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Contents: Original Research

Neonatal Morbidity of Small- and Large-for-Gestational-Age Neonates Born at Term in Uncomplicated Pregnancies

Chauhan, Suneet P. MD; Rice, Madeline Murguia PhD; Grobman, William A. MD, MBA; Bailit, Jennifer MD, MPH; Reddy, Uma M. MD, MPH; Wapner, Ronald J. MD; Varner, Michael W. MD; Thorp, John M. Jr MD; Leveno, Kenneth J. MD; Caritis, Steve N. MD; Prasad, Mona DO, MD; Tita, Alan T. N. MD, PhD; Saade, George MD; Sorokin, Yoram MD; Rouse, Dwight J. MD; Tolosa, Jorge E. MD; ; MSCE, for the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network

Author Information
doi: 10.1097/AOG.0000000000002199

Small for gestational age (SGA) or large for gestational age (LGA) occurs in approximately 20% of pregnant women and are associated with adverse outcomes.1 Newborns who are SGA (ie, birth weight less than the 10th percentile), compared with those who are appropriate for gestational age (AGA; birth weight 10th to 90th percentile), are at increased risk for stillbirth, seizures, sepsis, intraventricular hemorrhage, necrotizing enterocolitis, hypoxic–ischemic encephalopathy, and neonatal mortality.2 Newborns who are LGA (ie, birth weight greater than the 90th percentile) are at increased risk of stillbirth, traumatic delivery, mechanical ventilation, brachial plexus palsy, and neonatal mortality.1,3,4

The frequency of aberrant fetal growth is higher in women with complications of pregnancy. Small for gestational age, for example, occurs in 17–32% of women with hypertensive diseases and LGA occurs in 24–39% of women with diabetes. Additionally, neonatal morbidity is higher in these populations when aberrant growth occurs.5–9 Conversely, although women without apparent pregnancy complications also have newborns with aberrant growth, there is a paucity of data detailing whether these neonates are at increased risk of neonatal morbidity. Resolving this evidence gap has implications with regard to understanding whether ultrasonographic screening for fetal growth among women with uncomplicated pregnancies has the potential to decrease a clinically significant portion of neonatal morbidity.

Correspondingly, the objective of this analysis was to compare the neonatal morbidity among SGA, AGA, and LGA neonates in women without medical or obstetric complications at term (37 weeks of gestation or greater). We hypothesized that, compared with AGA neonates, those born SGA would be more likely to have hypoxic morbidity and those born LGA would be more likely to have traumatic morbidity.

MATERIALS AND METHODS

This is a secondary analysis of an observational obstetric cohort (Assessment of Perinatal Excellence) of women and their neonates born in 25 geographically dispersed medical centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Maternal demographics, peripartum outcomes, and neonatal morbidities were collected on all women who had a live fetus on admission and delivered a newborn of at least 23 weeks of gestation on randomly selected days representing one third of deliveries over a 3-year period. Data from all charts were abstracted by certified research personnel. Neonatal data were collected until discharge, death, or until 120 days of age, whichever came first. Several steps were undertaken to ensure data quality. First, before selecting final data collection fields, we conducted a 2-week pilot study to evaluate the data collection process, quality of the data, and frequency of missing data. The final data collection fields were based on the information gathered during this pilot phase. During the data collection process, all data were subjected to ongoing data edits to ensure accuracy. The study was approved by the institutional review board at each participating center under a waiver of informed consent. Full details on study methods and the technique of data collection have been previously published.10

Women were included in this secondary analysis if they delivered nonanomalous singletons between 37 0/7 and 42 6/7 weeks of gestation and had a pregnancy that had been dated by last menstrual period and first- or second-trimester ultrasonography, first- or second-trimester ultrasonography alone, or assisted reproductive technology. A pregnancy was considered complicated if a woman had any of the following: diabetes (pregestational or gestational), chronic hypertension, history of deep venous thrombus or pulmonary embolism, nonobstetric comorbidity (eg, cardiac disease), thrombophilia, anticoagulant use, placenta previa, placental abruption, or—at admission for delivery—deep venous thrombosis, asthma exacerbation at delivery, or hypertensive disease of pregnancy (gestational hypertension, preeclampsia, or eclampsia). In the absence of these conditions, women were considered to have apparently uncomplicated pregnancies. Furthermore, a post hoc sensitivity analysis was conducted excluding women with a diagnosis of suspected intrauterine growth restriction or nonreassuring fetal status at the time of admission.

Size for gestational age was estimated per methods of Alexander et al11 (personal communication, G. Alexander, 2000) using neonatal gestational age at delivery, birth weight and sex, and maternal race–ethnicity to categorize newborns into three groups: SGA (birth weight less than the 10th percentile for gestational age), AGA (birth weight 10th–90th percentile for gestational age; reference group), and LGA (birth weight greater than the 90th percentile for gestational age).

The primary outcome for SGA was a composite neonatal morbidity potentially related to hypoxic events and included any of the following: Apgar score less than 5 at 5 minutes, seizure, bronchopulmonary dysplasia, persistent pulmonary hypertension of the newborn, culture-proven sepsis, cardiopulmonary resuscitation within the first 24 hours, hypoxic–ischemic encephalopathy, grade III or IV intraventricular hemorrhage grade, grade II or III necrotizing enterocolitis, ventilator support within 24 hours, or death before discharge. The primary outcome for LGA newborns was a composite neonatal morbidity potentially related to traumatic events and included any of the following: Apgar score less than 5 at 5 minutes, seizure, cardiopulmonary resuscitation within the first 24 hours, ventilator support within 24 hours, hypoxic–ischemic encephalopathy, osseous fracture, intracranial hemorrhage other than intraventricular hemorrhage, brachial plexus palsy, facial nerve palsy, or death before discharge.

Comparative analyses of aberrant growth category (SGA, AGA, LGA) were performed with the χ2 test or Fisher exact test for categorical variables and the Wilcoxon rank-sum test for continuous variables. Log Poisson relative risks with 95% CIs, adjusted for potential confounding factors (nulliparity, body mass index [BMI, calculated as weight (kg)/[height (m)]2], insurance status, and neonatal sex), were calculated. SAS 9.2 was used for the analyses. All tests were two-tailed and P<.05 was used to define statistical significance. No imputation for missing data was performed.

RESULTS

Of the 115, 502 women in the Assessment of Perinatal Excellence study, 63,436 (55%) had uncomplicated pregnancies at term and were eligible for this analysis (Fig. 1). Among these women, 7.9% (n=4,983) had an SGA neonate and 8.3% (n=5,253) had an LGA neonate.

Fig. 1.
Fig. 1.:
Analysis cohort inclusion. APEX, Assessment of Perinatal Excellence. *Adequate pregnancy dating was defined as a pregnancy dated by last menstrual period and first- or second-trimester ultrasonogram, first- or second-trimester ultrasonogram alone, or assisted reproductive technology. Categories not mutually exclusive. A pregnancy was considered complicated if the woman had any of the following: diabetes (pregestational or gestational), chronic hypertension, history of deep venous thrombus or pulmonary embolism, hypertensive disease of pregnancy (gestational hypertension or preeclampsia) with an onset before delivery hospital admission, thrombophilia excluding MTHFR, anticoagulant use, previa, or any of the following as a reason for delivery hospital admission: vaginal bleeding or abruption, deep venous thrombus, asthma exacerbation, seizures, or other nonobstetric maternal medical condition. In absence of these conditions, a woman was considered to have an uncomplicated pregnancy.Chauhan. Neonatal Morbidity of SGA and LGA Neonates. Obstet Gynecol 2017.

Several maternal characteristics differed significantly based on whether a woman had an SGA, AGA, or LGA neonate. Maternal age, race–ethnicity, cigarette use, cocaine or methamphetamine use, and BMI at delivery differed for women who delivered an AGA newborn compared with those with aberrant growth (Table 1). Similarly, the gestational age at delivery differed significantly among groups. Approximately 29% of women with an SGA neonate and 42% of women with an LGA neonate delivered at 40 weeks of gestation or later. The frequency of cesarean delivery did not differ between those with SGA compared with AGA neonates, but was significantly different for women with LGA and AGA neonates (Table 2).

Table 1.
Table 1.:
Maternal Characteristics
Table 2.
Table 2.:
Intrapartum Characteristics

The absolute frequencies of a composite neonatal morbidity were less than 2% for the three groups of newborns (Table 3). The three most common morbidities among SGA neonates were ventilator support within 24 hours of birth (0.5%), Apgar score less than 5 at 5 minutes (0.4%), and hypoxic–ischemic encephalopathy (0.4%). For LGA neonates, the three most common morbidities were fracture (1.0%), brachial plexus palsy (0.4%), and ventilator support (0.3%). Hypoxic composite neonatal morbidity was higher in SGA neonates than in AGA neonates, and traumatic composite neonatal morbidity was higher in LGA neonates than in AGA neonates (Table 3). After adjusting for confounding factors, the significant differences among groups remained: hypoxic composite neonatal morbidity was 44% higher in neonates with SGA than in those with AGA, and traumatic composite neonatal morbidity was 88% higher in neonates with LGA than in those with AGA (Table 4). Other factors associated with the composite neonatal morbidity outcomes that were studied included nulliparity, male sex, and BMI at delivery (Table 4). Private insurance was associated with a lower frequency of the traumatic composite neonatal morbidity outcome. The results were similar after women with a diagnosis of intrauterine growth restriction or nonreassuring fetal status at the time of admission were excluded from analysis (Table 5).

Table 3.
Table 3.:
Hypoxic and Traumatic Neonatal Morbidity and Growth
Table 4.
Table 4.:
Full Multivariable Models for Hypoxic and Traumatic Neonatal Morbidity and Growth
Table 5.
Table 5.:
Sensitivity Analysis Evaluating Hypoxic and Traumatic Neonatal Morbidity and Growth After Excluding Women With a Diagnosis of Intrauterine Growth Restriction or Nonreassuring Fetal Status at the Time of Admission

DISCUSSION

Our analysis demonstrates that even among women who have an otherwise uncomplicated term pregnancies, hypoxic composite neonatal morbidity and traumatic composite neonatal morbidity were significantly increased among SGA (1.1%) and LGA (1.9%) neonates, respectively. Specifically, compared with AGA neonates, those who were SGA had a 44% higher risk of hypoxic composite neonatal morbidity and those who were LGA had an 88% higher risk of traumatic composite neonatal morbidity. Although the composite neonatal morbidity, as defined, occurred in less than 2% of newborns with aberrant growth, two points are worth noting. First, adverse outcomes included in the composite are severe with the potential for long-term sequelae. Second, the size of the population at risk for these adverse neonatal outcomes is large with approximately 470,000 SGA and LGA neonates born annually in the United States12 among women with uncomplicated pregnancies.

This report differs from prior studies on the extremes of fetal growth in that these studies included a general obstetric population2,4 or women with comorbidities like hypertensive disease5–7 or diabetes.8,9 In contrast, our study population was limited to women with uncomplicated pregnancies who delivered at term. Also, unlike most prior reports on abnormal growth, we simultaneously evaluated the outcomes of SGA and LGA neonates in one study population. Additionally, unlike prior publications,13 we were able to define a study group of women with uncomplicated pregnancies that excluded those with a wide variety of potential complicating factors. The criteria for gestational age were based on established criteria and thus ascertainment of abnormal growth was more reliable than that of prior publications that used birth certificate data sets.1

The limitations of the analysis should be acknowledged. Our analysis was based on the actual birth weight, which is unknowable with exactitude14 and is not helpful to clinicians managing pregnancy. Although we excluded several conditions that constitute high-risk pregnancies, some unrecognized complications (eg, thrombophilia) were potentially present in these apparently uncomplicated pregnancies. It is uncertain what proportions of SGA or LGA neonates were detected by clinicians and how antepartum care, including fetal surveillance, and intrapartum management may have been influenced.15–19 Nevertheless, 28% of SGA neonates (Table 2) were delivered at 40 weeks of gestation or later, suggesting that many of these cases were not known before delivery (ie, clinicians aware of fetal growth restriction typically recommend delivery no later than 39 weeks of gestation). The parent data set did not include stillbirths occurring before admission and may thus have excluded the most extreme adverse outcomes for SGA and LGA.2,3 Because the data are observational, it is unknown whether increasing the detection of abnormal growth and interventions would improve the composite neonatal morbidity.20–22

Notwithstanding the limitations, the strengths of the analysis include ascertainment of data directly from the charts by trained research personnel from 25 geographically and demographically diverse populations.10 Additionally, uniform definitions of neonatal outcomes were prespecified and included outcomes that are associated with long-term sequelae.

These findings have implications with regard to whether routine third-trimester ultrasonographic surveillance in women with uncomplicated pregnancies may or may not be clinically beneficial.23,24 Our results suggest that women with uncomplicated pregnancies experience fetal growth aberration, which is associated with increased severe neonatal morbidity. This fetal growth aberration (in this and prior studies) is not well ascertained15,16,25–30 and detection may have be associated with improved outcomes related to antepartum surveillance and interventions.2,4,17,18 Accordingly, it is possible that third-trimester ultrasonography, despite the known vagaries of accurate fetal weight estimation31 and iatrogenic neonatal morbidity,30,32 could screen for fetal growth aberration in women with uncomplicated pregnancies and guide intervention that improves neonatal outcomes.2,4,17,18,21,22 We, however, emphasize that before such a practice is implemented, evidence from clinical trials is needed to demonstrate that any theoretical benefits are cost-effective and translate to actual clinical improvement.

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