Volume 45, Issue 1 - Highlight: Preterm Labor

Background: The safety of preventive progestogen therapy for preterm birth remains to be established. This meta-analysis aimed to evaluate the effects of preventive progestogen therapy on neonatal mortality. Methods: Randomized controlled trials (RCTs) on the preventive use of progestogen therapy, published between October 1971 and November 2015, were identified by searching MEDLINE/PubMed, EMBASE, Scopus, ClinicalTrials.gov, Cochrane Library databases, CINAHL, POPLINE, and LILACS using “progesterone” and “preterm birth” as key terms. We conducted separate analyses according to the type of progestogen administered and plurality of the pregnancy. Results: Twenty-two RCTs provided data on 11,188 neonates. Preventive progestogen treatment in women with a history of preterm birth or short cervical length was not associated with increased risk of neonatal death compared to placebo in all analyzed progestogen types and pregnancy conditions. The pooled relative risks (95% confidence interval) of neonatal mortality were 0.69 (0.31–1.54) for vaginal progestogen in singleton pregnancies, 0.6 (0.33–1.09) for intramuscular progestogen in singleton pregnancies, 0.96 (0.51–1.8) for vaginal progestogen in multiple pregnancies, and 0.96 (0.49–1.9) for intramuscular progestogen in multiple pregnancies. Conclusions: The results of this meta-analysis suggest that administration of preventive progestogen treatment to women at risk for preterm birth does not appear to negatively affect neonatal mortality in single or multiple pregnancies regardless of the route of administration.

Preterm birth (PTB) represents a heavy burden in modern obstetrics as it is a major cause of perinatal morbidity and mortality. After the introduction of transvaginal sonography (TVS) screening, secondary prevention of PTB has been re-evaluated on the basis of pre-existing cervical length (CL) and meanwhile the cervical pessary has become an object of increasing interest. This device consists of a silicone cone acting mechanically, that can be easily placed or removed, but whose efficacy is still controversial. Therefore, this study aims to review the most recent evidence regarding its efficacy for prevention of PTB, together with the correct position, the evidence regarding the mechanism of action, the exclusion criteria for pessary placement and the reasons for precocious removal. Overall, it is well tolerated and there are no reports on severe associated side effects. Finally, we discuss published data regarding cervical pessary efficacy. Although results are still conflicting, it seems however to be an effective method for preventing PTB, both in singleton and multiple pregnancies, but further evidence is needed.

Aim: To assess the contemporary maternal and neonatal outcomes following expectant management of preterm premature rupture of membranes (PPROM) prior to 24 weeks’ gestation and to identify prognostic indicators of this morbid presentation. Methods: We performed a systematic review in the Pubmed and EMBASE databases to identify the primary (perinatal mortality, severe neonatal morbidity and serious maternal morbidity) and secondary (neonatal survival and morbidity) outcomes following expectant management of previable PPROM. Results: Mean latency between PPROM and delivery ranged between 20 and 43 days. Women with PPROM <24 weeks had an overall live birth rate of 63.6% and a survival-to-discharge rate of 44.9%. The common neonatal morbidities were respiratory distress syndrome, bronchopulmonary dysplasia and sepsis. The majority of neonatal deaths within 24 h post birth were associated with pulmonary hypoplasia, severe intraventricular haemorrhage and neonatal sepsis. The common maternal outcomes were chorioamnionitis and caesarean sections. The major predictors of neonatal survival were later gestational age at PPROM, adequate residual amniotic fluid levels, C-reactive protein <1 mg/dL within 24 h of admission and PPROM after invasive procedures. Conclusion: Pregnancy latency and neonatal survival following previable PPROM has improved in recent years, although neonatal morbidity remains unchanged despite recent advances in obstetric and neonatal care. There is heterogeneity in management practices across centres worldwide.

Objective: Müllerian anomalies are associated with increased risk of miscarriage, intrauterine growth restriction (IUGR) and preterm birth. While a commonly implicated cause is restricted expansion of endometrial cavity, alternatively it could be due to abnormal placentation. We sought to examine clinical and histopathologic factors associated with preterm delivery in women with Müllerian anomalies. Study design: One hundred and eleven singleton pregnancies in 85 women were analyzed retrospectively. There were 42 pregnancies with bicornaute, 24 with unicornuate, 24 with septate, 19 with didelphys and one each with arcuate and T-shaped uterus. Primary outcomes included gestational age at delivery, placental histopathology, placenta previa and accreta. Results: Twenty-eight (25.2%) of pregnancies were delivered prior to term. Of those, only 14 (50%) were due to preterm labor or preterm premature rupture of membranes (PPROM). Histological evidence of placental malperfusion was present in 22% of all pregnancies and those delivered at an earlier median gestational age [34 (IQR 31–37) vs. 37 weeks (IQR 34–39); P=0.001]. Malperfusion was more common in preterm than in full term births (46% vs. 14%; P=0.04). Conversely, inflammation was not more common in preterm compared to term deliveries (17.9% vs. 16.9%; P=0.89). Five pregnancies had placenta previa, three of which were complicated by accreta. Conclusion: Placental malperfusion, rather than inflammation, was more commonly associated with preterm births in women with uterine anomalies.

Aim: Our aim is to evaluate the effect of nifedipine on fetoplacental hemodynamic parameters. Methods: A retrospective study was conducted at a tertiary center with 30 patients for whom nifedipine treatment was used as a tocolytic therapy for preterm labor. Initiation of this treatment was at 31.6±2.5 weeks of gestation. We combined the pulse Doppler imaging parameters with grayscale imaging via the Bernoulli theorem, which is called the “continuity equation”, to get the fetoplacental perfusion (FPP). Evaluated parameters were the resistance index (RI), the pulsatility index (PI), systole/diastole ratios (S/D), the velocity-time integral of the umbilical artery (VTI), the radius of the umbilical artery, the peak systolic velocity and the mean pressure gradient in the umbilical artery. From these parameters, the FPP was acquired. Results: We found that the RI, the PI and the S/D ratio did not change after treatment with nifedipine. The mean pressure gradient, the VTI and the peak systolic velocity increased after treatment with nifedipine. Nifedipine increases FPP from 166±73.81 beat.cm 3 /min to 220±83.3 beat.cm 3 /min. Discussion: Although nifedipine had no effect on the PI, the RI or the S/D, it increased the mean pressure gradient, the VTI and FPP.

Aim: The present observational study aimed to clarify the effects of sleep disorders on threatened premature delivery, especially preterm uterine contraction. Methods: The participants included 122 healthy singleton pregnant women. The Pittsburgh sleep quality index was used to evaluate the quality of sleep during the previous month at the initial examination and at 16, 24, and 32 weeks of gestation; scores >5 indicate poor sleep. Threatened premature delivery was defined as preterm uterine contraction >6 times/h and requiring tocolytic therapy before 37 weeks of gestation. We analyzed the relationship between poor sleep and threatened premature delivery. Results: Poor sleep affected 27% (n=33) at the initial examination, 34% (n=41) at 16 weeks, 37% (n=45) at 24 weeks, and 41% (n=50) at 32 weeks of gestation. There were 23 patients (19%) with threatened premature delivery. Poor sleep affected 35% and 25% of patients with threatened and non-threatened premature delivery at the initial examination, respectively, 52% and 29% at 16 weeks, 48% and 34% at 24 weeks, and 43% and 40% at 32 weeks of gestation. Conclusions: Sleep disorders at 16 weeks of gestation were the most significantly associated with threatened premature delivery.

There is well-established literature indicating change in partner as a risk for preeclampsia, yet the research on the risk of preterm birth after a change in partners has been sparse and inconsistent. Using a population of California live born singletons, we aimed to determine the risk of preterm birth after a change in partner between the first and second pregnancies. The risk of preterm and early term delivery in the second pregnancy was calculated for mothers who did or did not change partners between births with the referent group as women who delivered both pregnancies at term and did not change partners. Adjusted odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated. Relative to women who delivered at 39 weeks or later in the second pregnancy and did not change partners, preterm birth risks were somewhat lower for women who changed partners between the first and second pregnancies compared to those women who did not change partners. For example, 10.6% of women who did not change partners and delivered their second pregnancy before 34 weeks also delivered their first pregnancy before 34 weeks, while 8.5% of women who changed partners delivered before 34 weeks. Findings suggest partner change may alter the risk of preterm birth.

Objective: Despite decades of research on risk indicators of spontaneous preterm birth (PTB), reliable biomarkers are still not available to screen or diagnose high-risk pregnancies. Several biomarkers in maternal and fetal compartments have been mechanistically linked to PTB, but none of them are reliable predictors of pregnancy outcome. This systematic review was conducted to synthesize the knowledge on PTB biomarkers identified using multiplex analysis. Materials and methods: Three electronic databases (PubMed, EMBASE and Web of Science) were searched for studies in any language reporting the use of multiplex assays for maternal biomarkers associated with PTB published from January 2005 to March 2014. Results: Retrieved citations (3631) were screened, and relevant studies (33) were selected for full-text reading. Ten studies were included in the review. Forty-two PTB-related proteins were reported, and RANTES and IL-10 (three studies) followed by MIP-1β, GM-CSF, Eotaxin, and TNF-RI (two studies) were reported more than once in maternal serum. However, results could not be combined due to heterogeneity in type of sample, study population, assay, and analysis methods. Conclusion: By this systematic review, we conclude that multiplex assays are a potential technological advancement for identifying biomarkers of PTB, although no single or combination of biomarkers could be identified to predict PTB risk.

Objective: The most important parameter in prediction of preterm birth is the cervical length measured by transvaginal ultrasound. In cases with mid-range cervical length (10–30 mm), prediction of preterm birth is difficult. In these cases, testing for cervicovaginal fluid fetal fibronectin (fFN) can improve prediction. However, it is unclear whether transvaginal ultrasound itself influences the fFN result. The purpose of this study was to evaluate this issue independent of gestational age and cervical length. Methods: A prospective evaluation study with 96 cases of pregnant women at 20–41 weeks of gestation was conducted in a tertiary perinatal center. A comparison of cervicovaginal fFN samples before and immediately after transvaginal ultrasound was performed. Fetal fibronectin was measured using the Hologic Rapid fFN 10Q system. It was analyzed quantitatively and qualitatively with ≥50 ng/mL as threshold for “positive”. Changes in fFN values following transvaginal ultrasound were measured. Results: Ninety-six percent (69/72) of women with a fFN concentration of <26 ng/mL before ultrasound had a corresponding fFN value <26 ng/mL after ultrasound. Ninety-three percent (13/14) of women with a fFN concentration of ≥100 ng/mL before ultrasound had a corresponding fFN value ≥100 ng/mL after ultrasound. In 80% (4/5) of women with a positive fFN sample but with a value <100 ng/mL, it turned negative (<50 ng/mL) after ultrasound. For fFN concentrations ≥100 ng/mL, there are high random fluctuations in the measurement results. Conclusions: Fetal fibronectin values of <26 ng/mL (for “negative”) and ≥100 ng/mL (for “positive”) from samples taken after ultrasound provide the same qualitative information as when sampled before ultrasound. For the correct interpretation however, quantitative analysis is necessary.

Objective: To evaluate diagnostic accuracy of quantitative fetal fibronectin (qfFN) test in predicting preterm birth (PTB) risk <34 weeks’ gestation or within 14 days from testing. We explored the predictive potential of the test in five-predefined PTB risk categories based on predefined qfFN thresholds (<10, 10–49, 50–199, 200–499 and ≥500 ng/mL). Methods: Measurement of cervicovaginal qfFN with Rapid fFN 10Q System (Hologic) in 126 women with singleton pregnancy (23–33 weeks’ gestation) reporting signs and symptoms indicative of preterm labour (PTL). Results: For PTB prediction risk <34 weeks’ gestation, sensitivity decreased from 100% to 41.7% and specificity increased from 0% to 99.1% with increasing fFN thresholds. Positive predictive value (PPV) increased from 9.5% to 83.3% with increasing qfFN thresholds, while negative predictive value (NPV) was higher than 90% among the fFN-predefined categories. Diagnostic accuracy results showed an area under a receiving operator characteristic (ROC) curve of 84.5% (95% CI, 0.770–0.903). For delivery prediction within 14 days from the testing, sensitivity decreased from 100% to 42.8% and specificity increased from 0% to 100% with increasing fFN thresholds. Diagnostic accuracy determined by the ROC curve was 66.1% (95% CI, 0.330–0.902). Conclusions: The QfFN thresholds of tests are a useful tool to distinguish pregnant women for PTB prediction risk <34 weeks’ gestation.

Aim: To evaluate the influence of cervical length (CL) and parity as prediction factors for assessment of cesarean section (CS) risk in women with premature rupture of membranes (PROM) at term and unfavorable cervix, undergoing induction of labor (IOL) with dinoprostone intracervical gel. Methods: A prospective study involved 50 nulliparous and 51 multiparous women admitted for IOL. Pre-induction CL was measured and delivery outcomes were recorded. Results: Nulliparous women were younger than the multiparous (26.6±5.2 vs. 30.5±4.9; P<0.001) and had longer pre-induction CL (35.6±5.5 vs. 31.5±4.8; P<0.001) and induction-delivery interval (582 vs. 420 min; P<0.001). There was no difference in the mode of delivery, CS indications, Apgar score, neonatal weight, the rate of neonatal intensive care unit admission and perinatal death in respect of parity. CL was significantly shorter in vaginal vs. cesarean deliveries regardless of parity (31.4 vs. 38.8 mm, P<0.001, respectively). Cut-off values of CL for predicting CS were 37.5 mm in nulliparae and 34.5 mm in multiparae. Conclusions: CLs of 37.5 mm in nulliparae and 34.5 mm in multiparae were determined as the cut-off values in predicting CS risk in women with PROM at term and unfavorable cervix.

Purpose: To determine the diagnostic accuracy of insulin-like growth factor binding protein-1/alpha fetoprotein (Amnioquick duo+ ® ) compared with traditional clinical assessment (TCA) of nitrazine, ferning and pooling for the diagnosis of prelabor rupture of membranes (PROM). Methods: A double-blinded, multicenter clinical study was conducted between February 2015 and August 2015 among pregnant women presenting with symptoms or features suggestive of PROM between 24 and 42 weeks gestation. Confirmation of PROM was done after delivery based on the presence of any two of these criteria: delivery within 48 h to 7 days, evidence of chorioamnionitis, membranes explicitly ruptured at delivery and adverse perinatal outcomes strongly correlated with prolonged PROM. Sensitivity, specificity and accuracy were outcome measures assessed. Results: Two hundred and thirty-six women were recruited. Three women were excluded from the final analysis due to lack of follow-up data and failure to meet inclusion criteria. Two hundred and thirty-three women had complete data for analysis. The specificity and sensitivity values for TCA were 76.2% and 85.2%, which were lower than those of Amnioquick duo+, which were 97.6% and 97.9%, respectively. The accuracy of Amnioquick duo+ was statistically higher (97.9% vs. 83.7%; RR=1.17; 95%CI=1.10–1.24; P<0.001). In equivocal cases (pooling=negative), the accuracy of Amnioquick duo+ vs. TCA was 98.4% vs. 69.4% (RR=1.42; 95%CI=1.20–1.68; P<0.001) at ≥34 weeks gestation and 100.0% vs. 71.4% (RR=1.40; 95%CI=1.07–1.83; P=0.021) at <34 weeks gestation. Conclusion: The performance matrix of Amnioquick duo+ ® was superior to that of TCA for diagnosing PROM even in equivocal cases.

Objectives: To evaluate a community-based intervention trial for the prevention of preterm birth. Methods: This trial was conducted on pregnant women in the Amakusa area, and in the Hitoyoshi-Kuma area, both in Japan. Prophylactic oral antibiotics were recommended for pregnant women with high-risk on preterm birth. The subjects were also encouraged to undergo a periodontal examination. An explanation of proper tooth brushing was given and full mouth scaling was allowed if deemed necessary. Results: Of 720 consented subjects in the Amakusa area and of 373 in the Hitoyoshi-Kuma area, bacterial vaginosis was found in 100 (13.9%) Amakusa residents and 71 (19.0%) Hitoyoshi-Kuma residents. Prophylactic antibiotics were prescribed for 93 Amakusa residents and 39 Hitoyoshi-Kuma residents. Among subjects who underwent a periodontal examination, periodontal disease was found in 47.7% of Amakusa residents and 59.7% of Hitoyoshi-Kuma residents. Periodontal health was improved among these women by a nonsurgical intervention during their pregnancy. Comparing the incidences of very low birth weight (VLBW) with the averages during the preceding 6 years in each area, the incidences of VLBW was 46.4% lower in Amakusa and 69.7% Hitoyoshi-Kuma during the study year. Conclusions: A community-based multifaceted intervention might reduce the incidence of VLBW infants.

Objective: To investigate the maternal complications associated with cesarean section (CS) in the extremely preterm period according to the gestational week (GW) and to indication of delivery. Study design: This is a retrospective case-referent study with a review of medical records of women who delivered at 22–27 weeks of gestation (n=647) at two level III units in Sweden. For abdominal delivery, gestational length was stratified into 22–24 (n=105) and 25–27 (n=301) weeks. For comparison, data on women who underwent a CS at term were identified in a register-based database. Results: The rate of CS in extremely preterm births was 62.8%. There was no difference in the complication rates, but types of incisions other than the low transverse incision were required more often at 22–24 (18.1%) weeks than at 25–27 GWs (9.6%) (P=0.02). Major maternal complications occurred in 6.6% compared with 2.1% in the extremely preterm and term CS, respectively (P<0.01). A maternal indication of extremely preterm CS increased the risk of complications. Conclusions: Almost two-thirds of the births at 22–27 GWs had an abdominal delivery. No increase in short-term morbidity was observed at 22–24 weeks compared to 25–27 weeks. CS performed extremely preterm had more major complications recorded than cesarean at term. The complications are driven by the underlying maternal condition.

Objective: The risk of neonatal respiratory morbidity between indicated deliveries vs. spontaneous deliveries has not been consistent in previous studies, in spite of the traditional belief that chronic intrauterine stress might have protective effect on fetal lung maturation. We hypothesized that the heterogeneous etiology of indicated preterm delivery may obscure the relationship between the etiologies of preterm birth and neonatal respiratory morbidity. To address this issue, we divided the indicated preterm birth (PTB) into medically-indicated (without fetal compromise) PTB and maternal/fetal-indicated PTB, and compared the neonatal respiratory morbidity according to the etiology of late PTB. Study design: Neonatal respiratory morbidities were examined in neonates who were delivered between 34+0 and 36+6 weeks of gestation according to the etiology of PTB: 1) medically-indicated PTB (but without fetal compromise), 2) maternal/fetal-indicated PTB, or 3) spontaneous PTB such as preterm labor or preterm premature rupture of membranes. Results: A total of 710 late preterm neonates were included in the study population, including 31 cases of medically-indicated PTB, 202 cases of maternal/fetal-indicated PTB, and 477 cases of spontaneous PTB. The rate of composite respiratory morbidity in cases of medically-indicated PTB is higher than both maternal/fetal-indicated PTB and spontaneous PTB (19% in medically-indicated PTB, 6% in maternal/fetal-indicated PTB, and 7% in spontaneous PTB). This difference between medically-indicated PTB and maternal/fetal-indicated PTB remained significant after adjustment for confounding variables. Conclusion: The medically-indicated PTB is associated with highest risk of neonatal respiratory morbidity in late PTB.

Background: Infants <32 weeks’ gestation should not be exposed to topical iodine and its avoidance is recommended during pregnancy and breast feeding. Exposure to contrast media and topical iodine is frequently used in many preterm neonates. Aim: To determine whether thyrotropin levels in preterm infants are affected by exposure to intrapartum/neonatal topical iodine and/or the use of iodinated contrast media. Design: Infants <32 weeks’ gestation were recruited. Maternal and neonatal exposures to iodinated contrast media and topical iodine were recorded; levels of thyrotropin and thyroxine were measured from blood-spot cards on postnatal days 7, 14, 28 and the equivalent of 36 weeks’ gestation. Results: One hundred and twenty-five infants were exposed to topical iodine/contrast media and 48 infants were unexposed. No infants were treated for hypothyroidism; three infants (exposed group) had transient hyperthyrotropinaemia. Mean thyrotropin levels were significantly higher on postnatal days 7, 14 and 28 in infants exposed to topical iodine prior to caesarean section compared to unexposed infants, a relationship which persisted after adjustment. Conclusions: In the context of this study, neonatal thyroid dysfunction was seen following exposure to iodine via caesarean section but not via exposure to contrast media.