A comparison of three tocolytics for preterm labor: a randomized clinical trial

Abstract

Objective: To compare the efficacy and maternal side effects of nifedipine (N), magnesium sulfate (M), and indomethacin (I) for acute tocolysis.

Methods: In this single center randomized trial, women in preterm labor 24–32 weeks’ gestation received intravenous M, oral N, or I suppositories. The primary outcomes of interest were arrest of preterm labor (>48?h, ≥7 days), gestational age at delivery, and maternal side effects.

Results: Over a 38-month period, 301 women were allocated to receive M (90), N (114), or I (90). Gestational age at delivery (p?=?0.551) or arrest of labor >48?h, >7 days were similar between the three groups (p?=?0.199, 0.654). Hypotension and tachycardia were more common in N patients compared to women receiving M or I (p?=?0.003, 0.009). Patients receiving I had more fetal ductal constriction or oligohydramnios compared to M or N (p?=?0.001, 0.020) but, I women were tested more often. There was one case of pulmonary edema in the M group and one with plural effusion in the N group.

Conclusion: There were no differences in efficacy or in major maternal safety issues between the three tocolytic agents. Since there is no FDA approved tocolytic to treat preterm labor, clinicians should use the tocolytic that has afforded them the best results with the least maternal/neonatal side effects.     

Tocolysis in women with advanced preterm labor: a secondary analysis of a randomized clinical trial

Objective: To compare the efficacy of tocolytic treatment with indomethacin (I), magnesium sulfate (M) and nifedipine (N) for acute tocolysis in women with advanced cervical dilation (4–6?cm).

Methods: A single center, randomized trial was carried out involving patients in preterm labor (cervix 1–6?cm). Secondary analysis of women with advanced cervical dilation (cervix 4–6?cm) at 24–32 weeks’ gestation who received intravenous M, oral N or I suppositories comprised this study population.

Results: Over 38 months, 92 women with advanced cervical dilation were randomized to one tocoloytic type. Days gained in utero (11.7) and percent remaining undelivered at 48?h (60.8%), 72?h (53.1%) and >7 days (38.3%) were similar regardless of tocolytic employed (p?=?0.923, 0.968, 0.791, 0.802, respectively). Likewise, gestational age at delivery (30.7?±?3.2) was similar between groups (p?=?0.771). Finally, neonatal statistics were not different when stratified by tocolytic treatment.

Conclusion: There were no statistical differences between tocolytics in treating women with advanced cervical dilation. All offered significant days gained in utero after therapy, a high percentage remaining undelivered after 48 or 72?h and after 7 days. It would appear from data that there may be advantages to tocolytic treatment even in women with advanced cervical dilation.     

Prediction of delivery among women with early preterm labor by means of clinical characteristics alone

OBJECTIVE: This study was undertaken to assess whether individual clinical factors or combinations thereof could be used to accurately predict the risk of delivery within 1 week of admission among women with preterm labor and minimal cervical dilatation. STUDY DESIGN: We performed a case-control study of patients admitted to our institution with preterm labor and minimal cervical dilatation. A case patient was a patient who sought treatment with uterine contractions between 24 and 34 weeks' gestation with cervical dilatation 70 potential predictors was recorded. Statistical analysis consisted of bivariate and multivariable methods. We also generated a multivariable clinical predictive model with the purpose of detecting a proportion as high as possible of those destined to be delivered within 1 week (high sensitivity). We estimated that we would need 50 case patients and 150 control subjects to detect an odds ratio of 2.5 for risk factors with a prevalence of 20%, an alpha error of.05, a beta error of.20, and a control subject/case patient ratio of 3:1. RESULTS: Three variables were eligible for inclusion in our logistic models according to the bivariate analyses-bleeding on admission, substance abuse, and admission white blood cell count >/=14,000 cells/microL. The simplest and most favorable model included only 2 variables, bleeding and substance abuse, and yielded a sensitivity of 46% and a specificity of 76%. The full 3-variable model had similar test characteristics. For no model were we able to achieve a sensitivity >/=50%. CONCLUSION: The results of this case-control study suggest that combinations of clinical factors do not yield an adequate level of discrimination to be used alone for predicting the likelihood of delivery within 1 week among patients with minimal degrees of cervical dilatation.     

Hospitalization for women with arrested preterm labor: a randomized trial

OBJECTIVE: To determine whether hospitalization of women with arrested preterm labor has an effect on delivery at 36 weeks or greater when compared with women discharged home. METHODS: All women with a singleton gestation and a diagnosis of arrested preterm labor with intact membranes between 24 and 33 weeks, 4 days of gestation were randomly assigned to home or hospital management. Upon completion of a dexamethasone course, women assigned to outpatient management were promptly discharged, and women in the inpatient group were advised to continue hospitalization until 34 weeks. Decreased activity was encouraged in both groups. Bed rest was not strictly enforced. The primary outcome was delivery at 36 weeks or greater. RESULTS: A total of 101 women of a planned 188 were enrolled at the time of an interim analysis. There was no difference in the primary study outcome between the 2 groups and the trial was terminated. Among the hospitalized women, 71% reached 36 weeks or greater, compared with 72% of those discharged home (P = .89). The mean cervical dilatation in hospitalized women was 2.7 +/- 0.5 cm, compared with 2.6 +/- 0.5 cm in women discharged home (P = .16). The overall length of hospital stay for the women allocated to hospitalization was 16 +/- 13 days. CONCLUSION: Compared with hospitalization, outpatient management of women with arrested preterm labor and intact membranes had no effect on the rate of preterm birth. LEVEL OF EVIDENCE: I.     

The impact of fetal gender and ethnicity on the risk of spontaneous preterm delivery in women with symptoms of preterm labor

Objective: The objective of this study is to evaluate the relation among fetal gender, ethnicity, and preterm labor (PTL) and preterm delivery (PTD).

Methods: A secondary analysis was performed of a prospective cohort study including women with symptoms of PTL between 24 and 34 weeks. The proportion of women carrying a male or female fetus at the onset of PTL was calculated. Gestational age at delivery and risk of PTD of both fetal genders was compared and interaction of fetal gender and maternal ethnicity on the risk of PTD was evaluated.

Results: Of the 594 included women, 327 (55%) carried a male fetus. Median gestational age at delivery in women pregnant with a male fetus was 37 5/7 (IQR 34 4/7–39 1/7) weeks compared with 38 1/7 (IQR 36 0/7–39 5/7) weeks in women pregnant with a female fetus (p?=?0.032). The risk of PTD did not differ significantly. In Caucasians, we did find an increased risk of PTD before 37 weeks in women pregnant with a male fetus (OR 1.9 (95% CI 1.2–3.0)).

Conclusions: The majority of women with PTL are pregnant with a male fetus and these women deliver slightly earlier. Race seems to affect this disparity.     

Progesterone supplementation for prevention of preterm labor: A randomized controlled trial

ObjectiveTo evaluate the efficacy of intramuscular progesterone in prevention of preterm labor in high risk cases.DesignRandomized controlled trial.SettingAin Shams Maternity hospital.Materials and methodsSingleton pregnant women in their second trimester with a history of previous preterm labor were divided into two groups: progesterone group: received 17-α-hydroxy progesterone caproate (Cidolut depot) one dose of 250mg IM once weekly until 36weeks and placebo group: received standard dose of placebo IM per week. Follow up till delivery.ResultsThe mean gestational age was 37.4±1.5 in progesterone group vs. 34.7±2.4 in placebo group (P<0.05). In the progesterone group 8 of 25 women delivered before completion of 37 weeks of gestation (32%) and 17 women delivered full term (68%). In placebo group, 13 of 25 women delivered before completion of 37weeks of gestation (52%) and 12 women delivered full term (48%).ConclusionOur findings support 17-α-hydroxy progesterone as a successful drug in the prevention and decreasing the rate of recurrent preterm labor.     

Presentation to delivery interval in women with early preterm delivery presenting with preterm labor: the effect of gestational age

Background: To evaluate the association between gestational age at presentation and interval to delivery in women with early spontaneous preterm delivery (PTD).

Methods: A retrospective cohort study of women who presented with threatened preterm labor (tPTL) and intact membranes and had a spontaneous PTD <34 weeks in a university-affiliated hospital (2009–2015). The interval from presentation to delivery was compared between different gestational age subgroups.

Results: Of 67 550 deliveries during the study period, 252 met inclusion criteria. This cohort was divided to three gestational age subgroups at presentation: 24–28^6/7 weeks (n?=?83), 29–31^6/7 weeks (n?=?61) and 32–33^6/7 weeks (n?=?108). Median time from presentation to delivery was 24.5?h. An inverse relation was observed between gestational age at presentation and admission–delivery interval (group A: 74.7?h, group B: 21.0?h, group C: 14.0?h, p?Conclusion: Gestational age at presentation is inversely related to admission–delivery interval in women with tPTL and intact membranes.     

Oligohydramnios is an independent risk factor for perinatal morbidity among women with pre-eclampsia who delivered preterm

Purpose: The purpose of this study is to determine the relationship between oligohydramnios and adverse maternal and neonatal outcomes in a unique cohort of preterm pre-eclamptic patients.

Materials and methods: A retrospective matched case–control study comparing 81 preterm parturients (28 0/7 and 36 6/7 weeks) with pre-eclampsia and oligohydramnios to 81 preterm pre-eclamptic patients with a normal amniotic fluid index (AFI).

Results: About 4.8 percent of all our preterm pre-eclamptic patients had oligohydramnios. Patients in the study group showed a trend toward being older than 35 years (18.5%% versus 27.2%) and were more likely more likely to be primi-parous, and have previously delivered a small for gestational age (SGA) or a dead fetus (p?=?.012, .039, and .032). Severity of pre-eclampsia, including HELLP and eclampsia as well as gestational age at delivery did not differ statistically between the study groups (p?=?.47, .516). Growth restricted fetuses were more common in the study group (p?p?=?.046). Post-partum complications, pre-eclampsia during the puerperium, admission to intensive care units, and MgSO₄ treatment were more common in the control group (p?=?.028, .012, .008). But study group patients had more cesarean sections (p?=?.011). Neonates of study group parturients had lower fetal weight, were more likely to be SGA, and experience fetal distress during labor (p?=?.001, .001, and .03). Following delivery, they were more likely to have anemia and stay longer in neonatal intensive care unit (NICU) (p?=?.017, .017). A multivariate logistic regression analysis showed that oligohydramnios, but not the severity of pre-eclampsia, significantly affected Composite Neonatal Outcome {Apgar scores at 1 &; 5?min (<5 and <7, respectively), neonatal death, umbilical cord pH <7.1, fetal distress (category III fetal heart rate tracing), fetal anemia, fetal hypoglycemia}.

Conclusions: Oligohydramnios is an independent risk factor for early neonatal morbidity in preterm pre-eclamptic patients. AFI <5?cm can be used as one component in the educated decision for delivery of these patients.

Brief rationale

The significance of oligohydramnios in pregnancies complicated by preterm delivery, preeclampsia or both is controversial. By comparing two relatively large, almost similar, cohorts of preterm preeclamptic parturient with and without oligohydramnios we demonstrated that Amniotic Fluid Index <5 cm is associated with a significant neonatal morbidity. This question was not previously addressed in proper manner aside one, much smaller, study that was under powered to address this topic. We innovate by illustrating the significance of oligohydramnios and its association with subsequent neonatal morbidity. Thus, we conclude that the presence of oligohydramnios in women with preterm preeclampsia can be a factor in the decision for or against conservative management of these patients.     

Vaginal progesterone after tocolytic therapy in threatened preterm labor

Objective: The aim of this study was retrospective evaluation of progesterone efficacy in pregnant patients with preterm uterine contractions. Material: 190 women hospitalized at 1st Department of Obstetrics and Gynecology, Medical University of Warsaw, in 2007–2010, with symptoms of threatened preterm labor were enrolled in the study. 94 women were treated with tocolytics and steroids (control group), while 96 women received additionally 200?mg of progesterone vaginally until delivery or 34th weeks of gestation (progesterone group). Results: The mean gestational age at admission was 27 weeks in progesterone group and 28 weeks in control group. Cervical length was similar in both groups. There were no significant differences in week of delivery between groups, but the progesterone group had significant increase in prolongation of pregnancy (7.6 versus 6.3 weeks, p?=?0.039). Vaginal progesterone was associated with reduction of delivery before 34 weeks (9.8% versus 35.3%; p?=?0.002) and neonatal birth weight <1500?g (3.2% versus 20.6%; p?=?0.011) only in patients presenting with uterine contractions after 27 weeks. Conclusion: The administration of vaginal progesterone after tocolysis in threatened preterm labor is associated with prolongation of pregnancy. The reduction of deliveries before 34 weeks was observed in patients presenting with contractions after 27 weeks gestation.     

Risk factors for spontaneous preterm delivery after arrested episode of preterm labor

Introduction: We aimed to identify specific risk factors for spontaneous preterm delivery (PTD) among women with arrested preterm labor (PTL).

Method: A retrospective study of women admitted due to imminent PTL and intact membranes, which did not progress to PTD within 24?h from admission. Eligibility was limited to singleton gestations at 24?+?0/7–33?+?6/7 weeks of gestations with no known chromosomal or structural anomalies. All women were treated with corticosteroids and tocolysis. Comparison was made between those who delivered at <37?+?0/7 weeks of gestation (study group) to women who delivered at ≥37?+?0/7 weeks of gestation (controls).

Results: Overall, 301 women were recruited, of which 85 (28.2%) delivered before 37?+?0/7 weeks and 216 (71.8%) delivered at term. Advanced cervical dilatation was found to be an independent risk factor for PTD [for women with no past PTD: adjusted odds ratio (aOR) 1.66, 95% CI: 1.06–2.61 for each 1?cm dilatation; for women with past PTD: aOR 2.81, 95% CI: 1.02–7.73 for each 1?cm dilatation]. Among women without past PTD, additional independent risk factors for PTD were earlier gestational week at admission (OR: 1.20, 95% CI: 1.09–1.32 for each earlier week) and short cervical length (OR: 1.04, 95% CI: 1.01–1.08 for each decrease of 1?mm in cervical length).

Conclusion: Advanced cervical dilatation, earlier gestational age at the episode of arrested PTL, and short cervical length are specific risk factors for PTD in women with arrested PTL. These findings may assist in counseling women and direct further investigation.     

Cervilenz assessment of cervical length compared to fetal fibronectin in the prediction of preterm delivery in women with threatened preterm labor

Objective.?To determine whether cervical length (CL) measured by the Cervilenz? measuring device is an effective screening tool for the prediction of preterm delivery (PTD) compared to fetal fibronectin (fFN).

Methods.?We evaluated fFN and CL among women who enrolled into a randomized control trial (RCT) comparing management algorithms for threatened preterm labor between 24 and 34 weeks' gestation. In all subjects, fFN was collected, with CL determined in blinded fashion. The sensitivity, specificity, and positive and negative predictive values (NPV) for fFN or Cervilenz in prediction of PTD within 7 days or prior to 37 weeks were determined.

Results.?Fifty-two subjects were evaluated. CL?<30?mm correlated with PTD?<7 days (r?=?0.31, p?=?0.04) and fFN positivity (r?=?0.43, p?=?0.006). CL?<30?mm and fFN had excellent NPV for PTD?<7 days (97.1 vs. 97.3%), and the area under the receiver operator characteristic curves were similar for prediction of PTD?<7 days (76.6 vs. 75.2%, p?=?0.71) or?<37 weeks (56.7 vs. 55.2%, p?=?0.71).

Conclusions.?Measurement of CL with Cervilenz appears to be equivalent to fFN in screening symptomatic women for PTD within 7 days or prior to 37 weeks. Given cost and turnaround time with fFN testing, Cervilenz represents a promising new tool for real time, clinically useful results in the management of women with threatened preterm labor.     

Maintenance tocolysis with oral micronized progesterone for prevention of preterm birth after arrested preterm labor

Objective

To evaluate the efficacy of maintenance therapy with oral micronized progesterone (OMP) for prolongation of pregnancy in cases of arrested preterm labor.

Methods

Ninety women at 24–34 weeks of singleton pregnancy with intact membranes and arrested preterm labor were randomly allocated to receive OMP (n = 45) or placebo (n = 45) daily until 37 weeks or delivery, whichever was earlier. Outcome parameters were compared using Student t test, χ² test, Fisher exact test, and log-rank χ² test.

Results

OMP significantly prolonged the latency period (33.29 ± 22.16 vs 23.07 ± 15.42 days; P = 0.013). Log-rank analysis revealed a significant difference in mean time to delivery between the 2 groups (P = 0.014). There were significantly fewer preterm births (33% vs 58%; P = 0.034) and low birth weight neonates (37% vs 64%; P = 0.017), and significantly higher mean birth weight (2.44 ± 0.58 vs 2.14 ± 0.47 kg; P = 0.009) in the OMP group. Perinatal outcomes and adverse effects were similar in the 2 groups.

Conclusion

Maintenance tocolysis with OMP significantly prolonged pregnancy and decreased the number of preterm births.Clinical Trial Registry of India: CTRI/2011/10/002043.