In this population-based prospective cohort study, we evaluated the associations of fetal first trimester crown–rump length with kidney growth and function in childhood. We did not observe consistent associations of fetal first trimester growth with kidney outcomes in childhood.
Some methodological issues need to be addressed. We used a subgroup of a large population-based prospective cohort study to examine the kidney consequences of fetal first trimester growth restriction. Only mothers with a first trimester crown–rump measurement and a reliable first day of their last period were eligible for entry into the study, and women meeting these criteria represented only a small subgroup of the full study. We used the first day of the last menstrual period in women with a regular menstrual cycle to date gestational age since we could not measure the timing of ovulation and implantation. It is therefore possible that a misclassification of gestational age could have occurred [25]. Of the eligible subgroup, blood samples had been collected from 67 % of all children. Our results would be biased if the results differed between children with and without follow-up measurements at the age of 6 years. Although this possibility seems unlikely, we cannot exclude it. Children for whom no blood samples were available had a lower mean birth weight than their counterparts for whom blood samples were available. Our results would be biased if the associations of first trimester growth with childhood kidney function differed between children with and without blood samples. Since smaller numbers of blood samples were available in children with lower birth weight, our observed effect estimates may be underestimated. Glomerular number cannot be evaluated in vivo, but kidney size and glomerular number correlate in pathological studies in childhood and adulthood [26, 27, 28]. We estimated the GFR using the Schwartz formula [20], which is based on serum creatinine levels, and the Zappitelli formula [21], which is based on serum cystatin C levels; both formulas have been validated in pediatric populations. The eGFR was higher when calculated based on creatinine concentrations than on cystatin C concentrations, a difference which is in line with previous studies [29]. However, no difference in results were observed when we used eGFR based on creatinine concentrations compared to cystatin C concentrations, and we found no differences in outcomes between those formulas. It has been suggested that serum cystatin C levels may be the superior biomarker for evaluating kidney function compared to serum creatinine levels [30]. However, to date it is not clear which formula provides the best estimation of the GFR [30]. We used a random urine sample to determine the albumin to creatinine ratio to evaluate microalbuminuria. Since intra-individual variation in urinary albumin secretion may be large, the variability would probably have been lower if we collected first morning void samples [31]. Finally, although we adjusted for several potential confounders, residual confounding might still be a problem because of the observational design of the study.
Growth and development rates are higher in fetal life than in childhood. The highest rate of organogenesis in humans occurs during the first trimester. The first trimester may therefore be a critical period in terms of developing risk factors for diseases in later life. We adopted an approach used in previous studies focused on fetal first trimester growth in relation to birth outcomes and cardiovascular outcomes and used quintiles for fetal first trimester growth [12, 14]. No major differences in results were observed when we used tertiles of fetal first trimester growth instead of quintiles. Longitudinal studies, including studies based on the same cohort as that in the present study, have shown associations of impaired first trimester growth with increased risks of premature birth, low birth weight and being small for gestational age at birth [12, 32, 33]. Results from this cohort study have also previously shown that fetal first trimester growth restriction is associated with cardiovascular risk factors in childhood [14]. The analyses in this study were performed in a healthy population, with the majority of children born at term and normal weight for gestational age. To the best of our knowledge, no other human studies have evaluated the associations of first trimester growth with kidney function in later life. Nephrogenesis starts around week 5 of gestation, and the first nephrons begin to form at approximately week 9 [34]. Nephrogenesis continues during gestation and stops around week 34–36 [10]. Against this background, our aim was to identify the role of first trimester fetal development in kidney development.
Using data from the same cohort as that enrolled in the present study, we previously reported that lower fetal growth from second trimester onwards is associated with lower combined kidney volume and eGFR in childhood [8]. Also, a previous study among children born preterm showed that size for gestational age is correlated with kidney volume at the ages of 0, 3 and 18 months, which implies that impaired fetal growth has consequences for kidney growth in infancy [35]. Some studies on fetal growth impairment have shown a slight catch-up kidney growth postnatally in small for gestational age infants, but the results are inconclusive [35, 36]. The current study extends these previous findings since it is focused on first trimester of pregnancy, a period of which little is known in relation to kidney outcomes. We did not observe consistent associations of fetal first trimester growth with kidney outcomes in childhood.
Smaller kidneys with fewer nephrons will lead to compensatory glomerular hyperfiltration, which might be beneficial in the short term but can lead to glomerulosclerosis and impaired kidney function in later life [1]. Hyperfiltration might increase renal mass while glomerular number is relatively low [37]. However, it is not possible to distinguish hypertrophy or normal growth by ultrasonography. Also, it is not known when hypertrophy exactly occurs, and it is difficult to determine whether glomerular enlargement is caused by glomerular hyperfiltration [38, 39]. In the present study, we observed an inverse association between fetal first trimester crown–rump length and kidney volume in childhood, which we cannot fully explain. This finding is in line with the results of a previous study from the same cohort which showed that the lowest tertile of gestational age-adjusted abdominal circumference in the third trimester is associated with a larger relative fetal kidney volume [40]. Renal hypertrophy may be one explanation for this inverse association; however, more studies are needed to replicate our findings and to identify the underlying mechanisms.
We performed multiple statistical tests. However, since the kidney outcomes were highly correlated, we did not adjust analyses for multiple testing. Therefore, the observed association between the lowest first trimester crown–rump length and kidney volume should be interpreted carefully and may be a chance finding. Decreased fetal growth might lead to impaired kidney function by other mechanisms than smaller kidneys; for example, multiple studies have suggested that epigenetic changes in response to adverse fetal exposures lead to developmental adaptations [6, 41, 42].
In conclusion, we did not observe associations between fetal first trimester growth restriction and kidney size and function in childhood. These findings do not support the hypothesis that the first trimester is a critical period for kidney function in later life, and further studies on this hypothesis are needed.