Current Pediatric Research

Abstract

Background: Leptin and adiponectin, which are primarily produced by adipose tissue, have recently been identified as key mediators in the foetal developmental process. Modulation of these adipokines in early life, therefore, provides potential opportunities to improve or reverse the adverse complications associated with an abnormal foetal developmental profile. Aim: The purpose of this study was to determine the effect of maternal dietary habits on foetal leptin and adiponectin levels on foetal developmental outcomes. Subjects and Methods: Sixty-two mothers between the ages of 18 years and 38 years, as well as their full-term neonates, were enrolled in this study, whether they had a normal delivery or a Cesarean section, with no birth complications. All mothers were subjected to a full pregnancy history in order to determine their gestational age, as well as a full examination that included measuring and recording all of their anthropometric measurements. Clinical examinations were performed on newborns, and the Apgar score was also recorded. Newborns were classified as Small for Gestational Age (SGA), Appropriate for Gestational Age (AGA), or Large for Gestational Age (LGA) based on their birth weight (LGA). ELIZA measured leptin and adiponectin levels in both mother's serum and cord blood serum. Results: Mothers who consumed fish and fats during pregnancy were not at risk of having SGA babies, and SGA babies had significantly lower adiponectin levels than AGA and LGA babies. Leptin levels increased significantly as they passed from SGA to LGA. Leptin distribution was significantly higher in infants of mothers who consumed daily breakfast during pregnancy than in infants of mothers who did not consume breakfast. Infant adiponectin distribution was significantly higher in infants of mothers who ate regular fats than in infants of mothers who ate a low fat diet. Infant adiponectin distribution was significantly higher in infants of mothers who consumed sugary drinks once per day than in infants of mothers who did not consume sugary drinks. Furthermore, there is a significant positive correlation between infant weight, infant length, infant head circumference, infant mid-arm circumference, and levels of both infant leptin and infant adiponectin. A highly significant negative correlation was found between mother adiponectin and infant leptin levels, while a highly significant positive correlation was found between mother leptin and infant leptin levels. Conclusion: This study shed light on the important role of maternal nutrition during pregnancy in foetal body fat composition. This study also provides clear evidence for the influence of leptin and adiponectin on foetal development.

Keywords

Maternal nutrition, Leptin, Adiponectin, Gestational age, Fetal developmental profile.

Introduction

Poor maternal nutrition during pregnancy can have an impact on the course of the pregnancy and foetal growth, resulting in lower GA and poor intrauterine growth [1]. It is well known that GA and birth weight are important predictors of neonatal survival and health [2]. Leptin and adiponectin are the most common hormones associated with adipose depots that influence metabolism and energy homeostasis [3]. The placenta, as well as maternal and foetal adipose tissues, produces leptin during pregnancy, which regulates foetal growth. Leptin has been shown in animal models to play a role in the growth and maturation of the heart, brain, kidneys, and pancreas [4]. Fetal leptin is primarily derived from foetal adipose tissue, whereas the placenta primarily produces leptin for the maternal side [5].

Leptin is detectable in the second trimester and its level rises from the middle of the third trimester to term, according to the reservoir of foetal adipose tissue, as it is commonly synthesized by White Adipose Tissues (WAT) and released into the circulation proportionally to body fat mass [6,7]. This means that foetalleptin levels rise in tandem with foetal growth [8]. It is worth noting that early-life increases in leptin concentrations are thought to play a role in brain development [9]. It also has protective effects on paediatric neurological diseases [10].Adiponectin is an insulin-stimulating hormone produced by adipose tissue that increases fatty acid and glucose absorption as well as catabolism in muscle and liver [11]. Adiponectin may play a role in foetal growth and development because insulin regulates it to a large extent [12]. As a result, it is possible to propose that high levels of adiponectin in the placenta and foetus are associated with foetal growth [13].

However, Sivan et al. proposed that neonatal adiponectin is derived primarily from foetal tissues rather than maternal or placental tissues, and studies on newborn infants show that serum adiponectin levels are positively related to birth weight and leptin levels [14,15]. These findings are supported by Saito et al. who found that adiponectin levels are significantly higher in Large for Gestational Age (LGA) and Appropriate for Gestational Age (AGA) neonates than in Small for Gestational Age (SGA) neonates (SGA) [16]. Adiponectin's role in brain development is noteworthy because it has been discovered that adiponectin acts locally in the brain to govern key processes of brain physiology such as neuronal excitability and synaptic plasticity, neuroprotection, neurogenesis, and glial cell activation regulation [17].

As a result, adipokines like leptin and adiponectin, which are primarily produced by adipose tissue, have been identified as key molecules in processes underlying many phenotypic traits associated with embryonic programming. As a result, manipulating adipokines early in life has revealed potential options for improving or reversing the unfavourable consequences of atypical programming, as well as insight into some of the mechanisms implicated in the development of chronic disease across the life course [18].

Aim of the work

This study was undertaken to explore the impact of fetal leptin and adiponectin that may result from the maternal dietary habits during pregnancy on the developmental outcomes of the neonates.

Subjects and Methods

Sixty-two mothers and their neonates were recruited from the obstetrics and gynecology department, El Galaa teaching hospital. Parental written informed consent was obtained from all study participants after explaining the aim and the implementation procedures of the study. Inclusion criteria included women between 18 years and 38 years of age and their full-term babies from normal delivery or cesarean section, without any birth complications like perinatal asphyxia, or acute fetal suffering signs. Exclusion criteria included women presenting with diabetes, preeclampsia, anti-phospholipid syndrome, connective tissue diseases, chronic infection, alcoholism, or smoking during pregnancy.

All mothers were subjected to a full history of pregnancy to detect their gestational age, a full examination that included measuring and recording of all their anthropometric measurements. All anthropometric measurements have been obtained using standardized equipment and following the recommendations of the international biological program [19]. Maternal anthropometric measurements were made on the participants wearing a minimum amount of clothing. The weights of pregnant women were measured using a digital weighing balance with a sensitivity of 100 g. Total gestational weight gain was estimated by subtracting the early first trimester weight (self-reported in the hospital interview) from the last measured weight before delivery and a nutrition sheet including a questionnaire about the maternal nutritional food intake during pregnancy. A semi-structured questionnaire and a data record form were used to collect information about the mother’s profile.

The pediatrician performed a thorough clinical examination on the neonates, which included a chest, heart, abdomen, and central nervous system examination. The Apgar score, which ranges from 1 to 10, was also used to assess neonatal condition at birth at 1 and 5 minutes after delivery. Infants were scored on a scale of 0 to 2 in five categories (skin colour, muscle tone, reflexes, respiratory effort, and heart rate), and the total score was calculated by adding the points from each category [20]. Anthropometric data was collected prior to the start of breast feeding. Without diapers, newborns were weighed (in kilograms) on an electronic digital infant scale (Laka).The length (in centimeters) was measured in the supine position, using a stadiometer (Seca 416) composed of a stationary head-board and a movable foot board. Head and mid upper arm circumferences (cm) were also measured [21]. Newborns were assigned to small for gestational age SGA (lower than 10th percentile), appropriate for gestational age AGA (between 10th and 90th percentile) and large for gestational age LGA (higher than 90th percentile). 

 Venous blood samples (5 ml) were withdrawn from each mother participating in the study immediately before labor, and 5 ml were taken from the cord blood. The serum of the mother's blood and the cord blood were separated by centrifugation under cooling at 4°C for 10 min and stored at 200°C for determination of leptin and adiponectin by ELIZA using Glory Science (USA) according to manufacturer's manuals. This study was conducted in strict accordance with the regulations and guidelines of the ethics committee for medical research of the national research centre, which approved the study protocol under the registration number (20-122).

Statistical analysis

Statistical analysis was performed using the Statistical Package for Social Sciences (SPSS) version 21 for windows (IBM Corp., Armonk, NY, USA). Continuous data was expressed as mean standard deviation, minimum, maximum. Pearson’s correlation analysis was conducted to evaluate the association between continuous exposure and continuous covariates. Categorical data was expressed as frequencies and percentages, and was analyzed with the two-tailed chi square test. Continuous data was compared according to nutritional groups and social factors using Mann-Whitney and Kruskal-Wallis as nonparametric tests. Multiple linear regression analysis was done to identify the effect of multiple maternal factors on a dependent variable (infant serum leptin). P<0.05 was accepted as statistically significant.

Results

A total of 62 mother-newborn pairs were enrolled in this study. The mean of maternal age was 26.03 ± 5.267 years. Mothers mean of BMI were 30.519 ± 5.835.The mean of gestational age was 37.60 ± 1.38 weeks. The maternal and neonatal demographic, anthropometric and laboratory data are shown in Table 1.

Table 1. Demographic, anthropometric and laboratory data of mothers and their infants.

Tables 2-7 illustrates the effect of mother's nutrition on gestational age categories. The results reveal insignificant association (p>0.05) between mother's breakfast and gestational age regarding AGA and SGA (Table 2) as well as AGA and LGA (Table 3). The data in Table 4 show that mothers with irregular fish consumption are more at risk of having infants SGA comparing with frequent fish consumption one or more days in a week (p=0.031). The results of Table 5 also demonstrate that mothers with irregular fat consumption are more at risk of having SGA infants compared to those with regular fat consumption (p=0.003). Moreover, the findings of Table 6 indicate that there is no significant association between frequent sugary drinks taken by the mother and gestational age (p>0.05) regarding AGA and SGA. The data in Table 7 display that there is no significant associations between maternal intake of fish or sugary drinks and having infants LGA (p>0.05). However, mothers who are eating fat once per week or more are more at risk of having LGA infants compared to those not having fat in diet (p=0.04).

Table 2. Effect of mother's breakfast during pregnancy on gestational age categories: Comparison between small for gestational and appropriate for gestational age.

Table 3. Effect of mother's breakfast during pregnancy on gestational age categories: Comparison between large for gestational and appropriate for gestational age.

Table 4. Effect of other nutritional factors during pregnancy on gestational age categories: Comparison between small for gestational and appropriate for gestational age. *: p<0.05 is significant.

Table 5. Effect of other nutritional factors during pregnancy on gestational age categories: Comparison between large for gestational and appropriate for gestational age. *: p<0.05 is significant.

The findings in Table 6 show that leptin distribution in infants of mothers with regular breakfast intake is significantly higher than that of mothers with irregular daily breakfast (p=0.033). Infant adiponectin distribution of mothers with high consumption of fat is significantly higher than that of mothers with low fat intake (p=0.013). Moreover, infants adiponectin distribution of mothers taking fat more than once per week is significantly higher than that of mothers taking fat once per week (p=0.013). Infant adiponectin distribution of mothers taking sugary drinks once per day is significantly higher than that of mothers not taking sugary drinks per day (p=0.008). However, leptin distribution in infants of mothers not taking sugary drinks is significantly lower than that in infants of mothers taking frequent sugary drinks once or more per day (p=0.027).

Table 6. Effect of mother nutritional factors during pregnancy on serum adiponectin and leptinlevels. *: p<0.05 is significant.

Table 7 represents the effect of delivering time on serum adiponectin and leptin levels in mothers and their infants, infant adiponectin distribution of mothers delivered in winter is significantly higher than that of mothers delivered in summer (p=0.002), While, mother leptin distribution is significantly higher in those delivered in summer than those delivered in winter (p=0.001).

Table 7. Effect of delivery time on serum adiponectin and leptin levels. *: p<0.05 is significant.

The results in Table 8 reveal a highly significant positive correlation between infant weight, infant length, and infant head circumference with infant adiponectin level.

A significant positive correlation is noticed between infant mid arm circumference and infant adiponectin level. A highly significant positive correlation is found between infant weight, infant length, infant head circumference, and infant mid arm circumference with infant leptin level. A significant positive correlation is detected between infant weight and infant mid arm circumference with mother's weight.

A highly significant negative correlation is observed between infant weight and infant length with mother's adiponectin level and a significant negative correlation is detected between infant mid arm circumference and mother's adiponectin level. Also, the data in Table 8 indicate the presence of a highly significant negative correlation between mother's adiponectin levels and mother's leptin as well as infant leptin levels. A highly significant negative correlation is found between infant adiponectin level and mother's leptin level. Mother’s leptin level shows a highly significant positive correlation with infant leptin level.

Table 8. Correlation between mother and infant anthropometric measurements and Apgar scoring. * and **: Correlation is significant at the 0.05 level.

To further analysis the effect of different factors on infant leptin level, we conducted multiple linear regression analysis using infant leptin as a dependent variable and mother's characteristic manifestations. The data in Table 9 show that infants with high leptin levels are significantly associated with mothers taking breakfast daily, taking fats once per week, delivering in winter, mothers of low serum adiponectin, mothers of increasing height, and mothers with infants of low Apgar score in first minute and high Apgar score in fifth minutes.

Table 9. Multiple linear regression analysis for factors affecting infant leptin. *: p<0.05 is significant.

Discussion

The purpose of this study was to elucidate the effect of maternal nutrition on gestational age and the construction of adipose tissue in fetuses. Also, our aim was extended to examine the implications of neonatal leptin and adiponectin on the fetal developmental profile.

In the present study, we found that mothers taking fish during pregnancy were not at risk of having infants with SGA. This result matched the study of Amezcua-Prieto et al. who stated that women with a total intake of marine n-3 fatty acids during pregnancy had a low risk of having a SGA newborn [22]. N-3LCPUFAs pass through the placental circulation during pregnancy, affect fetal development and extend the gestation time [23]. The improved fetal growth could be due to the fact that n-3 LCPUFAs raise the ratio of prostacyclin to thromboxane, lowering blood viscosity and encouraging increased placental blood flow, both of which are beneficial to fetal growth [24]. It is worth mentioning that the high consumption of fish and sea food is likely to be profitable for the offspring, as maternal fish intake in pregnancy has been associated with positive fetal neurodevelopmental outcomes [25].

The results of the current work indicated that mothers who were eating fat more than once/week during pregnancy were not at risk of having infants with SGA. This finding is on par with that of the study by Mani et al. which elucidated that high consumption of dietary fat in early pregnancy is linked with increased birth weight and decreased risk of SGA [26].

The tabulated results in the present study demonstrated that leptin distribution in infants of mothers taking daily breakfast during pregnancy was significantly higher than in infants of mothers not taking daily breakfast during pregnancy. It has been reported that a nutrient-rich and energy-appropriate diet during pregnancy is crucial for optimal development and growth of the fetus [27]. According to the reservoirs of fetal adipose tissue, fetal leptin can be detected as early as the second trimester, and its concentration increases from the middle of the third trimester towards term [6]. This means that fetal leptin levels increase in parallel with fetal development [8]. Moreover, fetal leptin has been found to be positively correlated with neonatal weight [28].

This correlation reflects the increment of adipose tissue along with gestational progress, especially during late gestation [29]. It is worth noting that the release of neonatal leptin precedes neonatal adiponectin of mothers taking breakfast regularly during pregnancy. This phenomenon was explained by Leipala et al. who stated that neonatal leptin is liberated by adipocytes in late stages of differentiation but adiponectin is secreted only by fully differentiated adipose cells [30]. Thus, fetal leptin secretion started before fetal adiponectin release, as shown in the current study.

Our results demonstrated that the neonatal adiponectin level of mothers having regular fat in their diet was significantly higher than that of infants of mothers with irregular fat consumption. As mentioned above, the high intake of fats is correlated with increased birth weight and a decreased risk of SGA [26]. Prenatal growth and gestational age play a crucial role in adipose tissue maturation and deposition, altering adipokine production, endocrine release and metabolic functions [30]. The histology of adipose tissue in newborns revealed two populations of cells; small cells that do not store fat and larger cells that contain fat but have a smaller width than adult fat cells. These cells are responsible for enhanced adiponectin generation in neonates [31]. The current findings show that the infant adiponectin distribution of mothers taking sugary drinks once per day was significantly higher than that of infants of mothers not taking sugary drinks per day. In accordance with our results, Lustig reported an increased glucose transfer to the fetus from sugar-sweetened beverages during pregnancy that may result in insulin-mediated effects on offspring adiponectin levels, as adiponectin is a well-known insulin-sensitive hormone that plays a vital role in glucose and lipid metabolism [32,33]. It has also been confirmed in fetal lambs, that an enhancement in fetal glucose feeding during late gestation stimulates fetal adipose tissue deposition [34]. Thus, sugary drinks during pregnancy lead to high fat deposition in the fetus and, in turn, high adiponectin levels.

The infant leptin distribution of mothers not taking sugary drinks during pregnancy was lower than that of infants of mothers taking sugary drinks during pregnancy. The study by Tomoo and his co-workers indicated that leptin is principally produced by the white adipose tissue and liberated into the circulation proportionally to the quantity of body fat mass [7]. Thus, the absence of sugary drinks during pregnancy causes a reduction in fetal adiposity, which in turn leads to the lowering of fetal leptin levels as shown in the present work. So, leptin and adiponectin could be applied as markers for adipose tissue development and the amount of adipose tissue in the fetus [30].

In this study, the infant adiponectin distribution of mothers delivered in winter was significantly higher than that of mothers delivered in summer. In winter, if the maternal temperature descends, umbilical or uterine blood flow will be decreased. Reduced umbilical flow can put fetal and placental nutrition, oxygenation, and metabolic waste disposal at risk. The increase in the fetal metabolic rate due to cold stress will reduce hypothermia and increase the energy demand [35]. Fetal energy demands utilize carbohydrates as the primary fuel, which accounts for 80% of fetal energy. Although the placenta maintains a continuous interrupted supply of maternal glucose to the fetus, the fetal glucose metabolism depends on fetal insulin production to enhance the utilization of glucose by sensitive tissues [36]. As adiponectin enhances insulin sensitivity and improves glucose metabolism, so adiponectin increases in fetal compartments [37].

As shown in the present results, mother leptin distribution was significantly higher in those delivered in summer than in those delivered in winter. The study of Al-Azraqi found that heat stress significantly increases leptin concentrations in the exposed group compared to the thermo neutral control group [38]. The oxidative stress induced by heat stress has been found to increase lipid peroxidation [39]. The increased fat oxidation was found to be correlated with an increased leptin concentration [40].

The data in this study demonstrated that SGA infants have significantly lower adiponectin than AGA and LGA. Also, significant differences in leptin between the three groups were detected with an increase in leptin level passing from SGA to LGA. The depletion in adiponectin level in SGA is comparable to that obtained in the study of Kamoda et al. [41] which indicated that the level of serum adiponectin shows a significant decline in SGA than in AGA neonates owing to the decreased quantity of brown adipose tissue in SGA neonates. Our results go hand in hand with the study of Martinez-Cordero et al. which recorded lower leptin levels in SGA than in AGA infants [42].

As a result, it appears that gestational age, which indicates maturity, is a significant operator of leptin levels in the fetus. In the present approach, a highly significant positive correlation has been detected between infant weight, infant length, infant head circumference and infant adiponectin level. A significant positive correlation has been detected between infant mid arm circumference and infant adiponectin level. These findings come in line with more than one study as adiponectin levels were assigned to be affected by being born SGA and weight gain [43]. Also, strong positive correlations between adiponectin level at birth and weight, length, head circumference, and gestational age have been reported [44].

Hansen-Pupp et al. stated that adiponectin concentrations at birth have a significant positive correlation with anthropometric measures and gestational age at birth[45]. In terms of the mechanism by which adiponectin regulates growth, it has been established that fetal adiponectin has a role in both insulin sensitivity and the availability of nutrients such as fatty acids, which may affect both fetal and childhood growth [46]. This positive correlation is compatible with the suggestion that in newborns the adipose tissue is composed mainly of small, newly differentiated adipocytes that lack the factors that are responsible for inhibition of adiponectin production. Thus, the prevalence of small adipocytes in newborns’ adipose tissue may explain the extremely high levels of adiponectin in cord blood. A highly significant positive correlation has been found in the present study between infant weight, infant length, infant head circumference, infant mid arm circumference and infant leptin level.

In term infants, leptin levels showed a positive correlation with birth weight, gain in fat mass, and Body Mass Index (BMI) [47]. Compelling evidence indicates the role of leptin in fetal growth and development [48]. Leptin levels of neonates at birth have been found to be positively correlated with BMI and head circumference [47]. This could indicate either a basic association with adipose tissue or an active involvement of leptin in fetal growth, as leptin is known to influence both fetal and neonatal development, including head circumference [49]. Moreover, leptin deficiency has been linked to alterations in brain volume and structure [50]. In accordance with our results, it has been reported that in full-term newborns, the leptin and adiponectin levels showed a strong correlation with all anthropometric variables [51].

The current results demonstrated a significant positive correlation between infant weight, infant mid arm circumference and mother weight. Rijvi et al. recorded that there is a strong association between maternal weight gain and the birth weight of the fetus[52]. There was a proportional increase in mean birth weight with an increase in maternal weight gain throughout pregnancy, and this increase was statistically significant. Our finding shows parallelism with the study of Nagmoti et al. which demonstrated a positive association between maternal BMI and weight with neonatal parameters [53].

This suggests that maternal size has the greatest impact on neonatal growth as measured by birth weight, length, and head circumference [54]. A highly significant negative correlation has been found between infant weight, infant length and mother's adiponectin level. A significant negative correlation has been detected between infant mid arm circumference and mother's adiponectin level. The association between maternal adiponectin concentration and fetal growth is less clear. A negative correlation between mother's adiponectin and fetal birth weight has been reported by the study of Ong et al. [55]. The maternal blood adiponectin levels were significantly lower than those of the umbilical blood and the cord blood adiponectin was positively associated with anthropometric measures at birth [56].

The data in this study indicated the presence of a highly significant negative correlation between mother's adiponectin levels and mother's leptin as well as infant leptin levels. During pregnancy, there is an elevated level of leptin in the mother’s body due to the enhancement of total fat content [57]. And this leads to a decrease in the mother's adiponectin concentration [58]. Human pregnancy is connected with increased food intake, which prevents maternal nutrient depletion and allows for enhanced nutrient delivery to the growing fetus, in contrast to leptin's normal influence on satiety [59]. Injection of leptin directly into the brains of pregnant Sprague-Dawley rats had little effect on lowering food intake, according to the study by Ladyman et al. [60].

This disparity is caused by central leptin resistance, which arises during the second trimester of human pregnancy and is thought to be caused by a decrease in hypothalamic ObRb expression [61]. As a result elevated leptin concentrations and signaling play a significant role in control of food intake during pregnancy. These data imply that fetal leptin levels are directly related to fetal fat mass (as in adults), with the mother's contribution being minor [62]. As shown in the present work, a highly significant negative correlation has been found between infant adiponectin level and mother's leptin level. This was related to the study of Dridi et al., which found a negative association between cord adiponectin and mother's weight gain [63]. The mechanisms that control fetal plasma adiponectin levels are largely unclear.

The present results revealed a highly significant negative correlation between mother's leptin level and mother's adiponectin level and this is in concurrence with Manoharan et al. [58] study which revealed that the level of adiponectin is negatively correlated with body fat. The amount of leptin in the body is proportional to the amount of adipose tissue present [64]. Since the quantity of adipose tissue in the maternal body increases during pregnancy, the level of adiponectin decreases [65]. Mother's leptin level showed a highly significant positive correlation with infant leptin level. This coincides with Lucasa et al. study which showed higher leptin concentrations in both cord blood and post-delivery maternal serum [66]. During pregnancy, there is an elevated concentration of leptin in the mother’s body due to the increase in total fat content, production of this adipokine in the human placenta, and increasing energy requirements of the mother, placenta, and fetus [57].

Leptin is thought to have a role in maximizing the availability of substrates needed for fetal growth, particularly through mobilizing maternal fat stores, which are linked to the newborn's birth weight. According to Perichart-Perera et al. the concentration of leptin during pregnancy may be a predictor of newborn size at birth and is linked to the mother's weight [67]. Multiple linear regression analysis revealed that infants' leptin levels are significantly dependent on maternal characteristics and manifestations during pregnancy, such as taking daily breakfast and fat once per week, delivering in winter, increasing height, decreasing Apgar score in the first minute, increasing Apgar score in the fifth minute, and adiponectin decreasing levels.

Finally, it is important to mention that leptin has a possible role in brain development, neurogenesis, particularly during the development of the CNS, [68-70]. Leptin has also been shown to enhance cognition through the regulation of hippocampal function. Moreover, leptin can significantly improve Camp-Response Element Binding Protein (CREB) phosphorylation via the MAP kinase/extracellular signal-regulated protein kinase (ERK1/2) pathway [71]. ERK1/2 phosphorylation (pERK1/2) can directly activate the protein signaling cascade regulating a variety of cellular processes such as nerve growth, survival, and neuroplasticity. Similarly, adiponectin may help restore neuronal insulin signalling, which is crucial for synaptic plasticity and memory, by modulating glutamate receptor trafficking [72].

Conclusion

The outcomes of this research shed light on the significance of maternal nutrition during pregnancy and its impact on fetal body fat composition. This study provides clear evidence of the influence of the fetal fat secretome (leptin and adiponectin) on the overall fetal developmental profile, including central nervous system development, which may pave the way for later neurodevelopmental consequences.

Acknowledgment

The authors would like to express their gratitude to all study participants (children, moms and their families, and clinic staff members) for their time and effort.

References

1. Vinding RK, Stokholm J, Sevelsted A, et al. Fish oil supplementation in pregnancy increases gestational age, size for gestational age, and birth weight in infants: A randomized controlled trial. J Nutr 2019; 149(4): 628-34.
2. Kramer MS, Demissie K, Yang H, et al. The contribution of mild and moderate preterm birth to infant mortality. Fetal and infant health study group of the Canadian perinatal surveillance system. JAMA 2000; 284(7): 843-9.
3. Pittas AG, Joseph NA, Greenberg AS. Adipocytokines and insulin resistance. J Clin Endocrinol Metab 2004; 89(2): 447-52
4. Aguirre PV, Tene CE, Toro-Equihua MD, et al. Comparison of leptin levels in neonates born to mothers with high or low gestational weight gain. J Pediatr Endocrinol Metab 2020; 33(4): 517-23.
5. Luo Z, Nuyt A, Delvin E, et al. Maternal and fetal leptin, adiponectin levels and associations with fetal insulin sensitivity. Obesity (Silver Spring) 2013; 21(1): 210-6.
6. Tzschoppe A, Struwe E, Rascher W, et al. Intrauterine growth restriction (IUGR) is associated with increased leptin synthesis and binding capability in neonates. Clin Endocrinol (Oxf) 2011; 74(4): 459-66.
7. Tomoo O, Shigeru T, Nobuhiko N, et al. Early postnatal alteration of body composition in preterm and small-forgestational-age infants: Implications of catch-up fat. Pediatr Res 2015; 77(1-2): 136-42.
8. Gomez L, Carrascosa A, Yeste D, et al. Leptin values in placental cord blood of human newborns with normal intrauterine growth after 30-42 weeks of gestation. Horm Res 1999; 51(1): 10-4.
9. Bouret SG, Simerly RB. Development of leptin-sensitive circuits. J Neuroendocrinol 2007; 19(18): 575-82.
10. Devirgiliis C , Zalewski PD, Perozzi G, et al. Zinc fluxes and zinc transporter genes in chronic diseases. Mutat Res 2007; 622(1-2): 84-93.
11. Volberg V, Heggeseth B, Harley K, et al. Adiponectin and leptin trajectories in mexicanamerican children from birth to 9 Years of Age. Plos ONE 2013; 8(10): 1-10.
12. Waki H, Yamauchi T, Kamon J, et al. Impaired multimerization of human adiponectin mutants associated with diabetes. Molecular structure and multimer formation of adiponectin. J Biol Chem 2003; 278(41): 40352-63.
13. Daryasari SRF, Tehranian N, Kazemnejad A, et al. Adiponectin levels in maternal serum and umbilical cord blood at birth by mode of delivery: Relationship to anthropometric measurements and fetal sex. BMC Pregnancy Childbirth 2019; 19(1): 1-6.
14. Sivan E, Mazaki-Tovi S, Pariente C, et al. Adiponectin in human cord blood: Relation to fetal birth weight and gender. J Clin Endocrinol Metab 2003; 88(12): 5656-60.
15. Chan TF, Yuan SSF, Chen HS, et al. Correlations between umbilical and maternal serum adiponectin levels and neonatal birthweights. Acta Obstet Gynecol Scand. 2004;83:165-9.
16. Saito M, Nishimura K, Nozue H, et al. Changes in serum adiponectin levels from birth to term equivalent age are associated with postnatal weight gain in preterm infants. Neonatology 2011; 100(1): 93-8.
17. Pousti F, Ahmadi R, Mirahmadi F, et al. Adiponectin modulates synaptic plasticity in hippocampal dentate gyrus. Neurosci Lett 2018; 662: 227-32.
18. Reynolds CM, Vickers MH. The role of adipokines in developmental programming: evidence from animal models. J Endocrinology 2019; 242(1): T81-94.
19. Hiernaux J, Tanner JM, Weiner JS, et al. Growth and physical studies. In: Human Biology: A guide to field methods. (2nd edn) Blackwell Scientific Publications, London. Oxford: UK, 1969. PMid: 5403554
20.  Apgar V, Holaday DA, James LS, et al. Evaluation of the newborn infant; second report. J Am Med Assoc 1958; 168(15): 1985-8.
21. http://www. who.int/childgrowth/publications/technical_ report_pub/en/index.html.
22. Amezcua-Prieto C, Martínez-Galiano J, Salcedo-Bellido I, et al. Maternal seafood intake and the risk of small for gestational age newborns: A case-control study in Spanish women. BMJ Open 2018; 8(e020424): 1-8.
23. Imhoff-Kunsch B, Briggs V, Goldenberg T, et al. Effect of n-3 long-chain polyunsaturated fatty acid intake during pregnancy on maternal, infant, and child health outcomes: a systematic review. Paediatr Perinat Epidemiol 2012; 26(Suppl 1): 91-107.
24. Rogers I, Emmett P, Ness A, et al. Maternal fish intake in late pregnancy and the frequency of low birth weight and intrauterine growth retardation in a cohort of British infants. J Epidemiol Community Health 2004; 58(6): 486-92.
25. Venter C, Brown KR, Maslin K, et al. Maternal dietary intake in pregnancy and lactation and allergic disease outcomes in offspring. Pediatr Allergy Immunol 2017; 28(2): 135-43.
26. Mani I, Dwarkanath P, Thomas T, et al. Maternal fat and fatty acid intake and birth outcomes in a South Indian population. Int J Epidemiol 2016; 45(2): 523-31.
27. Saunders CM, Rehbinder EM, Carlsen KCL, et al. Food and nutrient intake and adherence to dietary recommendations during pregnancy: A Nordic mother-child population-based cohort. Food Nutr Res 2019; 63(3676): 1-11.
28. Kyriakakou M, Malamitsi-Puchner A, Militsi H, et al. Leptin and adiponectin concentrations in intrauterine growth restricted and appropriate for gestational age fetuses, neonates, and their mothers. Eur J Endocrinol 2008; 158(3): 343-8.
29. Carrera JM, Devesa R, Carrera M. Dynamics of fetal growth. In textbook of perinatal medicine. 1998; pp: 1140-1147.
30. Leipala JA, Raivio KO, Sarnesto A, et al. Intrauterine growth restriction and postnatal steroid treatment effects on insulin sensitivity in preterm neonates. J Pediatrics 2002; 141(4): 472-6.
31. Koester-Weber T, Valtueña J, Breidenassel C, et al. Reference values for leptin, cortisol, insulin and glucose, among European adolescents and their association with adiposity: the HELENA study. Nutr Hosp 2014; 30(5): 1181-90.
32. Robert L. Obesity before birth. Maternal and prenatal influences on the offspring, Springer. 2011.
33. De Oliveira C, de Mattos ABM, Biz C, et al. High-fat diet and glucocorticoid treatment cause hyperglycemia associated with adiponectin receptor alterations. Lipids Health Dis 2011; 10: 11.
34. Stevens D, Alexander G, Bell AW. Effect of prolonged glucose infusion into fetal sheep on body growth, fat deposition and gestation length. J Dev Physiol 1990; 13(5): 277-281.
35. Laburn HP, Faurie A, Goelst K, et al. Effects on fetal and maternal body temperatures of exposure of pregnant ewes to heat, cold, and exercise. J Appl Physiol 2002; 92(2): 802-8.
36. Hay W. Placental-fetal glucose exchange and fetal glucose metabolism. Trans Am Clin Climatol Assoc 2006; 117: 321-40
37. Qiao L, Yoo HS, Madon A, et al. Adiponectin enhances mouse fetal fat deposition. Diabetes 2012; 61(12): 3199-207.
38. Al-Azraqi A. Pattern of leptin secretion and oxidative markers in heat-stressed pigeons. Int J Poult Sci 2008; 7(12): 1174-6.
39. Silvestro A, Scopacasa F, Oliva G, et al. Vitamin C prevents endothelial dysfunction induced by acute exercise in patients with intermittent claudication. Atherosclerosis 2002; 165(2): 277-83.
40. Okereke NC, Huston-Presley L, Amini SB, et al. Longitudinal changes in energy expenditure and body composition in obese women with normal and impaired glucose tolerance. Am J Physiol Endocrinol Metab 2004; 287(3): E472-9.
41. Kamoda T, Saitoh H, Saito M, et al. Serum adiponectin concentrations in newborn neonates in early postnatal life. Pediatr Res 2004; 56(5): 690-93.
42. Martinez-Cordero C, Amador-Licona NA, Guizar-Mendoza JM, et al. Body fat at birth and cord blood levels of insulin, adiponectin, leptin and insulin-like growth factor 1 in small for gestational age infants. Arch Med Res 2006; 37(4): 490-4.
43. Siahanidou T, Mandyla H, Papassotiriou GP, et al. Circulating levels of adiponectin in preterm infants. Arch Dis Child Fetal Neonatal Ed 2007; 92(4): f286-90.
44. Blakstad E, Moltu S, Nakstad B, et al. Enhanced nutrition improves growth and increases blood adiponectin concentrations in very low birth weight infants. Food Nutr Res 2016; 60(33171): 1-11.
45. Hansen-Pupp I, Hellgren G, Hard AL, et al. Early surge in circulatory adiponectin is associated with improved growth at near term in very preterm infants. J Clin Endocrinol Metab 2015; 100(6): 2380-7.
46. Aye IL, Powell TL, Jansson T. Review: Adiponectin–the missing link between maternal adiposity, placental transport and fetal growth? Placenta 2013; 34(Suppl): S40-5.
47. van Poelje MW, van de Lagemaat M, Lafeber HN, et al. Relationship between fat mass measured by dual-energy X-ray absorptiometry and leptin in preterm infants between term age and 6 months’ corrected age. Horm Res Paediatr 2014; 82(6): 405-10.
48. Mazaki-Tovi S, Vaisbuch E, Romero R. Adipokines and pathophysiology of pregnancy complications-The role of leptin and adiponectin. Fetal Matern Med Rev 2013; 24(4): 232-59.
49. Bozzola E, Meazza C, Arvigo M, et al. Role of adiponectin and leptin on body development in infants during the first year of life. Ital J Pediatr 2010; 36(26): 1-8.
50. London ED, Berman SM, Chakrapani S, et al. Short-term plasticity of gray matter associated with leptin deficiency and replacement. J Clin Endocrinol Metab 2011; 96(8): E1212-20.
51. Palchevska S, Krstevska M, Shukarova E, et al. Comparing preterm and term newborns serum adiponectin and leptin concentrations and their correlations with anthropometric parameters. Maced J Med Sci 2012; 5(3): 317-23.
52. Rijvi S, Abbasi S, Karmakar A, et al. A study on maternal weight gain and its correlation with birth weight of baby at term. Anwer Khan Mod Med Coll J 2018; 9(1): 22-28.
53. Nagmoti SA, Walvekar PR, Mallapur MD. Association between body mass index of mother and anthropometry of newborn. Int J Med Res Health Sci 2015; 4(4): 796-8.
54. Koepp UMS, Andersen LF, Dahl-Joergensen K, et al. Maternal pre-pregnant body mass index, maternal weight change and offspring birth weight. Acta Obstet Gynecol Scand 2012; 91(2): 243-9.
55. Ong GKB, Hamilton JK, Sermer M, et al. Maternal serum adiponectin and infant birth weight: the role of adiponectin isoform distribution. Clin Endocrinol (Oxf) 2007; 67(1): 108-14.
56. Zhang D, Wang X, Lu X-Y. Adiponectin exerts neurotrophic effects on dendritic arborization, spinogenesis, and neurogenesis of the dentate gyrus of male mice. Endocrinology 2016; 157(7): 2853-69.
57. Perez-Perez A, Toro A, Vilarino-Garcia T, et al. Leptin action in normal and pathological pregnancies. J Cell Mol Med 2018; 22: 716-27.
58. Manoharan B, Bobby Z, Dorairajan G, et al. Adipokine levels and their association with insulin resistance and fetal outcomes among the newborns of Indian gestational diabetic mothers. Saudi Med J 2019; 40: 353-9.
59. Sparks J, Girard J, Battaglia F. An estimate of the caloric requirements of the human fetus. Biol Neonate 1980; 38(3-4): 113-9.
60. Ladyman S, Grattan DR. Region-specific reduction in leptin-induced phosphorylation of signal transducer and activator of transcription-3 (STAT3) in the rat hypothalamus is associated with leptin resistance during pregnancy. Endocrinology 2004; 145(8): 3704-11.
61. Grattan DR, Ladyman SR, Augustine RA. Hormonal induction of leptin resistance during pregnancy. Physiol Behav 2007; 91(4): 366-374.
62. Jaquet D, Leger J, Levy-Marchal C, et al. Ontogeny of leptin in human fetuses and newborns: Effect of intrauterine growth retardation on serum leptin concentrations. J Clin Endocrinol Metab.1998; 83: 1243-6.
63. DridiS,Taouis M. Adiponectin and energy homeostasis: consensus and controversy. J Nutr Biochem 2009; 20(11): 831-9.
64. Lacroix M, Battista MC, Doyon M, et al. Higher maternal leptin levels at second trimester are associated with subsequent greater gestational weight gain in late pregnancy. BMC Pregnancy Childbirth 2016; 16(62): 1-9.
65. Teler J, Dabrowska-Zamojcin E, Prystacki T, et al. The role of adiponectin and leptin in gestational diabetes mellitus. Perinatol Neonatol Ginekol 2013; 6: 168-71.
66. Lucasa M, Dewaillya E, Mucklea G, et al. Gestationalage and birth weight in relation to n-3 fatty acids among Inuit (Canada). Lipids 2004; 39(7): 617-26.
67. Perichart-Perera O, Muñoz-Manrique C, Reyes-López A, et al.Metabolic Markers during pregnancy and their association with maternal and newborn weight status. PLoS ONE 2017; 12(7): 1-12.
68. Bouret SG. Neurodevelopmental actions of leptin. Brain Res 2010; 1350: 2-9.
69. Garza JC, Guo M, Zhang W, et al. Leptin increases adult hippocampal neurogenesis in vivo and in vitro. J Biol Chem 2008; 283(26): 18238-47.
70. Doherty GH, Beccano-Kelly D, Yan SD, et al. Leptin prevents hippocampal synaptic disruption and neuronal cell death induced by amyloid β. Neurobiol Aging 2013; 34(1): 226-37.
71. Dhar M, Wayman GA, Zhu M, et al. Leptin-induced spine formation requires TrpC channels and the CaM kinase cascade in the hippocampus. J Neurosci 2014; 34(30): 10022-33.
72. Zhao W-Q, Chen H, Quon MJ, et al. Insulin and the insulin receptor in experimental models of learning and memory. Eur J Pharmacol 2004; 490(1-3): 71-81.