the Developmental Origin of Health and Disease theory.

STUDY DESIGN, SIZE, DURATION
The relation between early growth and later cardiometabolic risk profile was studied in the MEDIUM-KIDS study, a prospective observational cohort study in children born after an IVF/ICSI treatment. In 131 children (48.1% males) at the average age of 9.4 years, cardiometabolic outcomes were assessed and growth data from birth until age 9 years were collected from child welfare centers.

PARTICIPANTS/MATERIALS, SETTINGS, METHODS
The following cardiometabolic outcomes were assessed: blood pressure, skinfolds, lipid spectrum, hair cortisone and glucose and insulin levels. Data on maximum skin perfusion after transdermal delivery of acetylcholine as a measure of endothelial function were collected.
Growth charts were obtained electronically from child welfare centers, which offer free consultations and vaccinations to all Dutch children. At these centers, height and weight are recorded at predefined ages. Growth was defined as z-score difference in weight between two time points. Multivariable linear regression analysis was used to model the relation between growth and cardiometabolic outcomes. The following growth windows were –studied simultaneously in each model: 0–1 month, 1–3 months, 3–6 months, 6–11 months, 11–24 months and 2–6 years. The model was adjusted for height growth in all intervals except for 0–1 month.

MAIN RESULTS AND THE ROLE OF CHANCE
In multivariable linear regression analyses, multiple growth windows were positively associated with blood pressure, for example growth from 2–6 years was significantly related to systolic blood pressure: B = 4.13, P = 0.005. Maximum skin perfusion after acetylcholine was negatively associated with height-adjusted weight gain from 2 to 6 years: B = −0.09 (log scale), P = 0.03. Several growth windows (weight 1–3 months, 3–6 months, 6–11 months, 11–24 months, 2–6 years) were positively linked with total adiposity. Lipids, glucose tolerance indices and cortisone were not related to growth.

LIMITATIONS, REASONS FOR CAUTION
This study is of modest size and of observational nature, and we did not include a control group. Therefore, we cannot assess whether the observed associations are causal. It is also not possible to analyze if our observations are specific for, or exacerbated in, the ART population. Ideally, a control group of naturally conceived siblings of IVF/ICSI children should simultaneously be studied to address this limitation and to assess the impact of the ART procedure without the influence of parental (subfertility) characteristics.

WIDER IMPLICATIONS OF THE FINDINGS
The results of this study contribute to our understanding of the reported increased risk for hypertension in ART offspring. We speculate that early, accelerated growth may be involved in the reported increased risk for hypertension in ART offspring, with endothelial dysfunction as a possible underlying mechanism. However, additional research into the mechanisms involved is required.

STUDY FUNDING/COMPETING INTEREST(S)
The study was financially supported by the March of Dimes, grant number #6-FY13-153. The sponsor of the study had no role in study design, data collection, data analysis, data interpretation or writing of the paper. The authors have no conflict of interest to declare.

TRIAL REGISTRATION NUMBER
NTR4220