Materials and Methods
The study was conducted from July 2011 through March 2014 at a single perinatal center. This study was approved by the Institutional Review Board at Saint Louis University. This was a prospective observational study in women with PPROM who consented to undergo TVCL measurement after admission.
Eligible women included nonlaboring patients, ages ≥16, with singleton gestation who presented with PPROM between the gestational age (GA) of 23 weeks 5 days–33 weeks 6 days. PPROM was diagnosed by history and physical examination, which included documentation of nitrazine- or fern-positive pooled vaginal fluid obtained by sterile speculum examination. In equivocal cases a placental alpha microgobulin-1 protein assay was performed from the vaginal fluid sample. GA was calculated from the first day of the last normal menstrual period and an ultrasound in early pregnancy when available. Women were excluded prior to enrollment for labor (defined as painful uterine contractions ≥12 in an hour and cervical dilation of >3 cm confirmed by digital examination), for being non-English speaking, or for having had >1 digital examination following PPROM. Following study enrollment women were excluded for a variety of reasons ( Figure 1 ).
All women were hospitalized and placed on modified bed rest. TVCL was performed within 72 hours of admission using the CLEAR guidelines. Measurements of the TVCL were taken after visualizing the endocervical canal in its entirety for 3-5 minutes, with an empty maternal bladder. Calipers were placed where the anterior and posterior walls of the cervix were sonographically opposed and the shortest technically best measurements were used. The presence of funneling was noted. AFI was recorded at the time of the TVCL measurement. Prophylactic antibiotics used included ampicillin 2 g intravenously every 6 hours and azithromycin 500 mg intravenously daily for 2 days, followed by oral amoxicillin 250 mg every 8 hours and azithromycin 500 mg daily for 5 days. Two doses of 12 mg betamethasone were given intramuscularly, 24 hours apart. Tocolysis was generally administered during transport. Additional digital examinations were prohibited without visual evidence of cervical change. Expectant management was followed until 34+ weeks’ gestation.
Our primary endpoint was a latency period within 7 days from performance of the TVCL at admission. To provide a more meaningful risk assessment for clinical purposes, TVCL and AFI were analyzed as dichotomous variables as ≤2.0 and >2.0 cm for TVCL, and ≤5 and >5 cm for AFI. Sensitivity, specificity, and predictive values were used to examine whether the presence of TVCL, AFI, or a combination of both characteristics affected the risk of delivery within 7 days.
Comparative analyses were undertaken to determine whether other variables affected latency. Demographic, medical, obstetrical, sonographic, and delivery variables were recorded such as GA at PPROM, history of PPROM or preterm delivery, tobacco and drug use, history of cervical procedures, visual cervical dilation at admission, presence of vaginal bleeding, digital examination performed prior to admission, and presence or absence of funneling at the TVCL assessment.
We based our preliminary sample size estimates on previously published PPROM data from Tsoi et al. In that study of women with a CL ≤2.0 cm, 76% delivered within 7 days compared to only 29% of women with a TVCL >2.0 cm. To detect a similar magnitude of difference with a power of 0.8, alpha <0.05, a sample size of at least 18 women per TVCL comparison groups were required.
Differences in demographic characteristics, medical/obstetrical history, and clinical/delivery characteristics were compared between women who delivered ≤7 days vs >7 days using χ 2 , Fisher exact test, and independent Students t test for continuous variables that were normally distributed. The nonparametric Kolmogorov-Smirnov test was used for continuous variables that were not normally distributed. Cox regression was used to compare the relationships of latency from PPROM to delivery and from CL to delivery. The independent predictability of statistically significant univariate characteristics on latency from initial TVCL was examined by multiple logistic regression. Sensitivity, specificity, and predictive value were calculated for TVCL (≤2.0 cm and >2.0 cm) and AFI (≤5.0 cm and >5.0 cm) in relation to the latency period of 7 days. Positive predictive value (PPV) was defined as the probability for delivery within 7 days from the TVCL. Negative predictive value (NPV) was defined as the probability of remaining pregnant >7 days. A P value < .05 was used to denote statistical significance. All analyses were performed using software (SPSS, Version 21.0; IBM Corp, Armonk, NY).
Results
In all, 129 singleton women with suspected PPROM consented for the study. Figure 1 illustrates the reasons for postconsent exclusions: 106 were included for final analysis.
Subjects were between 18-41 years of age, with approximately 90% of cases occurring <35 years. The body mass index (BMI) ranged between 19.6–64.8 kg/m 2 . All transported women had corticosteroids, tocolysis, and latency antibiotics initiated for transfer. Approximately one third of women had a single vaginal examination performed at the referring hospital prior to the TVCL assessment. A third of women had a closed cervix visualized on sterile speculum examination on admission. In all, 68 women (64%) had a TVCL performed within 1 day of PPROM, 92 (87%) within 2 days, and 103 (97%) within 3 days. The mean TVCL was 2.5 ± 1.3 cm (1 SD); 29% had a TVCL ≤1.5 cm and 19%, ≤1.0 cm. Of cases, 10% had anhydramnios at admission. Using a Cox regression we assessed latency interval from performance of the TVCL in relation to latency interval from PPROM. Accordingly there was no significant difference in delivery rates within 7 days of PPROM and 7 days of initial TVCL: 49/106 (46.2%) and 51/106 (48.1%), respectively.
The univariate relationships of demographic, medical, obstetrical, sonographic, and delivery variables for ≤7 days and >7 days of latency from the TVCL measurement are summarized in Tables 1-3 . CL and AFI were each significantly associated with delivery within 7 days. The median TVCL was significantly shorter and an AFI (≤5 cm) was significantly more frequent in women who delivered ≤7 days. A latent period ≤7 days was also significantly associated with a later GA at TVCL, prior preterm birth, prior PPROM, illicit drug use, and uterine contractions.
| Demographic | ≤7 d (n = 51) | >7 d (n = 55) | P value | ||
|---|---|---|---|---|---|
| Maternal age, y | 25.0 | (22.0–32.0) | 25.0 | (20.0–30.0) | 1.00 |
| Nulliparous | 25 | 49.0 | 24 | 43.6 | .58 |
| Race | |||||
| Caucasian | 26 | 51.0 | 33 | 60.0 | |
| African American | 23 | 45.1 | 21 | 38.2 | .58 |
| Other | 2 | 3.9 | 1 | 1.8 | |
| Body mass index, kg/m 2 | 29.3 | (24.5–33.8) | 27.8 | (23.3–35.2) | .21 |
| Smoking | 21 | 41.2 | 19 | 34.5 | .48 |
| Illicit drug use | 10 | 19.6 | 3 | 5.5 | < .05 |
| Insurance | |||||
| Private | 11 | 21.6 | 13 | 24.1 | .10 |
| Medicaid | 33 | 64.7 | 25 | 46.3 | |
| Self-pay | 7 | 13.7 | 16 | 29.6 | |
| Medical history | |||||
| Asthma | 10 | 19.6 | 5 | 9.1 | .12 |
| Obstetrical history | |||||
| Pregnancy with PPROM | 12 | 23.5 | 2 | 3.6 | < .01 |
| Preterm birth | 17 | 33.3 | 6 | 10.9 | < .01 |
| Cervical incompetence | 3 | 5.9 | 2 | 3.6 | .67 |
| LEEP or cone biopsy | 5 | 9.8 | 4 | 7.3 | .74 |
| Characteristic | ≤7 d (n = 51) | >7 d (n = 55) | P value | ||
|---|---|---|---|---|---|
| Maternal transports | 36 | 70.6 | 43 | 79.6 | .28 |
| Gestational age at PPROM, wk | 31.4 | (29.4–33.0) | 28.7 | (26.9–31.0) | < .001 |
| Gestational age at first cervical length, wk | 31.6 | (29.4–33.1) | 28.9 | (27.0–31.3) | < .001 |
| Duration from PPROM to first cervical length, d | 1.0 | (1.0–2.0) | 1.0 | (1.0–2.0) | 1.00 |
| Digital cervical examinations following PPROM | |||||
| 0 | 31 | 60.8 | 38 | 69.1 | .37 |
| 1 | 20 | 39.2 | 17 | 30.9 | |
| Cervical dilation at admission, cm | 1.0 | (0.0–2.0) | 1.0 | (0–1.0) | .21 |
| Vaginal bleeding prior to PPROM | 10 | 19.6 | 7 | 12.7 | .34 |
| Uterine contractions any time before PPROM | 18 | 35.3 | 10 | 18.2 | < .05 |
| Uterine contractions immediately before PPROM | 14 | 27.5 | 5 | 9.1 | < .05 |
| Uterine contractions after PPROM | 27 | 52.9 | 14 | 25.9 | < .01 |
| Positive group-B streptococcus culture | 12 | 24.0 | 15 | 27.3 | .70 |
| Positive gonococcus or chlamydia DNA | 2 | 3.9 | 3 | 5.6 | 1.00 |
| Cervical length, cm | 2.1 | (0.9–3.1) | 3.0 | (1.9–3.7) | < .01 |
| Amniotic fluid index, cm | 3.5 | (1.3–5.3) | 5.2 | (2.7–8.4) | < .05 |
| Funneling | 8 | 16.0 | 13 | 23.6 | .33 |
| Fetal presentation at first ultrasound | |||||
| Cephalic | 37 | 72.5 | 37 | 67.3 | .41 |
| Breech | 13 | 25.5 | 14 | 25.5 | |
| Transverse | 0 | 0.0 | 03 | 5.5 | |
| Funic | 1 | 2.0 | 1 | 1.8 | |
| Characteristic | ≤7 d (n = 51) | >7 d (n = 55) | P value | ||
|---|---|---|---|---|---|
| Gestational age at delivery, wk | 31.9 | (29.4–33.9) | 31.5 | (29.3–33.5) | .69 |
| Birthweight, g | 1685 | (1415–2116) | 1723 | (1348–2183) | .28 |
| Duration from PPROM to delivery, d | 4.0 | (3.0–6.0) | 16.0 | (11.0–22.3) | < .001 |
| Duration from first cervical length to delivery, d | 3.0 | (2.0–4.0) | 15.0 | (10.0–20.0) | < .001 |
| Cord prolapse after PPROM | 2 | 3.9 | 2 | 3.7 | 1.00 |
| Delivery | |||||
| Spontaneous delivery | 39 | 76.5 | 41 | 75.9 | |
| Indicated delivery | 9 | 17.6 | 6 | 11.1 | .34 |
| Induced for ≥34 wk | 3 | 5.9 | 7 | 13.0 | |
| Mode of delivery | |||||
| Vaginal | 33 | 64.7 | 32 | 59.3 | .57 |
| Cesarean | 18 | 35.3 | 22 | 40.7 | |
| Clinical chorioamnionitis | 8 | 15.7 | 12 | 22.7 | .39 |
| Histological chorioamnionitis | 31 | 70.5 | 37 | 80.4 | .27 |
| Funisitis | 17 | 38.6 | 25 | 54.3 | .14 |
| Endometritis | 1 | 2.0 | 3 | 5.0 | .62 |
Using significant variables from univariate analyses a stepwise multiple logistic regression model was performed ( Table 4 ).
| ≤7 d from initial cervical length | |||
|---|---|---|---|
| Characteristic | OR | 95% CI | P value |
| Prior pregnancy with PPROM | 10.62 | 1.84–61.45 | < .01 |
| Gestational age at cervical length, wk | 1.35 | 1.12–1.63 | < .01 |
| Uterine contractions after PPROM | 5.55 | 1.91–16.11 | < .01 |
| Cervical length, cm | 0.65 | 0.44–0.97 | < .05 |
| Amniotic fluid index (≤5 cm) | 4.69 | 1.58–13.93 | < .01 |
We examined screening parameters for TVCL and AFI as dichotomous variables for the prediction of the latent period of 1 week from TVCL ( Table 5 ). In all, 42 women (40%) had a TVCL ≤2 cm while 62 (59%) had an AFI ≤5 cm. Of 105 women, 26 (25%) had a combination of both TVCL ≤2 cm and AFI ≤5 cm, while 27 of 105 women (26%) had neither characteristic. Having a combination of low TVCL and low AFI did not increase the PPV of delivery within 7 days (58% for low TVCL/low AFI compared to either characteristic alone, 62% for low TVCL, and 58% for low AFI) ( Table 5 ). Only 3 of 27 women (11%) who had neither characteristic delivered within 7 days. The NPV overall for TVCL >2 cm was 61%. The NPV changed when TVCL >2 cm was analyzed together with an AFI ≤5 cm (42%) and AFI >5 cm (89%) ( Table 5 ).
| Variable | Sensitivity | Specificity | PPV | NPV |
|---|---|---|---|---|
| TVCL ≤2 vs >2 cm (n = 106) | 26/51 = 51% | 39/55 = 71% | 26/42 = 62% | 39/64 = 61% |
| AFI ≤5 vs >5 cm (n = 105) | 36/50 = 72% | 29/55 = 53% | 36/62 = 58% | 29/43 = 67% |
| TVCL <2 vs >2 cm in women with AFI ≤5 cm (n = 62) | 15/36 = 42% | 15/26 = 58% | 15/26 = 58% | 15/36 = 42% |
| TVCL <2 vs >2 cm in women with AFI >5 cm (n = 43) | 11/14 = 76% | 24/29 = 83% | 11/16 = 69% | 24/27 = 89% |
Tables 6 and 7 describe the analysis of these testing parameters stratified by a GA in women ≤30 and >30 weeks, respectively. Compared to the overall cohort the NPV of these tests were enhanced in women ≤30 weeks at PPROM. In women >30 weeks at PPROM the PPV of delivery within a week was enhanced. These findings further highlight the importance of GA as an independent risk factor for latency.
