Influence of birth-related maternal and neonatal factors on the levels of energy metabolism mediators in infants born at 32 or fewer weeks of gestation

Abstract

Background

Energy metabolism mediators, which include the adipokines (leptin, adiponectin, ghrelin) and insulin-like growth factor 1 [IGF-1], are hormone-like proteins, produced and expressed in the placenta and fetal membranes, with properties featuring metabolic adaptation and inflammatory processes. Due to the complexity of the metabolic adaptation of preterm neonates during the transition to extrauterine life, it becomes essential to recognize the factors that influence the alteration of the adipokines and IGF-1 levels in the early postpartum stage.

This study assessed the significance of maternal-fetal-neonatal factors in predicting the levels of leptin, adiponectin, ghrelin, and IGF-1 in preterm infants born at 32 or fewer weeks of gestation, during the early stage of postnatal adaptation.

Methods

Energy metabolism mediator levels were measured in urine samples obtained from extremely (less than 28 weeks) and very (28–32 weeks) preterm infants, within 48 h after their birth, and before the initiation of enteral nutrition. The urine samples were analyzed using enzyme-linked immunosorbent assay (ELISA) kits. The collected data included all birth-related maternal and neonatal factors such as maternal age, race/ethnicity, hypertensive disorders of pregnancy, diabetes, gravidity, parity, type of pregnancy, mode of delivery, and antenatal use of corticosteroids, antibiotics, magnesium sulfate, Apgar scores at 1 and 5 min, gestational age, and birth weight. We investigated the correlation between the levels of the tested mediators, the significance of the differences in their average levels based on the dichotomized maternal and neonatal factors, and the effect of the selected factors, in multiple regression models. Data from the regression models constructed for leptin, adiponectin, ghrelin, and IGF-1 are presented as regression coefficient β with Standard Error (SE) of β, coefficient of determination (R²), and adjusted R². Before including the factor in regression models, we tested for the multicollinearity effect. Two-sided P values <0.05 were considered statistically significant.

Results

Among the 70 studied infants, 47.1% were male, 40.6% were white, 28.6% were extremely preterm, and 18.6% were born with a weight <750 grams. Except for a mild interplay between the adiponectin and IGF-1 levels, there was no correlation between the levels of the other studied mediators. Up to 20% variation in the tested energy metabolism mediator levels was dependent on some of the birth-related maternal and neonatal characteristics. For instance, leptin levels were reduced in association with male gender (-0.493 [0.190], p < 0.02) and increased in infants born to primigravids (0.562 [0.215], p < 0.02). Adiponectin levels were increased in infants born to nulliparous as compared to multiparous women (0.400 [0.171], p < 0.03). Ghrelin levels were reduced in males (-0.057 [0.026], p < 0.04). IGF-1 levels were increased in the urine of extremely preterm neonates (0.357 [0.111], p < 0.01) and preterm infants born with an Apgar less than three at 1 min (0. 340 [p < 0.153], p < 0.04).

Conclusions

Nearly one-fifth of the variation in the urinary levels of the adipokines (leptin, adiponectin, ghrelin) and IGF-1 during the early postnatal stage in infants born at 32 or fewer weeks of gestation was predicated on one or more of the maternal and neonatal factors such as the infant’s sex, extreme preterm gestation, a low Apgar score at 1 min, or birth to nulliparous women or primigravida mothers. Further studies will be required to explain the role of energy metabolism mediators in the postnatal adaptation of preterm-born infants.

Keywords:

• Preterm birth
• maternal factors
• intrapartum/neonatal characteristics
• postpartum levels
• energy metabolism mediators

Introduction

Energy metabolism mediators, including adipokines (leptin and adiponectin, ghrelin) and insulin-like growth factor 1 [IGF-1], are a diverse group of proteins with interrelated hormone-like functional activities, produced and expressing receptors in placenta and fetal membranes [1–4]. Such proteins actively participate in intrauterine growth and development [5–7], infection, and inflammation by activating macrophages and anti-inflammatory cytokines, reducing the release of pro-inflammatory factors [8–10], and programming metabolic disorders during adulthood [11,12]. Preterm neonates and those born small for gestational age (SGA) have reduced levels of adiponectin, leptin, and/or ghrelin [13–16], which may underlie their potential maladaptive responses to early metabolic distresses [11].

Transition to extrauterine life, especially in infants born prematurely and those with restricted intrauterine growth, is a complex adaptive process associated with metabolic and hormonal changes [17]. Data from animal models identified the reversal of the negative impact of fetal undernutrition on the offspring’s growth after leptin treatment [12] and supported the participation of adipokines in postpartum adaptation. Notably, the endocrine and hormonal factors that are part of the transition to extrauterine life [17] can also be affected by the different maternal and intrapartum conditions [18]. Current knowledge regarding the contribution of the various pregnancy and birth-related maternal and neonatal factors to the levels of energy metabolism mediators during metabolic adaptation and in reflecting preterm infant growth is still insufficient. Since the urinary adipokine and IGF-1 levels during the early postnatal stage of life predicted the levels attained in the preterm infants when they achieved full enteral feeding [19], it becomes relevant to identify the maternal-fetal-neonatal factors that predispose to the alteration of adipokine and IGF-1 levels during the early postnatal stage of life in preterm-born neonates. This report presents an appraisal of the relationship between birth-related maternal and neonatal factors and the levels of leptin, adiponectin, ghrelin, and IGF-1 in urine obtained from preterm neonates born at a gestational age (GA) of 32 or fewer weeks, within the first 48 h after their birth, and before the initiation of any enteral feeding. To the best of our knowledge, the present study is among the first to measure leptin, adiponectin, ghrelin, and IGF-1 levels in the urine of very preterm infants. We hypothesized that during the early postnatal stage of life in premature-born infants, birth-related maternal and neonatal factors may alter the levels of energy metabolism mediators. Discovering the contribution of such factors to the variation in the levels of the energy metabolism mediators may help us better understand the adaptive capabilities of the very or extremely preterm-born neonate to the postnatal environment at an early stage of life.

Materials and methods

This report is part of a prospective study to analyze leptin, adiponectin, ghrelin, and IGF-1 levels in the urine of preterm-born infants pre- and post-initiation of full enteral feeding. The levels of energy metabolism mediators in urine obtained within 48 h of birth and before the initiation of any enteral feeding were used as a baseline for comparison with the levels obtained after achieving full enteral feeding to identify the association of leptin, adiponectin, ghrelin, and IGF-1 with the proportional intake of maternal milk and weight gain in very preterm neonates [19]. We asked mothers who were negative for human immunodeficiency virus (HIV) and had delivered infants with a GA of 32 or fewer weeks and without any congenital malformations to participate in this study. The study was approved by the Institutional Review Board at Rutgers Robert Wood Johnson Medical School (IRB # 0220120055). This report contains an analysis of the demographic and birth-related maternal and neonatal data obtained from the medical records and measurement of energy metabolism mediators in the urine of preterm infants, collected within 48 h of birth and before the initiation of any enteral feeding. Maternal, intrapartum, and neonatal clinical data and demographic information, including maternal race/ethnicity, were obtained from the medical records of the studied infants. The collected variables included: maternal age, race/ethnicity, hypertensive disorders of pregnancy (HDP), diabetes, gravidity (primigravida, multigravida), parity (nulliparity, multiparity), gestational age (GA) in completed weeks, type of pregnancy (singleton, multiple), mode of delivery (cesarean, vaginal), preterm premature rupture of membranes (PPROM), and intrapartum treatment (corticosteroids and magnesium sulfate [MgSO4]), Apgar score at 1 and 5 min, and birth weight (BW). We used growth charts for preterm infants [20] to identify the small for gestational age infants (SGA) with BW below the 10th percentile. The studied infants were classified as extremely preterm and very preterm if their GA was less than 28 weeks and 28 to 32 weeks, respectively. Micro-preemies were defined by their BW being less than 750 grams. Low Apgar Scores at 1 min and 5 min were defined as an Apgar score less than 3 at 1 min or less than 6 at 5 min [21].

Urine sample collection

The urine samples were collected within the first 48 h of life and before the initiation of any enteral feeding. Approximately 3 ml of urine was obtained from each of the study participants by placing cotton gauze in their diapers, transferring the urine-soaked gauze to 20 ml syringes, and then squeezing out the urine from the gauze into preservative-free containers. Urine samples were centrifuged at 2000 g for 5 min, aliquoted, and then stored at −80 °C in microplastic containers until further assay. After completing the study enrollment and specimen collection, the urine samples were thawed at room temperature and processed further for the assays. Using urine specimens to measure these proteins has previously been validated by comparing them with levels obtained from serum [22–24].

Urine sample analysis

Urinary levels of leptin, adiponectin, ghrelin, and IGF-1 levels were measured using enzyme-linked immunosorbent assay (ELISA) kits: (i) Human Leptin (R&D Systems, Minneapolis, MN, USA) with assay sensitivity of 0.128 ng/mL (range 0.3–20 ng/mL); (ii) Human Adiponectin (R&D Systems, Minneapolis, MN, USA) with assay sensitivity of 0.891 ng/mL (range 3.9–250 ng/mL); (iii) Human Ghrelin (EMD Millipore Corporation, Billerica, MA, USA) with assay sensitivity 0.03 ng/mL (range 0.05–5 ng/mL); and Human IGF-1 (R&D Systems, Minneapolis, MN, USA) with assay sensitivity 0.0138 ng/mL (range 0.125–8 ng/mL). Each sample was assayed in duplicate, and measurements were carried out per the manufacturer’s protocol using a SpectraMax i3 multi-mode microplate reader (Molecular et al., USA). We assigned zero for urine levels of leptin, adiponectin, ghrelin, and IGF-1 below the detection limit. We measured specific gravity, the ratio of the relative density of urine to water to total soluble solids [25], to normalize the leptin, adiponectin, ghrelin, and IGF-1 levels in the urine.

Statistical analysis

We checked the distribution of the leptin, adiponectin, ghrelin, and IGF-1 levels for normality using the Shapiro-Wilk test. We performed correlation analysis to identify the relationship between the tested mediators, analysis of variance (ANOVA) to identify the differences in the leptin, adiponectin, ghrelin, and IGF-1 levels by the dichotomized maternal and neonatal characteristics coded as 0 (No) and 1 (Yes) if the event was present, and multiple regression analysis by constructing models for each of the energy metabolism mediators. Maternal and neonatal factors that showed a significant difference in the levels of each tested mediator were included in the regression models. We tested for the multicollinearity effect [26] before including the factor in the regression models. Data is presented as mean with a 95% confidence interval (95%CI), Pearson’s correlation coefficients (r), regression coefficient (β) with a standard error (SE) of β, as well as the unadjusted and adjusted coefficient of determination (R² and adjusted R²). Two-sided P values <0.05 were considered statistically significant. All statistical analyses were conducted using STATISTICA 13.2 (TIBCO et al., USA).

Results

Among the 84 enrolled infants, urine samples were obtained from 70 subjects within 48 h after birth and prior to the initiation of trophic feeding (10 ml/kg/day). The studied group included 47.1% males, 40.6% whites, and 28.6% extremely preterm (GA <28 weeks). The mean BW and GA of the studied neonates were 1184 grams (95%CI 1098, 1269) and 28.7 weeks (95%CI 28.1, 29.4), respectively. All the studied infants received a standardized starter parenteral nutrition solution (40 ml/kg/day, containing 2 g protein per 40 ml solution), and the total fluid volume infused was 80 ml/kg/day or more (the difference in volume was made up with a 5% or 10% dextrose solution), starting soon after their admission to the NICU. Thereafter, the infants received total parental nutrition, which included minerals, trace elements, multivitamins, and 0.5 g/kg/day lipids as a 20% soybean emulsion yielding 2 kcal/mL. All infants born with GA <28 weeks and 48% of those born with GA 28–32 weeks were on parental nutrition during the first two days of life. Among the infants born with GA 28–32 weeks, 52% received total parental nutrition on the first day of life. The mean GA (weeks) and BW (grams) of the very preterm-born infants who received only parental nutrition for 48 h after birth and those who were started on trophic feedings after the first day of life were comparable (29.9, 95%CI 29.3, 30.5 vs. 30.4, 95%CI 29.9, 31.0, p = 0.21) and (1336, 95%CI 1228, 1443 vs. 1390, 95%CI 1302, 1478, p = 0.42), respectively.

Energy mediator levels and maternal and infant characteristics

The leptin, adiponectin, ghrelin, and IGF-1 levels were normally distributed. The range, mean, and 95%CI of the leptin, adiponectin, ghrelin, and IGF-1 levels in the urine samples are shown in the Supplementary Table. Except for the mild interplay between the adiponectin and IGF-1 levels (r = 0.24, p < 0.05), there was no correlation between the levels of the other studied mediators.

We compared the tested energy metabolism mediator levels for the maternal (Table 1) and neonatal (Table 2) factors. As shown in Table 1, neonates born to primigravida had increased levels of leptin; infants born to nulliparous mothers, mothers with hypertensive disorders of pregnancy (HDP), or who received intrapartum steroids had increased levels of adiponectin; and neonates born to mothers older than 35 years of age had increased levels of ghrelin. None of the analyzed maternal factors affected the urinary levels of IGF-1. As compared to their female counterparts, male neonates had decreased levels of leptin and ghrelin; extremely preterm neonates had increased levels of adiponectin, ghrelin, and IGF-1; and extremely low birth weight infants and infants with an Apgar score <3 at 1 min and an Apgar score <6 at 5 min had increased levels of ghrelin and IGF-1 (Table 2). Birth-related maternal and neonatal variables that significantly impacted the average levels of the tested energy metabolism mediators were selected for inclusion in the multiple regression models. As shown in Table 3, GA but not BW was included in the models for ghrelin and IGF-1 because of the multicollinearity effect of BW with GA (r = 0.8 and R2 = 0.88). The greyed-out (shaded) cells represent the variables that were not selected for inclusion in each of the regression models (Table 3). Among all the factors included in the model, regression analysis revealed a significant association of male sex with decreased levels of leptin and ghrelin; birth at extremely preterm gestation; and Apgar <3 at 1 min with increased levels of IGF-1; birth to primigravida and nulliparous mothers with increased leptin and adiponectin levels, respectively. The adjusted R² (Table 3) indicates the contribution of these factors to nearly 16%-20% of the variation in the leptin, adiponectin, ghrelin, and IGF-1 levels. The contribution of other factors that were included in the model to the alteration of the tested energy metabolism mediator levels did not reach statistical significance.

Table 1. Maternal characteristics and their infants’ adipokines and IGF-1 levels

Factors	Mean, 95% CI (ng/mL).
	Leptin	Adiponectin	Ghrelin	IGF-1
Maternal age			*
<35 y (n = 46)	3.36 (3.09, 3.62)	4.30 (4.08, 4.52)	1.07 (1.01, 1.12)	2.73 (2.60, 2.86)
>35 y (n = 22)	3.22 (2.87, 3.56)	4.30 (3.92, 4.70)	1.13 (1.10, 1.16)	2.72 (2.53, 2.91)
White race
Yes (n = 26)	3.52 (3.21, 3.83)	4.39 (3.97, 4.80)	1.11 (1.07, 1.15)	2.69 (2.50, 2.88)
No (n = 38)	3.26 (2.98, 3.54)	4.27 (4.08, 4.46)	1.11 (1.07, 1.15)	2.73 (2.60, 2.87)
Primigravidity	**
Yes (n = 18)	3.75 (3.35, 4.15)	4.57 (4.10, 5.03)	1.08 (1.01, 1.16)	2.55 (2.23, 2.87)
No (n = 50)	3.13 (2.90, 3.37)	4.20 (4.01, 4.00)	1.09 (1.04, 1.14)	2.76 (2.60, 2.92)
Nulliparity		***
Yes (n = 32)	3.47 (3.12, 3.82)	4.60 (4.31, 4.89)	1.13 (1.09, 1.16)	2.72 (2.57, 2.87)
No (n = 38)	3.19 (2.95, 3.41)	4.07 (3.85, 4.29)	1.10 (1.06, 1.15)	2.74 (2.59, 2.88)
Singleton
Yes (n = 39)	3.41 (3.11, 3.71)	4.44 (4.17, 4.71)	1.13 (1.09, 1.17)	2.71 (2.48, 2.94)
No (n = 29)	3.18 (2.91, 3.46)	4.13 (3.88, 4.37)	1.09 (1.04, 1.13)	2.70 (2.56, 2.85)
Steroids^£		**
Yes (n = 50)	3.29 (3.05, 3.53)	4.46 (4.23, 4.69)	1.09 (1.04, 1.14)	2.75 (2.5, 2.93)
No (n = 18)	3.48 (3.08, 3.88)	3.92 (3.67, 4.17)	1.10 (1.01, 1.18)	2.60 (2.42, 2.78)
Antibiotics
Yes (n = 29)	3.40 (3.06, 3.73)	4.33 (3.98, 4.68)	1.10 (1.06, 1.15)	2.76 (2.62, 2.89)
No (n = 41)	3.25 (2.98, 3.51)	4.30 (4.09, 4.51)	1.12 (1.08, 1.16)	2.71 (2.56, 2.86)
MgSO4 ^€
Yes (n = 15)	3.32 (2.99, 3.66)	4.43 (4.03, 4.84)	1.09 (1.02, 1.17)	2.76 (2.46, 3.06)
No (n = 55)	3.31 (3.06, 3.55)	4.28 (4.06, 4.49)	1.12 (1.09, 1.15)	2.72 (2.62, 2.83)
PPROM^á
Yes (n = 11)	3.02 (2.44, 3.60)	4.26 (3.91, 4.61)	1.14 (1.07, 1.22)	2.88 (2.74, 3.02)
No (n = 59)	3.37 (3.15, 3.58)	4.32 (4.11, 4.53)	1.11 (1.08, 1.14)	2.70 (2.58, 2.82)
CS^â
Yes (n = 54)	3.29 (3.05, 3.52)	4.30 (4.09, 4.50)	1.11 (1.08, 1.14)	2.75 (2.63, 2.86)
No (n = 15)	3.40 (2.97, 3.82)	4.32 (3.82, 4.81)	1.11 (1.04, 1.19)	2.67 (2.43, 2.91)
HDP^¥		*
Yes (n = 22)	3.43 (2.95, 3.92)	4.61 (4.26, 4.96)	1.09 (1.05, 1.14)	2.62 (2.38, 2.87)
No (n = 47)	3.25 (3.05, 3.46)	4.16 (3.94, 4.38)	1.12 (1.08, 1.16)	2.78 (2.68, 2.88)
Diabetes
Yes (n = 4)	2.95 (2.40, 3.50)	3.96 (3.59, 4.32)	1.13 (1.06, 1.20)	2.53 (1.80, 3.25)
No (n = 65)	3.34 (3.12, 3.56)	4.32 (4.13, 4.52)	1.09 (1.04, 1.13)	2.72 (2.57, 2.87)

^£ Steroids, Steroids within 7 days before delivery.

^¥ HDP, hypertensive disorders of pregnancy.

^â CS, cesarean section.

^€MgSO4, magnesium sulfate.

^á PPROM, preterm premature rupture of membranes

* p < 0.05–0.02.

** p < 0.01.

*** p < 0.001.

Table 2. Neonatal characteristics and their adipokines and IGF-1 levels.

Factors	Mean, 95% CI (ng/mL)
	Leptin	Adiponectin	Ghrelin	IGF-1
Sex	*		*
Male (n = 33)	3.05 (2.74, 3.35)	4.46 (4.18, 4.74)	1.08 (1.04, 1.12)	2.71 (2.53, 2.88)
Female (n = 37)	3.55 (3.29, 3.80)	4.46 (3.91, 4.38)	1.14 (1.11, 1.18)	2.75 (2.63, 2.87)
GA		**	**	***
<28 w (n = 20)	3.31 (2.84, 3.77)	4.96 (4.39, 5.96)	1.17 (1.13, 1.20)	2.99 (2.91, 3.09)
>28 w (n = 50)	3.31 (3.08, 3.54)	4.16(3.94, 4.39)	1.09 (1.06, 1.12)	2.63 (2.50, 2.76)
BW			*	**
<750 g (n = 13)	3.29 (2.73, 3.85)	4.61 (4.23, 4.98)	1.17 (1.12, 1.22)	3.05 (2.95, 3.14)
>750 g (n = 57)	3.32 (3.09, 3.54)	4.24 (4.03, 4.45)	1.10 (1,07, 1.13)	2.66 (2.54, 2.77)
SGA
Yes (n = 4)	2.63 (0.99, 4.27)	4.78 (3.49, 6.06)	1.09 (0.95, 1.23)	2.72 (2.05, 3.40)
No (n = 66)	3.35 (3.15, 3.56)	4.28 (4.09, 4.47)	1.11 (1.08, 1.14)	2.73 (2.63, 2.84)
Apgar 1 min			**	*
<3 (n = 10)	3.16 (2.26, 4.05)	4.45 (3.93, 4.97)	1.20 (1.15, 1.24)	2.99 (2.84, 3.14)
>3 (n = 60)	3.34 (3.14, 3.54)	4.29 (4.09, 4.49)	1.10 (1.07, 1.13)	2.69 (2.57, 2.80)
Apgar 5 min			*	*
<6 (n = 10)	3.04 (2.04, 4.03)	4.29 (3.83, 4.75)	1.18 (1.13, 1.27)	3.00 (2.84, 3.15)
> 6 (n = 60)	3.35 (3.16, 3.55)	4.31 (4.11, 4.52)	1.09 (1.07, 1.13)	2.69 (2.58, 2.80)

SGA, small for gestational age.

* p < 0.05–0.02.

** p < 0.01.

*** p < 0.001.

Table 3. Multiple regression models for each of the energy metabolism mediators presented as regression coefficient β with a Standard Error (SE) of β.

Factors	Models
	Leptin	Adiponectin	Ghrelin	IGF-1
Sex	−0.493 (0.190)		−0.057 (0.026)
Male (1) vs. Female (0)	p < 0.02		p < 0.04
GA (weeks)		0.338 (0.201)	0.047 (0.032)	0.357 (0.111)
<28 (1) vs. >28 (0)		p = 0.10	p = 0.21	p < 0.01
Apgar Score 1 min			0.043 (0.046)	0.340 (0.153)
<3 (1) vs. >3 (0)			p = 0.36	p < 0.04
Apgar Score 5 min			0.045 (0.049)	−0.138 (0.166)
<6 (1) vs. > 6 (0)			p = 0.36	p = 0.41
Maternal age (years)			−0.044 (0.029)
>35 (1) vs. <35 (0)			p = 0.14
Primigravida	0.562 (0.215)
Yes (1) vs. No (0)	p < 0.02
Nulliparity		0.400 (0.171)
Yes (1) vs. No (0)		p < 0.03
HDP		0.304 (0.181)
Yes (1) vs. No (0)		p = 0.10
Steroids		0.353 (0.200)
Yes (1) vs. No (0)		p = 0.08
R^2 /Adjusted R^2	0.187/0.162	0.262/0.215	0.231/0.167	0.199/0.162
	p < 0.02	p < 0.001	p < 0.01	p < 0.01

Steroids, Steroids within 7 days before delivery; HDP, Hypertensive Disorders of Pregnancy; R² and adjusted R², identify the unadjusted and adjusted coefficient of determination.

Shaded cells represent variables not selected for inclusion in each regression model.

Discussion

The present study is among the first to determine the birth-related maternal and neonatal factors that alter the postpartum levels of leptin, adiponectin, ghrelin, and IGF-1 in the urine of infants born at gestational age 32 or fewer weeks. The variations of up to 20% in the levels of the tested energy metabolic mediators were predisposed by one or more factors such as male sex for the reduction in leptin and ghrelin; extreme prematurity and a low Apgar score at 1 min for an increase of IGF-1; primigravida for the increase of leptin; and nulliparity for an increase of adiponectin.

To our knowledge, no prior study has analyzed the role of birth-related maternal and neonatal factors in predicting the postpartum levels of energy metabolism mediators in the urine of very/extremely preterm-born neonates. Studies acknowledge higher levels of cord blood leptin [27–29], adiponectin [27], and ghrelin [27] in term than in preterm neonates, perhaps due to abdominal adiposity that determines the levels of cord blood adipokines [30]. Similar to our findings, studies have reported the association of the male sex with the reduction of leptin [28,29,31,32] and no a relationship between the infant’s sex and adiponectin [33]. Vatten et al. [31] identified the role of male sex in the reduction of IGF-1 in the cord blood of term neonates but this was demonstrated in our study. Like other investigators who studied leptin levels in cord blood [34], we too found a lack of effect of antenatal steroids on the alteration of leptin levels in the urine of preterm neonates. Our findings that preterm infants born to primigravida women have an increased probability of having higher leptin levels and those born to nulliparous mothers for having higher adiponectin levels than their counterparts are novel because, to our knowledge, none of the other studies analyzed such factors in relationship with postnatal levels of adipokines and IGF-1 in preterm or term neonates. Increased adiponectin levels in the studied preterm infants born to nulliparous mothers could be attributable to higher adiponectin concentrations in nulliparous women. We [35] and others [36] have shown increased levels of adiponectin in the breast milk of nulliparous mothers. Obeidat et al. [37] reported that nulliparous women have higher serum leptin levels as compared to multiparous mothers, which could explain why infants born to primigravida mothers have higher leptin levels as compared with infants born to multigravidas. However, more evidence will be required to explain the association of parity and gravidity in the alteration of the leptin and adiponectin levels. Our study findings show that increased levels of IGF-1 are more likely in extremely preterm-born infants and in those with a low 1-min Apgar score, which may reflect a compensatory reaction due to the multisystemic effect of IGF-1, including its participation in the glucose and lipid metabolism as well as the promotion of growth and survival [38]. Because of this effect, the authors [38] proposed initiating clinical trials to evaluate the benefits of IGF-1 replacement therapy in preterm-born infants. The direct correlation recorded in our study between the levels of IGF-1 and adiponectin supports their functional interplay that could help promote adiponectin-associated functional activities, including fat storage and immune system activation [4] in extremely preterm-born neonates.

This study has some limitations, including the use of a convenience sample of very/extremely preterm infants admitted to the NICU at a single children’s hospital, which could limit the external validity of the reported results. The lack of information about the pre-pregnancy body mass index (BMI) did not allow the identification of the association of maternal BMI with the alteration of postpartum levels of adipokines. However, there is some inconsistency in the reported findings, showing a direct association of maternal BMI with cord blood leptin [35,39] but no relationship with adiponectin [39].

Conclusion

Either individual or a combination of various birth-related maternal and neonatal characteristics, including male sex, extremely preterm gestation, low Apgar score at 1 min, gravidity, and parity, could predispose to up to 20% variance in the urinary levels of leptin, adiponectin, ghrelin, and or IGF-1 during the critical early postnatal stage of life in preterm infants born with GA of 32 or fewer weeks. Further studies should investigate the discrepancy in the character and importance of the observed associations to understand their effects on the postnatal adaptation of very preterm-born infants.

Ethical approval

This research complies with the guidelines for human studies and was conducted ethically by the World Medical Association Declaration of Helsinki. The study protocols were reviewed and approved by the Institutional Review.

Parental consent

Written informed consent was obtained from the study participants’ mothers before collecting the urine samples.

Acknowledgment

We would like to express our most sincere appreciation to the infants and their families as well as the nursing staff in the NICU for their participation and commitment to this research project.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The data that support the findings of this study are available from the corresponding author, [AP], upon reasonable request

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.