The phenotype of spontaneous preterm birth: application of a clinical phenotyping tool

Abstract

Objective Spontaneous preterm birth (SPTB) is a complex condition that is likely a final common pathway with multiple possible etiologies. We hypothesized that a comprehensive classification system could appropriately group women with similar STPB etiologies, and provide an explanation, at least in part, for the disparities in SPTB associated with race and gestational age at delivery. Study Design Planned analysis of a multicenter, prospective study of singleton SPTB. Women with SPTB < 34 weeks were included. We defined 9 potential SPTB phenotypes based on clinical data, including infection/inflammation, maternal stress, decidual hemorrhage, uterine distention, cervical insufficiency, placental dysfunction, premature rupture of the membranes, maternal comorbidities, and familial factors. Each woman was evaluated for each phenotype. Delivery gestational age was compared between those with and without each phenotype. Phenotype profiles were also compared between women with very early (20.0–27.9 weeks) SPTB vs. those with early SPTB (28.0–34.0 weeks), and between African-American and Caucasian women. Statistical analysis was by t-test and chi-square as appropriate. Results The phenotyping tool was applied to 1025 women with SPTB who delivered at a mean 30.0 (+/− 3.2) weeks gestation. Of these, 800 (78%) had ≥2 phenotypes. Only 43 (4.2%) had no phenotypes. The 281 women with early SPTB were more likely to have infection/inflammation, decidual hemorrhage, and cervical insufficiency phenotypes (all p≤0.001). African-American women had more maternal stress and cervical insufficiency but less decidual hemorrhage and placental dysfunction compared to Caucasian women (all p<0.05). Gestational age at delivery decreased as the number of phenotypes present increased. Conclusions Precise SPTB phenotyping classifies women with SPTB and identifies specific differences between very early and early SPTB and between African-Americans and Caucasians.

The interaction between maternal race/ethnicity and chronic hypertension on preterm birth

“…10,[13][14][15][16][17][18] The association of chronic hypertension with preterm birth, both medically indicated and spontaneous, has been reported in multiple studies. 8,11,[15][16][17][18][19] The role of endothelial dysfunction and abnormal placentation has been posited in the literature as a mechanism for spontaneous preterm birth as well as intrauterine fetal growth restriction and small-for-gestational-age neonates. 17 Data also suggest that different maternal racial/ethnic backgrounds confer a different degree of risk for chronic hypertension, although many of these data are confounded by multiple socioeconomic factors, such as diet, living conditions, and access to medical care.…”

“…4 Various etiologies for racial/ethnic disparities in preterm delivery have been hypothesized, from segregationist neighborhood policies to maternal stress and (epi)genetic factors. [5][6][7][8] Despite welldocumented health disparities, the relationship of comorbid conditions, such as chronic hypertension, to maternal race/ ethnicity and preterm birth has received limited attention in the literature. 9,10 Multiple studies have shown the prevalence of chronic hypertension in pregnancy to be increasing, with current rates estimated to be between 1% and 10% in the United States.…”

Cluster analysis of spontaneous preterm birth phenotypes identifies potential associations among preterm birth mechanisms

“…14 (See Table 1) Category clinical factors were classified into levels of evidence as providing “strong”, “moderate”, and “possible” evidence of the phenotype. Cluster analysis was used to classify 1028 unique SPTB cases.…”

“…We applied the phenotype tool to more than 1000 women with SPTB, were able to classify over 95% of women into one or more phenotype categories, and demonstrated that most cases of SPTB have evidence of two or more phenotypes present and that phenotypes vary by gestational age at delivery and by race. 14 Assigning a phenotype that suggests similar underlying etiology or etiologies for SPTB among a group of women will likely result in an enhanced ability to identify genes or pathways associated with that phenotype.…”

The Canadian Preterm Birth Network: a study protocol for improving outcomes for preterm infants and their families

“…Evidence suggests that preterm birth is a syndrome attributable to multiple pathological processes 22,23 and that neonatal outcomes may be different based on the reasons for preterm birth. We will collect data on 7 categories of preterm birth (premature rupture of membranes, infection, hemorrhage, hypertensive disorders of pregnancy, other forms of medically indicated preterm birth, multiple births and idiopathic preterm birth) and attempt to link these to neurodevelopmental outcomes.…”