Journal of Clinical Endocrinology & Metabolism
, doi:10.1210/jc.2008-0562
The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 10 4027-4032
Copyright © 2008 by The Endocrine Society
Adaptive Changes in Neonatal Hormonal and Metabolic Profiles Induced by Fetal Growth Restriction
Jacques Beltrand,
Rasa Verkauskiene,
Ramona Nicolescu,
Oliver Sibony,
Pascal Gaucherand,
Didier Chevenne,
Olivier Claris and
Claire Lévy-Marchal
Institut National de la Santé et de la Recherché Médicale Unit 690 (J.B., R.V., R.N., C.L.-M.) and Service de chirurgie gynécologique-obstétrique (O.S.) et Service de biochimie et hormonolgie (D.C.), Hôpital Robert Debré, Paris, FR-75019, France; Université Paris 7 (J.B., R.V., R.N., C.L.-M.), 75205 Paris Cedex 13, France; and Service de chirurgie gynécologique-obstétrique (P.G.) et Service de médecine néonatale (O.C.), Hôpital Edouard Herriot, Lyon, FR-69437, France
Address all correspondence and requests for reprints to: Jacques Beltrand, M.D., Institut National de la Santé et de la Recherché Médicale Unit 690, Hôpital Robert Debré, 48 Boulevard Sérurier, 75019 Paris, France. E-mail: beltrand{at}me.com.
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Abstract
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Context: Birth weight (BW) is usually taken as a surrogate of fetal growth. However, BW per se is not relevant enough in assessing fetal growth restriction, which by itself may alter body composition, metabolic, and hormonal profiles at birth (irrespective of BW), reflecting the necessary adaptive changes in metabolism under poor fetal environment.
Objective: Our objective was to measure body composition, hormonal, and metabolic parameters at birth in relation to both BW and fetal growth velocity.
Methods: A total of 235 pregnancies at risk of low BW were included, and newborns were observed at birth. Fetal growth velocity was calculated as the change in customized percentiles of estimated fetal weight between 22 wk gestational age and birth. Newborns were ranked in descending order of fetal growth velocity and divided in three equal tertiles.
Results: The lower fetal growth velocity tertile showed a severe fetal growth restriction (–52% ± 21%) and was significantly associated with reduced lean and fat mass (P < 0.001 and 0.02, respectively). Insulin concentration was significantly related to fetal growth velocity (P = 0.006) and fat mass (P = 004) but not to BW (grams), whereas fetal growth velocity (P = 0.002) and BW (P < 0.001) but not fat mass had a significant effect on IGF-I concentration at birth.
Conclusion: Fetal growth restriction induces changes in body composition and metabolism suggestive of a higher insulin sensitivity independently from BW itself, reflecting adaptive changes to an adverse fetal nutritional environment.
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Introduction
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Since the introduction of the so-called Barker’s hypothesis, a large body of research has focused on low birth weight as a risk factor for metabolic diseases in adulthood (1, 2). Epidemiological studies have reported a strong association between low birth weight and type 2 diabetes, but the mechanisms underlying this association remain unclear even if animal models have shown that the origins took place during fetal life (3, 4, 5). The period of postnatal catch-up growth appears to be a crucial time for the development of insulin resistance linking fetal period to type 2 diabetes (6, 7, 8). Along this pathway, data emphasize the critical role of both pre- and postnatal nutritional signals. Recently, the concept of developmental mismatch has been proposed to explain the intricacy between fetal life, postnatal growth and metabolic disorders (9). According to this concept, developmental responses to environmental stimuli may be either disruptive or adaptive. For the latter, the advantage needs to be immediate but may arise from a predictive adaptive response made in expectation of the future environment. Such predictive adaptive response would be made during the phase of developmental plasticity to optimize the phenotype for the probable environment of the mature organism. When there is a match between the predicted and actual mature environment, these predictive adaptive responses are appropriate and assist survival. Conversely, inadequate predictions increase the risk of disease (9). This model thus encompasses the evidence focusing both on embryonic/fetal and infant/childhood cues and implies that deleterious events such as deleterious nutritional environment could modify fetal and neonatal metabolism. In this respect, birth weight and its percentile are epidemiological data that are not appropriate to appreciate this environment and its consequences on fetal growth. Birth weight is a final result of growth in utero but does not reflect fetal growth pattern, in particular when birth weight is within the normal range for gestational age. In addition to gestational age and gender, other pregnancy characteristics, such as maternal height and weight before pregnancy, parity, and ethnicity account for a large part of variation in fetal growth velocity and weight at birth (10). On the one hand, small babies who are simply small as a result of adaptation to maternal size can be separated from those who have suffered from fetal growth restriction. On the other hand, even in infants born appropriate-for-gestational age birth weight may have failed to reach their genetic potential of intrauterine growth because of fetal growth restriction. Therefore, birth weight by itself is not sufficient to identify fetal growth restriction. It has recently been shown that customized fetal growth estimation, adjusting for maternal and fetal characteristics, allows a precise evaluation of fetal growth restriction by identifying newborns who have failed to reach their genetic potential of growth and who are at a high risk of adverse neonatal outcome (11, 12, 13, 14, 15). However, in these studies, altered fetal growth was not regarded when birth weight was in the normal range of the distribution. In the present study, we aimed at following fetal growth in pregnancies considered at risk of delivering a newborn with a low birth weight or height and/or fetal growth restriction because of maternal medical condition. We used a prospective and standardized protocol to monitor dynamic changes in estimated fetal weight (EFW) so that fetuses with regular growth can be separated from those with restricted growth. We hypothesized that fetal growth restriction would induce changes in body composition and metabolic parameters at birth irrespective of birth weight itself. These changes would reflect the adaptive metabolic response occurring in the fetus facing an adverse environment.
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Subjects and Methods
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The study population was formed of 235 newborns included between May 2004 and May 2007 in the CASyMIR cohort, which principal aim is to assess prenatal and postnatal growth patterns in relationship with the later insulin sensitivity and metabolic profile in childhood. Study infants were born from Caucasian women recruited during their first or second trimester of pregnancy in two French maternities (Robert Debré Hospital in Paris and Edouard Herriot Hospital in Lyon) and considered at risk for delivering small-for-gestational age babies. Inclusion criteria were preexisting hypertension, smoking more than five cigarettes per day, a previous history of small-for-gestational-age baby either in a previous pregnancy or among parents, a history of pregnancy-induced hypertensive disorder, maternal height less than 152 cm corresponding to –2 SD of the mean height for French women, uterine malformations, abnormal uterine or umbilical artery Doppler, and small fetal size at second trimester ultrasound examination [abdominal circumference and/or femoral length at 22 wk gestation (WG) below the 10th percentile according to French references (16)]. Newborns presenting fetal or neonatal diseases that could affect body composition or hormonal status at birth were excluded. Indeed, TORCH (toxoplasma, other, rubella, cytomegalovirus, and herpes) infection and congenital malformation were exclusion criteria. Newborns presenting with severe adverse neonatal outcomes resulting in hospitalization in an intensive care unit with an artificial nutritional support in the first days of life were excluded as well. Birth weight of newborns was recorded within 10 g by midwives using an electronic scale. Birth length was measured on a standard infants’ measuring board within 1 mm. Fat mass at birth was evaluated at d 3 of postnatal life by measurement of skinfold thickness as previously reported (17). Triceps, subscapular, biceps, and suprailiac skinfold thickness measurements were made with skinfold calipers (Harpenden skinfold caliper; Baty International Ltd., Burgess Hill, West Sussex, UK) by a trained pediatrician dedicated to the study. Two separate measurements were taken by the same operator on the left part of the body, and the mean was recorded. Various indexes were calculated: sum of skinfold thicknesses and central to peripheral ratio [(suprailiac skinfold + subscapular skinfold/sum of skinfold) x 100]. Brachial circumference was corrected for triceps skinfolds [brachial circumference (centimeters) – 3.14 x triceps skinfold (centimeters)] to reflect the muscular circumference of the arm. The study protocol was approved by the ethical committee of Paris-Saint Louis Medical School (René Diderot Paris University), and all parents gave written informed consent.
Assessment of fetal growth
The date of conception was determined from the ultrasound examination at 12 WG. Fetal growth was assessed every 4 wk by ultrasound from 22–36 WG. All four ultrasound scans were performed by the same observer for each woman under a standardized protocol according to the guidelines of College des Echographistes de France (Rapport du comité technique de l’echographie de diagnostic prénatal. Collège français d’échographie fetale, April 2005, www.cfef.org). EFW was calculated using the second Hadlock formula, which includes abdominal and head circumferences and femur length measurements at 22–24, 26–28, 30–32, and 34–36 WG (18). The four measurements of EFW and birth weight were then converted to customized percentiles that were calculated for each case with a computer program, Centile calculator version 5.12.1, which adjusts for parity, gender, maternal weight and height, and ethnic group [gestation-related optimal weight (GROW) program, 5.15, and Centile calculator software version 5.12.1., March 2007, www.gestation.net]. Coefficients for these physiological variables based on 40,000 ultrasound-dated pregnancies in Nottingham are contained in the software. Fetal growth velocity was calculated as the change in EFW percentiles from 22 WG until birth and was expressed as change in percentiles by day of gestation (19, 20). Regular fetal growth was defined by no loss in percentiles of estimated fetal weight between 22 WG and delivery (fetal growth velocity close to 0). By contrast, a more negative fetal growth velocity was considered to reflect a higher degree of fetal growth restriction.
Hormonal analyses
Mixed venous and arterial umbilical cord blood samples were collected from all infants The obtained cord blood samples were centrifuged, and serum was separated and stored at –80 C until analysis. Serum IGF-I was measured by an immunoradiometric assay (IRMA) kit (IGF-I-RIACT) from Cis Bio International (Gif-sur-Yvette, France) and serum IGF-binding protein-3 (IGFBP-3) by an IRMA kit (ACTIVE IGFBP-3 IRMA) from DSL (Cergy Pontoise, France). Serum insulin was measured by an IRMA kit (BI-INS-IRMA) from Cis Bio. Cross-reactivity with proinsulin and derived metabolites was less than 1%. Assay sensitivity was 3.0 pmol/liter. Quantitative insulin sensitivity check index (QUICKI) was calculated using the following formula: 1/(log insulinemia + log glycemia).
Statistical analyses
All analyses were performed using the JMP software version 7 (SAS Inc., Meylan, France). Newborns were divided in three tertiles with respect to fetal growth velocity. Umbilical cord IGF-I and insulin concentrations were log transformed before analysis to normalize distributions. Data are given as mean ± SD. The 
2 test was used to compare proportions between groups. Continuous variables were compared using ANOVA in univariate models. To further assess the effect of fetal growth restriction on metabolic parameters, a multivariate linear model was constructed including fetal growth velocity as the explanatory variable and gender, gestational age, and birth weight as covariates.
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Results
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Altogether, 235 newborns were included in the study. At birth, they were ranked in descending order with respect to the changes in customized percentiles between 22 WG and birth and stratified in three tertiles. Characteristics of these tertiles are given in Table 1
. Maternal and paternal anthropometric characteristics (weight, height, and body mass index) were not different across the three tertiles of fetal growth velocity (Table 2). Multiparous women were slightly less numerous in the third tertile (59, vs. 68 and 69% in the first and the second tertile, P = 0.006).
The two higher tertiles of fetal growth velocity included newborns with regular or sub-regular fetal growth. No changes in percentiles of EFW were detected in the first tertile. In the second tertile, a mean loss of –11.7 ± 7.8 percentiles was detected. By contrast, the third group demonstrated a real fetal growth restriction as indicated by the mean change in percentiles (–52.5 ± 21.3). This fetal growth restriction had a significant effect on birth weight but not on birth length or on head circumference. Fetal growth restriction affected birth weight regardless of birth weight pattern as reflected by a lower mean birth weight percentile in the third group (17.3 ± 10 percentiles) but not reaching the classical cutoff limit of small for gestational age.
Fetal growth restriction was associated with thinness at birth as shown by a significantly lower ponderal index in the lower fetal growth velocity tertile of newborns. Skinfold thickness values were significantly lower in the lower tertile of fetal growth, reflecting a reduced fat mass in the newborns with an actual fetal growth restriction. However, fat mass distribution was not affected by fetal growth restriction because the central to peripheral skinfold thickness ratio was similar across the tertiles. Furthermore, a deleterious effect of fetal growth restriction on lean mass was documented by the significantly different mean circumference of the arm, adjusted on triceps skinfold taken as a surrogate for lean mass. Because decreased fat mass seemed to be associated with restricted fetal growth, we then studied hormonal profile in cord blood to further determine whether fetal growth restriction itself was associated with changes in metabolic and hormonal markers. Fetal growth restriction was significantly associated with a decreased cord insulin level, whereas plasma glucose was similar across the tertiles. QUICKI, an insulin sensitivity index, showed a trend toward higher insulin sensitivity in the lower tertile of fetal growth velocity, although this did not reach statistical significance. Surprisingly, mean triglycerides level was significantly increased in this lower tertile. Fetal growth restriction was also significantly associated with a significant decrease in IGF-I and IGFBP-3.
Determinants of cord insulin and IGF-I
To determine whether fetal or neonatal factors affect fetal hormonal profile, cord insulin and IGF-I concentrations were analyzed using multivariate analyses as shown in Tables 3 and 4. The relationship between log-transformed cord insulin and IGF-I and birth weight, skinfold thickness sum, gestational age, gender, and fetal growth velocity was tested. Fetal growth velocity appeared to be an important determinant of the two hormonal cord concentrations. By contrast, birth weight was not a significant and independent determinant of cord blood insulin. As expected, fat mass, assessed by the sum of the skinfold thickness, was the second independent determinant of cord insulin concentration. IGF-I was significantly related to birth weight but not to the skinfold thickness sum, reflecting the strongest association between lean mass and IGF-I level.
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Discussion
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In this study, we hypothesized that adaptive changes in fetal metabolism are primarily linked to the fetal growth pattern as a reflection of fetal environment. For this purpose, we measured fetal growth velocity in a prospective way using EFW and the method of customized percentiles. EFW at each time point was transformed in percentiles, and the change in percentiles between 22 WG and birth was calculated. This change in percentiles was used to assess fetal growth pattern and to identify fetal growth restriction preventing the fetus from reaching his genetic potential of growth. This method allowed us to detect fetal growth restriction during the second part of pregnancy (between 22 WG and birth) only but not before 22 WG. We hypothesized that fetal growth restriction occurring during this part of the pregnancy results mostly from a deleterious fetal environment with a decreased nutrient delivery to the fetus as a major consequence. This is illustrated, for example, in preeclampsia where fetal growth restriction due to placental vascular abnormalities occurs mostly in the second part of the pregnancy. The data presented here suggest that fetal growth restriction induces decreased fat and lean mass. Fat mass as a whole was decreased in case of severe fetal growth restriction as assessed by the sum of the skinfold thickness, but the distribution was not affected as reflected by the central/peripheral skinfold thickness ratio, which was similar in the three tertiles. Such changes were associated with a decrease in cord insulin and IGF-I concentrations. Lower fat mass at birth has already been reported in small-for-gestational-age newborns or in animal models of fetal growth restriction (21, 22). In our study, fetal growth restriction had an effect on skinfold thickness irrespective of birth weight, indicating that fat mass at birth would reflect the lower nutrient disposal.
In absence of fetal diseases, fetal growth restriction is a symptom reflecting the deleterious fetal environment induced by placental abnormalities or extrauterine conditions (toxic, maternal disease). In most cases, such conditions are associated with an altered nutrient delivery to the fetus, which in turn compromises the development of organs prone to energy storage. It has also been suggested in the thrifty phenotype hypothesis and later in the more appropriate developmental mismatch theory that changes in fetal metabolism would occur to preserve survival and fetal growth of vital organs (9, 23). Some authors have suggested that insulin resistance, as a consequence of fetal programming would be detectable as early as birth (24, 25). However, it has also been proposed that changes in insulin sensitivity induced by the fetal environment aims at ameliorating nutrient disposal and utilization and finally fetal growth (26, 27). In this respect, an increase in insulin sensitivity would be a physiological adaptation to fetal growth restriction because insulin is the major hormonal determinant of fetal growth. This concept has already been illustrated in small-for-gestational age newborns. At 48 h of life, these newborns displayed an increased insulin sensitivity contrasting with the lack of suppression of lipolysis as indicated by higher free fatty acid levels (28). Moreover, in a sheep model of fetal growth restriction, insulin sensitivity and glucose utilization in utero have been shown to be increased (29). We report a trend toward higher QUICKI in the tertile of newborns with fetal growth restriction. This result has to be regarded with caution because QUICKI is an index that takes fasting values of insulin and glucose. Here, these two parameters have been measured on cord blood with metabolic conditions different from the ones classically used to calculate QUICKI. However, it is concordant with the lower cord insulin level for the same plasma glucose level, reflecting a likely higher insulin sensitivity in case of fetal growth restriction irrespective of birth weight. The multivariate analysis showed that birth weight per se was not an independent determinant of cord insulin, whereas fat mass significantly affected insulin concentration. Both fetal growth velocity and fat mass contributed independently to the variance of cord insulin concentration, suggesting that the classical association between low birth weight and changes in cord blood insulin is a reflection of metabolic changes induced by fetal growth restriction that can be detected irrespective of birth weight.
The increase in triglyceride levels reported here could reflect an adaptive response in fetal metabolism as well with utilization of an alternate source of fuel substrates. The association of higher triglycerides and lower free fatty acids has been reported in small-for-gestational-age newborns (30). We suggest that the lower insulin concentration would reduce circulating triglycerides hydrolysis, which in turn would lead to reduced peripheral adipose deposition.
IGF-I is closely related to fat-free mass in childhood (31, 32, 33). IGFs play a crucial role in fetal growth, more specifically in growth of lean mass, organs, and skeleton (34). It has been shown that IGF secretion during fetal life is not under the control of GH but is mediated by fetal insulin release and therefore indirectly by nutrient supply. Here, we report that cord insulin is a determinant of IGF-I secretion, which is reduced in case of fetal growth restriction. On the other hand, this lower level could be due to a possible compensatory mechanism to increase the availability of free IGF-I. In another study focused on the association between cord lipids, cord insulin, and body composition at birth, an indirect relationship between IGF-I and fat mass via the modulation of lipids metabolism has been suggested (35). The authors reported an inverse relationship between IGF-I and triglycerides. The lower IGF-I level reported here could then participate in changes in the newborn metabolism.
In conclusion, our data contribute to the understanding of the pathway between a low birth weight and the risk of type 2 diabetes later in life. The early development of insulin resistance as a consequence of the mismatch between predicted and actual postnatal environment has been shown to be an important element of the natural history of such a morbid association. Our data suggest that a deleterious fetal environment and more specifically fetal growth restriction induces changes in fetal metabolism to protect immediate fetal survival, reflecting the adaptive response of the metabolic pathway to the unfavorable nutritional environment. Later in life, the mismatch between postnatal and fetal environment would favor postnatal changes in body composition during catch-up growth and the development of insulin resistance (36) to reset child’s growth to follow his/her initial and genetic growth trajectory.
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Acknowledgments
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We acknowledge the nurse and midwife staff of the maternities and the skillful technical assistance of Aurore Foureau and Samia Deghmoun.
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Footnotes
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Disclosure Summary: J.B., R.V., R.N., P.G., O.C., P.S., and D.C. have nothing to declare. C.L.M. received lectures fees from Pfizer Inc., Novo Nordisk Inc., and Lilly Inc.
This work was supported by grants from the Institut National de la Santé et de la Recherché Médicale (INSERM), the Programme Hospitalier de Recherché Clinique AOM-06136, and Pfizer Inc. J.B. was supported by a fellowship from the Institut Danone (France, 2006). R.V. and R.N. received fellowships from the Fench Ministry of Foreign Affairs [Programme Charcot (France 2006 and 2007)].
First Published Online August 5, 2008
Abbreviations: BW, Birth weight; EFW, estimated fetal weight; IGFBP-3, IGF-binding protein-3; IRMA, immunoradiometric assay; QUICKI, quantitative insulin sensitivity check index; WG, weeks of gestation.
Received March 10, 2008.
Accepted July 29, 2008.
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Abstract
Introduction
