Materials and Methods
This was a planned analysis of a multicenter, prospectively collected case-control study of women enrolled in the Eunice Kennedy Shriver National Institute for Child Health and Human Development Genomic and Proteomic Network for Preterm Birth Research. Briefly, women were recruited across 8 clinical sites from November 2007 through January 2011. Cases consisted of women who delivered singleton pregnancies from 20.0-33.9 weeks’ gestation after the spontaneous onset of labor (PTB cases). Women with PPROM who labored and delivered at <34 weeks’ gestation were also included as cases. Women with iatrogenic or medically indicated preterm deliveries (eg, because of preeclampsia or growth restriction) were excluded. A concomitant diagnosis of preeclampsia was not an exclusion, provided that the woman had spontaneous onset of preterm labor as defined earlier.
Clinical and demographic data were collected by trained research nurses. Research nurses conducted in-person interviews with participants and abstracted additional clinical and demographic data from medical records. Participating women were interviewed before hospital discharge from their delivery encounter whenever possible; all interviews were performed within 14 days of delivery. Data that were collected included demographics; medical, social, family, and obstetric histories; obstetric course, and complications during the current pregnancy (including intrapartum course, mode of delivery, and neonatal outcomes). Women also completed questionnaires to evaluate anxiety (Beck anxiety index), depression (Beck depression inventory), and perceived stress (Perceived stress scale). In addition, participants were asked to indicate their attitude and the attitude of their partner with respect to pregnancy. This study was approved by the Institutional Review Board at each center, and written, informed consent was obtained from all participants.
A phenotyping tool was designed by the authors (M.S.E., T.A.M., M.W.V.) to group maternal social, demographic, family history, and obstetric factors into 9 potential underlying SPTB categories. These categories include (1) infection/inflammation, (2) decidual hemorrhage, (3) maternal stress, (4) cervical insufficiency, (5) uterine distention, (6) placental dysfunction, (7) PROM, (8) maternal comorbidities, and (9) familial factors ( Table 1 ). Within each of the 9 categories, clinical factors were classified as providing strong, moderate, and possible evidence of the phenotype. Any of the listed criteria were sufficient for phenotype classification; it was not required that all criteria be met within each classification ( Table 1 ). A phenotype profile was assigned to each woman by assessment of whether she met criteria for each of the 9 phenotypes. Next, the phenotype profiles of women with very early PTB (delivering the current gestation at 20.0-27.9 weeks’ gestation) were compared with those with early PTB (delivery at 28.0-33.9 weeks’ gestation). Finally, we examined phenotype profiles by self-reported race/ethnicity.
| Phenotype | Evidence | ||
|---|---|---|---|
| Strong | Moderate | Possible | |
| Infection /inflammation a | Histologic chorioamnionitis or funisitis | Clinical chorioamnionitis that requires intrapartum antibiotic treatment | Clinical endometritis that requires postpartum antibiotic treatment |
| Positive placental culture or presence of placental viral inclusions | Placental pathologic evidence positive for deciduitis, villitis, microabscess, arteritis, and/or phlebitis | Major antenatal maternal systemic infection (pneumonia, pyelonephritis, pancreatitis, hepatitis) | |
| Symptomatic urinary tract infection | |||
| Sexually transmitted disease diagnosed at any time during pregnancy (chlamydia, gonorrhea, trichomoniasis, HIV) | |||
| Decidual hemorrhage a | Hemosiderin deposits or tightly adherent clot on placental pathologic evaluation | Placental pathologic evidence demonstrating 1-25% or unspecified percentage of hemorrhage on fetal or maternal interface | Trauma to abdomen or motor vehicle accident during pregnancy |
| At least 25% hemorrhage on fetal or maternal interface on placental pathologic evaluation | Active vaginal bleeding plus at least 1 of the following events: | Vaginal bleeding during pregnancy, not otherwise specified | |
| (1) Nonreassuring fetal heart tones, uterine tenderness, or uterine tachysystole | Placenta previa | ||
| (2) Clinical diagnosis of abruption that requires delivery | |||
| Maternal stress | Moderate-to-severe depression/anxiety that requires medication treatment during pregnancy | Beck Depression Index score that indicates severe depression | Mild to moderate depression/anxiety not requiring medication treatment |
| Perceived stress score “very high” or life stressors questionnaire indicated “severe distress” | Illicit drug use or current binge alcohol use during pregnancy | ||
| High risk socioeconomic risk factor: income less than poverty level, less than a high school degree | |||
| Cervical insufficiency | Cervical dilation ≥2 cm at <28 weeks’ gestation in the absence of labor | Cervical length <1.50 cm at <28 weeks’ gestation in the absence of labor | Cervical length 1.50-2.50 cm at <28 weeks’ gestation in the absence of labor |
| Cervical length <0.5 cm at <28 weeks’ gestation in the absence of labor | Cervical length 1.50-2.5 cm at <28 weeks’ gestation AND hourglassing membranes/marked funneling | History of cervical conization procedure or loop electro-excision procedure | |
| At least 1 pregnancy loss at <24 weeks’ gestation because of painless cervical dilation | |||
| Uterine distension a | N/A | Polyhydramnios (4-quadrant amniotic fluid index >25 cm or single deepest pocket >8 cm) | Sonographically confirmed presence of uterine fibroid tumors |
| Birthweight >90% for gestational age | Placental weight >90% for gestational age | ||
| Placental dysfunction a | Birthweight <3% for gestational age and gender | Birthweight <10% for gestational age and gender | Placental calcifications on pathologic evaluation |
| Placental weight <3% for gestational age | Placental weight <10% for gestational age | Umbilical artery cord Doppler S/D ratio >4 cm/sec but no evidence of absent- or reversed-end diastolic flow | |
| At least 25% placental infarction on pathologic evaluation | Absent end diastolic flow on cord Doppler before delivery | Meconium staining on placental pathologic evaluation | |
| Reverse end diastolic flow on cord Doppler before delivery | Any placental infarction with no percentage listed or <25% on placental pathologic evaluation | Velamentous cord insertion on placental pathologic evaluation | |
| Preeclampsia with severe features or eclampsia | Four quadrant amniotic fluid index <5 cm or single deepest pocket <2 cm on ultrasound scan | ||
| Preeclampsia without severe features | |||
| Preterm premature rupture of membranes | Preterm premature rupture of membranes diagnosed with sterile speculum examination, dye test, or AmniSure b at least 48 hours before the onset of labor | Preterm premature rupture of membranes diagnosed with sterile speculum examination, dye test, or AmniSure b 12-48 hours before the onset of labor | History of preterm premature rupture of membranes and delivery at <37 weeks’ gestation in a previous pregnancy |
| Maternal comorbidities | Class B or higher diabetes mellitus | Gestational diabetes mellitus in the current gestation | N/A |
| Chronic hypertension | Other medical condition that affects a major organ system, not otherwise specified (ie, pulmonary disease, renal disease, autoimmune disease, history of seizures) | ||
| Systemic lupus erythematosus | |||
| Antiphospholipid antibody syndrome | |||
| Chronic renal failure or insufficiency | |||
| Familial | At least 1 first-degree relative with a history of spontaneous preterm birth | At least 1 first-degree relative with a history of medically indicated preterm birth | At least 1 second-degree relative with a history of medically indicated preterm birth |
| At least 1 second-degree relative with history of spontaneous preterm birth | |||
a Placental pathologic information was available for only 195 women (19%). When pathologic evidence of each phenotype was noted, it was included in the classification. The frequency of placental pathologic evidence availability did not vary with gestational age epoch
b AmniSure ROM Test; AmniSure International LLC, Boston, MA.
Statistical analysis was performed with STATA software (version 12.1; Stat Corporation, College Station, TX). Comparisons were made with the use of the Student t test, χ 2 test, analysis of variance, and the Pearson correlation coefficient, as appropriate.
Results
The phenotyping tool (was applied to the data from 1025 women with SPTB at <34 weeks’ gestation, including 281 women with very early SPTB (20.0-27.9 weeks’ gestation; Table 1 ). Basic demographics and baseline characteristics, compared by delivery gestational age epoch, are shown in Table 2 . Most of the women (800; 78%) met criteria for >1 phenotype, although 43 women (4%) had no evidence of any phenotypes ( Table 3 ). We observed an inverse relationship between the number of phenotypes and gestational age at delivery, because those with multiple phenotypes delivered earliest ( r 2 = –0.110; P < .001; Table 3 ).
| Characteristic | Very early spontaneous preterm birth: 20.0-27.9 weeks’ gestation (n = 281) | Early spontaneous preterm birth: 27.0-33.9 weeks’ gestation (n = 744) | P value |
|---|---|---|---|
| Maternal age, y a | 25.3 ± 5.8 | 25.7 ± 6.0 | .422 |
| Maternal race, n (%) | .004 | ||
| White | 174 (61.9) | 522 (70.2) | |
| Black | 84 (29.9) | 150 (20.2) | |
| Other | 23 (8.2) | 72 (9.7) | |
| Hispanic ethnicity, n (%) | 63 (22.4) | 148 (19.9) | .372 |
| Married, n (%) | 122 (43.4) | 390 (52.4) | .010 |
| Nulliparous, n (%) | 141 (50.2) | 340 (45.7) | .200 |
| Previous preterm delivery <37 weeks’ gestation, n (%) | 69 (24.6) | 222 (29.8) | .094 |
| Maternal prepregnancy body mass index, kg/m 2 a | 27.1 ± 7.2 | 25.4 ± 6.5 | < .001 |
| Cigarette use during pregnancy, n (%) | 54 (19.2) | 138 (18.6) | .807 |
| Delivery gestational age, wk a | 25.5 ± 1.6 | 31.7 ± 1.7 | < .001 |
| Total count of distinct phenotypes | Women, n (%) | Mean delivery gestational age, mean ± SD |
|---|---|---|
| 0 | 43 (4.2) | 30.7 ± 3.2 |
| 1 | 182 (17.8) | 30.5 ± 2.9 |
| 2 | 273 (26.6) | 30.1 ± 3.3 |
| 3 | 296 (28.9) | 29.9 ± 3.2 |
| 4 | 148 (14.4) | 29.5 ± 3.3 |
| 5 | 64 (6.2) | 29.8 ± 3.3 |
| 6 | 15 (1.5) | 28.4 ± 3.0 |
| 7 | 4 (0.4) | 30.5 ± 2.7 |
The number and percentage of women with each of the 9 clinical phenotypes and the corresponding mean delivery gestational age are shown in Table 4 . The maternal stress phenotype was most common; more than one-half of all women with SPTB had strong, moderate, or possible evidence of maternal stress. Infection/inflammation (38%), PPROM (35%), familial (32%), and decidual hemorrhage (31%) were the next most common phenotypes.
| Phenotype | Cases of spontaneous preterm birth with phenotype (from total n = 1025), n (%) | Delivery gestational age, wk ± SD | P value | |
|---|---|---|---|---|
| With phenotype | Without phenotype | |||
| Infection/inflammation | ||||
| Strong evidence | 86 (8.4) | 29.1 ± 3.4 | 30.1 ± 3.2 | .006 |
| Moderate evidence | 98 (9.6) | 28.3 ± 3.6 | 30.2 ± 3.1 | < .001 |
| Possible evidence | 272 (26.5) | 29.9 ± 3.2 | 30.0 ± 3.2 | .620 |
| Any evidence | 388 (37.9) | 29.6 ± 3.4 | 30.3 ± 3.1 | < .001 |
| Decidual hemorrhage | ||||
| Strong evidence | 4 (0.4) | 27.6 ± 4.0 | 30.0 ± 3.2 | .131 |
| Moderate evidence | 150 (14.6) | 29.4 ± 3.4 | 30.1 ± 3.2 | .008 |
| Possible evidence | 202 (19.7) | 29.1 ± 3.5 | 30.2 ± 3.1 | < .001 |
| Any evidence | 316 (30.8) | 29.3 ± 3.5 | 30.3 ± 3.1 | < .001 |
| Maternal stress | ||||
| Strong evidence | 47 (4.6) | 31.3 ± 2.7 | 29.9 ± 3.2 | .005 |
| Moderate evidence | 306 (29.9) | 30.1 ± 3.3 | 30.0 ± 3.2 | .646 |
| Possible evidence | 422 (41.2) | 29.6 ± 3.2 | 30.3 ± 3.2 | .001 |
| Any evidence | 580 (56.6) | 29.8 ± 3.2 | 30.2 ± 3.2 | .081 |
| Cervical insufficiency | ||||
| Strong evidence | 68 (6.6) | 27.1 ± 2.6 | 30.2 ± 3.2 | < .001 |
| Moderate evidence | 51 (5.0) | 28.2 ± 2.7 | 30.1 ± 3.2 | < .001 |
| Possible evidence | 22 (2.2) | 28.0 ± 2.5 | 30.0 ± 3.2 | .003 |
| Any evidence | 119 (11.6) | 27.7 ± 2.7 | 30.3 ± 3.2 | < .001 |
| Uterine distension | ||||
| Strong evidence | — | — | — | — |
| Moderate evidence | 175 (17.1) | 30.2 ± 2.8 | 30.0 ± 3.3 | .448 |
| Possible evidence | 43 (4.2) | 30.3 ± 3.0 | 30.0 ± 3.2 | .539 |
| Any evidence | 212 (20.7) | 30.2 ± 2.9 | 30.0 ± 3.3 | .418 |
| Placental dysfunction | ||||
| Strong evidence | 39 (3.8) | 30.8 ± 3.0 | 30.0 ± 3.2 | .114 |
| Moderate evidence | 84 (8.2) | 30.2 ± 3.4 | 30.0 ± 3.2 | .643 |
| Possible evidence | 55 (5.4) | 30.2 ± 3.3 | 30.0 ± 3.2 | .639 |
| Any evidence | 122 (11.9) | 30.0 ± 3.4 | 30.0 ± 3.2 | .855 |
| Preterm premature rupture of membranes | ||||
| Strong evidence | 211 (20.6) | 30.0 ± 3.0 | 30.0 ± 3.3 | .950 |
| Moderate evidence | 141 (13.8) | 30.6 ± 3.2 | 29.9 ± 3.2 | .014 |
| Possible evidence | 49 (4.8) | 29.7 ± 3.0 | 30.0 ± 3.2 | .440 |
| Any evidence | 362 (35.3) | 30.2 ± 3.1 | 29.9 ± 3.3 | .078 |
| Maternal comorbidities | ||||
| Strong evidence | 87 (8.5) | 30.7 ± 2.7 | 29.9 ± 3.3 | .029 |
| Moderate evidence | 182 (17.8) | 30.4 ± 3.1 | 29.9 ± 3.2 | .040 |
| Possible evidence | — | — | — | — |
| Any evidence | 216 (21.1) | 30.3 ± 3.1 | 29.9 ± 3.2 | .102 |
| Familial | ||||
| Strong evidence | 227 (22.2) | 30.4 ± 3.0 | 29.9 ± 3.3 | .023 |
| Moderate evidence | 143 (14.0) | 29.9 ± 3.4 | 30.0 ± 3.2 | .801 |
| Possible evidence | — | — | — | — |
| Any evidence | 331 (32.3) | 30.2 ± 3.2 | 29.9 ± 3.2 | .113 |
Women with any evidence of cervical insufficiency delivered, on average, >2.5 weeks earlier than those without any evidence of cervical insufficiency. Those with any evidence of decidual hemorrhage and those with any evidence of inflammation or infection also delivered significantly earlier (1.0 weeks and 0.7 weeks, respectively), compared with those without evidence of the phenotype ( Table 4 ). Women with strong evidence of decidual hemorrhage or cervical insufficiency delivered at the earliest gestational ages. For other phenotypes, women delivered later with the phenotype than without it. For example, those women with strong evidence of maternal comorbidities or familial phenotypes delivered between 0.5 and 0.8 weeks later than those who did not.
The distribution of phenotypes among women with very early SPTB (20.0-27.9 weeks’ gestation) and early SPTB (28.0-33.6 weeks’ gestation) were compared, and several differences were noted ( Table 5 ). Among women with very early SPTB, the distributions of phenotypes differed from the overall cohort. Although maternal stress remained the most common phenotype (60%) and was similar among gestational age epochs, infection/inflammation (47% vs 35%; P < .001) and decidual hemorrhage (39% vs 28%; P < .001), and cervical insufficiency (25% vs 7%; P < .001) were substantially more common among those with very early SPTB (all P ≤ .001; Table 5 ).
| Phenotype | Very early spontaneous preterm birth 20.0-27.9 wks’ gestation (n = 281), n (%) | Early spontaneous preterm birth 28.0-33.9 wks’ gestation (n = 744), n (%) | P value |
|---|---|---|---|
| Infection/inflammation | |||
| Strong evidence | 33 (11.7) | 53 (7.1) | .017 |
| Moderate evidence | 48 (17.1) | 50 (6.7) | < .001 |
| Possible evidence | 83 (29.5) | 189 (25.4) | .181 |
| Any evidence | 131 (46.6) | 257 (34.5) | < .001 |
| Decidual hemorrhage | |||
| Strong evidence | 3 (1.1) | 1 (0.13) | .033 |
| Moderate evidence | 50 (17.8) | 100 (13.4) | .079 |
| Possible evidence | 76 (27.1) | 126 (16.9) | < .001 |
| Any evidence | 109 (38.8) | 207 (27.8) | .001 |
| Maternal stress | |||
| Strong evidence | 8 (2.9) | 39 (5.2) | .102 |
| Moderate evidence | 80 (28.5) | 226 (30.4) | .552 |
| Possible evidence | 132 (47.0) | 290 (39.0) | .020 |
| Any evidence | 168 (59.8) | 412 (55.4) | .204 |
| Cervical insufficiency | |||
| Strong evidence | 49 (17.4) | 19 (2.6) | < .001 |
| Moderate evidence | 25 (8.9) | 26 (3.5) | < .001 |
| Possible evidence | 11 (3.9) | 11 (1.5) | .016 |
| Any evidence | 70 (24.9) | 49 (6.6) | < .001 |
| Uterine distension | |||
| Strong evidence | — | — | — |
| Moderate evidence | 49 (17.4) | 126 (16.9) | .849 |
| Possible evidence | 10 (3.6) | 33 (4.4) | .532 |
| Any evidence | 58 (20.6) | 154 (20.7) | .984 |
| Placental dysfunction | |||
| Strong evidence | 8 (2.9) | 31 (4.2) | .325 |
| Moderate evidence | 23 (8.2) | 61 (8.2) | .994 |
| Possible evidence | 14 (5.0) | 41 (5.5) | .738 |
| Any evidence | 33 (11.7) | 89 (12.0) | .923 |
| Preterm premature rupture of membranes | |||
| Strong evidence | 52 (18.5) | 159 (21.4) | .311 |
| Moderate evidence | 32 (11.4) | 109 (14.7) | .176 |
| Possible evidence | 14 (5.0) | 35 (4.7) | .852 |
| Any evidence | 86 (30.6) | 276 (37.1) | .052 |
| Maternal comorbidities | |||
| Strong evidence | 14 (5.0) | 73 (9.8) | .013 |
| Moderate evidence | 36 (12.8) | 146 (19.6) | .011 |
| Possible evidence | — | — | — |
| Any evidence | 46 (16.4) | 170 (22.9) | .023 |
| Familial | |||
| Strong evidence | 51 (18.2) | 176 (23.7) | .058 |
| Moderate evidence | 41 (14.6) | 102 (13.67) | .716 |
| Possible evidence | — | — | — |
| Any evidence | 84 (29.9) | 247 (33.2) | .313 |
| None of the above phenotypes | 8 (2.9) | 35 (4.7) | .186 |
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