Further evidence that an episode of preterm labor is a pathologic state: involvement of the insulin-like growth factor system

Abstract

Objective:

Approximately 47% of women with an episode of preterm labor deliver at term; However, their infants are at greater risk of being small for gestational age and for neurodevelopmental disorders In these cases, a pathologic insult may disrupt the homeostatic responses sustaining pregnancy. We tested the hypothesis of an involvement of components of the insulin-like growth factor (IGF) system.

Methods:

This is a cross-sectional study in which maternal plasma concentrations of pregnancy-associated plasma protease (PAPP)-A, PAPP-A2, insulin-like growth factor-binding protein 1 (IGFBP-1), and IGFBP-4 were determined in the following groups of women: 1) no episode of preterm labor, term delivery (controls; n=100); 2) episode of preterm labor, term delivery (n=50); 3) episode of preterm labor, preterm delivery (n=100); 4) pregnant women at term not in labor (n=61); and 5) pregnant women at term in labor (n=61). Pairwise differences in maternal plasma concentrations of PAPP-A, PAPP-A2, IGFBP-1, and IGFBP-4 among study groups were assessed by fitting linear models on log-transformed data and included adjustment for relevant covariates. Significance of the group coefficient in the linear models was assessed via t-scores, with p < 0.05 deemed a significant result.

Results:

Compared to controls, 1) women with an episode of premature labor, regardless of a preterm or a term delivery, had higher mean plasma concentrations of PAPP-A2 and IGFBP-1 (each, p<0.05); 2) women with an episode of premature labor who delivered at term also had a higher mean concentration of PAPP-A (p<0.05); and 3) acute histologic chorioamnionitis and spontaneous preterm labor were not associated with significant changes in these analytes.

Conclusion:

An episode of preterm labor involves the IGF system, supporting the view that the premature activation of parturition is a pathologic state, even in those women who delivered at term.

Mini-Summary

What does this study add to current knowledge?

Approximately 47% of patients diagnosed with an episode of preterm labor deliver at term. However, infants born to these women are more likely to be small for gestational age and are at greater risk for neurodevelopmental disorders. Herein, we report that women with an episode of preterm labor, regardless of whether they delivered preterm or at term, had higher plasma concentrations of pregnancy-associated plasma protease (PAPP)-A2 and insulin-like growth factor-binding protein 1 (IGFBP-1).

What are the main clinical implications?

The insulin-like growth factor system is involved in the pathologic nature of an episode of preterm labor, even when pregnancy reaches its full term.

Introduction

Preterm birth affects 10% of pregnancies worldwide and is the consequence of spontaneous preterm labor in two-thirds of cases [1, 2]. We propose that spontaneous labor at term results from physiologic activation of the common pathway of parturition [3], while premature labor leading to preterm delivery is the result of pathologic activation of this pathway [3–5], which can be synchronous or asynchronous [3, 4, 6].

An episode of premature labor is a frequent cause for hospital admission in pregnant women [7, 8]. There is a widespread belief that an episode of premature labor that resolves spontaneously or after treatment with tocolysis, leading to term delivery, is benign [9]. For this reason, some clinicians refer to these circumstances as false premature labor. However, there is now persuasive evidence that newborns delivered at term after an episode of premature labor are more likely to be small for gestational age (SGA) [10–13] and are at greater risk for developing neurodevelopmental disorders [14], attention deficit hyperactivity disorders [15], and autism [16]. In addition, their placentas more frequently display lesions of maternal vascular malperfusion [10, 17, 18]. Collectively, these observations suggest that a proportion of episodes of premature labor, even if followed by a term delivery, may represent a pathologic state.

In line with the association of an episode of premature labor and the delivery of an SGA neonate, key components of the insulin-like growth factor (IGF) system involved in the regulation of fetal growth and abundantly expressed at the maternal-fetal interface are differentially expressed in preterm birth [19,20]. For example, increased amounts of insulin-like growth factor-binding protein 1 (IGFBP-1) in the cervicovaginal fluid are predictive of preterm delivery in women presenting with symptoms of spontaneous preterm labor [21]. Moreover, the altered ratio of maternal blood IGFBP-4 concentration compared to that of sex hormone-binding globulin is predictive of early preterm birth in asymptomatic pregnant women in mid-gestation [22]. In addition, placental or decidual altered expression of pregnancy-associated plasma proteases (PAPP-A and PAPP-A2) is associated with preterm birth due to various pregnancy complications [23, 24].

To further explore this hypothesis, we aimed to assess key components of the IGF system in pregnancy by measuring the maternal plasma concentrations of IGFBP-1, IGFBP-4, PAPP-A, and PAPP-A2. Therefore, current study was conducted to compare maternal plasma concentrations of these four proteins among patients with a normal pregnancy, those with an episode of premature labor who subsequently delivered at term, and those with an episode of premature labor resulting in preterm delivery, with and without placental evidence of acute histologic chorioamnionitis. The same analytes were also tested in the maternal plasma of patients at term with and without labor to assess whether the abovementioned components of the IGF system were also altered in the physiologic process of parturition.

Materials and Methods

Study design and participants

This cross-sectional study was conducted at Wayne State University, the Detroit Medical Center, and the Pregnancy Research Branch, NICHD/NIH/DHHS. Patients were enrolled at Hutzel Women’s Hospital of the Detroit Medical Center (Detroit, Michigan, USA). The following groups of women were included in this study: 1) women without an episode of premature labor who delivered at term (n=100; controls); 2) women with an episode of premature labor who delivered at term (n=50); 3) women with an episode of premature labor who delivered preterm (n=100); 4) pregnant women at term not in labor (n= 61); and 5) pregnant women at term in labor (n= 61). Women who delivered preterm were sub-classified into groups of those with (n=50) or without (n=50) acute histologic chorioamnionitis. With 50 samples per group in the comparison between preterm delivery with and without acute histologic chorioamnionitis, we had >90% power to detect a difference of 0.65 standard deviations or more at a significance level of 0.05. For all other comparisons, the statistical power was sufficient to detect even smaller effect sizes.

All patients provided written informed consent prior to the collection of plasma samples. The collection and use of human materials for research purposes were approved by the Institutional Review Boards of Wayne State University, the Detroit Medical Center, and the NICHD.

Clinical definitions

Premature labor was diagnosed in the presence of regular uterine contractions associated with cervical changes in patients between 20 and 36^6/7 weeks of gestation [25–27]. The control group comprised patients with an uncomplicated (no medical or surgical complications) pregnancy who delivered a term (≥37 weeks of gestation) neonate with a birthweight between the 10^th and 90^th percentiles for gestational age [28]. Preterm delivery was defined as the birth of a neonate <37 weeks of gestation due to spontaneous preterm labor. Term labor was confirmed by the presence of regular uterine contractions associated with cervical changes after 37 completed weeks of gestation (included patients at different stages of cervical dilation). Term delivery was defined as the birth of a neonate after 37 completed weeks of gestation [29]. An SGA neonate was diagnosed when the birthweight was below the 10^th percentile for gestational age, according to an established reference range [28]. A diagnosis of acute histologic chorioamnionitis was made according to the established criteria, including staging and grading [30–32].

Sample collection and immunoassays for PAPP-A, PAPP-A2, IGFBP-1, and IGFBP-4

Maternal plasma samples were collected at the time of hospital admission from women with an episode of premature labor and from those in labor at term, whereas such samples from controls were collected during scheduled prenatal visits. Maternal plasma concentrations of PAPP-A, PAPP-A2, IGFBP-1, and IGFBP-4 were determined using commercially available sensitive and specific enzyme-linked immunosorbent assays (ELISA). The ELISA kits were validated for plasma determinations of the analytes and tested for matrix interference. The inter- and intra-assay coefficients of variation were 4.82% and 1.61% for PAPP-A, 10.91% and 4.08% for PAPP-A2, 2.54% and 1.18% for IGFBP-1, and 9.73% and 3.52% for IGFBP-4, respectively. The sensitivities were <0.35 ng/ml for PAPP-A, <0.18 ng/ml for PAPP-A2, <0.05 ng/ml for IGFBP-1, and <0.06 ng/ml for IGFBP-4.

For some maternal plasma samples, there was not enough volume to determine the concentrations of all four analytes; therefore, data were missing for up to five samples in the group with an episode of premature labor who delivered at term and in up to eight samples in the group with an episode of premature labor who delivered preterm, depending on the analyte. Laboratory personnel who performed the assays were masked to the clinical information.

Placental histopathologic examination

Placentas were collected in the Labor and Delivery Unit or Operating Room at Hutzel Women’s Hospital of the Detroit Medical Center and transferred to the Perinatology Research Branch laboratory. Sampling was conducted according to protocols of the Perinatology Research Branch, as previously described [31–36]. A minimum of five full-thickness sections of the chorionic plate, three sections of the umbilical cord, and three chorioamniotic membrane rolls from each case were examined by placental pathologists who were masked to clinical data. They diagnosed the presence or absence of acute histologic chorioamnionitis in patients clinically diagnosed with premature labor.

Statistical Analysis

Pairwise differences in maternal plasma concentrations of PAPP-A, PAPP-A2, IGFBP-1, and IGFBP-4 in samples collected preterm were assessed by utilizing linear models in which data were log transformed to improve normality. Relevant covariates adjusted for in the analyses were selected using stepwise backward elimination from among the following: gestational age at sampling, sample storage time, body mass index, maternal age, and parity. When comparing term and preterm delivery groups, samples collected before 26^3/7 weeks of gestation were removed to match the distribution of samples. The comparison between the term groups was performed using the same methods. The significance of the group variable coefficient was assessed via t-test, with p<0.05 deemed a significant result. Analysis was performed using the R statistical language and environment (www.r-project.org).

Results

Demographics and clinical characteristics of the study population

A total of 372 patients were included in this study. The demographics and clinical characteristics of the control group and of women with an episode of premature labor (with either a term or a preterm delivery) are displayed in Table 1. Patients with premature labor had intact membranes but were not differentiated into subgroups based on the use of tocolytics, antibiotics, or steroids. There were no significant differences in maternal age and gestational age at blood sampling among the three groups. The distribution of gestational age at sampling in each group is shown in Figure 1. Women who had an episode of premature labor and delivered at term had lower weight and height, were more likely to be parous, and delivered smaller neonates at an earlier gestational age compared to the control group (p < 0.05). The frequency of delivery of an SGA neonate was higher in women with an episode of premature labor who delivered at term (16%) or delivered preterm (6%), when compared to the control group (p < 0.05). Compared to women with premature labor who delivered at term, women with premature labor who presented with slightly more advanced cervical dilation (3.8 vs. 2.5 cm) received magnesium/tocolysis treatment less frequently (40% vs. 62%) (all, p <0.05; Table 1).

Table 1.

Demographics and clinical characteristics of the preterm groups

	Controls N=100	PTL_TD N=50	PTL_PTD N=100
Age (years)	21.5 (19.8–25)	22 (19–25)	22 (20–25)
Body mass index (Kg/m2)	25.8 (22.3–30.1)	24.7 (20.6–27.6)	24.9 (21.2–28.3)
Height (cm)	162.6 (157.5–167.6)	160 (155.6–165.1)*	162.6 (157.5–165.1)
Weight (kg)	67.4 (59–79.7)	59.4 (53.2–72.1)*	65.5(54.9–74.2)
Nulliparity	43 (43%)	11(22%)*	28 (28%)
GA at sample (weeks)	32.3 (29.1–35.6)	32.7 (30.5–34.9)	33.9 (31–35.7)
GA at delivery (weeks)	39.7 (38.9–40.6)	38.7 (37.8–39.2)*	34.3 (31.7–35.9)*
Female neonate	49 (49%)	23 (46%)	50 (50%)
Birthweight (g)	3280 (3166.2–3531.2)	2987.5 (2785–3251.2)*	2205.5 (1618.8–2622.5)*
Birthweight percentile	44(32.8–58.3)	31.5(18.4–48.2)*	34.2(22.5–44.5)*
SGA neonate (<10th)	0	8(16%)*	6(6%)

Data are presented as median (interquartile range) or number (%). Statistically significant differences were assessed by group comparisons with term delivery controls (Fisher’s exact test for categorical variables and two-sided Wilcoxon test for continuous variables):

^*p < 0.05.

GA, gestational age; PTD, preterm delivery; PTL, premature labor; SGA, small for gestational age; TD, term delivery

Figure 1.

Gestational age (weeks) at blood sampling in women without an episode of premature labor who delivered a term neonate (control group), women with an episode of premature labor who delivered at term (PTL_TD group), and women with an episode of premature labor who delivered preterm (PTL_PTD group). Box-and-whisker plots (median, interquartile range, and range) display the distribution of gestational age in each group.

Plasma concentrations of PAPP-A, PAPP-A2, IGFBP-1, and IGFBP-4 in patients with an episode of premature labor who subsequently delivered either preterm or at term

Women with an episode of premature labor, regardless of whether they subsequently delivered at term or preterm, had significantly higher mean maternal plasma concentrations of PAPP-A2 and IGFBP-1 than the control group. The adjusted fold changes for PAPP-A2 were 1.37 (p=0.04) and 1.36 (p=0.012) in the groups that delivered at term and preterm, respectively (shown in Figure 2B). The adjusted fold changes for IGFBP-1 were 1.32 (p=0.04) and 1.42 (p=0.003) in the groups that delivered at term and preterm, respectively (shown in Figure 2C). Women with an episode of premature labor who delivered at term, but not those who delivered preterm, also had a significantly higher mean maternal plasma concentration of PAPP-A than controls (adjusted fold change=1.28, p=0.03) (shown in Figure 2A). There were no significant differences in any of the four analytes between women with an episode of premature labor who delivered preterm compared to those who delivered at term (shown in Figure 2A–2D).

Figure 2.

Plasma concentrations of PAPP-A (A), PAPP-A2 (B), IGFBP-1 (C), and IGFBP-4 (D) in women without an episode of premature labor who delivered a term neonate (control group, N=100), women with an episode of premature labor who delivered at term (PTL_TD group, N=50), and women with an episode of premature labor who delivered preterm (PTL_PD group, N=100). Each p value was derived from pairwise comparison between groups by utilizing linear models in which data were log transformed to improve normality. Relevant covariates to adjust for in the analyses were selected by the use of stepwise backward elimination from among the following: gestational age at sampling, sample storage time, body mass index, maternal age, and parity. Box-and-whisker plots (median, interquartile range, and range) display the distribution of analyte values.

Acute histologic chorioamnionitis was not associated with changes in plasma concentrations of PAPP-A, PAPP-A2, IGFBP-1, and IGFBP-4 in patients who delivered preterm

A subgroup analysis of women with an episode of premature labor who delivered preterm was performed to assess the effect of acute histologic chorioamnionitis on the changes in the maternal plasma analytes concentrations. There were no differences in maternal characteristics between these two subgroups of women, yet those who had acute histologic chorioamnionitis delivered earlier (32.9 vs. 35.5 weeks) and were more likely to have received antenatal steroids compared to those without acute histologic chorioamnionitis (58% vs. 30%). Gestational age at sampling was also lower in cases compared to those without acute histologic chorioamnionitis (median 32.4 vs. 34.6 weeks) (p < 0.05, for all). There were no significant differences in the mean plasma concentrations of PAPP-A, PAPP-A2, IGFBP-1, and IGFBP-4 between patients with or without acute histologic chorioamnionitis after adjusting for gestational age at blood draw and for relevant maternal characteristics (see Table 2).

Table 2.

Plasma concentrations (ng/mL) of PAPP-A, PAPP-A2, IGFBP-1, and IGFBP-4 in patients who delivered preterm with and without histologic chorioamnionitis

	Without histologic chorioamnionitis n=50	With histologic chorioamnionitis n=50	p
PAPP-A	1066 + 706 a	1101 + 706b	0.18
PAPP-A2	7.5 + 5.1 a	6.5 + 4.9c	0.71
IGFBP-1	49.4 + 32.5 a	63.4 + 51.4b	0.34
IGFBP-4	5.5 + 2.4 a	5.2 + 2.1b	0.41

Data are presented as mean ± SD; data are available for the following number of cases:

n=45;

^b:n=48;

^c:n=47.

Spontaneous labor at term was not associated with changes in plasma concentrations of PAPP-A, PAPP-A2, IGFBP-1, and IGFBP-4

Demographics and clinical characteristics of women at term in labor and those not in labor are shown in Table 3. Women in the term in labor group were younger, had lower body mass index, were more likely to be parous, and delivered smaller neonates compared to those in the term no labor group (all p < 0.05, Table 3). Figure 3 displays maternal plasma concentrations of PAPP-A, PAPP-A2, IGFBP-1 and IGFBP-4 among patients at term gestation. The presence or absence of labor at term was not associated with changes in analyte concentrations after adjusting for gestational age at blood draw and for relevant maternal characteristics.

Table 3.

Demographics and clinical characteristics of the term groups

	Term no labor n=61	Term labor n=61
Age (years)	25 (22–29)	23 (20–27)
Body mass index (kg/m2)	27.9 (25.9–35.6)	26.6 (21.9–30.7)
Height (cm)	160 (157.5–167.6)	162.6 (160–167.6)
Weight (kg)	77.6 (63.5–87.9)	69.2 (59–82.7)
Nulliparity	5 (8.2%)	22 (36.1%)
GA age at sample (weeks)	39.6 (39.3–40)	39.7 (39.3–40.4)
GA at delivery (weeks)	39.6 (39.3–40)	39.7 (39.3–40.4)
Female neonate	22 (36.1%)	29 (47.5%)
Birthweight (g)	3440 (3175–3640)	3285 (3100–3455)
Birthweight percentile	51.1 (35.4–67.9)	39 (29.9–52.8)

Data are presented as median (interquartile range) or number (%). Statistically significant differences were assessed by group comparisons with the term no labor group (Fisher’s exact test for categorical variables and two-sided Wilcoxon test for continuous variables):

^*p < 0.05.

GA, gestational age.

Figure 3.

Plasma concentrations of PAPP-A (A), PAPP-A2 (B), IGFBP-1 (C), and IGFBP-4 (D) in women without labor (TNL, N=61) and in those with labor at term (TL, N=61). Box-and-whisker plots (median, interquartile range and range) display the distribution of analyte values.

Discussion

Principal findings of the study

1) Women with an episode of premature labor, regardless of whether they delivered preterm or at term, had higher mean plasma concentrations of PAPP-A2 and IGFBP-1 than the control group. Moreover, women with an episode of premature labor who subsequently delivered at term also had a higher mean plasma concentration of PAPP-A; 2) in women with spontaneous preterm labor and delivery, the mean plasma concentration of any of the four analytes did not differ in the presence or absence of histologic evidence of acute chorioamnionitis; and 3) labor at term was not associated with changes in the plasma concentrations of PAPP-A, PAPP-A2, IGFBP-1, and IGFBP-4.

An episode of premature labor that does not result in a preterm delivery may not be a benign condition

An episode of premature labor that resolves spontaneously or after tocolysis and that results in a term delivery is often labeled as false premature labor. The traditional view has been that an episode of premature labor represents a risk factor for the recurrence of another episode of premature labor or of a preterm delivery [37] but that overall it is a benign event without long-term consequences. However, accumulating evidence suggests that such is not always the case. Two retrospective studies reported that pregnant women who experience an episode of premature labor and deliver at term have a higher frequency of delivering an SGA neonate than those who deliver preterm [10, 13]. Moreover, in a prospective cohort study, an episode of premature labor had an odds ratio of 3.9 (95% confidence interval [CI], 1.3–11.4) for the delivery of an SGA neonate at term [12]. Longitudinal studies in fetal growth reported that neonates delivered at term, after an episode of premature labor, were smaller at birth and were more likely to present with fetal growth deceleration at the time of subsequent fetal biometry [11]. The excess of SGA neonates in women with an episode of premature labor who deliver at term has been attributed to the greater frequency of placental lesions of maternal vascular malperfusion [10, 17, 18] and utero-placental ischemia leading to fetal growth deceleration. The ischemic insult may not be sufficient to lead to a preterm birth but may compromise the growth of the fetus. The findings from the current study suggest that women who delivered after an episode of premature labor delivered an SGA neonate more frequently than the control group, supporting this view.

Importantly, infants at the age of two years, born at term after an episode of suspected premature labor, scored lower on the Global Cognitive Index in the test’s components (cognition, fine and gross motor skills, memory, receptive language, speed of processing, and visual motor coordination) [14] and were at greater risk of attention deficit hyperactivity disorders [15] and autism [16] than those who were born at term but did not experience an episode of premature labor.

The data presented in the current study show that patients with an episode of premature labor who did not progress to preterm delivery displayed biochemical changes in components of the IGF system that are not present in the physiologic process of labor at term. These biochemical changes are suggestive of a pathologic state that can expose the fetus and the mother to an adverse outcome. In addition, they provide a biological background for the findings reported in the recent literature on this topic.

The components of the IGF system

The placenta, an endocrine organ, produces hormones and growth regulatory proteins to support fetal growth and development [38, 39]. These molecules are secreted into the maternal circulation while gestational age advances and are considered candidate biomarkers for pregnancy complications [40]. A growing body of evidence supports that components of the IGF system play a central role in the regulation of fetal growth [41–44] and that they are dysregulated at the maternal-fetal interface and in the biological fluids of women with preeclampsia [24, 45–53], hemolysis, elevated liver enzymes, low platelet count (HELLP) syndrome [54, 55], intrauterine growth restriction [20, 22, 46, 50 56–59], and gestational diabetes mellitus [23] as well as preterm prelabor rupture of the membranes [21, 46], preterm birth [46, 50, 60, 61], and fetal death [46].

The IGF system includes IGFs, IGF receptors, and IGFBPs as well as metalloproteinases that specifically cleave IGFBPs [42–44, 62–65]. The expression and function of these components of the IGF system are precisely regulated by the mother and the fetus. IGFs expressed by fetal tissues (e.g., mesenchymal core of chorionic villi, extravillous and villous trophoblasts) [66] exert an autocrine role promoting trophoblast metabolism, proliferation, differentiation, and migration [42–44, 64, 66–68]. The bioavailability of IGFs at the maternal-fetal interface is modulated by six maternal IGFBPs (IGFBP-1 to IGFBP-6) mainly produced by the decidua [63, 65, 66, 69]. IGFBP-1 is also known as placental protein 12 [70, 71], pregnancy-associated endometrial alpha1-globulin [72], and placental alpha-1-microglobulin (PAMG-1) [73]. IGFBP-1 is expressed predominantly in the decidua compared to all other human tissues, where it is one of the most abundant proteins and from where it is secreted into the amniotic fluid [74, 75]. IGFBP-4 is also considerably expressed in the decidua as well as in other human tissues [64, 66].

Two metalloproteinases, PAPP-A and PAPP-A2, can cleave the IGFBPs, decrease their affinity for IGFs, and enhance the activity of IGFs [76–78]. Of interest, PAPP-A and PAPP-A2 are predominantly expressed at the maternal-fetal interface, mainly by the syncytiotrophoblast or by the decidua [51, 79, 80]. Therefore, given the tissue-specific expression patterns, changes in body fluid concentrations of the IGF system components may reflect either a placental or a decidual insult.

Higher expression of IGFBP-1 and PAPP-A2 in women with an episode of premature labor but not in those with labor at term: an abnormal decidual activation?

In the present study, women with an episode of premature labor, regardless of whether they subsequently delivered preterm or at term, had higher mean maternal plasma concentrations of IGFBP-1 and PAPP-A2 compared to the control group. The dysregulated expression of the two decidual proteins suggests that an episode of premature labor involves an abnormal activation of the decidua. Moreover, since labor at term was not associated with changes in the maternal blood concentrations of these two analytes, similar to the lack of changes in their expression at the maternal-fetal interface in term labor [24, 81], our observations represent further evidence that distinct mechanisms are implicated in the activation of the common terminal pathway of parturition in preterm and term gestations [82].

The role of IGFBP-1 and PAPPA2 in the prediction of preterm delivery and other obstetrical complications has been the subject of previous reports. For example, bedside tests detecting IGFBP-1 (or PAMG-1) in the cervicovaginal fluid are available to predict preterm delivery in women presenting with symptoms of spontaneous preterm labor [83–89]. Moreover, IGFBP-1 (or PAMG-1) in the cervicovaginal fluid has been proposed as a test for ruptured membranes [90–94]. The present study focused on maternal blood rather than on cervicovaginal fluid.

In the current study, there were no significant changes in maternal plasma concentrations of IGFBP-4, either in the presence of an episode of spontaneous preterm labor or in women in labor at term. Previous studies reported that, in asymptomatic pregnant women in mid-gestation, the IGFBP-4 to sex hormone-binding globulin (SHBG) ratio is predictive of early preterm birth, both medically indicated and spontaneous [95, 96]. Differences in tissue distribution and in the regulation of endometrial/decidual expression of IGFBP-4 [62, 97, 98] may account, at least in part, for the lack of alterations observed in the different study groups included in this study.

Strengths and Limitations

This is the most comprehensive study examining proteins of the IGF system in the maternal blood of women with an episode of premature labor and in women with labor at term. Yet, for some maternal plasma samples, there was not enough volume to determine the concentrations of all four analytes. A longitudinal study design would allow more detailed insight into the changes in the IGF system before and after an episode of premature labor occurs.

Conclusion

The evidence presented in this study suggests that women with an episode of preterm labor have biochemical changes in the maternal circulation of proteins that participate in the IGF system. These changes cannot be simply attributed to labor because they are not present in women with term parturition. The biological significance and the mechanisms responsible for the changes reported herein are still to be elucidated.

Data Availability Statement

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author at romeror@mail.nih.gov (Dr. Romero).