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. Author manuscript; available in PMC: 2013 Jan 9.
Published in final edited form as: J Dev Orig Health Dis. 2011 Oct;2(5):280–290. doi: 10.1017/S2040174411000298

Biological indicators of the in-utero environment and their association with birthweight for gestational age

Nicole M Talge 1,*, Claudia Holzman 1, Patricia K Senagore 2, Mark Klebanoff 3, Rachel Fisher 4
PMCID: PMC3540987  NIHMSID: NIHMS426080  PMID: 23316271

Abstract

Birthweight for gestational age (BW/GA) has been associated with risk of adverse health outcomes. Biological indices of pregnancy complications, maternal mid-pregnancy serum biomarkers, and placental pathology may shed light on these associations, but at present, they are most often examined as single entities and offer little insight about overlap. Additionally, these indices are typically assessed in relation to the extremes of the BW/GA distribution, leaving open the question of how they relate to the entire BW/GA distribution. Addressing issues such as these may help elucidate why postnatal health outcomes vary across the BW/GA continuum.

In this study, we focused on a subset of women who participated in the Pregnancy Outcomes and Community Health (POUCH) study (N=1371). We examined BW/GA (i.e., gestational age and sex-referenced z-scores) in relation to obstetric complications, second trimester maternal serum screening results, and histologic evidence of placental pathology along with maternal demographics, anthropometrics, and substance use. In adjusted models, mean reductions in BW/GA z-scores were associated with preeclampsia (β= −.70, 95%CI −1.04, −.36), high maternal serum alpha fetoprotein (MSAFP: β= −.28, 95%CI −.43, −.13), unconjugated estriol (uE3: β= −.31 per .5 MoM decrease, 95%CI −.41, −.21), and high levels of maternal obstructive vascular pathology in the placenta (MV-O: β= −.46, 95%CI −.67, −.25). Findings were similar when preterm infants, SGA, or LGA infants were removed. Future research is needed to examine how the factors studied here might directly mediate or mark risk when evaluating associations between BW/GA and postnatal health outcomes.

Keywords: birthweight, pregnancy complications, alpha fetoproteins, estriol, placenta

Introduction

Birthweight for gestational age (BW/GA) has been associated with numerous health outcomes including risk of cardiovascular disease and diabetes, low IQ, and psychopathology.1-4 Such findings are often interpreted within the framework of the developmental origins of adult health and disease hypothesis (DOHaD), which postulates that deleterious influences during sensitive periods (e.g., prenatal period) have long-lasting effects on later development and health. Deleterious influences in the prenatal period are commonly inferred from reductions in BW/GA continuum and are not limited to those born small-for-gestational age (SGA) 5,6 or preterm.4,7

Ideally, investigators should turn their attention to pregnancy-related mediators and markers of BW/GA that may more accurately identify and specify future health risk related to the in-utero environment.1,8 Challenges include selecting relevant mediators/markers to consider and comprehensive modeling to detect overlap. The human and animal literatures have focused heavily on the role of maternal malnutrition and stress in explaining associations between BW/GA and postnatal health outcomes, 9-11 while the role of other factors associated with pregnancy health have received comparatively less attention. In addition, clinical scenarios (e.g,. hypertensive disorders, gestational diabetes), biomarkers (e.g., maternal serum alpha fetoprotein), and evidence of placental pathology have been studied most often as separate entities and in relation to BW/GA at the extremes of the distribution. 12-17,18-20 Yet, links between BW/GA and postnatal health outcomes span the BW/GA continuum, suggesting that mediators/markers of the in-utero environment should be similarly evaluated across the full distribution of BW/GA.

In this hypothesis-generating investigation, we used data from the Pregnancy Outcomes and Community Health (POUCH) Study to examine associations between biological indicators of the in-utero environment and BW/GA. These data are unique in that they bring together commonly-studied factors associated with BW/GA (demographics, anthropometrics, substance use, clinical-level diagnosis of pregnancy complications) and biologic measures considered in separate studies. The selection of measures was guided by evidence linking particular obstetric complications with BW/GA (e.g., preeclampsia, gestational diabetes), the wide availability of maternal serum biomarkers used in routine pregnancy health screening (i.e., high maternal serum alpha-fetoprotein, beta human chorionic gonadotropin, unconjugated estriol),18,21,22 and an ever-growing appreciation for the role of placental processes in supporting intrauterine growth.23-25 Our goals were to evaluate: 1) associations between these biological indicators of pathology and BW/GA in a series of adjusted models, and 2) whether any observed associations remained following the removal of preterm, small-, or large-for-gestational age infants.

Methods

Participants

The POUCH Study, designed to examine etiological pathways leading to premature delivery, enrolled 3019 women between 15 and 27 weeks of gestation from 52 prenatal clinics in five Michigan communities.26 Eligibility criteria included English proficiency and a singleton pregnancy with no known birth defects, chromosomal anomalies, or preexisting diabetes; data reflect one pregnancy per participant. All women exhibiting maternal serum alpha-fetoprotein (MSAFP) ≥ 2.0 multiples of the median (MoM) were invited to participate in the study (7% of the cohort), and women with MSAFP <2.0 MoM were stratified by race/ethnicity and sampled into the cohort. For a subset oversampled for African-American race, high MSAFP, and preterm delivery, hereafter referred to as the subcohort (N=1371), in-depth medical record abstraction was performed and placental samples were collected for later gross and histological examination. This sampling scheme was employed to maximize resources when investigating at-risk subgroups,26 but use of sampling weights in analyses produces results that reflect the entire cohort. All subcohort women were eligible for inclusion in the present analysis, 1122 (81%) of whom had placental samples evaluated to date. This study was approved by the Institutional Review Boards of Michigan State University and all participating medical centers.

Measures

Obstetric Complications

Evidence of gestational diabetes (GDM), hypertensive disorders (i.e., chronic hypertension (CH), gestational hypertension (GH), preeclampsia (PE)), and placental abruption (PA) was abstracted from medical charts by trained staff nurses. A team of clinicians and the principal investigator reviewed this evidence and applied established criteria to assign the diagnostic categories, which included: GDM (failed 3-hour glucose tolerance test, failed glucose screen (> 190 mg/dl) accompanied by a fasting glucose > 95 mg/dl, or explicit diagnosis in the medical records,27 CH (diastolic blood pressure (DBP) > 90 or systolic blood pressure (SBP) > 140 on at least two occasions prior to 20 weeks, medical record diagnosis, or use of hypertension medication), GH (no CH, DBP > 90 or SBP > 140 on at least two occasions after 20 weeks), and PE (same criteria as GH plus evidence of proteinuria),28-30 and PA (documented signs/symptoms of PA (e.g., significant bleeding not attributable to dilation) or retroplacental hematoma visualized on prenatal ultrasound).31

Maternal Mid-Pregnancy Serum Biomarkers

MSAFP, unconjugated estriol (uE3), and beta human chorionic gonadotropin (bHCG) levels were abstracted from medical records, which were calculated as multiples of the median (MoM) adjusted for maternal race, weight, and gestational age at sampling by the laboratory. Because the POUCH Study oversampled women with MSAFP at ≥ 2.0 MoM, this value was used to dichotomize women according to this same threshold, whereas levels of uE3 and bHCG were allowed to vary continuously.

Placental Pathology

Placentas were obtained from 88% of the subcohort, and 92% of these have been evaluated to date by the study pathologist who was blind to all clinical circumstances surrounding delivery. Seven samples (five from the placental disc, two from the membrane roll) were examined per placenta. Microscopic evidence of vascular pathology was evaluated and grouped into five constructs which have been detailed elsewhere.32 Briefly, these include: Maternal Vascular–Obstructive (MV-O) (e.g., decidual vessel atherosis), Maternal Vascular–Developmental (MV-D) (e.g., abnormal/incomplete conversion of the uterine spiral arteries), Maternal Vascular–Disturbance of Integrity (MV-I) (e.g., retroplacental hemorrhage and decidual bleeding), Fetal Vascular–Obstructive (FV-O) (e.g., thromboses), and Fetal Vascular–Disturbance of Integrity (FV-I) (e.g., fetal to maternal hemorrhage).32 Scores for each of the five constructs, assigned on the distribution of findings in term, normal MSAFP deliveries, were dichotomized at approximately the top quintile to describe high and not high levels of vascular pathology.32

Placentas were also examined for evidence of histologic chorioamninoitis (HCA) according to a grading and staging scheme described elsewhere.33 Evidence of inflammation was described as none, mild, or severe, based on the concentration and location of polymorphonuclear leukocytes (PMNL) and presence of necrotizing inflammation or PMNL karyorrhexis.

Birthweight for gestational age (BW/GA)

Sex- and gestational-age referenced norms were used to calculate birthweight for gestational age z-scores (BW/GAz), using birthweight, gestational age, and sex information abstracted from the participants’ medical records.34 Gestational age was estimated using last menstrual period unless it was unavailable or differed from the ultrasound estimate (at < 25 weeks) by more than two weeks. In these cases (20% of the subcohort), the ultrasound-based estimate was employed in data analysis. Infants were identified as small- or large-for-gestational-age using estimates corresponding to the 10th and 90th percentiles, respectively.34

Additional Variables

At POUCH Study enrollment, maternal self-reports of race (non-Hispanic white, black), parity (primiparous, multiparous), education (< 12, = 12, > 12 years), Medicaid assistance, age (< 20, 20-30, ≥ 30 years), height, and pre-pregnancy weight were obtained along with their self-reported use of tobacco, alcohol, and illicit drugs (marijuana, heroin, cocaine/crack, methamphetamines) during the index pregnancy. All variables were analyzed categorically, except height which was analyzed continuously. Maternal height and pre-pregnancy weight were used to calculate body mass index (BMI) (kg/m2).

Statistical Analysis

To investigate associations among the factors listed above and BW/GAz, general linear models (GLMs) were performed. All analyses, both unadjusted and adjusted, were weighted for the oversampling of high MSAFP in the POUCH cohort and oversampling of high MSAFP, African-American race, and preterm delivery in the subcohort using PROC SURVEYREG (SAS 9.1).

We first examined associations among maternal demographics, anthropometrics, substance use, and BW/GAz to identify a base model of covariates. Characteristics associated with BW/GAz (p≤.10 or change in remaining estimates by ≥ 10%) were carried forward and compared to each set of obstetric complication indices separately. Using the same criteria, items from each of these analyses were entered into a single GLM to examine the extent to which each was associated with BW/GAz after adjusting for the others. This final model was repeated following the removal of preterm (< 37 weeks’ gestation), small-for-gestational age (SGA) or large-for-gestational age (LGA) infants to examine if these groups partially or fully accounted for any findings that were observed. The variable inflation factor (VIF) was < 10 for every variable in every analysis, suggesting that multicollinearity did not jeopardize the validity of the model estimates.

Results

In the POUCH subcohort, 25% self-identified as African American, 51% had 12 or fewer years of education, 49% received Medicaid, and 47% exhibited pre-pregnancy BMIs in the recommended range. Approximately 20% of women reported using tobacco, alcohol, or illicit drugs at some point during their pregnancy prior to enrollment; additionally, 10% of women had hypertensive disorders, 5% had GDM, and 1% experienced placental abruption. Approximately 10-39% of placentas exhibited high levels of a particular vascular pathology construct; 53% and 9% had evidence of mild and severe HCA, respectively (weighted percents; Table 1).

Table 1.

Maternal characteristics, obstetric complications, maternal mid-pregnancy serum biomarkers, and placental pathology

POUCH Subcohort
N = 1371
 POUCH Subcohort
Full Terms only
N = 1036
N (%) (Weighted %) N (%) (Weighted %)
Demographics & Anthropometrics
 Race
  White/Other 792 (58) (75) 567 (55) (76)
  African-American 579 (42) (25) 469 (45) (23)
 Parity
  Primiparous 577 (42) (42) 433 (42) (41)
  Multiparous 793 (58) (58) 603 (58) (59)
 Maternal Education (years)
  < 12 317 (23) (23) 240 (23) (18)
  = 12 388 (28) (28) 290 (28) (27)
  > 12 666 (49) (49) 506 (49) (55)
 Maternal Age (years)
  < 20 243 (18) (18) 185 (18) (14)
  20-30 776 (57) (57) 589 (57) (57)
  ≥30 352 (25) (28) 262 (25) (28)
 Medicaid
  No 586 (43) (51) 595 (57) (52)
  Yes 783 (57) (49) 440 (43) (48)
 Pre-pregnancy BMI (kg/m2)
  < 18.5 65 (5) (4) 47 (5) (4)
  18.5-24.9 609 (44) (47) 458 (44) (46)
  25-29.9 305 (22) (23) 238 (23) (23)
  ≥30 392 (29) (26) 293 (28) (26)
Substance Use
 Tobacco Use
  None/Quit prior to pregnancy 1111 (81) (82) 841 (81) (83)
  Yes 260 (19) (18) 195 (19) (17)
 Alcohol Use
  None 1126 (83) (82) 855 (83) (82)
  Any 234 (17) (18) 173 (17) (18)
 Illicit Drug Use
  None 1079 (79) (81) 809 (78) (81)
  Any 288 (21) (19) 224 (22) (19)
Obstetric Complications
 Hypertensive Disorders
  None 1222 (89) (90) 946 (91) (91)
  Preeclampsia 44 (3) (3) 17 (2) (2)
  Gestational Hypertension 56 (4) (4) 42 (4) (3)
  Chronic Hypertension 49 (4) (3) 31 (3) (4)
 Gestational Diabetes
  No 1304 (95) (95) 989 (94) (95) 20
  Yes 67 (5) (5) 47 (6) (5)
 Placental Abruption
  No 1328 (97) (99) 1023 (99) (99)
  Yes 43 (3) (1) 13 (1) (1)
Maternal Serum Biomarkers
 Unexplained High MSAFP
  Normal (< 2.0 MoM) 1161 (85) (97) 871 (84) (97)
  High (≥ 2.0 MoM) 210 (5) (3) 165 (16) (3)
 uE3a (MoM) 1.09 (.01) 1.06 (.01) 1.07 (.32) 1.06 (.01)
 bHCGa (MoM) 1.25 (.02) 1.20 (.02) 1.25 (.69) 1.20 (.02)
Placental Pathology
 Maternal Vascular Pathology N = 1122b N = 829b
  Obstructive (e.g., infarcts) Not High 993 (89) 736 (89)
High 129 (11) 93 (11)
  Integrity (e.g., bleeding) Not High 873 (79) 667 (80)
High 249 (21) 162 (20)
  Developmental Not High 974 (90) 736 (91)
High 148 (10) 93 (9)
 Fetal Vascular Pathology
  Obstructive (e.g., infarcts) Not High 882 (77) 655 (77)
High 240 (23) 174 (23)
  Integrity (e.g., bleeding) Not High 659 (60) 530 (63)
High 463 (40) 299 (37)
 Histologic Chorioamnionitis
  None 447 (39) 280 (36)
  Mild 540 (51) 456 (54)
  Severe 135 (10) 93 (9)
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a

Mean (standard error)

b

Sample sizes reflect placental samples evaluated to date.

Note. Missing data from POUCH subcohort: Parity (N=1), Medicaid (N=3), Alcohol Use (N=11), Illicit Drug Use (N=4), bHCG (N=68), uE3 (N=67).

Though not the focus of this study, we found that all maternal demographic, anthropometric, and substance use variables were significantly associated with BW/GAz in their expected directions (e.g., tobacco use, shorter height, lower BMI, lower education were associated with lower BW/GAz). Table 2 presents the unadjusted associations between the main study variables and BW/GAz; βs for categorical and continuous variables represent mean differences and slopes, respectively. BW/GAz was related to PE (β= −.63, 95% CI −.95, −.38), GDM (β=.62, 95% CI .23, 1.00) and two maternal serum biomarkers (high MSAFP: β= −.24, 95% CI −.39, −.10; uE3 (per .5 MoM decrease): β= −.29, 95% CI −.39, −.19). Among women with available placental data, high MV-O and presence of severe HCA were associated with a .62 and .33 mean decrease in BW/GAz, respectively.

Table 2.

Unadjusted associations between pregnancy complication indices and birth weight z-scores

Birthweight z-score
POUCH Subcohort N = 1371
 POUCH Subcohort terms only N = 1036
β (95% CI) β (95% CI)
Obstetric Complications
 Hypertensive Disorders
  None (ref) --- --- --- ---
  Preeclampsia −.66* (−.95, −.38) −.67* (−1.08, −.26)
  Gestational Hypertension .22 (−.12, .57) .25 (−.13, .63)
  Chronic Hypertension −.13 (−.45, .18) −.11 (−.49, .26)
 Gestational Diabetes ( ref= None) .62* (.23, 1.00) .66* (.23, 1.09)
 Placental Abruption ( ref = None) −.18 (−.50, .15) −.11 (−.68, .46)
Maternal Serum Biomarkers
  Unexplained MSAFP ( ref = Normal) −.24* (−.39, −.10) −.26* (−.41, −.10)
  uE3 (per .5 MoM decrease) −.29* (−.39, −.19) −.28* (−.39, −.16)
  bHCG (per .5 MoM decrease) .02 (−.03, .07) .02 (−.04, .08)
Placental Pathology N=1122a N = 829a
 Maternal Vascular Pathology
  Obstructive (e.g., infarcts) (ref = Not High) −.63* (−.86, −.41) −.63* (−.88, −.38)
  Integrity (e.g., bleeding) (ref = Not High) .06 (−.13, .24) .06 (−.15, .27)
  Developmental (ref = Not High) −.12 (−.39, .14) −.12 (−.44, .21)
 Fetal Vascular Pathology
  Obstructive (e.g., infarcts) (ref = Not High) −.08 (−.28, .11) −.04 (−.25, .17)
  Integrity (e.g., bleeding) (ref = Not High) .11 (−.05, .26) .12 (−.05, .30)
 Histologic Chorioamnionitis
  None (ref) --- --- --- ---
  Mild −.14 (−.30, .03) −.15 (−.32, .03)
  Severe −.38* (−.59, −.19) −.40* (−.63, −.17)
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*

p < .05

a

Sample sizes reflect placental samples evaluated to date.

In adjusted GLMs, all demographic, anthropometric, and substance use variables remained significantly associated with BW/GAz, except for alcohol and illicit drug use. As a result, these two variables were dropped from subsequent analyses, and those that remained comprised a base model to which the remaining sets of variables were separately compared. For obstetric complications, PE was associated with a decrease in BW/GAz (β= −.68, 95% CI −1.05, −.32) and GDM was associated with an increase in BW/GAz (β=.48, 95%CI .11, .84). For maternal serum biomarkers, high MSAFP and lower levels of uE3 remained associated with decreases in BW/GAz (MSAFP: β= −.31, 95% CI −.46, −.15; uE3 (per .5 MoM decrease): β = −.31, 95% CI −.41, −.21). Among the placental pathology constructs, only high MV-O remained significantly associated with decreases in BW/GAz (MV-O: β= −.45, 95% CI −.67, −.24). Associations between severe HCA and BW/GAz were attenuated and dropped below significance thresholds (β= −.14, 95%CI −.37, .01).

Because they were associated with BW/GAz in the above adjusted analyses, PE, GDM, MSAFP, uE3, and MV-O were entered into a simultaneous GLM with the base model to evaluate whether they retained their association with BW/GAz (Table 3). With the exception of GDM, results indicated that they did and that the model accounted for 25% of the variance in BW/GAz. The adjusted βs for biological indices approximated or exceeded those for demographics, anthropometrics, or substance use (e.g., tobacco use: β = −.43, 95%CI) in relation to BW/GAz.

Table 3.

Adjusted associations between pregnancy complication indices and birth weight z-scores in the POUCH subcohort prior to and following the removal of small- (SGA) or large-for gestational age (LGA) births a

Birthweight z-score
POUCH Subcohort N = 1371
 POUCH Subcohort SGAs Removed N = 1220
 POUCH Subcohort LGAs Removed N = 1229
β (95% CI) β (95% CI) β (95% CI)
Obstetric Complications
 Hypertensive Disorders
  None (ref) --- --- --- --- --- ---
  Preeclampsia −.70* (−1.04, −.36) −.58* (−.89, −.26) −.47* (−.80, −.13)
  Gestational Hypertension .18 (−19, .54) .11 (−.26, .47) .14 (−.12, .40)
  Chronic Hypertension −.30 (−.66, .07) −.44* (−.79, −.09) −.08 (−37, .21)
 Gestational Diabetes (ref = None) .30 (−.10, .69) .47* (.12, .82) −.02 (−31, .27)
Maternal Serum Screening
  High MSAFP (ref= Normal) −.28* (−.43, −.13) −.21* (−.35, −.06) −.19* (−.33, −.05)
  uE3 (per .5 MoM decrease) −.31* (−.41, −.21) −.22* (−.30, −.12) −.25* (−.33, −.17)
Placental Pathology N =1122b N = 1000b N =1005b
 Maternal Vascular Pathology
  Obstructive (ref = Not High) −.46* (−.67, −.25) −.21* (−.51, −.10) −.33* (−.54, −.13)
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*

p < .05

a

Adjusted for maternal demographics/anthropometrics (race, parity, maternal education, Medicaid status, pre-pregnancy BMI, maternal height), self-reported substance use (tobacco, alcohol), and all variables in this table.

b

Sample sizes reflect placental samples evaluated to date.

The BW/GAz associations with PE, MSAFP, uE3, and MV-O persisted and were minimally affected following the removal of infants born preterm (N=335), and were slightly attenuated after removal of infants born SGA or LGA (Tables 3 and 4). All models accounted for 19-27% of BW/GAz depending upon whether preterms, SGAs, and LGAs were excluded.

Table 4.

Adjusted associations between pregnancy complication indices and birth weight z-scores among term POUCH subcohort deliveries (≥ 37 weeks), prior to and following the removal of term small- (SGA) or large-for-gestational-age (LGA) birthsa

Birthweight z-score
POUCH Subcohort Terms Only N = 1036
 POUCH Subcohort Term SGAs Removed N = 909
 POUCH Subcohort Term LGAs Removed N = 934
β (95% CI) β (95% CI) β (95% CI)
Obstetric Complications
 Hypertensive Disorders
  None (ref) --- --- --- --- --- ---
  Preeclampsia −.86* (−1.31, −.41) −.67* (−1.12, −.23) −.64* (−1.08, −.20)
  Gestational Hypertension .20 (−.20, .60) .09 (−.31, .50) .19 (−.09, .48)
  Chronic Hypertension −.31 (−73, .12) −.49* (−.89, −.09) −.10 (−.44, .23)
 Gestational Diabetes (ref = None) .29 (−14, .72) .49* (.10, .88) −.04 (−.36, .27)
Maternal Serum Screening
  High MSAFP (ref= None) −.31* (−.47, −.16) −.27* (−.43, −.11) .21* (−.36, −.06)
  uE3 (per .5 MoM decrease) −.31* (−.42, −.20) −.21* (−.31, −.05) −.27* (−.37, −.17)
Placental Pathology N = 829b N = 727b N = 750b
 Maternal Vascular Pathology
  Obstructive (ref = Not High) .45* (−.68, −.23) −.33* (−.56, −.11) −.29* (−.51, −.08)
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*

p < .05

a

Adjusted for maternal demographics/anthropometrics (race, parity, maternal education, Medicaid status, pre-pregnancy BMI, maternal height), self-reported substance use (tobacco, alcohol), and all variables in this table

b

Sample sizes reflect placental samples evaluated to date.

Discussion

We evaluated whether BW/GA, which has been associated with many postnatal health outcomes, was related to maternal serum biomarkers and placental pathology after other known influences on growth were taken into account (e.g., maternal demographics, anthropometrics, substance use). Our findings suggest that beyond these influences and clinical-level diagnosis of obstetric complications, high MSAFP, lower levels of uE3, and high levels of maternal obstructive vascular pathology were independently and robustly associated with reductions in BW/GA. These findings were maintained irrespective of whether preterms, SGAs or LGAs were excluded from the analysis, suggesting that factors identified in our analyses are associated with reductions across the BW/GA distribution.

Though originally developed as a non-invasive screen for aneuploidy and other congenital anomalies, studies suggest that even in the absence of these conditions, maternal serum biomarkers are associated with aspects of maternal and fetal health (e.g., intrauterine growth restriction) 18,21 and placental functioning.35 Of the biomarkers traditionally included in the “triple screen,” high MSAFP and low uE3 have been the most consistently associated with reductions in fetal growth and birthweight.19,22,36,37 The present study not only replicates these findings, but extends them by examining their contribution to BW/GA beyond other indices of pregnancy health (e.g., placental pathology).

The mechanisms underlying high MSAFP in the absence of neural tube defects or ventral wall abnormalities are unclear. One hypothesis is that high MSAFP is a marker for disturbances to the maternal-fetal interface, reflecting the leakage of AFP from the fetal circulation and amniotic fluid into the maternal bloodstream;18 previous studies have linked unexplained high MSAFP with aspects of placental pathology.35 While high levels of disruption to fetal vessel integrity (FV-I) were unrelated to birthweight z-scores in our study, this may be because the “high” cutpoint for FV-I was constrained by our sample distribution and captured the upper 39%. MSAFP may be a more specific measure of disturbances to FV-I since its clinical cutpoint of 2.0 MoM applies to only 3-5% of screened populations.

Independent of high MSAFP, lower levels of uE3 were also associated with decreases in BW/GA. uE3 has been interpreted as an indicator of fetal well-being, given that by the second trimester, nearly 90% of circulating maternal serum estriol concentration is derived from the substrate dehydroepiandrosterone sulfate (DHEA-S) produced by the fetal adrenals (DHEA-S is converted to androgens and aromatized by placental sulfatases to produce estriol).18 Low levels of uE3 can thus reflect decreases in fetal production of DHEA-S or placental sulfatase activity.38,39 However, it is unclear what specific aspect of fetal physiological functioning low concentrations of DHEA-S might reflect (e.g., reduced adrenal sensitivity, decreased central stimulation), whether it is a proxy for less than optimal fetal organ function, or whether it directly influences growth through interactions with other hormones.40 Additionally, a constitutionally smaller fetus might secrete lower amounts of DHEA-S as a function of its smaller size. We do not believe this explains our findings because women who self-identified as Asian, a population often described as delivering constitutionally-smaller babies,14 exhibited higher levels of uE3 than either White or Black women (data not shown). Furthermore, sensitivity to body size would undermine the clinical utility of uE3 as a screening tool.

High MV-O was consistently associated with decreases in BW/GA. While the presence of maternal thrombotic lesions has been previously reported among SGAs,41 our finding was observed in term deliveries, across the BW/GA distribution, and following adjustment for many factors including the presence of other types of vascular pathology and maternal hypertensive conditions. There was minimal overlap across the vascular pathology constructs;32 thus, we believe the findings were not affected by multicollinearity. High MV-O likely reflects significant underperfusion of the placenta which impedes nutrient, waste, and gas exchange that supports fetal development and growth.42

The POUCH sample is demographically diverse with data on multiple biological indicators of pregnancy health, thus providing a unique opportunity to address our study objectives. However, there are some limitations worthy of mention. First, we employed growth standards based upon the birthweight distributions for live births. Because growth restricted fetuses preferentially deliver at earlier gestational ages, our operationalization of BW/GA likely underestimates the degree of growth restriction present among preterm infants and as such, may underestimate the contribution of preterm delivery and SGA birth to the findings reported here.43,44 Although efforts to develop population-based intrauterine growth standards are underway, they require further validation. Second, as illustrated by models accounting for less than 27% of the variance in BW/GAz, the biological measures addressed here do not represent an exhaustive list of factors that might influence birthweight and/or long-term health outcomes. For example, original formulations of the DOHaD hypothesis and much of the associated animal literature have identified maternal undernutrition as one potential mechanism through which BW/GA might be associated with later disease.8,45 Although data on maternal nutritional intake are unavailable in the POUCH Study, we employed pre-pregnancy BMI as a very rough proxy for pre-pregnancy undernutrition. We did not use pregnancy weight gain since this measure incorporates the weight of the fetus. (However, analyses replacing pre-pregnancy BMI with categorical or continuous measures of pregnancy weight gain did not alter any study findings.) We recognize that pre-pregnancy BMI is not a proxy for nutritional information, but it might identify women at risk for extreme under- or over-nutrition during pregnancy. Third, we assumed that missing data (e.g. placental pathology) from a particular weighted stratum were representative of that stratum in our adjusted analyses.

It will be important to evaluate associations among MSAFP, uE3, MV-O and health outcomes in childhood and beyond, determining whether these indices add risk information beyond BW/GA. This approach is consistent with recommendations by other investigators regarding the need to identify biological mediators of long-term health outcomes.2,46,47 That said, we recognize the limitations of the association models explored here, and though these associations are biologically-plausible, they are not meant to imply direct causality. Additionally, given the breadth of work investigating the contribution of maternal malnutrition to size at birth, it will be helpful to contextualize the findings reported here using adjusted models that include more detailed information regarding maternal diet and/or nutritional status.

A number of interpretational caveats are also important to consider when thinking about links between the indices of complications described here and risk for postnatal heath outcomes. First, although our investigation centered around factors that have been considered indicators of pathology during pregnancy, their relevance to understanding the development of later health problems depends upon the biological plausibility of their contributions to the particular outcome of interest. Second, attempts to link in-utero biological measures with postnatal health problems may be undermined by the inability to differentiate in-utero “programming” effects from genetic and postnatal environment effects that also mediate patterns of familial risk.48,49 For example, do obstructive lesions in the placenta (i.e., high MV-O) decrease BW/GA and alter fetal physiological systems involved in the etiology of cardiovascular disease? Or, are these same placental lesions proxies for a maternal thrombophilic profile that places offspring at risk for reductions in BW/GA as well as cardiovascular disease later in life? The overarching goal of our analyses was intended to be hypothesis-generating and was not designed to provide causal or predictive models of BW/GA.

Our findings reinforce the idea that size at birth, including BW/GA, are composite measures representing a myriad of influences, including those that are interpreted as innocuous (e.g., maternal height), helpful (e.g., adequate nutrition), or harmful (e.g., preeclampsia) to perinatal health. Therefore, we and others argue that it is important to move beyond measures of birth size in studies investigating the perinatal origins of adult disease and instead identify specific exposures relevant to the long-term outcome of interest.25 Doing so will facilitate the development of effective prevention/intervention strategies designed to promote health during pregnancy and beyond. Nonetheless, we show that there are meaningful biological clues about where infants fall in the BW/GA distribution beyond the clinical diagnosis of pregnancy complications, and this may help elucidate why postnatal health outcomes vary across the entire BW/GA continuum.5,6,50

Acknowledgements

We would like to thank Dr. Bertha Bullen, Crista Valentine, and the POUCH study team for their contributions to data management as well as feedback ideas presented here. We also acknowledge the work contributed by the histotechnicians in the MSU Investigative Histopathology Laboratory. This study was supported by the Perinatal Epidemiological Research Initiative Program [Grant 20-FY04-37y] from the March of Dimes Foundation, the National Institute of Child Health and Human Development and the National Institute of Nursing Research [Grant R01 HD34543], the Thrasher Research Foundation [Grant 02816-7], and the Centers for Disease Control and Prevention [Grant U01 DP000143-01] to Claudia Holzman and a National Institute of Child Health and Human Development Postdoctoral Fellowship (HD046377) to Nicole Talge via the Michigan State University Department of Epidemiology. Dr. Klebanoff was supported by Intramural funds from the NIH, NICHD and is now the Director of the Ohio Perinatal Research Network, Nationwide Children’s Hospital, Columbus, OH.

ABBREVIATIONS

bHCG

(beta human chorionic gonadotropin)

CH

(chronic hypertension)

DBP

(diastolic blood pressure)

DHEA-S

(dehydroepiandrosterone sulfate)

FV-I

(fetal vessel-integrity)

FV-O

(fetal vessel-obstructive)

GDM

(gestational diabetes mellitus)

GH

(gestational hypertension)

HCA

(histologic chorioamnionitis)

GLM

(general linear models)

LGA

(large for gestational age)

MSAFP

(maternal serum alpha-fetoprotein)

MV-D

(maternal vascular-developmental)

MV-I

(maternal vascular-integrity)

MV-O

(maternal vascular-obstructive)

PE

(preeclampsia)

POUCH Study

(Pregnancy Outcomes and Community Health Study)

SBP

(systolic blood pressure)

SGA

(small for gestational age)

uE3

(unconjugated estriol)

Footnotes

Statement of Interest

None.

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