Prediction of preterm birth in twin gestations using biophysical and biochemical tests




Biophysical tests


Transvaginal sonographic cervical length


Single measurement


Transvaginal sonographic assessment of cervical length (CL) is an effective tool for predicting preterm birth, particularly in asymptomatic women with a singleton gestation or those at a higher risk of spontaneous preterm birth. In 2010, a systematic review and metaanalysis assessed the value of a single transvaginal sonographic CL measurement for the prediction of spontaneous preterm birth in women with twin gestations. Twenty-one studies involving a total of 3523 women were included, of which 16 studies (3213 women) provided data on asymptomatic women and 5 (310 women) on patients with threatened preterm labor.


Among asymptomatic women, a CL ≤20 mm at 20-24 weeks of gestation had the following performance in predicting preterm birth at <32 and <34 weeks of gestation: pooled sensitivities, specificities, and positive and negative likelihood ratios of 39% and 29%, 96% and 97%, 10.1 and 9.0, and 0.64 and 0.74, respectively, increasing their pretest probabilities from 6.8-42.4%, and from 15.3-61.9%, respectively, whereas a CL >20 mm decreased the risk to 4.5% and 11.8%, respectively. A CL ≤25 mm at 20-24 weeks of gestation had a pooled positive likelihood ratio of 9.6 to predict preterm birth at <28 weeks of gestation. CL had a limited accuracy in predicting preterm birth at <37 weeks of gestation. Among women with an episode of preterm labor, the measurement of CL had a minimal predictive accuracy for preterm birth at <34 and <37 weeks of gestation (pooled sensitivities, specificities, and positive and negative likelihood ratios ranging between 49–79%, 32–74%, 1.2–1.9, and 0.7, respectively). Only one study (n = 87 women) reported on the predictive performance of CL for delivery within 7 days of testing, showing a sensitivity of 100% and a specificity of 31% (positive and negative likelihood ratios of 1.4 and 0.0, respectively) for a CL cutoff of 25 mm.


Three further systematic reviews published after this metaanalysis confirmed its findings in both asymptomatic and symptomatic women. In summary, a single measurement of transvaginal sonographic CL at 20-24 weeks of gestation is a good predictor of spontaneous preterm birth at <28, <32, and <34 weeks of gestation in asymptomatic women with twin gestations. In patients with symptoms of preterm labor, the measurement of CL has a low accuracy to predict preterm birth.


Change in CL over time


Seven studies (n = 1004) that assessed the predictive value for preterm birth of the change in CL over time in asymptomatic women with twin gestations were reviewed. Irrespective of the cutoff value used for defining CL shortening over time (≥2.5 mm at 18-28 weeks or ≥2.3 mm at 28-32 weeks ; >5, >10, or >15 mm between 15-20 and 25-30 weeks ; ≥20% between 18-24 weeks and 2-6 weeks later or between 22-27 weeks ; ≥2 mm/wk between 18-21 and 22-25 weeks ; >13% between 20-24 weeks and 4-5 weeks later ; and ≥25% between 20-23 weeks and 3-5 weeks later ), the predictive accuracy of this test for preterm birth at <28 to at <36 weeks of gestation was minimal to moderate, with most studies reporting sensitivities between 15-75%, specificities between 70-90%, and positive and negative likelihood ratios between 1.6-5.5 and 0.3-0.8, respectively. In addition, 5 of the 7 studies reported that the predictive accuracy of the change in CL over time was not significantly superior to that of a single measurement of CL at 18-24 weeks of gestation. The reasons why the predictive ability for preterm birth of change in CL over time did not differ significantly to that of a single measurement of CL at 20-24 weeks of gestation are not clear. One possible explanation could be the differences among studies in the timing and interval of CL measurements and the cutoff values used to define a positive test result (percent change in the CL over time vs absolute change). On the other hand, because no study compared CL between 15-19 and 20-24 weeks, it is likely that a short cervix at 20-24 weeks of gestation means that the patient had a longer cervix that became shorter before the first measurement of CL (early shortening).


Transvaginal sonographic cervical funneling


Seven studies (5 in asymptomatic women [n = 680] and 2 in patients with threatened preterm labor [n = 52] ) assessed the predictive performance of cervical funneling for preterm birth in twin gestations. We were able to pool results from 4 studies (n = 549 women) that evaluated cervical funneling at 18-26 weeks of gestation in asymptomatic women regardless of the parameter used for defining funneling. This analysis revealed that pooled sensitivities, specificities, and positive and negative likelihood ratios ranged between 24–53%, 87–94%, 2.2–6.1, and 0.5–0.8, respectively, to predict preterm birth at <32, <35, and <37 weeks of gestation. Another study (n = 131 women) reported a low predictive accuracy of 3 funneling-related parameters for preterm birth at <32 weeks of gestation in asymptomatic women with areas under the ROC curves that ranged between 0.50–0.70. Only 2 small studies (n = 26 women each) evaluated the predictive ability for preterm birth of cervical funneling in patients with threatened preterm labor. The predictive values for preterm birth at <34 and <37 weeks of gestation were low (sensitivities between 25-60%, specificities between 79-86%, and positive and negative likelihood ratios between 1.2-4.2 and 0.5-1.0, respectively). Overall, the available evidence suggests that the presence of cervical funneling during transvaginal sonography is not a clinically useful test to predict preterm birth in both asymptomatic and symptomatic women with twin gestations.


Uterine artery Doppler ultrasonography


We reviewed 3 studies (n = 707) assessing the accuracy of uterine artery Doppler ultrasonography during the second trimester of pregnancy to predict preterm birth in twin gestations. One study reported that a resistance index >95th percentile and the presence of notching at 18-24 weeks of gestation had low predictive values for preterm birth at <32 and <37 weeks of gestation (sensitivities, specificities, and positive and negative likelihood ratios between 13-26%, 92-95%, 2.5-3.4, and 0.8-0.9, respectively). Another study reported that a pulsatility index >95th percentile and the presence of bilateral notching at 22-24 weeks of gestation had sensitivities, specificities, and positive and negative likelihood ratios that ranged from 12–19%, 97–98%, 5.1–5.7, and 0.8–0.9, respectively, for predicting preterm birth at ≤32 weeks of gestation. A third study reported that an increased pulsatility index at 24-32 weeks of gestation had a low predictive value for adverse pregnancy outcomes including preterm birth. In summary, this evidence suggests that uterine artery Doppler ultrasonography has minimal to moderate ability to predict preterm birth in twin gestations.


Discordance in sonographic growth


Significant discordance in crown-rump length detected at the 11- to 14-week scan has been associated with a higher risk of adverse perinatal outcomes in twin gestations. We identified one systematic review and metaanalysis that assessed the predictive value of this test for several adverse perinatal outcomes including preterm birth at <34 weeks of gestation. Despite that crown-rump length discordance (≥10%) detected at 11-14 weeks was significantly associated with preterm birth at <34 weeks (relative risk, 1.49; 95% confidence interval [CI], 1.23–1.80), the predictive accuracy of this test was poor (pooled sensitivity, specificity, and positive and likelihood ratios of 14%, 91%, 1.5, and 1.0, respectively; 3 studies; n = 4360).


Two large cohort studies have reported on the predictive accuracy for preterm birth of intertwin discordant sonographic growth in the late first and second trimesters. One study (n = 960) assessed discordance in abdominal circumference (>10%), biparietal diameter (>10%), femur length (>10%), and estimated fetal weight (>10%) at 11-22 weeks of gestation as predictor for preterm birth at <34 weeks of gestation. In general, the predictive accuracy of these biometric data was low with sensitivities, specificities, and positive and negative likelihood ratios that ranged from 7–51%, 71–96%, 1.5–3.1, and 0.7–1.0, respectively. A recent retrospective cohort study (n = 2399) reported a poor predictive performance of discordance in abdominal circumference and estimated fetal weight at 20-22 weeks of gestation for preterm birth at <34 weeks of gestation (area under the ROC curve, 0.53; 95% CI, 0.49–0.56). In conclusion, discordant sonographic growth detected in the first or second trimester has a poor predictive accuracy for preterm birth, thus limiting its use in clinical practice.


Nuchal translucency


First-trimester fetal nuchal translucency combined with biochemical markers appears to be an acceptable screening test for aneuploidies in twin gestations. Only two studies have assessed nuchal translucency in predicting preterm birth in twin gestations. One small study including 20 monochorionic multiple gestations (18 twins and 2 triplets) uncomplicated by twin-to-twin transfusion syndrome or aneuploidies reported that 3 of the 4 gestations with increased nuchal translucency thickness in at least one fetus and 1 of the 16 with normal nuchal translucency thickness were delivered at <32 weeks of gestation (sensitivity of 75%, specificity of 94%, and positive and negative likelihood ratios of 12.0 and 0.3, respectively). A recent retrospective cohort study involving 177 monochorionic diamniotic twin gestations found that intertwin discordance in nuchal translucency (≥20%) was a poor predictor for preterm birth at <28 weeks of gestation (area under the ROC curve, 0.52; 95% CI, 0.42–0.61). These data have inherent limitations to allow firm conclusions other than suggesting that more studies are needed to determine the performance of first-trimester nuchal translucency as a predictive test for preterm birth in twin gestations.


Home uterine activity monitoring


To date, only the study by Newman et al (n = 59 women) has clearly reported on the predictive accuracy of home uterine activity monitoring (HUAM) for preterm birth in asymptomatic women with twin gestations. Contraction frequency was recorded with HUAM ≥2 times per day on ≥2 days per week from 22-24 weeks until delivery or 36 weeks. Data on HUAM were masked. Overall, HUAM had very low predictive accuracy for spontaneous preterm birth at <35 weeks of gestation with sensitivities that ranged between 12–50%, specificities between 73-95%, and positive and negative likelihood ratios between 0.6–2.5 and between 0.6–1.1, respectively. In addition, the Cochrane review that assessed the effectiveness of HUAM in both singleton and twin gestations concluded that this intervention does not have an impact on the frequency of preterm birth and perinatal mortality. In conclusion, HUAM is a poor predictor of spontaneous preterm birth among asymptomatic women with twin gestations, and its routine use in such patients does not reduce the rate of preterm birth and neonatal morbidity and mortality.




Biochemical tests


Cervicovaginal fetal fibronectin


In 2010, we published a systematic review and metaanalysis on the accuracy of cervicovaginal fetal fibronectin in predicting preterm birth in women with twin gestations. Fifteen studies (11 in asymptomatic women and 4 in patients with symptoms of preterm labor ) involving 1133 women with twin gestations were included in the review. Among asymptomatic women, cervicovaginal fetal fibronectin had limited accuracy in predicting preterm birth at <32, <34, and <37 weeks of gestation (pooled sensitivities, specificities, and positive and negative likelihood ratios ranging from 33-39%, 80-94%, 2.0-5.1, and 0.7-0.8, respectively). In 2014, a retrospective cohort study including 560 twin gestations reported similar predictive values for preterm birth at <32 weeks of gestation from either preterm labor or premature rupture of membranes. Among patients with threatened preterm labor, our study found that the test was most accurate in predicting spontaneous preterm birth within 7 days of testing (pooled sensitivity, specificity, and positive and negative likelihood ratios of 85%, 78%, 3.9, and 0.2, respectively). Only 1.6% of patients with an episode of preterm labor who tested negative for cervicovaginal fetal fibronectin delivered in the next week. Unfortunately, only 3 studies (n = 168) provided data for the metaanalysis. Based on these findings, cervicovaginal fetal fibronectin has low to moderate accuracy in predicting spontaneous preterm birth in both asymptomatic and symptomatic women with twin gestations.


Fetoplacental proteins/hormone-related biomarkers


Alpha-fetoprotein (AFP), human chorionic gonadotropin (hCG), and pregnancy-associated plasma protein (PAPP)-A have been used for the screening of fetal aneuploidy, neural tube defects, and other fetal abnormalities in the first or second trimesters of pregnancy. Abnormal values of these maternal serum analytes have also been associated with adverse pregnancy outcomes in women with normal fetuses. Although several studies have reported an inverse relationship between elevated maternal serum AFP levels in the second trimester of pregnancy and gestational age at birth in women with twin gestations uncomplicated by neural tube defects, only one study (n = 267) has reported on the accuracy of AFP to predict preterm birth in this population. The predictive ability of elevated maternal AFP levels (≥3.5 multiples of the median [MoM]) at 15-20 weeks for preterm birth at <34 weeks of gestation was poor (sensitivity of 30%, specificity of 88%, and positive and negative likelihood ratios of 2.4 and 0.8, respectively).


We identified 4 studies that evaluated the second-trimester serum levels of hCG (2 studies; n = 1868) or the first-trimester serum levels of free β-hCG (2 studies; n = 174) for predicting preterm birth among women with twin gestations and normal fetuses. Overall, the predictive performance of high maternal serum levels of hCG (≥5.0 MoM or >3 MoM ) or free β-hCG (>75th percentile or >90th percentile ) for preterm birth at <32, <34, and <37 weeks of gestation was low (sensitivities between 7-24%, specificities between 75-97%, and positive and negative likelihood ratios between 0.9-3.0 and between 0.9-1.0, respectively).


Three studies (n = 515) have assessed the accuracy of the measurement of first-trimester maternal serum levels of PAPP-A levels to predict preterm birth in women with twin gestations and normal fetuses. The overall predictive ability of low serum levels of PAPP-A (defined as ≤25th percentile, <10th percentile, or <5th percentile ) for preterm birth at <32, <34, <35, and <37 weeks of gestation was minimal (sensitivities ranging from 5-56%, specificities from 78-95%, and positive and negative likelihood ratios from 1.0-2.9 and 0.6-1.0, respectively).


Relaxin is a peptide hormone produced by the corpus luteum during pregnancy in response to stimulation by hCG. Elevated circulating maternal relaxin concentrations have been associated with an increased risk of preterm birth. We identified 2 studies that evaluated the association between maternal serum levels of relaxin and the risk of preterm birth in twin gestations. A study involving 28 asymptomatic women found that serum relaxin levels >2 SD above the mean (≥1.4 ng/mL) at ≤32 weeks had a sensitivity, specificity, and positive and negative likelihood ratios of 30%, 100%, ∞, and 0.7, respectively, for predicting preterm birth at ≤35 weeks of gestation. A larger study (n = 188) reported that relaxin levels >90th percentile at 24 weeks had sensitivities, specificities, and positive and negative likelihood ratios that ranged from 10–14%, 91–95%, 1.1–2.3, and 0.9–1.0, respectively, to predict spontaneous preterm birth at <32, <35, and <37 weeks of gestation.


To date, only 2 studies (n = 237) have reported on the value of phosphorylated insulin-like growth factor binding protein ( ph IGFBP)-1 measured in cervical secretions for the prediction of preterm birth in asymptomatic women with twin gestations. Overall, the measurement of ph IGFBP-1 had minimal predictive accuracy for preterm birth at <34 weeks of gestation (pooled sensitivity, specificity, and positive and negative likelihood ratios of 16%, 93%, 2.3, and 0.9, respectively). No study has evaluated ph IGFBP-1 in women with twin gestations and threatened preterm labor. Additional longitudinal studies are needed.


In summary, the determination of maternal serum levels of first- and second-trimester markers used for screening of fetal aneuploidies and neural tube defects and relaxin does not appear to be useful in predicting preterm birth in twin gestations. There is insufficient evidence to assess the predictive ability of the measurement of cervical ph IGFBP-1 for preterm birth.


Cytokines/chemokines


A considerable body of evidence supports a role for cytokines and chemokines in the mechanisms responsible for preterm labor and delivery and their potential use of biomarkers. In asymptomatic women with singleton gestations, measurement of serum, cervicovaginal and amniotic fluid concentrations of cytokines have been used for the prediction of spontaneous preterm delivery. We analyzed 2 studies that evaluated the predictive accuracy of cytokines for spontaneous preterm birth in twin gestations. A cohort study assessed the ability of interleukin (IL)-1α, IL-6, and IL-8 concentrations in cervicovaginal secretions at 24-34 weeks to predict spontaneous preterm birth in 101 women with twin gestations. IL-8, but not IL-1α or IL-6, was associated with a significant increase in the risk of spontaneous preterm birth at <37 weeks of gestation. However, the accuracy of IL-8 for predicting preterm birth at <37 weeks of gestation was low (sensitivity of 79%, specificity of 46%, and positive and negative likelihood ratios of 1.5 and 0.5, respectively). Recently, a secondary analysis of a randomized placebo-controlled trial investigating the preventive effect of vaginal progesterone on the risk of preterm delivery in diamniotic twin gestations reported on the association between cytokine levels in dried blood spots and the risk of spontaneous preterm birth in twin gestations. Concentrations of 24 inflammatory markers were measured upon enrollment into the study (18-25 weeks of gestation) and after 4-8 weeks of treatment. Among women in the placebo group (n = 265), only levels of IL-8 in the second blood sample were significantly increased in spontaneous deliveries <34 weeks of gestation compared with term deliveries ( P < .001). None of the other investigated inflammatory markers showed any statistically significant association with preterm birth. Although that study did not report on the predictive accuracy of IL-8 for preterm birth at <34 weeks of gestation, its authors concluded that circulating IL-8 levels cannot be used as a predictive marker for spontaneous preterm birth in twin gestations.


25-Hydroxyvitamin D


A recent study evaluated the relationship between maternal 25-hydroxyvitamin D concentrations at 24-28 weeks of gestation and preterm birth in a cohort of 211 twin gestations. Despite that a late second-trimester maternal 25-hydroxyvitamin D concentration <75 nmol/L was associated with a significant increase in the risk of preterm birth at <35 weeks of gestation, it cannot be used as a predictive test for preterm birth in twin gestations because of its low predictive values: sensitivity of 56%, specificity of 68%, and positive and negative likelihood ratios of 1.8 and 0.6, respectively.


Bacterial vaginosis


Three studies have assessed whether the presence of bacterial vaginosis is predictive of preterm birth in asymptomatic women with twin gestations. A study by Goldenberg et al (n = 147 women) reported that the presence of bacterial vaginosis at 24 and 28 weeks of gestation had very low predictive values for spontaneous preterm birth at <32, <35, and <37 weeks of gestation with sensitivities, specificities, and positive and negative likelihood ratios ranging between 0-23%, 78-82%, 0.6-1.0, and 1.0-1.2, respectively. Similar results were obtained in one study involving 101 asymptomatic women with twin gestations in which the presence of bacterial vaginosis at 24-34 weeks had a sensitivity, specificity, and positive and negative likelihood ratios of 14%, 92%, 1.8, and 0.9, respectively, for predicting spontaneous preterm birth at <37 weeks of gestation. Another study (n = 48 women) found no association between the presence of bacterial vaginosis at 22-34 weeks and preterm birth at <35 weeks of gestation. In conclusion, the presence of bacterial vaginosis has a very modest predictive ability for preterm birth in women with twin gestations.


Cervicovaginal endotoxin


Endotoxin is a component of the cell wall of gram-negative bacteria, which has been detected in the amniotic fluid of women with preterm labor and preterm premature rupture of membranes. The interaction between endotoxin and host cells leads to an increased synthesis of cytokines, chemokines, and lipid mediators that appear to be associated with preterm birth. Only one study has assessed the accuracy of the measurement of endotoxin in cervical fluid of women with twin gestations (n = 121 women) for predicting spontaneous preterm birth at <35 and <37 weeks of gestation. The presence of endotoxin in cervical fluid was not significantly associated with preterm birth or neonatal morbidity. That study did not report predictive values.




Biochemical tests


Cervicovaginal fetal fibronectin


In 2010, we published a systematic review and metaanalysis on the accuracy of cervicovaginal fetal fibronectin in predicting preterm birth in women with twin gestations. Fifteen studies (11 in asymptomatic women and 4 in patients with symptoms of preterm labor ) involving 1133 women with twin gestations were included in the review. Among asymptomatic women, cervicovaginal fetal fibronectin had limited accuracy in predicting preterm birth at <32, <34, and <37 weeks of gestation (pooled sensitivities, specificities, and positive and negative likelihood ratios ranging from 33-39%, 80-94%, 2.0-5.1, and 0.7-0.8, respectively). In 2014, a retrospective cohort study including 560 twin gestations reported similar predictive values for preterm birth at <32 weeks of gestation from either preterm labor or premature rupture of membranes. Among patients with threatened preterm labor, our study found that the test was most accurate in predicting spontaneous preterm birth within 7 days of testing (pooled sensitivity, specificity, and positive and negative likelihood ratios of 85%, 78%, 3.9, and 0.2, respectively). Only 1.6% of patients with an episode of preterm labor who tested negative for cervicovaginal fetal fibronectin delivered in the next week. Unfortunately, only 3 studies (n = 168) provided data for the metaanalysis. Based on these findings, cervicovaginal fetal fibronectin has low to moderate accuracy in predicting spontaneous preterm birth in both asymptomatic and symptomatic women with twin gestations.


Fetoplacental proteins/hormone-related biomarkers


Alpha-fetoprotein (AFP), human chorionic gonadotropin (hCG), and pregnancy-associated plasma protein (PAPP)-A have been used for the screening of fetal aneuploidy, neural tube defects, and other fetal abnormalities in the first or second trimesters of pregnancy. Abnormal values of these maternal serum analytes have also been associated with adverse pregnancy outcomes in women with normal fetuses. Although several studies have reported an inverse relationship between elevated maternal serum AFP levels in the second trimester of pregnancy and gestational age at birth in women with twin gestations uncomplicated by neural tube defects, only one study (n = 267) has reported on the accuracy of AFP to predict preterm birth in this population. The predictive ability of elevated maternal AFP levels (≥3.5 multiples of the median [MoM]) at 15-20 weeks for preterm birth at <34 weeks of gestation was poor (sensitivity of 30%, specificity of 88%, and positive and negative likelihood ratios of 2.4 and 0.8, respectively).


We identified 4 studies that evaluated the second-trimester serum levels of hCG (2 studies; n = 1868) or the first-trimester serum levels of free β-hCG (2 studies; n = 174) for predicting preterm birth among women with twin gestations and normal fetuses. Overall, the predictive performance of high maternal serum levels of hCG (≥5.0 MoM or >3 MoM ) or free β-hCG (>75th percentile or >90th percentile ) for preterm birth at <32, <34, and <37 weeks of gestation was low (sensitivities between 7-24%, specificities between 75-97%, and positive and negative likelihood ratios between 0.9-3.0 and between 0.9-1.0, respectively).


Three studies (n = 515) have assessed the accuracy of the measurement of first-trimester maternal serum levels of PAPP-A levels to predict preterm birth in women with twin gestations and normal fetuses. The overall predictive ability of low serum levels of PAPP-A (defined as ≤25th percentile, <10th percentile, or <5th percentile ) for preterm birth at <32, <34, <35, and <37 weeks of gestation was minimal (sensitivities ranging from 5-56%, specificities from 78-95%, and positive and negative likelihood ratios from 1.0-2.9 and 0.6-1.0, respectively).


Relaxin is a peptide hormone produced by the corpus luteum during pregnancy in response to stimulation by hCG. Elevated circulating maternal relaxin concentrations have been associated with an increased risk of preterm birth. We identified 2 studies that evaluated the association between maternal serum levels of relaxin and the risk of preterm birth in twin gestations. A study involving 28 asymptomatic women found that serum relaxin levels >2 SD above the mean (≥1.4 ng/mL) at ≤32 weeks had a sensitivity, specificity, and positive and negative likelihood ratios of 30%, 100%, ∞, and 0.7, respectively, for predicting preterm birth at ≤35 weeks of gestation. A larger study (n = 188) reported that relaxin levels >90th percentile at 24 weeks had sensitivities, specificities, and positive and negative likelihood ratios that ranged from 10–14%, 91–95%, 1.1–2.3, and 0.9–1.0, respectively, to predict spontaneous preterm birth at <32, <35, and <37 weeks of gestation.


To date, only 2 studies (n = 237) have reported on the value of phosphorylated insulin-like growth factor binding protein ( ph IGFBP)-1 measured in cervical secretions for the prediction of preterm birth in asymptomatic women with twin gestations. Overall, the measurement of ph IGFBP-1 had minimal predictive accuracy for preterm birth at <34 weeks of gestation (pooled sensitivity, specificity, and positive and negative likelihood ratios of 16%, 93%, 2.3, and 0.9, respectively). No study has evaluated ph IGFBP-1 in women with twin gestations and threatened preterm labor. Additional longitudinal studies are needed.


In summary, the determination of maternal serum levels of first- and second-trimester markers used for screening of fetal aneuploidies and neural tube defects and relaxin does not appear to be useful in predicting preterm birth in twin gestations. There is insufficient evidence to assess the predictive ability of the measurement of cervical ph IGFBP-1 for preterm birth.


Cytokines/chemokines


A considerable body of evidence supports a role for cytokines and chemokines in the mechanisms responsible for preterm labor and delivery and their potential use of biomarkers. In asymptomatic women with singleton gestations, measurement of serum, cervicovaginal and amniotic fluid concentrations of cytokines have been used for the prediction of spontaneous preterm delivery. We analyzed 2 studies that evaluated the predictive accuracy of cytokines for spontaneous preterm birth in twin gestations. A cohort study assessed the ability of interleukin (IL)-1α, IL-6, and IL-8 concentrations in cervicovaginal secretions at 24-34 weeks to predict spontaneous preterm birth in 101 women with twin gestations. IL-8, but not IL-1α or IL-6, was associated with a significant increase in the risk of spontaneous preterm birth at <37 weeks of gestation. However, the accuracy of IL-8 for predicting preterm birth at <37 weeks of gestation was low (sensitivity of 79%, specificity of 46%, and positive and negative likelihood ratios of 1.5 and 0.5, respectively). Recently, a secondary analysis of a randomized placebo-controlled trial investigating the preventive effect of vaginal progesterone on the risk of preterm delivery in diamniotic twin gestations reported on the association between cytokine levels in dried blood spots and the risk of spontaneous preterm birth in twin gestations. Concentrations of 24 inflammatory markers were measured upon enrollment into the study (18-25 weeks of gestation) and after 4-8 weeks of treatment. Among women in the placebo group (n = 265), only levels of IL-8 in the second blood sample were significantly increased in spontaneous deliveries <34 weeks of gestation compared with term deliveries ( P < .001). None of the other investigated inflammatory markers showed any statistically significant association with preterm birth. Although that study did not report on the predictive accuracy of IL-8 for preterm birth at <34 weeks of gestation, its authors concluded that circulating IL-8 levels cannot be used as a predictive marker for spontaneous preterm birth in twin gestations.


25-Hydroxyvitamin D


A recent study evaluated the relationship between maternal 25-hydroxyvitamin D concentrations at 24-28 weeks of gestation and preterm birth in a cohort of 211 twin gestations. Despite that a late second-trimester maternal 25-hydroxyvitamin D concentration <75 nmol/L was associated with a significant increase in the risk of preterm birth at <35 weeks of gestation, it cannot be used as a predictive test for preterm birth in twin gestations because of its low predictive values: sensitivity of 56%, specificity of 68%, and positive and negative likelihood ratios of 1.8 and 0.6, respectively.


Bacterial vaginosis


Three studies have assessed whether the presence of bacterial vaginosis is predictive of preterm birth in asymptomatic women with twin gestations. A study by Goldenberg et al (n = 147 women) reported that the presence of bacterial vaginosis at 24 and 28 weeks of gestation had very low predictive values for spontaneous preterm birth at <32, <35, and <37 weeks of gestation with sensitivities, specificities, and positive and negative likelihood ratios ranging between 0-23%, 78-82%, 0.6-1.0, and 1.0-1.2, respectively. Similar results were obtained in one study involving 101 asymptomatic women with twin gestations in which the presence of bacterial vaginosis at 24-34 weeks had a sensitivity, specificity, and positive and negative likelihood ratios of 14%, 92%, 1.8, and 0.9, respectively, for predicting spontaneous preterm birth at <37 weeks of gestation. Another study (n = 48 women) found no association between the presence of bacterial vaginosis at 22-34 weeks and preterm birth at <35 weeks of gestation. In conclusion, the presence of bacterial vaginosis has a very modest predictive ability for preterm birth in women with twin gestations.


Cervicovaginal endotoxin


Endotoxin is a component of the cell wall of gram-negative bacteria, which has been detected in the amniotic fluid of women with preterm labor and preterm premature rupture of membranes. The interaction between endotoxin and host cells leads to an increased synthesis of cytokines, chemokines, and lipid mediators that appear to be associated with preterm birth. Only one study has assessed the accuracy of the measurement of endotoxin in cervical fluid of women with twin gestations (n = 121 women) for predicting spontaneous preterm birth at <35 and <37 weeks of gestation. The presence of endotoxin in cervical fluid was not significantly associated with preterm birth or neonatal morbidity. That study did not report predictive values.




Combination of biophysical and biochemical tests


Combination of transvaginal sonographic CL and cervicovaginal fetal fibronectin


Two studies have reported on the ability of the combination of CL and cervicovaginal fetal fibronectin for predicting preterm birth among asymptomatic women with twin gestations. One study (n = 147) found that having either a CL ≤25 mm or a positive fetal fibronectin result, or both tests positive at 24 or 28 weeks of gestation, had a limited predictive accuracy for spontaneous preterm birth at <32, <35, and <37 weeks of gestation (sensitivities 26-83%, specificities 68-88%, and positive and negative likelihood ratios ranging from 1.7–3.3 and from 0.3–0.8, respectively). Another study (n = 155) reported that having either a CL <20 mm, a positive fetal fibronectin result, or both tests positive at 22-32 weeks of gestation had sensitivities, specificities, and positive and negative likelihood ratios that varied from 37-67%, 79-94%, 2.6-6.7, and 0.4-0.7, respectively, for predicting spontaneous preterm birth at all gestational ages considered. Two studies assessed the combination of CL and fetal fibronectin to predict preterm birth in women with threatened preterm labor. One study (n = 44) reported that having either a CL <20 mm or a positive fetal fibronectin result, or both tests positive, had a sensitivity, specificity, and positive and negative likelihood ratios of 67%, 62%, 1.8, and 0.5, respectively, to predict preterm birth at <34 weeks of gestation. A recent study assessed the predictive accuracy for spontaneous preterm birth of a sequential test (considered positive if CL ≤15 mm or CL between 16-30 mm with positive fetal fibronectin result) in 50 patients hospitalized for preterm labor between 24-34 weeks. Overall, the sequential test had a low predictive accuracy for delivery within 7 and 14 days of testing (positive and negative likelihood ratios around 2.0 and 0.3, respectively) and preterm birth at <34 and <37 weeks of gestation (positive and negative likelihood ratios about 1.5 and 0.6, respectively). The predictive values of the sequential test were not significantly different from those of the individual tests. In summary, there is no evidence that the combination of fetal fibronectin and CL is a better predictor of preterm birth than either CL or fetal fibronectin alone among both asymptomatic and symptomatic women with twin gestations.




Conclusions


The predictive accuracy of biophysical and biochemical tests proposed for the prediction of preterm birth in women with twin gestations is summarized in Table 2 . The ideal predictive test for preterm birth in both asymptomatic and symptomatic women with a twin gestation should be simple, innocuous, rapid, inexpensive, reproducible, and noninvasive, and have a high likelihood ratio to increase the probability of preterm birth in women with a positive test result, and a low likelihood ratio to confidently exclude preterm birth with a negative test result. In addition, in asymptomatic women, the test should be easy to perform early in gestation to allow for potential interventions to prevent not only preterm birth, but its associated perinatal morbidity and mortality. At the present time, it is evident that a single measurement of transvaginal sonographic CL <25 weeks of gestation appears to meet several characteristics to be considered a good predictive test for preterm birth among asymptomatic women. In the present review, we have shown that a CL ≤20 mm at 20-24 weeks of gestation had a pooled positive likelihood ratio of 10.1 for predicting preterm birth at <32 weeks of gestation, which would increase its pretest probability in the United States from 11.3% to 56.3%.


May 10, 2017 | Posted by in GYNECOLOGY | Comments Off on Prediction of preterm birth in twin gestations using biophysical and biochemical tests
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