Ultrasound Obstet Gynecol 2015; 45: 175–182 Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.14696
Cervical length in prediction of preterm birth after laser surgery for twin–twin transfusion syndrome R. PAPANNA*, L. K. MANN*, A. A. BASCHAT†, M. W. BEBBINGTON*, N. KHALEK‡, A. JOHNSON*, S. SNOWISE* and K. J. MOISE Jr* *Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, The Fetal Center at Children’s Memorial Hermann Hospital, UT Health - The University of Texas Medical School at Houston, TX, USA; †Center for Fetal Therapy, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA; ‡The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
K E Y W O R D S: cervical length; fetoscopy; laser photocoagulation; preterm delivery; twin–twin transfusion syndrome
ABSTRACT Objectives To determine the risk factors for spontaneous preterm delivery (PTD) or preterm prelabor rupture of membranes (PPROM) at < 34 weeks’ gestation after fetoscopic laser surgery for twin–twin transfusion syndrome and to identify the optimal threshold for preoperative cervical length (CL) that indicates a high risk for spontaneous PTD. Methods This was a secondary analysis of data prospectively collected from 449 patients at three fetal centers. CL measurements were obtained by preoperative transvaginal ultrasound, at a gestational age of 16–26 weeks. The risk factors associated with spontaneous PTD before 34 weeks’ gestation were determined using multivariable logistic regression analysis. We excluded patients with dual fetal demise and those with maternal or fetal indications for delivery without PPROM (n = 63). The optimal threshold for cervical length to predict spontaneous PTD before 34 weeks was determined using a receiver–operating characteristics (ROC) curve and Youden index. Additionally, the CL threshold for spontaneous PTD at 2-week intervals between 24 and 34 weeks was determined. Results Spontaneous PTD before 34 weeks occurred in 206 (53.4%) of the included patients. Only the preoperative CL was significantly associated with spontaneous PTD. The preoperative CL was normally distributed with a mean of 37.6 ± 10.3 mm (range, 5–66 mm). Maternal age and parity were positively associated, and gestational age at procedure and anterior placenta were negatively associated, with CL on multivariable linear regression analysis. The area under the ROC curve for predicting
spontaneous PTD with CL measurements was 0.61 (P = 0.02) and the optimal threshold was 28 mm with a Youden index of 0.19 (sensitivity and specificity of 92% and 27%, respectively). A CL measurement of < 28 mm increased the risk of spontaneous PTD for all gestational age thresholds. Conclusions Spontaneous PTD at < 34 weeks’ gestation is associated with a preoperative CL of < 28 mm. Preventive strategies should focus on this high-risk group. Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
INTRODUCTION Despite the success of fetoscopic laser surgery (FLS) for the treatment of severe twin–twin transfusion syndrome (TTTS), preterm delivery (PTD) with or without preterm prelabor rupture of membranes (PPROM) remains a major complication of this syndrome1 – 4 . The average gestational age at delivery ranges from 29 to 33 weeks, with wide variations between centers1,5 . Besides the obvious cost of caring for the premature infants, PTD is directly associated with long-term neurological deficits in TTTS4,6 , thus undermining the benefits of laser treatment. Among the known risk factors that have been associated with preterm delivery, cervical shortening is one2,7 – 10 . However, the nature of the association between cervical length (CL) and spontaneous PTD, and hence the threshold at which risk increases in cases of TTTS undergoing FLS, are still unknown. An understanding of this gap in our knowledge would help in developing preventive strategies that could be clinically tested.
Correspondence to: Dr R. Papanna, Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology & Reproductive Sciences, The University of Texas Medical School at Houston, 6431 Fannin St., Suite 3.274, Houston, TX 77030, USA (e-mail: [email protected]) Accepted: 4 October 2014
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ORIGINAL PAPER
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Additionally, factors that are associated with CL shortening are unknown. The rapid development of polyhydramnios in the recipient fetus increases intrauterine pressure and hence the stress on the cervix. However, the effects of polyhydramnios and maternal demographics on the distribution of CL at FLS remain unknown. The objectives of this study were (1) to determine the frequency distribution of preoperative CL and (2) to identify the threshold CL associated with an increased risk of spontaneous PTD before 34 weeks’ gestation.
SUBJECTS AND METHODS This was a secondary analysis of prospectively collected data from a consecutively enrolled cohort of patients who underwent FLS for TTTS at one of three fetal centers in the USA: University of Texas Medical School in Houston, TX; Children’s Hospital of Philadelphia in Philadelphia, PA; and the University of Maryland in Baltimore, MD. The study protocol was approved by the institutional review board (HSC-MS-10-0059) at the University of Texas Medical School at Houston and was subsequently approved in the other institutions. Data were obtained between October 2011 and December 2013 at the University of Texas Medical School, between April 2006 and December 2012 at the children’s Hospital of Philadelphia and between May 2007 and December 2012 at the University of Maryland. Briefly, patients with TTTS who were referred to the respective fetal center underwent a comprehensive ultrasound examination, including Doppler studies for diagnosis and staging based on the Quintero system11 . The preoperative CL of patients was measured using transvaginal ultrasound, with an empty urinary bladder, by an experienced sonographer. The CL was measured between the internal os and the external os, with complete visualization of the cervical canal. In the event of funneling, with or without fundal pressure, the point at which the amniotic sac ends in the cervical canal was used as the upper point of the CL measurement. Fetoscopic laser ablation was performed through a single port under local anesthetic in conjunction with intravenous sedation, or regional or general anesthesia. The placental vascular equator was identified and a diode laser was used to ablate all vascular anastomoses using a selective sequential method, with additional equatorial dichorionization – i.e. the ‘Solomon technique’ – if technically feasible. When needed, amnioinfusion, using lactated Ringer’s solution with nafcillin 1 g/L, was performed to improve visualization during fetoscopy. At the end of the procedure, placement of a collagen plug was at the discretion of the surgeon12 . Chorioamniotic separation was checked for on the day following surgery using ultrasound. All patients returned to their referring physicians for follow-up for the remainder of their pregnancy. Information regarding the patients’ pregnancy outcomes was collected prospectively through direct patient contact or from their referring physicians. Exclusion criteria for the cohort included triplet gestations and cases of selective reduction due to a
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
failed laser attempt. Additionally, we excluded patients who delivered before 34 weeks’ gestation owing to dual fetal demise, or in whom there were maternal or fetal indications for delivery without PPROM. The following preoperative variables were collected: maternal demographics (age, parity, history of previous PTD, smoking), staging of TTTS using Quintero criteria and CL (measured transvaginally). Operative variables included type of anesthesia, cannula diameter for the trocar entry, entry method (Seldinger’s13 vs direct entry with a sharp trocar) and volume of amnioinfusion. Postoperative variables included PPROM, defined as rupture of the membranes before 34 weeks’ gestation with clinical confirmation of pooling, ferning and/or a positive nitrazine test. The diagnosis of spontaneous PTD was determined based on the presence of active contractions with dilation of the cervix, as assessed by the delivering physician. This diagnosis was further verified by a maternal–fetal medicine specialist at each treatment center (R.P., M.W.B. or A.B.). The primary outcome was spontaneous PTD before 34 weeks’ gestation due to spontaneous preterm labor or PPROM. The University of Texas Medical School at Houston did not offer fetoscopic laser surgery to patients with a CL < 10 mm. The University of Maryland at Baltimore used a CL cut-off of < 5 mm and the Children’s Hospital of Philadelphia used a CL cut-off of < 20 mm for not offering treatment.
Statistical analysis Results are reported as mean ± SD or median (range). Data were compared using an unpaired t-test for normally distributed data and the Mann–Whitney U-test (non-parametric) for non-normally distributed data. Categorical data were compared using chi-square analysis or Fisher’s exact test. The baseline CL distribution was examined using a histogram and normality testing was performed using the Shapiro–Wilk normality test. Multivariable linear regression was performed to find the preoperative factors affecting CL. Multivariable logistic regression analysis was performed to predict the occurrence of the primary outcome using the preoperative and operative variables maternal age, gravidity, parity, history of PTD, body mass index, gestational age at procedure, CL, fetal weight discordance, stage of TTTS, cannula diameter, amnioinfusion, cervical cerclage, trocar entry type, Solomon procedure and collagen plug placement. On a subgroup analysis, the same risk factors were tested for predicting spontaneous PTD at < 24 weeks’, < 26 weeks’, < 28 weeks’, < 30 weeks’ and < 32 weeks’ gestation. Receiver–operating characteristics (ROC) curves were plotted to identify an optimal CL threshold for predicting spontaneous PTD at < 34 weeks’ gestation. In addition, the Youden index (J), was calculated to measure the overall diagnostic effectiveness. J is the maximum vertical distance or the difference between the ROC curve and the diagonal or chance line. It occurs at the cut-off that optimizes the predicting variable’s
Ultrasound Obstet Gynecol 2015; 45: 175–182.
Cervical length in TTTS differentiating ability when equal weight is given to sensitivity and specificity, and is calculated using the formula J = sensitivity + specificity – 114 . Statistical analysis was performed using STATA 12.1 statistical software (StataCorp., College Station, TX, USA), and P < 0.05 was considered to be statistically significant. Additionally, the STARD checklist for diagnostic accuracy studies was used (Table S1).
RESULTS A total of 449 patients were included in the cohort from three centers during the study period: the Children’s Hospital of Philadelphia, 211 patients; the University of Texas at Houston, 143 patients; and University of Maryland, 95 patients. The demographics of the cohort are illustrated in Table 1. The preoperative CL was normally distributed in all three centers (Figure 1). The preoperative factors that were associated with an increasing CL were maternal age and parity. The factors that were associated with a decreasing CL were increasing gestational age at procedure and anterior placenta (Table 2). The recipient maximum vertical pocket was not associated with CL. Of the 449 patients, 63 delivered before 34 weeks’ gestation owing to dual fetal demise or maternal/fetal indications without PPROM and were excluded from the subsequent analysis. Among the remaining 386 patients, spontaneous PTD at < 34 weeks occurred in 206 (53.4%) patients. The results from univariable analysis of the relevant clinical factors are presented in Table 3. Factors significantly associated with spontaneous PTD < 34 weeks were body mass index, CL, stage of TTTS, anterior placenta, cannula diameter, Solomon technique, collagen plug placement and amnioinfusion. Factors that were significant (P < 0.2) were included in the multivariable analysis. Multivariable logistic regression showed that only CL was a significant risk factor for spontaneous PTD at < 34 weeks’ gestation, with an odds ratio of 0.96 (95% CI, 0.94–0.98) (P < 0.0001). There were significant differences in the clinical outcomes based on spontaneous PTD at < 34 weeks, including PPROM, live birth and survival to the neonatal period (Table 3). The area under the ROC curve for predicting spontaneous PTD at < 34 weeks by CL measurements was 0.61 (P = 0.02) and the optimal threshold for CL, based on the highest Youden’s J statistic of 0.19, was 28 mm. The sensitivity, specificity, positive likelihood ratio and negative likelihood ratio for this cut-off were 92%, 27%, 3.76 and 0.78, respectively. The positive predictive and negative predictive values were 81% and 53%, respectively. The differences in clinical outcome, based on a CL cut-off of < 28 mm, are illustrated in Table 4. Gestational age at delivery was lower by 3 weeks (P < 0.0001) and the procedure-to-delivery interval was shorter by 27 days, in those with a CL < 28 mm (P < 0.0001), than in those with a CL of ≥ 28 mm. Both live-birth and neonatal-survival rates were lower in those with a CL of < 28 mm (P < 0.01). Kaplan–Meier survival analysis
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
177 Table 1 Demographics of 449 patients with twin–twin transfusion syndrome (TTTS) referred to one of three fetal centers in the USA for fetoscopic laser surgery (FLS) Characteristic
Distribution
Maternal age (years) Gravidity Parity Prior history of preterm delivery Body mass index (kg/m2 ) Gestational age at FLS (weeks) Growth discordance (%) Anterior placenta Cerclage placement TTTS stage I II III IV Maximum vertical pocket (cm) Preoperative Postoperative Cannula outer diameter 9 Fr 10 Fr 12 Fr Amnioreduction (mL) Number undergoing amnioinfusion Volume infused (mL) PPROM (< 34 weeks’ gestation) Gestational age at delivery (weeks) Spontaneous preterm birth Live births per pregnancy 0 1 2 Birth weight (g) Donor Recipient
29.5 ± 6.2 2 (1–8) 1 (0–6) 23 (5.1) 24.5 ± 7.6 20.7 ± 2.2 24 ± 14 185 (41.2) 6 (1.3) 31 (6.9) 191(42.5) 202 (45.0) 25 (5.6) 9.6 ± 5.8 7.5 ± 1.9 13 (2.9) 310 (69.0) 126 (28.1) 1567 ± 851 1500 (0–4600) 165 (36.7) 762 ± 679 145 (32.3) 31.9 ± 4.7 200 (44.5) 32 (7.1) 83 (18.5) 334 (74.4) 1588 ± 731 1853 ± 757
Data are shown as n (%), mean ± SD or median (range). PPROM, preterm prelabor rupture of membranes.
showed a significant difference in gestational age at delivery in those with a CL cut-off of < 28 mm compared with those with a CL of ≥ 28 mm (P < 0.001; Figure 2). The risk factors that were associated with spontaneous PTD at < 24, < 26, < 28 and < 30 weeks’ gestation were preoperative CL and a previous spontaneous PTD. For a spontaneous PTD at < 32 weeks, only CL was significantly associated. Data pertaining to the ROC curves and the corresponding Youden indices are presented in the Table 5. The Youden index was highest for those with PTD before 28 weeks, with a value of 0.30. The optimal cut-off for CL to predict spontaneous PTD was < 25 mm, with a sensitivity of 74.3% and specificity of 55.4%. The relationship between different CL cut-offs and their association with different gestational ages at delivery is presented in Table 6. Women with a CL of < 15 mm had a 25.0% chance, or a relative risk of 4.1, of a spontaneous PTD before 24 weeks’ gestation. A CL < 25 mm had a 32.7% chance, or relative risk of 3.4, of delivery before 28 weeks. The change in relative risk for spontaneous PTD at various gestational ages, with different CL cut-offs, was minimal, ranging from 1.4 to 4.1.
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Papanna et al. (a) 15
(b) 15
Frequency (%)
Frequency (%)
178
10 5 0
0
20
40
10 5 0
60
0
(c) 15
(d) 15 Frequency (%)
10 5 0
0
20
20
40
60
Cervical length (mm)
Frequency (%)
Cervical length (mm)
40
60
Cervical length (mm)
10 5 0
0
20
40
60
Cervical length (mm)
Figure 1 Frequency distribution of preoperative cervical length measurements in 449 women with twin–twin transfusion syndrome before fetoscopic laser surgery, from three fetal centers in the USA: (a) Children’s Hospital, Philadelphia (n = 211), (b) University of Maryland, Baltimore (n = 95) and (c) University of Texas, Houston (n = 143). (d) Frequency distribution for all 449 women. Solid lines represent fitted normal distribution curves for cervical length. Table 2 Multivariable linear regression analysis of risk factors for predicting preoperative cervical length in 449 women with twin–twin transfusion syndrome (TTTS) Covariate Constant Maternal age (years) Gravidity Parity Prior premature birth BMI (kg/m2 ) GA at procedure (weeks) Anterior placenta TTTS stage Fetal weight discordance Recipient MVP (cm)
Coefficient
P
48.8 0.24 −0.5 1.57 1.7 −0.08 −0.11 −2.9 −0.55 0.05 −0.007
< 0.0001* 0.004* 0.28 0.03* 0.4 0.22 0.001* 0.004* 0.435 0.17 0.93
*P < 0.05. BMI, body mass index; GA, gestational age; MVP, maximum vertical pocket.
Seven patients in the cohort had cervical cerclage. The CL measurements of these individual patients were 5, 10, 13, 15, 17, 19 and 24 mm. The median gestational age at delivery and procedure-to-delivery interval were 32.5 (range, 25.1–37.3) weeks and 85 (range, 45–119) days, respectively. There were only two patients with a CL of ≤ 10 mm (5 mm and 10 mm). Both had cervical cerclage placement during the FLS. In both cases, the pregnancies were complicated by PPROM and delivered at 34 weeks. Need for cerclage was not significantly associated with gestational age at delivery on multivariate analysis.
DISCUSSION This is a large study that evaluated the association between CL and the onset of spontaneous PTD or PPROM, after FLS. The main findings of the study are: (1) preoperative
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
CL in TTTS is normally distributed; (2) maternal age and parity are positively associated, and gestational age at procedure and anterior placenta are negatively associated, with CL; (3) the risk of spontaneous PTD before 34 weeks’ gestation is highest for a CL cut-off of < 28 mm; (4) a preoperative CL of < 28 mm reduces the pregnancy latency by approximately 3 weeks; and (5) the risk of spontaneous PTD before 24 weeks, at the threshold of viability, was highest for those with a CL of < 15 mm, although this was noted in only 3% of the treated TTTS cases in the cohort. The distribution of CL in our cohort was normal, with a mean ± SD of 38 ± 10 mm, similar to previously published data from uncomplicated twin gestations (mean CL, 32.3 ± 8.9 mm)15 – 17 . This was an unexpected finding, as we had anticipated a shorter mean CL and positively skewed distribution in the TTTS cohort. This was confirmed by the absence of a significant relationship between the maximum vertical pocket and CL. The relationship between CL and presence of anterior placenta was surprising and we do not have an explanation. The relative risk of spontaneous PTD at < 32 or < 34 weeks in those with a CL of < 25 mm was much lower (1.4–1.8 ×) after laser surgery for TTTS when compared with the relative risk of 6.9 for uncomplicated twin gestations16,17 . This suggests that pregnancies undergoing FLS are already at a higher risk for preterm birth, and CL is less relevant than in uncomplicated twin gestations. Our findings are similar to those previously published by Robyr et al.2 , who identified a short cervix as one of the risk factors associated with spontaneous PTD at < 34 weeks’ gestation. In addition, their study noted that parity increased the risk, and intrauterine demise of one fetus decreased the risk. The CL cut-off that was identified in our study was < 28 mm, whereas Robyr
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Table 3 Multivariable logistic regression analysis to determine factors associated with spontaneous preterm delivery (sPTD) before 34 weeks’ gestation and the difference in clinical outcomes of 386 women with twin–twin transfusion syndrome (TTTS), referred for fetoscopic laser surgery
Parameter Maternal age (years) Gravidity Parity Prior sPTD BMI (kg/m2 ) GA at procedure (weeks) Growth discordance (%) Cervical length (mm) TTTS stage I II III IV Anterior placenta Recipient MVP (mm) Cannula gauge 9 Fr 10 Fr 12 Fr Direct trocar entry Solomon technique Collagen plug placed Amnioinfusion Amnioreduction (mL) Clinical outcome PPROM Live births per pregnancy 0 1 2 Neonatal survivors 0 1 2
sPTD < 34 weeks (n = 206)
sPTD ≥ 34 weeks (n = 180)
29.4 ± 5.9 2 (1–7) 2 (0–4) 12 (5.8) 25 ± 7 20.8 ± 2.2 23.2 ± 14.4 35.4 ± 11.2
29.8 ± 6.3 2 (1–8) 2 (0–6) 7 (3.9) 24 ± 8 20.7 ± 2.1 24 ± 12.9 39.6 ± 9
11 (5.3) 79 (38.3) 103 (50.0) 13 (6.3) 93 (45.1) 10.6 ± 3.5
12 (6.7) 93 (51.7) 66 (36.7) 9 (5.0) 65 (36.1) 10.9 ± 3.4
3 (1.5) 133 (64.6) 70 (34.0) 79 (38.3) 106 (51.5) 36 (17.5) 84 (40.8) 1539 ± 893
7 (3.9) 133 (73.9) 40 (22.2) 62 (34.4) 73 (40.6) 20 (11.1) 57 (31.7) 1602 ± 831
133 (64.6)
12 (6.7)
23 (11.2) 42 (20.4) 141 (68.4)
1 (0.6) 36 (20.0) 143 (79.4)
35 (17.0) 40 (19.4) 131 (63.6)
1 (0.6) 36 (20.0) 143 (79.4)
Multivariable logistic regression: odds ratio (95% CI)
P 0.53 0.6 0.7 0.38 0.1* 0.89 0.61 0.0001* 0.05*
0.07* 0.41 0.018*
— — — — 1.00 (0.98–1.04) — — 0.96 (0.94–0.98) 1 1.05 (0.4–2.7) 1.9 (0.74–4.8) 1.5 (0.4–5.4) 1.1 (0.7–1.8) — 1 3.5 (0.7–18) 4.3 (0.75–24.9) — 1.28 (0.7–2.3) 0.94 (0.45–1.97) 1.1 (0.6–1.9) —
0.37 0.05* 0.08* 0.07* 0.48 < 0.0001* < 0.0001*
< 0.0001*
Data are given as mean ± SD, median (range) or n (%). *Only factors with P < 0.2 were included in multivariable logistic regression. BMI, body mass index; Fr, French scale; GA, gestational age; MVP, maximum vertical pocket; PPROM, preterm prelabor rupture of membranes < 34 weeks’ gestation. Table 4 Differences in clinical outcome according to a preoperative cervical length (CL) cut-off of 28 mm in 386 women with twin–twin transfusion syndrome referred for fetoscopic laser surgery Parameter Maternal age (years) BMI (kg/m2 ) GA at procedure (weeks) Recipient preoperative MVP (cm) Recipient postoperative MVP (cm) PPROM GA at delivery (weeks) Procedure-to-delivery interval (days) Live births per pregnancy 0 1 2 Neonatal survivors 0 1 2
CL < 28 mm (n = 69)
CL ≥ 28 mm (n = 317)
P
27.5 ± 6 25.7 ± 6.4 21.2 ± 2.3 11.5 ± 3.5 7.2 ± 1.8 35 (50.7) 29.5 ± 5 58 ± 35.3
30 ± 6 24 ± 7.7 20.7 ± 2.1 10.6 ± 3.4 7 ± 2.1 110 (34.7) 32.8 ± 4.5 85 ± 34.6
< 0.01 0.12 0.05 0.05 0.67 0.01 < 0.0001 < 0.0001 0.003
10 (14.5) 17 (24.6) 42 (60.9)
14 (4.4) 61 (19.2) 242 (76.3)
12 (17.4) 17 (24.6) 40 (58.0)
24 (7.6) 59 (18.6) 234 (73.8)
0.005
Data are given as n (%), mean ± SD or median (range). BMI, body mass index; GA, gestational age; MVP, maximum vertical pocket; PPROM, preterm prelabor rupture of membranes.
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Proportion of ongoing pregnancies (%)
100 75 50 25
10
0
20
30
34 weeks
40
Gestational age at delivery (weeks)
Figure 2 Kaplan–Meier survival plot showing difference in gestational age at spontaneous preterm delivery (PTD) in 386 cases of twin–twin transfusion syndrome for those with a cervical length ) and those with a CL ≥ 28 mm ( ) (CL) < 28 mm ( (P < 0.001). 34 weeks is the optimal threshold of CL for predicting spontaneous PTD.
et al.2 described a cut-off of 30 mm. The key differences between the study of Robyr et al. and ours are the larger sample size and our use of ROC curves to determine the optimal cut-off of CL for predicting spontaneous PTD at different gestational ages, including 24, 26, 28, 30 and 32 weeks. In our study, parity was not identified as a significant risk factor. However, a previous history of spontaneous PTD was a significant risk factor, which is consistent with the results of other studies in singleton and uncomplicated twin pregnancies18 – 20 . Chavira et al.7 have also shown that a short cervix is associated with an increased risk for early delivery but categorized the CL arbitrarily. In the study, eight out of 10 patients had cervical cerclage for a CL of < 15 mm. Additionally, the study did not evaluate other potential risk factors and did not specifically include spontaneous PTD as an outcome variable. In our previous study, CL was identified as one of the significant factors associated with gestational age at delivery10 . However, in the present study we did not limit our outcome to spontaneous PTD. Chmait et al.21 identified a short cervix as a risk factor for delivery within 21 days after surgery. However, they did not exclude dual fetal demise and scheduled preterm deliveries.
We had only seven patients who required cervical cerclage, which is an insufficient sample size in which to evaluate the effect on spontaneous PTD. However, our previous study of cerclage for a short cervix found no overall effect on gestational age at delivery22 . Additionally, removal of these patients from the analysis did not affect the outcomes. A possible benefit to cerclage was noted, however, when the CL was 15–20 mm. There are several strengths to our study. The sample size was large enough to study the effect of most relevant risk factors in a regression model. The data were prospectively collected in three different centers, thereby reducing recollection bias. However, there are also some limitations. The cohort did not have enough patients to examine the effect of a CL of < 10 mm owing to the systematic exclusion of these women from laser treatment by the respective centers. Although such exclusions were few in number, we have not systematically followed up these patients to report the findings. This high-risk group needs further prospective study. Exclusion of cases with a CL of < 10 mm should not affect our finding the optimal threshold, as it statistically adjusts for the increasing risk with changes in CL. Additionally, intraoperative complications such as iatrogenic septostomy, intra-amniotic bleeding, chorioamniotic separation and acute demise of one of the fetuses were not consistently documented to allow for their inclusion in the analysis. Some of these factors have been associated with an earlier gestational age at delivery8,21,23 . Inclusion of these factors may have improved the predictive capabilities. Measurement of CL in TTTS remains an important criterion to indicate transfer to a tertiary care center and to offer FLS. Based on the findings from this study, a short cervix increases the risk of spontaneous PTD. However, there is no clear threshold at which laser treatment should be considered futile owing to concerns about a previable delivery. Further studies are needed to evaluate the effect of a CL of < 10 mm on the risk of spontaneous PTD. Despite CL being a significant predictor, there appear to be other unknown factors that play a role in the early onset of preterm labor that need to be investigated. Preventive strategies in women with a short cervix that need to
Table 5 Risk factors and optimal cervical length (CL) cut-off for prediction of spontaneous preterm delivery (sPTD) or preterm prelabor rupture of membranes (PPROM), for different gestational age cut-offs, in 449 women with twin–twin transfusion syndrome GA at delivery (weeks) < 24 < 26 < 28 < 30 < 32 < 34
CL as a measure for predicting PTD
Significant risk factors* Odds ratio (95% CI) n/N
CL
Prior sPTD
AUC
P
Youden index
Optimal CL cut-off (mm)
Sensitivity (%)
Specificity (%)
29/442 40/436 56/429 97/419 147/410 209/386
0.96 (0.92–0.99) 0.95 (0.92–0.98) 0.94 (0.91–0.97) 0.96 (0.94–0.99) 0.96 (0.94–0.99) 0.96 (0.94–0.98)
3.4 (1.09–10.7) 3.4 (1.2–9.7) 2.97 (1.1–7.9) 3.15 (1.3–7.6) — —
0.62 0.64 0.67 0.61 0.60 0.61
0.05 0.04 0.04 0.03 0.03 0.02
0.23 0.27 0.30 0.23 0.19 0.19
25 25 25 24 26 28
71 73 74 77 90 92
51 55 55 43 29 27
*Factors found on multivariable logistic regression analysis including CL in mm, prior sPTD, body mass index, anterior placenta, cannula diameter, amnioinfusion, Solomon technique and collagen plug placement. AUC, area under receiver–operativing characteristics curve; GA, gestational age.
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Ultrasound Obstet Gynecol 2015; 45: 175–182.
Data are given as n (%) and relative risk (RR) (95% CI) for those that are statistically significant. Fisher’s exact test or Pearson χ2 used to compare each cell with rest of cohort. *P < 0.05. †P < 0.01. ‡P < 0.001. §RR ≥ 3.
— 1.8 (1.4–2.2) 1.8 (1.4–2.2) 1.7 (1.3–2.0) 1.4 (1.2–1.8) 9 (75.0) 22 (78.6)‡ 42 (76.4)‡ 56 (67.5)‡ 85 (54.8)‡ — 1.6 (1.1–2.3) 1.9 (1.5–2.5) 1.8 (1.4–2.8) 1.6 (1.3–2.1) 6 (50.0) 15 (53.6)* 32 (58.2)‡ 44 (53.0)‡ 68 (43.9)† < 15 < 20 < 25 < 30 < 35
12 (2.7) 28 (6.2) 55 (12.2) 83 (18.5) 155 (34.5)
3 (25.0)* 4.1 (1.4–11.8)§ 3 (25.0) 4 (14.3) — 6 (21.4)* 7 (12.7) — 10 (18.2)* 9 (10.8) — 14 (16.9)† 15 (9.7)* 2.1 (1.0–4.2) 23 (14.8)†
— 2.6 (1.2–5.6) 2.3 (1.2–4.5) 2.2 (1.3–4.2) 2.7 (1.5–4.8)
4 (33.3)* 9 (32.1)† 18 (32.7)‡ 23 (27.7)† 33 (21.3)‡
2.6 (1.2–6.2) 2.9 (1.6–5.2) 3.4 (2.1–5.4)§ 3.0 (1.9–4.9)§ 2.7 (1.7–4.5)
6 (50.0)* 11 (39.3)* 25 (45.5)‡ 32 (38.6)‡ 46 (29.7)†
2.0 (1.2–4.1) 1.9 (1.3–3.0) 2.4 (1.7–3.4) 2.1 (1.5–2.9) 1.8 (1.2–2.5)
n (%) n (%)
RR (95% CI)
RR (95% CI)
181
RR (95% CI) n (%) RR (95% CI) n (%) RR (95% CI) n (%) RR (95% CI) n (%) n (%) CL (mm)
< 34 weeks < 32 weeks < 30 weeks < 28 weeks < 26 weeks < 24 weeks
Gestational age at delivery
Table 6 Performance of cervical length (CL) cut-offs to predict spontaneous preterm delivery (sPTD) or preterm prelabor rupture of membranes (PPROM) at various gestational age (GA) cut-offs among 449 women with twin–twin transfusion syndrome
Cervical length in TTTS
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
be investigated include Arabin pessary24 , progesterone supplementation and cervical cerclage. In conclusion, CL is normally distributed in women undergoing laser surgery for TTTS and remains the most significant factor associated with spontaneous PTD. A CL of < 28 mm is the threshold for an increased risk, and preventive strategies should target this group of patients. Other pathophysiological processes involved in the onset of preterm labor in TTTS need to be investigated.
ACKNOWLEDGMENTS We would like to thank Karen Moise, Elisa Garcia and Noemi Boring at the Texas Fetal Center for data collection. This study was presented as an abstract at the Society for Gynecological Investigation at Florence, Italy on March 2014 and was also presented at the International Fetal Medicine and Surgery Society Conference on September 7–11, Cape Cod, MA, USA.
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SUPPORTING INFORMATION ON THE INTERNET The following supporting information may be found in the online version of this article: Table S1 STARD checklist for reporting of studies of diagnostic accuracy (version January 2003)
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Cervical length in prediction of preterm birth after laser surgery for twin–twin transfusion syndrome R. PAPANNA*, L. K. MANN*, A. A. BASCHAT†, M. W. BEBBINGTON*, N. KHALEK‡, A. JOHNSON*, S. SNOWISE* and K. J. MOISE Jr* *Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, The Fetal Center at Children’s Memorial Hermann Hospital, UT Health - The University of Texas Medical School at Houston, TX, USA; †Center for Fetal Therapy, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA; ‡The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
K E Y W O R D S: cervical length; fetoscopy; laser photocoagulation; preterm delivery; twin–twin transfusion syndrome
ABSTRACT Objectives To determine the risk factors for spontaneous preterm delivery (PTD) or preterm prelabor rupture of membranes (PPROM) at < 34 weeks’ gestation after fetoscopic laser surgery for twin–twin transfusion syndrome and to identify the optimal threshold for preoperative cervical length (CL) that indicates a high risk for spontaneous PTD. Methods This was a secondary analysis of data prospectively collected from 449 patients at three fetal centers. CL measurements were obtained by preoperative transvaginal ultrasound, at a gestational age of 16–26 weeks. The risk factors associated with spontaneous PTD before 34 weeks’ gestation were determined using multivariable logistic regression analysis. We excluded patients with dual fetal demise and those with maternal or fetal indications for delivery without PPROM (n = 63). The optimal threshold for cervical length to predict spontaneous PTD before 34 weeks was determined using a receiver–operating characteristics (ROC) curve and Youden index. Additionally, the CL threshold for spontaneous PTD at 2-week intervals between 24 and 34 weeks was determined. Results Spontaneous PTD before 34 weeks occurred in 206 (53.4%) of the included patients. Only the preoperative CL was significantly associated with spontaneous PTD. The preoperative CL was normally distributed with a mean of 37.6 ± 10.3 mm (range, 5–66 mm). Maternal age and parity were positively associated, and gestational age at procedure and anterior placenta were negatively associated, with CL on multivariable linear regression analysis. The area under the ROC curve for predicting
spontaneous PTD with CL measurements was 0.61 (P = 0.02) and the optimal threshold was 28 mm with a Youden index of 0.19 (sensitivity and specificity of 92% and 27%, respectively). A CL measurement of < 28 mm increased the risk of spontaneous PTD for all gestational age thresholds. Conclusions Spontaneous PTD at < 34 weeks’ gestation is associated with a preoperative CL of < 28 mm. Preventive strategies should focus on this high-risk group. Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
INTRODUCTION Despite the success of fetoscopic laser surgery (FLS) for the treatment of severe twin–twin transfusion syndrome (TTTS), preterm delivery (PTD) with or without preterm prelabor rupture of membranes (PPROM) remains a major complication of this syndrome1 – 4 . The average gestational age at delivery ranges from 29 to 33 weeks, with wide variations between centers1,5 . Besides the obvious cost of caring for the premature infants, PTD is directly associated with long-term neurological deficits in TTTS4,6 , thus undermining the benefits of laser treatment. Among the known risk factors that have been associated with preterm delivery, cervical shortening is one2,7 – 10 . However, the nature of the association between cervical length (CL) and spontaneous PTD, and hence the threshold at which risk increases in cases of TTTS undergoing FLS, are still unknown. An understanding of this gap in our knowledge would help in developing preventive strategies that could be clinically tested.
Correspondence to: Dr R. Papanna, Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology & Reproductive Sciences, The University of Texas Medical School at Houston, 6431 Fannin St., Suite 3.274, Houston, TX 77030, USA (e-mail: [email protected]) Accepted: 4 October 2014
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ORIGINAL PAPER
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Additionally, factors that are associated with CL shortening are unknown. The rapid development of polyhydramnios in the recipient fetus increases intrauterine pressure and hence the stress on the cervix. However, the effects of polyhydramnios and maternal demographics on the distribution of CL at FLS remain unknown. The objectives of this study were (1) to determine the frequency distribution of preoperative CL and (2) to identify the threshold CL associated with an increased risk of spontaneous PTD before 34 weeks’ gestation.
SUBJECTS AND METHODS This was a secondary analysis of prospectively collected data from a consecutively enrolled cohort of patients who underwent FLS for TTTS at one of three fetal centers in the USA: University of Texas Medical School in Houston, TX; Children’s Hospital of Philadelphia in Philadelphia, PA; and the University of Maryland in Baltimore, MD. The study protocol was approved by the institutional review board (HSC-MS-10-0059) at the University of Texas Medical School at Houston and was subsequently approved in the other institutions. Data were obtained between October 2011 and December 2013 at the University of Texas Medical School, between April 2006 and December 2012 at the children’s Hospital of Philadelphia and between May 2007 and December 2012 at the University of Maryland. Briefly, patients with TTTS who were referred to the respective fetal center underwent a comprehensive ultrasound examination, including Doppler studies for diagnosis and staging based on the Quintero system11 . The preoperative CL of patients was measured using transvaginal ultrasound, with an empty urinary bladder, by an experienced sonographer. The CL was measured between the internal os and the external os, with complete visualization of the cervical canal. In the event of funneling, with or without fundal pressure, the point at which the amniotic sac ends in the cervical canal was used as the upper point of the CL measurement. Fetoscopic laser ablation was performed through a single port under local anesthetic in conjunction with intravenous sedation, or regional or general anesthesia. The placental vascular equator was identified and a diode laser was used to ablate all vascular anastomoses using a selective sequential method, with additional equatorial dichorionization – i.e. the ‘Solomon technique’ – if technically feasible. When needed, amnioinfusion, using lactated Ringer’s solution with nafcillin 1 g/L, was performed to improve visualization during fetoscopy. At the end of the procedure, placement of a collagen plug was at the discretion of the surgeon12 . Chorioamniotic separation was checked for on the day following surgery using ultrasound. All patients returned to their referring physicians for follow-up for the remainder of their pregnancy. Information regarding the patients’ pregnancy outcomes was collected prospectively through direct patient contact or from their referring physicians. Exclusion criteria for the cohort included triplet gestations and cases of selective reduction due to a
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
failed laser attempt. Additionally, we excluded patients who delivered before 34 weeks’ gestation owing to dual fetal demise, or in whom there were maternal or fetal indications for delivery without PPROM. The following preoperative variables were collected: maternal demographics (age, parity, history of previous PTD, smoking), staging of TTTS using Quintero criteria and CL (measured transvaginally). Operative variables included type of anesthesia, cannula diameter for the trocar entry, entry method (Seldinger’s13 vs direct entry with a sharp trocar) and volume of amnioinfusion. Postoperative variables included PPROM, defined as rupture of the membranes before 34 weeks’ gestation with clinical confirmation of pooling, ferning and/or a positive nitrazine test. The diagnosis of spontaneous PTD was determined based on the presence of active contractions with dilation of the cervix, as assessed by the delivering physician. This diagnosis was further verified by a maternal–fetal medicine specialist at each treatment center (R.P., M.W.B. or A.B.). The primary outcome was spontaneous PTD before 34 weeks’ gestation due to spontaneous preterm labor or PPROM. The University of Texas Medical School at Houston did not offer fetoscopic laser surgery to patients with a CL < 10 mm. The University of Maryland at Baltimore used a CL cut-off of < 5 mm and the Children’s Hospital of Philadelphia used a CL cut-off of < 20 mm for not offering treatment.
Statistical analysis Results are reported as mean ± SD or median (range). Data were compared using an unpaired t-test for normally distributed data and the Mann–Whitney U-test (non-parametric) for non-normally distributed data. Categorical data were compared using chi-square analysis or Fisher’s exact test. The baseline CL distribution was examined using a histogram and normality testing was performed using the Shapiro–Wilk normality test. Multivariable linear regression was performed to find the preoperative factors affecting CL. Multivariable logistic regression analysis was performed to predict the occurrence of the primary outcome using the preoperative and operative variables maternal age, gravidity, parity, history of PTD, body mass index, gestational age at procedure, CL, fetal weight discordance, stage of TTTS, cannula diameter, amnioinfusion, cervical cerclage, trocar entry type, Solomon procedure and collagen plug placement. On a subgroup analysis, the same risk factors were tested for predicting spontaneous PTD at < 24 weeks’, < 26 weeks’, < 28 weeks’, < 30 weeks’ and < 32 weeks’ gestation. Receiver–operating characteristics (ROC) curves were plotted to identify an optimal CL threshold for predicting spontaneous PTD at < 34 weeks’ gestation. In addition, the Youden index (J), was calculated to measure the overall diagnostic effectiveness. J is the maximum vertical distance or the difference between the ROC curve and the diagonal or chance line. It occurs at the cut-off that optimizes the predicting variable’s
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Cervical length in TTTS differentiating ability when equal weight is given to sensitivity and specificity, and is calculated using the formula J = sensitivity + specificity – 114 . Statistical analysis was performed using STATA 12.1 statistical software (StataCorp., College Station, TX, USA), and P < 0.05 was considered to be statistically significant. Additionally, the STARD checklist for diagnostic accuracy studies was used (Table S1).
RESULTS A total of 449 patients were included in the cohort from three centers during the study period: the Children’s Hospital of Philadelphia, 211 patients; the University of Texas at Houston, 143 patients; and University of Maryland, 95 patients. The demographics of the cohort are illustrated in Table 1. The preoperative CL was normally distributed in all three centers (Figure 1). The preoperative factors that were associated with an increasing CL were maternal age and parity. The factors that were associated with a decreasing CL were increasing gestational age at procedure and anterior placenta (Table 2). The recipient maximum vertical pocket was not associated with CL. Of the 449 patients, 63 delivered before 34 weeks’ gestation owing to dual fetal demise or maternal/fetal indications without PPROM and were excluded from the subsequent analysis. Among the remaining 386 patients, spontaneous PTD at < 34 weeks occurred in 206 (53.4%) patients. The results from univariable analysis of the relevant clinical factors are presented in Table 3. Factors significantly associated with spontaneous PTD < 34 weeks were body mass index, CL, stage of TTTS, anterior placenta, cannula diameter, Solomon technique, collagen plug placement and amnioinfusion. Factors that were significant (P < 0.2) were included in the multivariable analysis. Multivariable logistic regression showed that only CL was a significant risk factor for spontaneous PTD at < 34 weeks’ gestation, with an odds ratio of 0.96 (95% CI, 0.94–0.98) (P < 0.0001). There were significant differences in the clinical outcomes based on spontaneous PTD at < 34 weeks, including PPROM, live birth and survival to the neonatal period (Table 3). The area under the ROC curve for predicting spontaneous PTD at < 34 weeks by CL measurements was 0.61 (P = 0.02) and the optimal threshold for CL, based on the highest Youden’s J statistic of 0.19, was 28 mm. The sensitivity, specificity, positive likelihood ratio and negative likelihood ratio for this cut-off were 92%, 27%, 3.76 and 0.78, respectively. The positive predictive and negative predictive values were 81% and 53%, respectively. The differences in clinical outcome, based on a CL cut-off of < 28 mm, are illustrated in Table 4. Gestational age at delivery was lower by 3 weeks (P < 0.0001) and the procedure-to-delivery interval was shorter by 27 days, in those with a CL < 28 mm (P < 0.0001), than in those with a CL of ≥ 28 mm. Both live-birth and neonatal-survival rates were lower in those with a CL of < 28 mm (P < 0.01). Kaplan–Meier survival analysis
Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.
177 Table 1 Demographics of 449 patients with twin–twin transfusion syndrome (TTTS) referred to one of three fetal centers in the USA for fetoscopic laser surgery (FLS) Characteristic
Distribution
Maternal age (years) Gravidity Parity Prior history of preterm delivery Body mass index (kg/m2 ) Gestational age at FLS (weeks) Growth discordance (%) Anterior placenta Cerclage placement TTTS stage I II III IV Maximum vertical pocket (cm) Preoperative Postoperative Cannula outer diameter 9 Fr 10 Fr 12 Fr Amnioreduction (mL) Number undergoing amnioinfusion Volume infused (mL) PPROM (< 34 weeks’ gestation) Gestational age at delivery (weeks) Spontaneous preterm birth Live births per pregnancy 0 1 2 Birth weight (g) Donor Recipient
29.5 ± 6.2 2 (1–8) 1 (0–6) 23 (5.1) 24.5 ± 7.6 20.7 ± 2.2 24 ± 14 185 (41.2) 6 (1.3) 31 (6.9) 191(42.5) 202 (45.0) 25 (5.6) 9.6 ± 5.8 7.5 ± 1.9 13 (2.9) 310 (69.0) 126 (28.1) 1567 ± 851 1500 (0–4600) 165 (36.7) 762 ± 679 145 (32.3) 31.9 ± 4.7 200 (44.5) 32 (7.1) 83 (18.5) 334 (74.4) 1588 ± 731 1853 ± 757
Data are shown as n (%), mean ± SD or median (range). PPROM, preterm prelabor rupture of membranes.
showed a significant difference in gestational age at delivery in those with a CL cut-off of < 28 mm compared with those with a CL of ≥ 28 mm (P < 0.001; Figure 2). The risk factors that were associated with spontaneous PTD at < 24, < 26, < 28 and < 30 weeks’ gestation were preoperative CL and a previous spontaneous PTD. For a spontaneous PTD at < 32 weeks, only CL was significantly associated. Data pertaining to the ROC curves and the corresponding Youden indices are presented in the Table 5. The Youden index was highest for those with PTD before 28 weeks, with a value of 0.30. The optimal cut-off for CL to predict spontaneous PTD was < 25 mm, with a sensitivity of 74.3% and specificity of 55.4%. The relationship between different CL cut-offs and their association with different gestational ages at delivery is presented in Table 6. Women with a CL of < 15 mm had a 25.0% chance, or a relative risk of 4.1, of a spontaneous PTD before 24 weeks’ gestation. A CL < 25 mm had a 32.7% chance, or relative risk of 3.4, of delivery before 28 weeks. The change in relative risk for spontaneous PTD at various gestational ages, with different CL cut-offs, was minimal, ranging from 1.4 to 4.1.
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(b) 15
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Figure 1 Frequency distribution of preoperative cervical length measurements in 449 women with twin–twin transfusion syndrome before fetoscopic laser surgery, from three fetal centers in the USA: (a) Children’s Hospital, Philadelphia (n = 211), (b) University of Maryland, Baltimore (n = 95) and (c) University of Texas, Houston (n = 143). (d) Frequency distribution for all 449 women. Solid lines represent fitted normal distribution curves for cervical length. Table 2 Multivariable linear regression analysis of risk factors for predicting preoperative cervical length in 449 women with twin–twin transfusion syndrome (TTTS) Covariate Constant Maternal age (years) Gravidity Parity Prior premature birth BMI (kg/m2 ) GA at procedure (weeks) Anterior placenta TTTS stage Fetal weight discordance Recipient MVP (cm)
Coefficient
P
48.8 0.24 −0.5 1.57 1.7 −0.08 −0.11 −2.9 −0.55 0.05 −0.007
< 0.0001* 0.004* 0.28 0.03* 0.4 0.22 0.001* 0.004* 0.435 0.17 0.93
*P < 0.05. BMI, body mass index; GA, gestational age; MVP, maximum vertical pocket.
Seven patients in the cohort had cervical cerclage. The CL measurements of these individual patients were 5, 10, 13, 15, 17, 19 and 24 mm. The median gestational age at delivery and procedure-to-delivery interval were 32.5 (range, 25.1–37.3) weeks and 85 (range, 45–119) days, respectively. There were only two patients with a CL of ≤ 10 mm (5 mm and 10 mm). Both had cervical cerclage placement during the FLS. In both cases, the pregnancies were complicated by PPROM and delivered at 34 weeks. Need for cerclage was not significantly associated with gestational age at delivery on multivariate analysis.
DISCUSSION This is a large study that evaluated the association between CL and the onset of spontaneous PTD or PPROM, after FLS. The main findings of the study are: (1) preoperative
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CL in TTTS is normally distributed; (2) maternal age and parity are positively associated, and gestational age at procedure and anterior placenta are negatively associated, with CL; (3) the risk of spontaneous PTD before 34 weeks’ gestation is highest for a CL cut-off of < 28 mm; (4) a preoperative CL of < 28 mm reduces the pregnancy latency by approximately 3 weeks; and (5) the risk of spontaneous PTD before 24 weeks, at the threshold of viability, was highest for those with a CL of < 15 mm, although this was noted in only 3% of the treated TTTS cases in the cohort. The distribution of CL in our cohort was normal, with a mean ± SD of 38 ± 10 mm, similar to previously published data from uncomplicated twin gestations (mean CL, 32.3 ± 8.9 mm)15 – 17 . This was an unexpected finding, as we had anticipated a shorter mean CL and positively skewed distribution in the TTTS cohort. This was confirmed by the absence of a significant relationship between the maximum vertical pocket and CL. The relationship between CL and presence of anterior placenta was surprising and we do not have an explanation. The relative risk of spontaneous PTD at < 32 or < 34 weeks in those with a CL of < 25 mm was much lower (1.4–1.8 ×) after laser surgery for TTTS when compared with the relative risk of 6.9 for uncomplicated twin gestations16,17 . This suggests that pregnancies undergoing FLS are already at a higher risk for preterm birth, and CL is less relevant than in uncomplicated twin gestations. Our findings are similar to those previously published by Robyr et al.2 , who identified a short cervix as one of the risk factors associated with spontaneous PTD at < 34 weeks’ gestation. In addition, their study noted that parity increased the risk, and intrauterine demise of one fetus decreased the risk. The CL cut-off that was identified in our study was < 28 mm, whereas Robyr
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Table 3 Multivariable logistic regression analysis to determine factors associated with spontaneous preterm delivery (sPTD) before 34 weeks’ gestation and the difference in clinical outcomes of 386 women with twin–twin transfusion syndrome (TTTS), referred for fetoscopic laser surgery
Parameter Maternal age (years) Gravidity Parity Prior sPTD BMI (kg/m2 ) GA at procedure (weeks) Growth discordance (%) Cervical length (mm) TTTS stage I II III IV Anterior placenta Recipient MVP (mm) Cannula gauge 9 Fr 10 Fr 12 Fr Direct trocar entry Solomon technique Collagen plug placed Amnioinfusion Amnioreduction (mL) Clinical outcome PPROM Live births per pregnancy 0 1 2 Neonatal survivors 0 1 2
sPTD < 34 weeks (n = 206)
sPTD ≥ 34 weeks (n = 180)
29.4 ± 5.9 2 (1–7) 2 (0–4) 12 (5.8) 25 ± 7 20.8 ± 2.2 23.2 ± 14.4 35.4 ± 11.2
29.8 ± 6.3 2 (1–8) 2 (0–6) 7 (3.9) 24 ± 8 20.7 ± 2.1 24 ± 12.9 39.6 ± 9
11 (5.3) 79 (38.3) 103 (50.0) 13 (6.3) 93 (45.1) 10.6 ± 3.5
12 (6.7) 93 (51.7) 66 (36.7) 9 (5.0) 65 (36.1) 10.9 ± 3.4
3 (1.5) 133 (64.6) 70 (34.0) 79 (38.3) 106 (51.5) 36 (17.5) 84 (40.8) 1539 ± 893
7 (3.9) 133 (73.9) 40 (22.2) 62 (34.4) 73 (40.6) 20 (11.1) 57 (31.7) 1602 ± 831
133 (64.6)
12 (6.7)
23 (11.2) 42 (20.4) 141 (68.4)
1 (0.6) 36 (20.0) 143 (79.4)
35 (17.0) 40 (19.4) 131 (63.6)
1 (0.6) 36 (20.0) 143 (79.4)
Multivariable logistic regression: odds ratio (95% CI)
P 0.53 0.6 0.7 0.38 0.1* 0.89 0.61 0.0001* 0.05*
0.07* 0.41 0.018*
— — — — 1.00 (0.98–1.04) — — 0.96 (0.94–0.98) 1 1.05 (0.4–2.7) 1.9 (0.74–4.8) 1.5 (0.4–5.4) 1.1 (0.7–1.8) — 1 3.5 (0.7–18) 4.3 (0.75–24.9) — 1.28 (0.7–2.3) 0.94 (0.45–1.97) 1.1 (0.6–1.9) —
0.37 0.05* 0.08* 0.07* 0.48 < 0.0001* < 0.0001*
< 0.0001*
Data are given as mean ± SD, median (range) or n (%). *Only factors with P < 0.2 were included in multivariable logistic regression. BMI, body mass index; Fr, French scale; GA, gestational age; MVP, maximum vertical pocket; PPROM, preterm prelabor rupture of membranes < 34 weeks’ gestation. Table 4 Differences in clinical outcome according to a preoperative cervical length (CL) cut-off of 28 mm in 386 women with twin–twin transfusion syndrome referred for fetoscopic laser surgery Parameter Maternal age (years) BMI (kg/m2 ) GA at procedure (weeks) Recipient preoperative MVP (cm) Recipient postoperative MVP (cm) PPROM GA at delivery (weeks) Procedure-to-delivery interval (days) Live births per pregnancy 0 1 2 Neonatal survivors 0 1 2
CL < 28 mm (n = 69)
CL ≥ 28 mm (n = 317)
P
27.5 ± 6 25.7 ± 6.4 21.2 ± 2.3 11.5 ± 3.5 7.2 ± 1.8 35 (50.7) 29.5 ± 5 58 ± 35.3
30 ± 6 24 ± 7.7 20.7 ± 2.1 10.6 ± 3.4 7 ± 2.1 110 (34.7) 32.8 ± 4.5 85 ± 34.6
< 0.01 0.12 0.05 0.05 0.67 0.01 < 0.0001 < 0.0001 0.003
10 (14.5) 17 (24.6) 42 (60.9)
14 (4.4) 61 (19.2) 242 (76.3)
12 (17.4) 17 (24.6) 40 (58.0)
24 (7.6) 59 (18.6) 234 (73.8)
0.005
Data are given as n (%), mean ± SD or median (range). BMI, body mass index; GA, gestational age; MVP, maximum vertical pocket; PPROM, preterm prelabor rupture of membranes.
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Proportion of ongoing pregnancies (%)
100 75 50 25
10
0
20
30
34 weeks
40
Gestational age at delivery (weeks)
Figure 2 Kaplan–Meier survival plot showing difference in gestational age at spontaneous preterm delivery (PTD) in 386 cases of twin–twin transfusion syndrome for those with a cervical length ) and those with a CL ≥ 28 mm ( ) (CL) < 28 mm ( (P < 0.001). 34 weeks is the optimal threshold of CL for predicting spontaneous PTD.
et al.2 described a cut-off of 30 mm. The key differences between the study of Robyr et al. and ours are the larger sample size and our use of ROC curves to determine the optimal cut-off of CL for predicting spontaneous PTD at different gestational ages, including 24, 26, 28, 30 and 32 weeks. In our study, parity was not identified as a significant risk factor. However, a previous history of spontaneous PTD was a significant risk factor, which is consistent with the results of other studies in singleton and uncomplicated twin pregnancies18 – 20 . Chavira et al.7 have also shown that a short cervix is associated with an increased risk for early delivery but categorized the CL arbitrarily. In the study, eight out of 10 patients had cervical cerclage for a CL of < 15 mm. Additionally, the study did not evaluate other potential risk factors and did not specifically include spontaneous PTD as an outcome variable. In our previous study, CL was identified as one of the significant factors associated with gestational age at delivery10 . However, in the present study we did not limit our outcome to spontaneous PTD. Chmait et al.21 identified a short cervix as a risk factor for delivery within 21 days after surgery. However, they did not exclude dual fetal demise and scheduled preterm deliveries.
We had only seven patients who required cervical cerclage, which is an insufficient sample size in which to evaluate the effect on spontaneous PTD. However, our previous study of cerclage for a short cervix found no overall effect on gestational age at delivery22 . Additionally, removal of these patients from the analysis did not affect the outcomes. A possible benefit to cerclage was noted, however, when the CL was 15–20 mm. There are several strengths to our study. The sample size was large enough to study the effect of most relevant risk factors in a regression model. The data were prospectively collected in three different centers, thereby reducing recollection bias. However, there are also some limitations. The cohort did not have enough patients to examine the effect of a CL of < 10 mm owing to the systematic exclusion of these women from laser treatment by the respective centers. Although such exclusions were few in number, we have not systematically followed up these patients to report the findings. This high-risk group needs further prospective study. Exclusion of cases with a CL of < 10 mm should not affect our finding the optimal threshold, as it statistically adjusts for the increasing risk with changes in CL. Additionally, intraoperative complications such as iatrogenic septostomy, intra-amniotic bleeding, chorioamniotic separation and acute demise of one of the fetuses were not consistently documented to allow for their inclusion in the analysis. Some of these factors have been associated with an earlier gestational age at delivery8,21,23 . Inclusion of these factors may have improved the predictive capabilities. Measurement of CL in TTTS remains an important criterion to indicate transfer to a tertiary care center and to offer FLS. Based on the findings from this study, a short cervix increases the risk of spontaneous PTD. However, there is no clear threshold at which laser treatment should be considered futile owing to concerns about a previable delivery. Further studies are needed to evaluate the effect of a CL of < 10 mm on the risk of spontaneous PTD. Despite CL being a significant predictor, there appear to be other unknown factors that play a role in the early onset of preterm labor that need to be investigated. Preventive strategies in women with a short cervix that need to
Table 5 Risk factors and optimal cervical length (CL) cut-off for prediction of spontaneous preterm delivery (sPTD) or preterm prelabor rupture of membranes (PPROM), for different gestational age cut-offs, in 449 women with twin–twin transfusion syndrome GA at delivery (weeks) < 24 < 26 < 28 < 30 < 32 < 34
CL as a measure for predicting PTD
Significant risk factors* Odds ratio (95% CI) n/N
CL
Prior sPTD
AUC
P
Youden index
Optimal CL cut-off (mm)
Sensitivity (%)
Specificity (%)
29/442 40/436 56/429 97/419 147/410 209/386
0.96 (0.92–0.99) 0.95 (0.92–0.98) 0.94 (0.91–0.97) 0.96 (0.94–0.99) 0.96 (0.94–0.99) 0.96 (0.94–0.98)
3.4 (1.09–10.7) 3.4 (1.2–9.7) 2.97 (1.1–7.9) 3.15 (1.3–7.6) — —
0.62 0.64 0.67 0.61 0.60 0.61
0.05 0.04 0.04 0.03 0.03 0.02
0.23 0.27 0.30 0.23 0.19 0.19
25 25 25 24 26 28
71 73 74 77 90 92
51 55 55 43 29 27
*Factors found on multivariable logistic regression analysis including CL in mm, prior sPTD, body mass index, anterior placenta, cannula diameter, amnioinfusion, Solomon technique and collagen plug placement. AUC, area under receiver–operativing characteristics curve; GA, gestational age.
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Ultrasound Obstet Gynecol 2015; 45: 175–182.
Data are given as n (%) and relative risk (RR) (95% CI) for those that are statistically significant. Fisher’s exact test or Pearson χ2 used to compare each cell with rest of cohort. *P < 0.05. †P < 0.01. ‡P < 0.001. §RR ≥ 3.
— 1.8 (1.4–2.2) 1.8 (1.4–2.2) 1.7 (1.3–2.0) 1.4 (1.2–1.8) 9 (75.0) 22 (78.6)‡ 42 (76.4)‡ 56 (67.5)‡ 85 (54.8)‡ — 1.6 (1.1–2.3) 1.9 (1.5–2.5) 1.8 (1.4–2.8) 1.6 (1.3–2.1) 6 (50.0) 15 (53.6)* 32 (58.2)‡ 44 (53.0)‡ 68 (43.9)† < 15 < 20 < 25 < 30 < 35
12 (2.7) 28 (6.2) 55 (12.2) 83 (18.5) 155 (34.5)
3 (25.0)* 4.1 (1.4–11.8)§ 3 (25.0) 4 (14.3) — 6 (21.4)* 7 (12.7) — 10 (18.2)* 9 (10.8) — 14 (16.9)† 15 (9.7)* 2.1 (1.0–4.2) 23 (14.8)†
— 2.6 (1.2–5.6) 2.3 (1.2–4.5) 2.2 (1.3–4.2) 2.7 (1.5–4.8)
4 (33.3)* 9 (32.1)† 18 (32.7)‡ 23 (27.7)† 33 (21.3)‡
2.6 (1.2–6.2) 2.9 (1.6–5.2) 3.4 (2.1–5.4)§ 3.0 (1.9–4.9)§ 2.7 (1.7–4.5)
6 (50.0)* 11 (39.3)* 25 (45.5)‡ 32 (38.6)‡ 46 (29.7)†
2.0 (1.2–4.1) 1.9 (1.3–3.0) 2.4 (1.7–3.4) 2.1 (1.5–2.9) 1.8 (1.2–2.5)
n (%) n (%)
RR (95% CI)
RR (95% CI)
181
RR (95% CI) n (%) RR (95% CI) n (%) RR (95% CI) n (%) RR (95% CI) n (%) n (%) CL (mm)
< 34 weeks < 32 weeks < 30 weeks < 28 weeks < 26 weeks < 24 weeks
Gestational age at delivery
Table 6 Performance of cervical length (CL) cut-offs to predict spontaneous preterm delivery (sPTD) or preterm prelabor rupture of membranes (PPROM) at various gestational age (GA) cut-offs among 449 women with twin–twin transfusion syndrome
Cervical length in TTTS
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be investigated include Arabin pessary24 , progesterone supplementation and cervical cerclage. In conclusion, CL is normally distributed in women undergoing laser surgery for TTTS and remains the most significant factor associated with spontaneous PTD. A CL of < 28 mm is the threshold for an increased risk, and preventive strategies should target this group of patients. Other pathophysiological processes involved in the onset of preterm labor in TTTS need to be investigated.
ACKNOWLEDGMENTS We would like to thank Karen Moise, Elisa Garcia and Noemi Boring at the Texas Fetal Center for data collection. This study was presented as an abstract at the Society for Gynecological Investigation at Florence, Italy on March 2014 and was also presented at the International Fetal Medicine and Surgery Society Conference on September 7–11, Cape Cod, MA, USA.
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SUPPORTING INFORMATION ON THE INTERNET The following supporting information may be found in the online version of this article: Table S1 STARD checklist for reporting of studies of diagnostic accuracy (version January 2003)
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