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Does one particular cesarean technique confer better maternal and neonatal outcomes?
EXPERT COMMENTARY
John M. Thorp Jr, MD, McAllister Distinguished Professor, Division Director, General Obstetrics and Gynecology, Vice Chair of Research, Department of Ob-Gyn, University of North Carolina Schools of Medicine and Public Health, Chapel Hill.
Five years ago one of our interns operating with the director of labor and delivery challenged him as to why we were not using evidenced-based surgical techniques for cesarean delivery. Bruised by the formidable (and at times misleading) club of “evidence-based medicine” that is held as sacrosanct by the modern obstetrician, the director responded to the charge by researching a systematic review on abdominal delivery that amalgamated studies of poor quality with precious few trials. He unilaterally decided that we needed an opening in the transparent portion of the drape overlying the incision site so that we might use “evidence” to prevent operative site infection. The end result: No change in the incidence of wound infections, and adhesive drapes that did not adhere well, thereby displacing the effluent of amniotic fluid and blood that are part of a cesarean delivery back into the first assistant’s socks, shoes, and clothing. It was as if the clock had been turned back to my early years as an attending when we had cloth drapes. So much for having an evidence-based protocol. I was thus elated at reading the results of the CORONIS trial.
Details of the study
The CORONIS trial, in which investigators randomly assigned almost 16,000 women from 7 countries (Argentina, Chile, Ghana, India, Kenya, Pakistan, and Sudan), used a sophisticated factorial design and followed up 13,153 (84%) of the women for 3 years. The investigators tested an array of technical questions about 5 intervention pairs used during abdominal delivery and reported the main outcomes of interest for each intervention, including:
- blunt versus sharp abdominal entry—no evidence of a difference in risk of abdominal hernias (adjusted risk ratio [RR], 0.66; 95% confidence interval [CI], 0.39–1.11)
- exteriorization of the uterus versus intra-abdominal repair—no evidence of a difference in risk of infertility (RR, 0.91; 95% CI, 0.71–1.18) or of ectopic pregnancy (RR, 0.50; CI, 0.15–1.66)
- single- versus double-layer closure of the uterus—no evidence of a difference in maternal death (RR, 0.78; 95% CI, 0.46–1.32) or a composite of pregnancy complications (RR, 1.20; 95% CI, 0.75–1.90)
- closure versus nonclosure of the peritoneum—no evidence of a difference in any outcomes relating to symptoms associated with pelvic adhesions, such as infertility (RR, 0.8; 95% CI, 0.61–1.06)
- chromic catgut versus polyglactin-910 sutures—no evidence of a difference in the main comparisons for adverse pregnancy outcomes in a subsequent pregnancy, such as uterine rupture (RR, 3.05; 95% CI, 0.32–29.29).
Strengths and limitations. The CORONIS trial included a large number of participants and had comprehensive follow-up, a rigorous data collection process, and the participation of many countries. The trial’s participating centers, however, were mostly large referral hospitals with high research interest; adverse outcomes might have been higher in other settings. As well, a lower incidence of subsequent pregnancy among participants limited the study’s power to detect differences in outcomes between the intervention pairs.
Conclusions. None of the alternative techniques produced any real benefits despite syntheses-suggested benefit reported in systematic reviews. Surgeon preference for cesarean delivery techniques likely will continue to guide clinical practice along with economic and institution factors.
A word to the wise: Evidence is not created equally, and pushing it into lumps does not increase its value.
--John M. Thorp Jr, MD
Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.
EXPERT COMMENTARY
John M. Thorp Jr, MD, McAllister Distinguished Professor, Division Director, General Obstetrics and Gynecology, Vice Chair of Research, Department of Ob-Gyn, University of North Carolina Schools of Medicine and Public Health, Chapel Hill.
Five years ago one of our interns operating with the director of labor and delivery challenged him as to why we were not using evidenced-based surgical techniques for cesarean delivery. Bruised by the formidable (and at times misleading) club of “evidence-based medicine” that is held as sacrosanct by the modern obstetrician, the director responded to the charge by researching a systematic review on abdominal delivery that amalgamated studies of poor quality with precious few trials. He unilaterally decided that we needed an opening in the transparent portion of the drape overlying the incision site so that we might use “evidence” to prevent operative site infection. The end result: No change in the incidence of wound infections, and adhesive drapes that did not adhere well, thereby displacing the effluent of amniotic fluid and blood that are part of a cesarean delivery back into the first assistant’s socks, shoes, and clothing. It was as if the clock had been turned back to my early years as an attending when we had cloth drapes. So much for having an evidence-based protocol. I was thus elated at reading the results of the CORONIS trial.
Details of the study
The CORONIS trial, in which investigators randomly assigned almost 16,000 women from 7 countries (Argentina, Chile, Ghana, India, Kenya, Pakistan, and Sudan), used a sophisticated factorial design and followed up 13,153 (84%) of the women for 3 years. The investigators tested an array of technical questions about 5 intervention pairs used during abdominal delivery and reported the main outcomes of interest for each intervention, including:
- blunt versus sharp abdominal entry—no evidence of a difference in risk of abdominal hernias (adjusted risk ratio [RR], 0.66; 95% confidence interval [CI], 0.39–1.11)
- exteriorization of the uterus versus intra-abdominal repair—no evidence of a difference in risk of infertility (RR, 0.91; 95% CI, 0.71–1.18) or of ectopic pregnancy (RR, 0.50; CI, 0.15–1.66)
- single- versus double-layer closure of the uterus—no evidence of a difference in maternal death (RR, 0.78; 95% CI, 0.46–1.32) or a composite of pregnancy complications (RR, 1.20; 95% CI, 0.75–1.90)
- closure versus nonclosure of the peritoneum—no evidence of a difference in any outcomes relating to symptoms associated with pelvic adhesions, such as infertility (RR, 0.8; 95% CI, 0.61–1.06)
- chromic catgut versus polyglactin-910 sutures—no evidence of a difference in the main comparisons for adverse pregnancy outcomes in a subsequent pregnancy, such as uterine rupture (RR, 3.05; 95% CI, 0.32–29.29).
Strengths and limitations. The CORONIS trial included a large number of participants and had comprehensive follow-up, a rigorous data collection process, and the participation of many countries. The trial’s participating centers, however, were mostly large referral hospitals with high research interest; adverse outcomes might have been higher in other settings. As well, a lower incidence of subsequent pregnancy among participants limited the study’s power to detect differences in outcomes between the intervention pairs.
Conclusions. None of the alternative techniques produced any real benefits despite syntheses-suggested benefit reported in systematic reviews. Surgeon preference for cesarean delivery techniques likely will continue to guide clinical practice along with economic and institution factors.
A word to the wise: Evidence is not created equally, and pushing it into lumps does not increase its value.
--John M. Thorp Jr, MD
Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.
EXPERT COMMENTARY
John M. Thorp Jr, MD, McAllister Distinguished Professor, Division Director, General Obstetrics and Gynecology, Vice Chair of Research, Department of Ob-Gyn, University of North Carolina Schools of Medicine and Public Health, Chapel Hill.
Five years ago one of our interns operating with the director of labor and delivery challenged him as to why we were not using evidenced-based surgical techniques for cesarean delivery. Bruised by the formidable (and at times misleading) club of “evidence-based medicine” that is held as sacrosanct by the modern obstetrician, the director responded to the charge by researching a systematic review on abdominal delivery that amalgamated studies of poor quality with precious few trials. He unilaterally decided that we needed an opening in the transparent portion of the drape overlying the incision site so that we might use “evidence” to prevent operative site infection. The end result: No change in the incidence of wound infections, and adhesive drapes that did not adhere well, thereby displacing the effluent of amniotic fluid and blood that are part of a cesarean delivery back into the first assistant’s socks, shoes, and clothing. It was as if the clock had been turned back to my early years as an attending when we had cloth drapes. So much for having an evidence-based protocol. I was thus elated at reading the results of the CORONIS trial.
Details of the study
The CORONIS trial, in which investigators randomly assigned almost 16,000 women from 7 countries (Argentina, Chile, Ghana, India, Kenya, Pakistan, and Sudan), used a sophisticated factorial design and followed up 13,153 (84%) of the women for 3 years. The investigators tested an array of technical questions about 5 intervention pairs used during abdominal delivery and reported the main outcomes of interest for each intervention, including:
- blunt versus sharp abdominal entry—no evidence of a difference in risk of abdominal hernias (adjusted risk ratio [RR], 0.66; 95% confidence interval [CI], 0.39–1.11)
- exteriorization of the uterus versus intra-abdominal repair—no evidence of a difference in risk of infertility (RR, 0.91; 95% CI, 0.71–1.18) or of ectopic pregnancy (RR, 0.50; CI, 0.15–1.66)
- single- versus double-layer closure of the uterus—no evidence of a difference in maternal death (RR, 0.78; 95% CI, 0.46–1.32) or a composite of pregnancy complications (RR, 1.20; 95% CI, 0.75–1.90)
- closure versus nonclosure of the peritoneum—no evidence of a difference in any outcomes relating to symptoms associated with pelvic adhesions, such as infertility (RR, 0.8; 95% CI, 0.61–1.06)
- chromic catgut versus polyglactin-910 sutures—no evidence of a difference in the main comparisons for adverse pregnancy outcomes in a subsequent pregnancy, such as uterine rupture (RR, 3.05; 95% CI, 0.32–29.29).
Strengths and limitations. The CORONIS trial included a large number of participants and had comprehensive follow-up, a rigorous data collection process, and the participation of many countries. The trial’s participating centers, however, were mostly large referral hospitals with high research interest; adverse outcomes might have been higher in other settings. As well, a lower incidence of subsequent pregnancy among participants limited the study’s power to detect differences in outcomes between the intervention pairs.
Conclusions. None of the alternative techniques produced any real benefits despite syntheses-suggested benefit reported in systematic reviews. Surgeon preference for cesarean delivery techniques likely will continue to guide clinical practice along with economic and institution factors.
A word to the wise: Evidence is not created equally, and pushing it into lumps does not increase its value.
--John M. Thorp Jr, MD
Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.
What is the optimal interval between administration of antenatal corticosteroids and preterm delivery?
In the early 1970s, as a direct by-product of basic science research on preterm birth using a sheep model, Liggins and Howie discovered that the administration of corticosteroids to women facing impending preterm birth could lower the risk not only of respiratory morbidity but also of intraventricular hemorrhage, necrotizing colitis, and death for their newborns. This discovery was confirmed in other clinical trials, and the novel strategy of a secondary therapy to reduce the sequelae of preterm birth became part of standard perinatal care. Despite this advance, numerous questions remain, including the proper dosing interval and number of doses of corticosteroids necessary to prevent the sequelae of preterm birth.
Authors explored births before 34 weeks’ gestation
To elucidate the proper dosing interval, Wilms and colleagues conducted a retrospective cohort study among women who received antenatal corticosteroids and delivered before 34 weeks’ gestation. Of the 254 infants who were delivered prematurely, those delivered within 7 days of the administration of corticosteroids had a reduced risk of requiring intervention in the NICU. The authors concluded that the efficacy of antenatal corticosteroids diminishes when the treatment-to-delivery interval exceeds 7 days.
Limitations of the study
The investigators admonish readers to carefully consider the timing of the first dose of corticosteroid therapy. Their conclusions are limited by 1) the retrospective nature of their research and 2) the fact that clinicians who cared for newborns in this study were aware of the timing of maternal corticosteroid administration.
Nevertheless, clinicians can draw pertinent points for day-to-day practice:
- The window of benefit seems to be time-limited, with a break-point and diminution at 7 days after administration of corticosteroids
- A second dose of antenatal corticosteroids may be of benefit in selected situations.
Repetitive dosing beyond two rounds 1 week apart appears to have no benefit, according to clinical trials of weekly versus one-time dosing. Moreover, repetitive dosing causes small but significant decrements in birth weight and head circumference. Whether these changes are associated with long-term harm remains unknown.
Other authors have drawn similar conclusions—but we need prospective randomized, controlled trials to clarify the issue of whether to repeat corticosteroid administration and, if so, how many doses are optimal and how often they should be given.
In women who are given antenatal corticosteroids for impending preterm birth, pay attention to the interval between administration and delivery. In this study, an interval of 7 days or less was associated with a reduced need for intervention in the NICU.
John M. Thorp, Jr, MD
We want to hear from you! Tell us what you think.
In the early 1970s, as a direct by-product of basic science research on preterm birth using a sheep model, Liggins and Howie discovered that the administration of corticosteroids to women facing impending preterm birth could lower the risk not only of respiratory morbidity but also of intraventricular hemorrhage, necrotizing colitis, and death for their newborns. This discovery was confirmed in other clinical trials, and the novel strategy of a secondary therapy to reduce the sequelae of preterm birth became part of standard perinatal care. Despite this advance, numerous questions remain, including the proper dosing interval and number of doses of corticosteroids necessary to prevent the sequelae of preterm birth.
Authors explored births before 34 weeks’ gestation
To elucidate the proper dosing interval, Wilms and colleagues conducted a retrospective cohort study among women who received antenatal corticosteroids and delivered before 34 weeks’ gestation. Of the 254 infants who were delivered prematurely, those delivered within 7 days of the administration of corticosteroids had a reduced risk of requiring intervention in the NICU. The authors concluded that the efficacy of antenatal corticosteroids diminishes when the treatment-to-delivery interval exceeds 7 days.
Limitations of the study
The investigators admonish readers to carefully consider the timing of the first dose of corticosteroid therapy. Their conclusions are limited by 1) the retrospective nature of their research and 2) the fact that clinicians who cared for newborns in this study were aware of the timing of maternal corticosteroid administration.
Nevertheless, clinicians can draw pertinent points for day-to-day practice:
- The window of benefit seems to be time-limited, with a break-point and diminution at 7 days after administration of corticosteroids
- A second dose of antenatal corticosteroids may be of benefit in selected situations.
Repetitive dosing beyond two rounds 1 week apart appears to have no benefit, according to clinical trials of weekly versus one-time dosing. Moreover, repetitive dosing causes small but significant decrements in birth weight and head circumference. Whether these changes are associated with long-term harm remains unknown.
Other authors have drawn similar conclusions—but we need prospective randomized, controlled trials to clarify the issue of whether to repeat corticosteroid administration and, if so, how many doses are optimal and how often they should be given.
In women who are given antenatal corticosteroids for impending preterm birth, pay attention to the interval between administration and delivery. In this study, an interval of 7 days or less was associated with a reduced need for intervention in the NICU.
John M. Thorp, Jr, MD
We want to hear from you! Tell us what you think.
In the early 1970s, as a direct by-product of basic science research on preterm birth using a sheep model, Liggins and Howie discovered that the administration of corticosteroids to women facing impending preterm birth could lower the risk not only of respiratory morbidity but also of intraventricular hemorrhage, necrotizing colitis, and death for their newborns. This discovery was confirmed in other clinical trials, and the novel strategy of a secondary therapy to reduce the sequelae of preterm birth became part of standard perinatal care. Despite this advance, numerous questions remain, including the proper dosing interval and number of doses of corticosteroids necessary to prevent the sequelae of preterm birth.
Authors explored births before 34 weeks’ gestation
To elucidate the proper dosing interval, Wilms and colleagues conducted a retrospective cohort study among women who received antenatal corticosteroids and delivered before 34 weeks’ gestation. Of the 254 infants who were delivered prematurely, those delivered within 7 days of the administration of corticosteroids had a reduced risk of requiring intervention in the NICU. The authors concluded that the efficacy of antenatal corticosteroids diminishes when the treatment-to-delivery interval exceeds 7 days.
Limitations of the study
The investigators admonish readers to carefully consider the timing of the first dose of corticosteroid therapy. Their conclusions are limited by 1) the retrospective nature of their research and 2) the fact that clinicians who cared for newborns in this study were aware of the timing of maternal corticosteroid administration.
Nevertheless, clinicians can draw pertinent points for day-to-day practice:
- The window of benefit seems to be time-limited, with a break-point and diminution at 7 days after administration of corticosteroids
- A second dose of antenatal corticosteroids may be of benefit in selected situations.
Repetitive dosing beyond two rounds 1 week apart appears to have no benefit, according to clinical trials of weekly versus one-time dosing. Moreover, repetitive dosing causes small but significant decrements in birth weight and head circumference. Whether these changes are associated with long-term harm remains unknown.
Other authors have drawn similar conclusions—but we need prospective randomized, controlled trials to clarify the issue of whether to repeat corticosteroid administration and, if so, how many doses are optimal and how often they should be given.
In women who are given antenatal corticosteroids for impending preterm birth, pay attention to the interval between administration and delivery. In this study, an interval of 7 days or less was associated with a reduced need for intervention in the NICU.
John M. Thorp, Jr, MD
We want to hear from you! Tell us what you think.
Can intrauterine growth restriction be present in the first trimester?
EXPERT COMMENTARY
Conventional perinatal wisdom, since the inception of obstetric ultrasonography (US), has been that disordered growth in utero occurs only in the second half of pregnancy; growth in the first half of pregnancy is believed to be uniform, with little variation among individuals. This assumption of uniform growth at the beginning of gestation allows us to create growth curves for populations and generate estimates of gestational age for individual fetuses from their growth parameters. Utilization of US for dating has pushed the mean gestational age at delivery back a few days, tightened the distribution around the mean, and lowered the prevalence of postdatism.
In this new study, Thorsell and colleagues question conventional wisdom and introduce a new notion that disordered intrauterine growth may be present in the first half of pregnancy as early as the first trimester. Women whose US evaluation at 16–18 weeks moved their due date forward more than 6 days were at increased risk of intrauterine growth restriction, preterm birth, and preeclampsia. Those whose due date was moved forward more than 6 days as a result of US dating at 12–14 weeks were at increased risk of growth restriction, but not preterm birth or preeclampsia. The authors call for increased surveillance for growth restriction in pregnancies in which US evaluation changes dates.
Weaknesses of the study
These findings are intriguing, but take them with a grain of salt. “Intendedness” of conception can, of course, be a marker of higher social status and resources, thereby linking “unintendedness” to poor dates (dates that need to be adjusted by US) and poor pregnancy outcomes. To prove their point, Thorsell and associates would have to repeat the study in women using ovulation-prediction methods or assisted reproduction (which would be confounded by subfertility and its link to poor perinatal outcomes). Such a study would not be feasible, given that a sample size of more than 27,000 women was required to demonstrate very mild effects in this investigation (risk ratios from 1.1 to 1.5).
This provocative study challenges convention but is not ready for incorporation into clinical practice routines. However, it may be prudent to monitor pregnancies in which US dating significantly changes the due date, keeping in mind a potential for intrauterine growth restriction.—JOHN M. THORP JR, MD
EXPERT COMMENTARY
Conventional perinatal wisdom, since the inception of obstetric ultrasonography (US), has been that disordered growth in utero occurs only in the second half of pregnancy; growth in the first half of pregnancy is believed to be uniform, with little variation among individuals. This assumption of uniform growth at the beginning of gestation allows us to create growth curves for populations and generate estimates of gestational age for individual fetuses from their growth parameters. Utilization of US for dating has pushed the mean gestational age at delivery back a few days, tightened the distribution around the mean, and lowered the prevalence of postdatism.
In this new study, Thorsell and colleagues question conventional wisdom and introduce a new notion that disordered intrauterine growth may be present in the first half of pregnancy as early as the first trimester. Women whose US evaluation at 16–18 weeks moved their due date forward more than 6 days were at increased risk of intrauterine growth restriction, preterm birth, and preeclampsia. Those whose due date was moved forward more than 6 days as a result of US dating at 12–14 weeks were at increased risk of growth restriction, but not preterm birth or preeclampsia. The authors call for increased surveillance for growth restriction in pregnancies in which US evaluation changes dates.
Weaknesses of the study
These findings are intriguing, but take them with a grain of salt. “Intendedness” of conception can, of course, be a marker of higher social status and resources, thereby linking “unintendedness” to poor dates (dates that need to be adjusted by US) and poor pregnancy outcomes. To prove their point, Thorsell and associates would have to repeat the study in women using ovulation-prediction methods or assisted reproduction (which would be confounded by subfertility and its link to poor perinatal outcomes). Such a study would not be feasible, given that a sample size of more than 27,000 women was required to demonstrate very mild effects in this investigation (risk ratios from 1.1 to 1.5).
This provocative study challenges convention but is not ready for incorporation into clinical practice routines. However, it may be prudent to monitor pregnancies in which US dating significantly changes the due date, keeping in mind a potential for intrauterine growth restriction.—JOHN M. THORP JR, MD
EXPERT COMMENTARY
Conventional perinatal wisdom, since the inception of obstetric ultrasonography (US), has been that disordered growth in utero occurs only in the second half of pregnancy; growth in the first half of pregnancy is believed to be uniform, with little variation among individuals. This assumption of uniform growth at the beginning of gestation allows us to create growth curves for populations and generate estimates of gestational age for individual fetuses from their growth parameters. Utilization of US for dating has pushed the mean gestational age at delivery back a few days, tightened the distribution around the mean, and lowered the prevalence of postdatism.
In this new study, Thorsell and colleagues question conventional wisdom and introduce a new notion that disordered intrauterine growth may be present in the first half of pregnancy as early as the first trimester. Women whose US evaluation at 16–18 weeks moved their due date forward more than 6 days were at increased risk of intrauterine growth restriction, preterm birth, and preeclampsia. Those whose due date was moved forward more than 6 days as a result of US dating at 12–14 weeks were at increased risk of growth restriction, but not preterm birth or preeclampsia. The authors call for increased surveillance for growth restriction in pregnancies in which US evaluation changes dates.
Weaknesses of the study
These findings are intriguing, but take them with a grain of salt. “Intendedness” of conception can, of course, be a marker of higher social status and resources, thereby linking “unintendedness” to poor dates (dates that need to be adjusted by US) and poor pregnancy outcomes. To prove their point, Thorsell and associates would have to repeat the study in women using ovulation-prediction methods or assisted reproduction (which would be confounded by subfertility and its link to poor perinatal outcomes). Such a study would not be feasible, given that a sample size of more than 27,000 women was required to demonstrate very mild effects in this investigation (risk ratios from 1.1 to 1.5).
This provocative study challenges convention but is not ready for incorporation into clinical practice routines. However, it may be prudent to monitor pregnancies in which US dating significantly changes the due date, keeping in mind a potential for intrauterine growth restriction.—JOHN M. THORP JR, MD
Q.Does cervical dysplasia raise the risk of preterm birth?
Expert Commentary
Preterm birth and cervical dysplasia share many risk factors, most of which are the progeny of low socioeconomic status. It is not surprising, therefore, that cervical dysplasia is a risk factor for pre-term birth independent of the treatment modality chosen for the precancerous condition. This large cohort study linking outpatient gynecologic records with childbirths from Australia found exactly that. It is the largest study so far to focus on pregnancy outcomes in women following diagnosis and treatment of dysplasia. Frustrating to both the obstetrician and the gynecologist is the fact that smoking is the only readily modifiable risk factor for preterm birth or cervical dysplasia.
Ablative procedures produce better pregnancy outcomes than excision
Beyond epidemiology, this paper bears an important message for clinicians and patients: Procedures that remove portions of the cervix, such as LEEP, diathermy, and cone biopsy, raise the risk of subsequent preterm birth, compared with less destructive ablative procedures such as laser ablation (as reported in the Up-date on Cervical Disease, by Thomas C. Wright, MD, in the March issue of this journal). This was also demonstrated in a large review of the subject.1 Therefore, for an optimal obstetrical outcome, ablative procedures are preferable to excisional ones in women who have not yet completed childbearing. Given that success rates are only slightly lower for ablative procedures than for destructive ones, a clinician can recommend ablation without fear of dysplasia progressing to invasive cancer.
Widespread HPV vaccination could help reduce preterm birth rate
This study highlights how a systematic program of human papillomavirus (HPV) vaccination in adolescents (male and female) before their coital debut could reduce the rate of preterm birth by eliminating the need for women to undergo excisional treatment for cervical dysplasia. The possibility for such improvement in birth outcomes should motivate those of us working to prevent preterm birth to advocate for societal investment in this approach. It also might alleviate concerns that HPV vaccination has the potential to disrupt family life by encouraging promiscuity. How can anyone argue against a program that will prevent cancer and preterm birth?
1. Kyrgiou M, Koliopoulos G, Martin-Hirsch P, Arbyn M, Prendiville W, Paraskevaidis E. Obstetric outcomes after conservative treatment for intraepithelial or early invasive lesions: a systematic review and meta-analysis of the literature. Lancet. 2006;367:489-498.
Expert Commentary
Preterm birth and cervical dysplasia share many risk factors, most of which are the progeny of low socioeconomic status. It is not surprising, therefore, that cervical dysplasia is a risk factor for pre-term birth independent of the treatment modality chosen for the precancerous condition. This large cohort study linking outpatient gynecologic records with childbirths from Australia found exactly that. It is the largest study so far to focus on pregnancy outcomes in women following diagnosis and treatment of dysplasia. Frustrating to both the obstetrician and the gynecologist is the fact that smoking is the only readily modifiable risk factor for preterm birth or cervical dysplasia.
Ablative procedures produce better pregnancy outcomes than excision
Beyond epidemiology, this paper bears an important message for clinicians and patients: Procedures that remove portions of the cervix, such as LEEP, diathermy, and cone biopsy, raise the risk of subsequent preterm birth, compared with less destructive ablative procedures such as laser ablation (as reported in the Up-date on Cervical Disease, by Thomas C. Wright, MD, in the March issue of this journal). This was also demonstrated in a large review of the subject.1 Therefore, for an optimal obstetrical outcome, ablative procedures are preferable to excisional ones in women who have not yet completed childbearing. Given that success rates are only slightly lower for ablative procedures than for destructive ones, a clinician can recommend ablation without fear of dysplasia progressing to invasive cancer.
Widespread HPV vaccination could help reduce preterm birth rate
This study highlights how a systematic program of human papillomavirus (HPV) vaccination in adolescents (male and female) before their coital debut could reduce the rate of preterm birth by eliminating the need for women to undergo excisional treatment for cervical dysplasia. The possibility for such improvement in birth outcomes should motivate those of us working to prevent preterm birth to advocate for societal investment in this approach. It also might alleviate concerns that HPV vaccination has the potential to disrupt family life by encouraging promiscuity. How can anyone argue against a program that will prevent cancer and preterm birth?
Expert Commentary
Preterm birth and cervical dysplasia share many risk factors, most of which are the progeny of low socioeconomic status. It is not surprising, therefore, that cervical dysplasia is a risk factor for pre-term birth independent of the treatment modality chosen for the precancerous condition. This large cohort study linking outpatient gynecologic records with childbirths from Australia found exactly that. It is the largest study so far to focus on pregnancy outcomes in women following diagnosis and treatment of dysplasia. Frustrating to both the obstetrician and the gynecologist is the fact that smoking is the only readily modifiable risk factor for preterm birth or cervical dysplasia.
Ablative procedures produce better pregnancy outcomes than excision
Beyond epidemiology, this paper bears an important message for clinicians and patients: Procedures that remove portions of the cervix, such as LEEP, diathermy, and cone biopsy, raise the risk of subsequent preterm birth, compared with less destructive ablative procedures such as laser ablation (as reported in the Up-date on Cervical Disease, by Thomas C. Wright, MD, in the March issue of this journal). This was also demonstrated in a large review of the subject.1 Therefore, for an optimal obstetrical outcome, ablative procedures are preferable to excisional ones in women who have not yet completed childbearing. Given that success rates are only slightly lower for ablative procedures than for destructive ones, a clinician can recommend ablation without fear of dysplasia progressing to invasive cancer.
Widespread HPV vaccination could help reduce preterm birth rate
This study highlights how a systematic program of human papillomavirus (HPV) vaccination in adolescents (male and female) before their coital debut could reduce the rate of preterm birth by eliminating the need for women to undergo excisional treatment for cervical dysplasia. The possibility for such improvement in birth outcomes should motivate those of us working to prevent preterm birth to advocate for societal investment in this approach. It also might alleviate concerns that HPV vaccination has the potential to disrupt family life by encouraging promiscuity. How can anyone argue against a program that will prevent cancer and preterm birth?
1. Kyrgiou M, Koliopoulos G, Martin-Hirsch P, Arbyn M, Prendiville W, Paraskevaidis E. Obstetric outcomes after conservative treatment for intraepithelial or early invasive lesions: a systematic review and meta-analysis of the literature. Lancet. 2006;367:489-498.
1. Kyrgiou M, Koliopoulos G, Martin-Hirsch P, Arbyn M, Prendiville W, Paraskevaidis E. Obstetric outcomes after conservative treatment for intraepithelial or early invasive lesions: a systematic review and meta-analysis of the literature. Lancet. 2006;367:489-498.
Predicting and preventing preterm birth
A 25-year-old primigravida with an intrauterine pregnancy at 26 weeks presents with contractions of moderate intensity every 4 minutes, intact membranes, and minimal vaginal bleeding. On digital exam, her cervix is soft, 50% effaced, and closed. Estimated fetal weight is 775 g.
You are at a Level I hospital in a rural community, 90 minutes from a tertiary nursery. What steps should you take first?
Tocolytics and antibiotics are the first steps. They may help to maximize the benefits of secondary strategies such as antenatal corticosteroids during transport to a tertiary care facility. In addition, assessment of fetal fibronectin levels and use of endovaginal ultrasound can supplement clinical judgment and improve prediction of outcomes. Their excellent negative predictive value can spare many women unnecessary and potentially harmful treatments.
This article discusses these measures in the context of an actual case.
The value of “secondary prevention”
Giving corticosteroids to enhance fetal lung and brain maturity and transporting the mother to a tertiary care center may not prevent preterm delivery, but they can mitigate some of the damage and are supported by the evidence.
Corticosteroids. Given the clear evidence of their efficacy, steroids should be administered once preterm birth appears likely. I would give steroids before maternal transport.
Betamethasone is preferable to dexamethasone, which may be toxic to the fetal central nervous system. However, dexamethasone is preferable to no therapy.
Contraindications to corticosteroids include systemic maternal or fetal infections and maternal endocrinopathies such as Cushing’s disease or poorly controlled diabetes.
Transport to tertiary care. A neonatal intensive care unit clearly benefits tiny babies. Clinicians should be aware of the pediatric capacity of their community hospitals and maintain a referral relationship with the nearest tertiary care centers. Conversely, clinicians on the receiving end of maternal transports should make every effort to expedite these referrals.
Is Local Care Too Risky?
Patricia and her family strongly prefer that she undergo treatment in her own community, if at all possible.
Signs and symptoms of preterm labor are poor predictors of preterm birth. Although most symptomatic women deliver at term, even the most clinically astute physician cannot predict when a symptomatic patient will deliver.
Which tocolytic is most effective?
Berkman ND, Thorp JM Jr, Lohr KN, et al. Tocolytic treatment for the management of preterm labor: a review of the evidence. Am J Obstet Gynecol. 2003;188:1648–1659.
No single drug is best. In this metaanalysis, magnesium, β-mimetics, calcium channel blockers, and nonsteroidal anti-inflammatory drugs (NSAIDs) performed about the same at prolonging the interval between onset of preterm labor and actual birth, compared with placebo or no treatment. Ethanol was less effective and “inappropriate.” Tocolytics are given to stop contractions (first-line therapy) and to maintain quiescence after an acute episode (maintenance therapy).
To determine the most effective tocolytic, we analyzed 16 studies of first-line therapy and 8 involving maintenance therapy, using the above 5 drug classes.
How 5 drugs compare
Estimated odds ratios suggest that, when used as first-line therapy, all the drugs except ethanol are about the same. Odds ratios ranged from 1.622 for β-mimetics to 2.485 for calcium channel blockers. (The odds ratio for NSAIDs was based on only 1 study.)
When we tested whether β-mimetics, calcium channel blockers, and magnesium sulfate had the same effects, compared with placebo, the results suggested that they do not. However, the body of literature was not large enough to establish this conclusively.
Overall, β-mimetics appear to lack superiority over the other drugs as first-line therapy and cause more maternal harms, while ethanol is “inappropriate” and no longer in use.
As maintenance therapy, none of the drugs appeared to have any benefit.
Maternal and fetal harms
We defined harms as “clinical markers and events that the authors of individual studies considered as adverse events or side effects.”
Among maternal harms were serious cardiac side effects, including arrhythmias, heart failure, and chest pain, linked to β-mimetics. Minor cardiovascular harms were also higher among women given β-mimetics. In addition, calcium channel blockers appeared to increase the risk of minor cardiovascular harms, but not as much as the β-mimetics.
Overall, maternal cardiac, metabolic, and psychologic harms were more prevalent among women taking β-mimetics. This may be due, at least in part, to the fact that studies of β-mimetics tended to look for these effects more than other studies did.
As for short-term fetal harms, we found “little consistent evidence” of them in the infants of women receiving these drugs, and the studies lacked sufficient data to evaluate potential long-term harms.
What later analyses found
After 1999, the cutoff year of our review, several relatively large studies showed the oxytocin antagonist atosiban to be effective as acute7,8and maintenance8 therapy, with a favorable side effect profile. Another trial9 compared 2 doses of magnesium (2 and 5 g per hour); the higher dose acted more quickly but with more side effects. These and other studies do not alter our conclusions about the effectiveness of tocolytic therapy—or the specifics of the 5 drugs studied.
2 useful markers
In the 1990s, 2 biologic markers were discovered that improve the precision of preterm birth risk assessment:
- fetal fibronectin (fFN) and
- endovaginal sonography (EVUSD).1
Use of EVUSD enables measurement of the cervix from the internal to external os. Cervices shorten before spontaneous birth.
These 2 tests, when positive (fFN detected or cervical length
I use a negative test to identify women who do not require further treatment or evaluation. If a patient has a negative fFN or EVUSD, I would not transport her to a tertiary care center. In fact, I would probably discharge her home with close follow-up.
3 concerns about the tests
Clinicians tend to have some concerns about incorporating these tests into their routines:
- How reliable is negative predictive value? Arguably, these tests perform better than clinical judgment and can spare many women unnecessary treatments.2 No test is perfect, however. These bio-markers should be adjuncts to—not replacements for—clinical wisdom.
- What about false results? With fFN, a proper collection kit with plastic tube and Dacron swab is critical because the molecule will adhere to glass or cotton, creating a false-negative result. A false-positive result can occur after recent coitus or a digital cervical exam; therefore, collect fFN specimens before checking the cervix. With EVUSD, the examinations require a moderate amount of skill.
- Which biomarker is best? Both fFN and EVUSD make independent and separate contributions to the prediction of preterm birth. Therefore, I use both.
Start Tocolysis And Antibiotics?
Patricia’s fFN and EVUSD tests are both positive. Should you start tocolysis and antibiotic therapy prior to transfer?
Metaanalysis suggests tocolysis, and antibiotics extend the interval between symptom onset and delivery.1The length of this prolongation can be measured in days, and no evidence suggests that prolonged pharmacotherapy has any benefit.
I would initiate both therapies while waiting for the mother to be moved to a tertiary center, even though neither therapy has been shown to improve perinatal outcome.
Tocolysis. We could find no differences among tocolytic drugs.3 Serious side effects are rare, but nuisance cardiovascular symptoms are frequent. Sympathomimetic drugs lead to lethargy, and magnesium is associated with malaise. Magnesium requires intravenous access and should be given only via infusion pump by trained personnel. That often means a nurse must accompany the patient to the Level III hospital.
Thus, for logistical reasons, I favor nonsteroidal anti-inflammatory drugs, of which indomethacin is the most widely studied. Indomethacin can be given by mouth or rectum, with minimal side effects. Harm to the fetus is rare if the drug is used acutely for only 48 to 72 hours (the maximum duration of any potential benefit).
Antibiotics. Current protocols calling for betalactam antibiotic therapy as prophylaxis against early-onset neonatal sepsis in preterm births have led to almost universal use of antibiotics among these patients. Our metaanalysis did not demonstrate superior pregnancy prolongation with any other regimen, so the one for group B strep prophylaxis provides a double benefit.4 As with tocolytics, there is no role for maintenance therapy.
When Contractions Cease
Patricia is transferred and completes her steroid therapy. Her symptoms and contractions cease. After a few days of observation and no cervical changes, she is discharged home. She asks about home therapies, work, activities, and sex.
Since our metaanalysis of tocolysis studies showed no efficacy for maintenance regimens, I do not recommend them except in this rare situation: when a woman has so much uterine activity without cervical change that she is unable to rest or complete her daily activities. In this case I would favor “as needed” doses of a β-mimetic drug by mouth.
Although home uterine activity monitors and subcutaneous tocolytic pumps are available, evidence suggests they are ineffective.1I seldom, if ever, use these devices.
Despite the almost universal recommendation that women at risk of preterm birth avoid physical and sexual activity, we lack evidence that bed rest or abstinence prolong pregnancy or prevent preterm birth.
Is sex allowed? When we studied both physical activity and sexuality in asymptomatic women at midpregnancy, neither was associated with spontaneous preterm birth.5,6 Therefore, I do not recommend restricting activity or sexual intercourse. Instead, I encourage women to carefully assess uterine activity. If certain behaviors appear to increase contractions, those behaviors should be limited.
Counsel her to trust her instincts. It is important to encourage the patient to trust her own instincts, so that an overzealous employer or partner cannot coerce or cajole her to do something that violates her internal sense of well-being.
The author reports no financial relationships relevant to this article.
1. Berkman ND, Thorp JM, Hartmann KE, et al. Management of Preterm Labor. Evidence Report/Technology Assessment #18. Rockville, Md: Agency for Healthcare Research and Quality; December 2000. AHRQ publication 01-E021.
2. Thorp JM, Jr. ACOG Committee on Practice Bulletins. Management of preterm labor. Obstet Gynecol. 2003;101:1039-1047.
3. Berkman ND, Thorp JM, Jr, Lohr KN, et al. Tocolytic treatment for the management of preterm labor: a review of the evidence. Am J Obstet Gynecol. 2003;188:1648-1659.
4. Thorp JM, Jr, Hartmann KE, Berkman ND, et al. Antibiotic therapy for the management of preterm labor: a review of the evidence. Am J Obstet Gynecol. 2002;186:587-592.
5. Sayle AE, Savitz DA, Thorp JM, Jr, Hertz-Picciotto I, Wilcox AJ. Sexual activity during late pregnancy and preterm delivery. Obstet Gynecol. 2001;97:283-289.
6. Evenson KR, Siega-Riz AM, Savitz DA, Leiferman JA, Thorp JM, Jr. Vigorous leisure activity and pregnancy outcome. Epidemiology. 2002;13:653-659.
7. Moutquin JM, Sherman D, Cohen H, et al. Double-blind, randomized, controlled trial of atosiban and ritrodine in the treatment of preterm labor: a multicenter effectiveness and safety study. Am J Obstet Gynecol. 2000;182:1191-1199.
8. Romero R, Sibai BM, Sanchez-Ramos L, et al. An oxytocin receptor antagonist (atosiban) in the treatment of preterm labor: a randomized, double-blind, placebo-controlled trial with tocolytic rescue. Am J Obstet Gynecol. 2000;182:1173-1183.
9. Terrone DA, Rinehart BK, Kimmel ES, May WL, Larmon JE, Morrison JC. A prospective, randomized, controlled trial of high and low maintenance doses of magnesium sulfate for acute tocolysis. Am J Obstet Gynecol. 2000;182:1477-1482.
A 25-year-old primigravida with an intrauterine pregnancy at 26 weeks presents with contractions of moderate intensity every 4 minutes, intact membranes, and minimal vaginal bleeding. On digital exam, her cervix is soft, 50% effaced, and closed. Estimated fetal weight is 775 g.
You are at a Level I hospital in a rural community, 90 minutes from a tertiary nursery. What steps should you take first?
Tocolytics and antibiotics are the first steps. They may help to maximize the benefits of secondary strategies such as antenatal corticosteroids during transport to a tertiary care facility. In addition, assessment of fetal fibronectin levels and use of endovaginal ultrasound can supplement clinical judgment and improve prediction of outcomes. Their excellent negative predictive value can spare many women unnecessary and potentially harmful treatments.
This article discusses these measures in the context of an actual case.
The value of “secondary prevention”
Giving corticosteroids to enhance fetal lung and brain maturity and transporting the mother to a tertiary care center may not prevent preterm delivery, but they can mitigate some of the damage and are supported by the evidence.
Corticosteroids. Given the clear evidence of their efficacy, steroids should be administered once preterm birth appears likely. I would give steroids before maternal transport.
Betamethasone is preferable to dexamethasone, which may be toxic to the fetal central nervous system. However, dexamethasone is preferable to no therapy.
Contraindications to corticosteroids include systemic maternal or fetal infections and maternal endocrinopathies such as Cushing’s disease or poorly controlled diabetes.
Transport to tertiary care. A neonatal intensive care unit clearly benefits tiny babies. Clinicians should be aware of the pediatric capacity of their community hospitals and maintain a referral relationship with the nearest tertiary care centers. Conversely, clinicians on the receiving end of maternal transports should make every effort to expedite these referrals.
Is Local Care Too Risky?
Patricia and her family strongly prefer that she undergo treatment in her own community, if at all possible.
Signs and symptoms of preterm labor are poor predictors of preterm birth. Although most symptomatic women deliver at term, even the most clinically astute physician cannot predict when a symptomatic patient will deliver.
Which tocolytic is most effective?
Berkman ND, Thorp JM Jr, Lohr KN, et al. Tocolytic treatment for the management of preterm labor: a review of the evidence. Am J Obstet Gynecol. 2003;188:1648–1659.
No single drug is best. In this metaanalysis, magnesium, β-mimetics, calcium channel blockers, and nonsteroidal anti-inflammatory drugs (NSAIDs) performed about the same at prolonging the interval between onset of preterm labor and actual birth, compared with placebo or no treatment. Ethanol was less effective and “inappropriate.” Tocolytics are given to stop contractions (first-line therapy) and to maintain quiescence after an acute episode (maintenance therapy).
To determine the most effective tocolytic, we analyzed 16 studies of first-line therapy and 8 involving maintenance therapy, using the above 5 drug classes.
How 5 drugs compare
Estimated odds ratios suggest that, when used as first-line therapy, all the drugs except ethanol are about the same. Odds ratios ranged from 1.622 for β-mimetics to 2.485 for calcium channel blockers. (The odds ratio for NSAIDs was based on only 1 study.)
When we tested whether β-mimetics, calcium channel blockers, and magnesium sulfate had the same effects, compared with placebo, the results suggested that they do not. However, the body of literature was not large enough to establish this conclusively.
Overall, β-mimetics appear to lack superiority over the other drugs as first-line therapy and cause more maternal harms, while ethanol is “inappropriate” and no longer in use.
As maintenance therapy, none of the drugs appeared to have any benefit.
Maternal and fetal harms
We defined harms as “clinical markers and events that the authors of individual studies considered as adverse events or side effects.”
Among maternal harms were serious cardiac side effects, including arrhythmias, heart failure, and chest pain, linked to β-mimetics. Minor cardiovascular harms were also higher among women given β-mimetics. In addition, calcium channel blockers appeared to increase the risk of minor cardiovascular harms, but not as much as the β-mimetics.
Overall, maternal cardiac, metabolic, and psychologic harms were more prevalent among women taking β-mimetics. This may be due, at least in part, to the fact that studies of β-mimetics tended to look for these effects more than other studies did.
As for short-term fetal harms, we found “little consistent evidence” of them in the infants of women receiving these drugs, and the studies lacked sufficient data to evaluate potential long-term harms.
What later analyses found
After 1999, the cutoff year of our review, several relatively large studies showed the oxytocin antagonist atosiban to be effective as acute7,8and maintenance8 therapy, with a favorable side effect profile. Another trial9 compared 2 doses of magnesium (2 and 5 g per hour); the higher dose acted more quickly but with more side effects. These and other studies do not alter our conclusions about the effectiveness of tocolytic therapy—or the specifics of the 5 drugs studied.
2 useful markers
In the 1990s, 2 biologic markers were discovered that improve the precision of preterm birth risk assessment:
- fetal fibronectin (fFN) and
- endovaginal sonography (EVUSD).1
Use of EVUSD enables measurement of the cervix from the internal to external os. Cervices shorten before spontaneous birth.
These 2 tests, when positive (fFN detected or cervical length
I use a negative test to identify women who do not require further treatment or evaluation. If a patient has a negative fFN or EVUSD, I would not transport her to a tertiary care center. In fact, I would probably discharge her home with close follow-up.
3 concerns about the tests
Clinicians tend to have some concerns about incorporating these tests into their routines:
- How reliable is negative predictive value? Arguably, these tests perform better than clinical judgment and can spare many women unnecessary treatments.2 No test is perfect, however. These bio-markers should be adjuncts to—not replacements for—clinical wisdom.
- What about false results? With fFN, a proper collection kit with plastic tube and Dacron swab is critical because the molecule will adhere to glass or cotton, creating a false-negative result. A false-positive result can occur after recent coitus or a digital cervical exam; therefore, collect fFN specimens before checking the cervix. With EVUSD, the examinations require a moderate amount of skill.
- Which biomarker is best? Both fFN and EVUSD make independent and separate contributions to the prediction of preterm birth. Therefore, I use both.
Start Tocolysis And Antibiotics?
Patricia’s fFN and EVUSD tests are both positive. Should you start tocolysis and antibiotic therapy prior to transfer?
Metaanalysis suggests tocolysis, and antibiotics extend the interval between symptom onset and delivery.1The length of this prolongation can be measured in days, and no evidence suggests that prolonged pharmacotherapy has any benefit.
I would initiate both therapies while waiting for the mother to be moved to a tertiary center, even though neither therapy has been shown to improve perinatal outcome.
Tocolysis. We could find no differences among tocolytic drugs.3 Serious side effects are rare, but nuisance cardiovascular symptoms are frequent. Sympathomimetic drugs lead to lethargy, and magnesium is associated with malaise. Magnesium requires intravenous access and should be given only via infusion pump by trained personnel. That often means a nurse must accompany the patient to the Level III hospital.
Thus, for logistical reasons, I favor nonsteroidal anti-inflammatory drugs, of which indomethacin is the most widely studied. Indomethacin can be given by mouth or rectum, with minimal side effects. Harm to the fetus is rare if the drug is used acutely for only 48 to 72 hours (the maximum duration of any potential benefit).
Antibiotics. Current protocols calling for betalactam antibiotic therapy as prophylaxis against early-onset neonatal sepsis in preterm births have led to almost universal use of antibiotics among these patients. Our metaanalysis did not demonstrate superior pregnancy prolongation with any other regimen, so the one for group B strep prophylaxis provides a double benefit.4 As with tocolytics, there is no role for maintenance therapy.
When Contractions Cease
Patricia is transferred and completes her steroid therapy. Her symptoms and contractions cease. After a few days of observation and no cervical changes, she is discharged home. She asks about home therapies, work, activities, and sex.
Since our metaanalysis of tocolysis studies showed no efficacy for maintenance regimens, I do not recommend them except in this rare situation: when a woman has so much uterine activity without cervical change that she is unable to rest or complete her daily activities. In this case I would favor “as needed” doses of a β-mimetic drug by mouth.
Although home uterine activity monitors and subcutaneous tocolytic pumps are available, evidence suggests they are ineffective.1I seldom, if ever, use these devices.
Despite the almost universal recommendation that women at risk of preterm birth avoid physical and sexual activity, we lack evidence that bed rest or abstinence prolong pregnancy or prevent preterm birth.
Is sex allowed? When we studied both physical activity and sexuality in asymptomatic women at midpregnancy, neither was associated with spontaneous preterm birth.5,6 Therefore, I do not recommend restricting activity or sexual intercourse. Instead, I encourage women to carefully assess uterine activity. If certain behaviors appear to increase contractions, those behaviors should be limited.
Counsel her to trust her instincts. It is important to encourage the patient to trust her own instincts, so that an overzealous employer or partner cannot coerce or cajole her to do something that violates her internal sense of well-being.
The author reports no financial relationships relevant to this article.
A 25-year-old primigravida with an intrauterine pregnancy at 26 weeks presents with contractions of moderate intensity every 4 minutes, intact membranes, and minimal vaginal bleeding. On digital exam, her cervix is soft, 50% effaced, and closed. Estimated fetal weight is 775 g.
You are at a Level I hospital in a rural community, 90 minutes from a tertiary nursery. What steps should you take first?
Tocolytics and antibiotics are the first steps. They may help to maximize the benefits of secondary strategies such as antenatal corticosteroids during transport to a tertiary care facility. In addition, assessment of fetal fibronectin levels and use of endovaginal ultrasound can supplement clinical judgment and improve prediction of outcomes. Their excellent negative predictive value can spare many women unnecessary and potentially harmful treatments.
This article discusses these measures in the context of an actual case.
The value of “secondary prevention”
Giving corticosteroids to enhance fetal lung and brain maturity and transporting the mother to a tertiary care center may not prevent preterm delivery, but they can mitigate some of the damage and are supported by the evidence.
Corticosteroids. Given the clear evidence of their efficacy, steroids should be administered once preterm birth appears likely. I would give steroids before maternal transport.
Betamethasone is preferable to dexamethasone, which may be toxic to the fetal central nervous system. However, dexamethasone is preferable to no therapy.
Contraindications to corticosteroids include systemic maternal or fetal infections and maternal endocrinopathies such as Cushing’s disease or poorly controlled diabetes.
Transport to tertiary care. A neonatal intensive care unit clearly benefits tiny babies. Clinicians should be aware of the pediatric capacity of their community hospitals and maintain a referral relationship with the nearest tertiary care centers. Conversely, clinicians on the receiving end of maternal transports should make every effort to expedite these referrals.
Is Local Care Too Risky?
Patricia and her family strongly prefer that she undergo treatment in her own community, if at all possible.
Signs and symptoms of preterm labor are poor predictors of preterm birth. Although most symptomatic women deliver at term, even the most clinically astute physician cannot predict when a symptomatic patient will deliver.
Which tocolytic is most effective?
Berkman ND, Thorp JM Jr, Lohr KN, et al. Tocolytic treatment for the management of preterm labor: a review of the evidence. Am J Obstet Gynecol. 2003;188:1648–1659.
No single drug is best. In this metaanalysis, magnesium, β-mimetics, calcium channel blockers, and nonsteroidal anti-inflammatory drugs (NSAIDs) performed about the same at prolonging the interval between onset of preterm labor and actual birth, compared with placebo or no treatment. Ethanol was less effective and “inappropriate.” Tocolytics are given to stop contractions (first-line therapy) and to maintain quiescence after an acute episode (maintenance therapy).
To determine the most effective tocolytic, we analyzed 16 studies of first-line therapy and 8 involving maintenance therapy, using the above 5 drug classes.
How 5 drugs compare
Estimated odds ratios suggest that, when used as first-line therapy, all the drugs except ethanol are about the same. Odds ratios ranged from 1.622 for β-mimetics to 2.485 for calcium channel blockers. (The odds ratio for NSAIDs was based on only 1 study.)
When we tested whether β-mimetics, calcium channel blockers, and magnesium sulfate had the same effects, compared with placebo, the results suggested that they do not. However, the body of literature was not large enough to establish this conclusively.
Overall, β-mimetics appear to lack superiority over the other drugs as first-line therapy and cause more maternal harms, while ethanol is “inappropriate” and no longer in use.
As maintenance therapy, none of the drugs appeared to have any benefit.
Maternal and fetal harms
We defined harms as “clinical markers and events that the authors of individual studies considered as adverse events or side effects.”
Among maternal harms were serious cardiac side effects, including arrhythmias, heart failure, and chest pain, linked to β-mimetics. Minor cardiovascular harms were also higher among women given β-mimetics. In addition, calcium channel blockers appeared to increase the risk of minor cardiovascular harms, but not as much as the β-mimetics.
Overall, maternal cardiac, metabolic, and psychologic harms were more prevalent among women taking β-mimetics. This may be due, at least in part, to the fact that studies of β-mimetics tended to look for these effects more than other studies did.
As for short-term fetal harms, we found “little consistent evidence” of them in the infants of women receiving these drugs, and the studies lacked sufficient data to evaluate potential long-term harms.
What later analyses found
After 1999, the cutoff year of our review, several relatively large studies showed the oxytocin antagonist atosiban to be effective as acute7,8and maintenance8 therapy, with a favorable side effect profile. Another trial9 compared 2 doses of magnesium (2 and 5 g per hour); the higher dose acted more quickly but with more side effects. These and other studies do not alter our conclusions about the effectiveness of tocolytic therapy—or the specifics of the 5 drugs studied.
2 useful markers
In the 1990s, 2 biologic markers were discovered that improve the precision of preterm birth risk assessment:
- fetal fibronectin (fFN) and
- endovaginal sonography (EVUSD).1
Use of EVUSD enables measurement of the cervix from the internal to external os. Cervices shorten before spontaneous birth.
These 2 tests, when positive (fFN detected or cervical length
I use a negative test to identify women who do not require further treatment or evaluation. If a patient has a negative fFN or EVUSD, I would not transport her to a tertiary care center. In fact, I would probably discharge her home with close follow-up.
3 concerns about the tests
Clinicians tend to have some concerns about incorporating these tests into their routines:
- How reliable is negative predictive value? Arguably, these tests perform better than clinical judgment and can spare many women unnecessary treatments.2 No test is perfect, however. These bio-markers should be adjuncts to—not replacements for—clinical wisdom.
- What about false results? With fFN, a proper collection kit with plastic tube and Dacron swab is critical because the molecule will adhere to glass or cotton, creating a false-negative result. A false-positive result can occur after recent coitus or a digital cervical exam; therefore, collect fFN specimens before checking the cervix. With EVUSD, the examinations require a moderate amount of skill.
- Which biomarker is best? Both fFN and EVUSD make independent and separate contributions to the prediction of preterm birth. Therefore, I use both.
Start Tocolysis And Antibiotics?
Patricia’s fFN and EVUSD tests are both positive. Should you start tocolysis and antibiotic therapy prior to transfer?
Metaanalysis suggests tocolysis, and antibiotics extend the interval between symptom onset and delivery.1The length of this prolongation can be measured in days, and no evidence suggests that prolonged pharmacotherapy has any benefit.
I would initiate both therapies while waiting for the mother to be moved to a tertiary center, even though neither therapy has been shown to improve perinatal outcome.
Tocolysis. We could find no differences among tocolytic drugs.3 Serious side effects are rare, but nuisance cardiovascular symptoms are frequent. Sympathomimetic drugs lead to lethargy, and magnesium is associated with malaise. Magnesium requires intravenous access and should be given only via infusion pump by trained personnel. That often means a nurse must accompany the patient to the Level III hospital.
Thus, for logistical reasons, I favor nonsteroidal anti-inflammatory drugs, of which indomethacin is the most widely studied. Indomethacin can be given by mouth or rectum, with minimal side effects. Harm to the fetus is rare if the drug is used acutely for only 48 to 72 hours (the maximum duration of any potential benefit).
Antibiotics. Current protocols calling for betalactam antibiotic therapy as prophylaxis against early-onset neonatal sepsis in preterm births have led to almost universal use of antibiotics among these patients. Our metaanalysis did not demonstrate superior pregnancy prolongation with any other regimen, so the one for group B strep prophylaxis provides a double benefit.4 As with tocolytics, there is no role for maintenance therapy.
When Contractions Cease
Patricia is transferred and completes her steroid therapy. Her symptoms and contractions cease. After a few days of observation and no cervical changes, she is discharged home. She asks about home therapies, work, activities, and sex.
Since our metaanalysis of tocolysis studies showed no efficacy for maintenance regimens, I do not recommend them except in this rare situation: when a woman has so much uterine activity without cervical change that she is unable to rest or complete her daily activities. In this case I would favor “as needed” doses of a β-mimetic drug by mouth.
Although home uterine activity monitors and subcutaneous tocolytic pumps are available, evidence suggests they are ineffective.1I seldom, if ever, use these devices.
Despite the almost universal recommendation that women at risk of preterm birth avoid physical and sexual activity, we lack evidence that bed rest or abstinence prolong pregnancy or prevent preterm birth.
Is sex allowed? When we studied both physical activity and sexuality in asymptomatic women at midpregnancy, neither was associated with spontaneous preterm birth.5,6 Therefore, I do not recommend restricting activity or sexual intercourse. Instead, I encourage women to carefully assess uterine activity. If certain behaviors appear to increase contractions, those behaviors should be limited.
Counsel her to trust her instincts. It is important to encourage the patient to trust her own instincts, so that an overzealous employer or partner cannot coerce or cajole her to do something that violates her internal sense of well-being.
The author reports no financial relationships relevant to this article.
1. Berkman ND, Thorp JM, Hartmann KE, et al. Management of Preterm Labor. Evidence Report/Technology Assessment #18. Rockville, Md: Agency for Healthcare Research and Quality; December 2000. AHRQ publication 01-E021.
2. Thorp JM, Jr. ACOG Committee on Practice Bulletins. Management of preterm labor. Obstet Gynecol. 2003;101:1039-1047.
3. Berkman ND, Thorp JM, Jr, Lohr KN, et al. Tocolytic treatment for the management of preterm labor: a review of the evidence. Am J Obstet Gynecol. 2003;188:1648-1659.
4. Thorp JM, Jr, Hartmann KE, Berkman ND, et al. Antibiotic therapy for the management of preterm labor: a review of the evidence. Am J Obstet Gynecol. 2002;186:587-592.
5. Sayle AE, Savitz DA, Thorp JM, Jr, Hertz-Picciotto I, Wilcox AJ. Sexual activity during late pregnancy and preterm delivery. Obstet Gynecol. 2001;97:283-289.
6. Evenson KR, Siega-Riz AM, Savitz DA, Leiferman JA, Thorp JM, Jr. Vigorous leisure activity and pregnancy outcome. Epidemiology. 2002;13:653-659.
7. Moutquin JM, Sherman D, Cohen H, et al. Double-blind, randomized, controlled trial of atosiban and ritrodine in the treatment of preterm labor: a multicenter effectiveness and safety study. Am J Obstet Gynecol. 2000;182:1191-1199.
8. Romero R, Sibai BM, Sanchez-Ramos L, et al. An oxytocin receptor antagonist (atosiban) in the treatment of preterm labor: a randomized, double-blind, placebo-controlled trial with tocolytic rescue. Am J Obstet Gynecol. 2000;182:1173-1183.
9. Terrone DA, Rinehart BK, Kimmel ES, May WL, Larmon JE, Morrison JC. A prospective, randomized, controlled trial of high and low maintenance doses of magnesium sulfate for acute tocolysis. Am J Obstet Gynecol. 2000;182:1477-1482.
1. Berkman ND, Thorp JM, Hartmann KE, et al. Management of Preterm Labor. Evidence Report/Technology Assessment #18. Rockville, Md: Agency for Healthcare Research and Quality; December 2000. AHRQ publication 01-E021.
2. Thorp JM, Jr. ACOG Committee on Practice Bulletins. Management of preterm labor. Obstet Gynecol. 2003;101:1039-1047.
3. Berkman ND, Thorp JM, Jr, Lohr KN, et al. Tocolytic treatment for the management of preterm labor: a review of the evidence. Am J Obstet Gynecol. 2003;188:1648-1659.
4. Thorp JM, Jr, Hartmann KE, Berkman ND, et al. Antibiotic therapy for the management of preterm labor: a review of the evidence. Am J Obstet Gynecol. 2002;186:587-592.
5. Sayle AE, Savitz DA, Thorp JM, Jr, Hertz-Picciotto I, Wilcox AJ. Sexual activity during late pregnancy and preterm delivery. Obstet Gynecol. 2001;97:283-289.
6. Evenson KR, Siega-Riz AM, Savitz DA, Leiferman JA, Thorp JM, Jr. Vigorous leisure activity and pregnancy outcome. Epidemiology. 2002;13:653-659.
7. Moutquin JM, Sherman D, Cohen H, et al. Double-blind, randomized, controlled trial of atosiban and ritrodine in the treatment of preterm labor: a multicenter effectiveness and safety study. Am J Obstet Gynecol. 2000;182:1191-1199.
8. Romero R, Sibai BM, Sanchez-Ramos L, et al. An oxytocin receptor antagonist (atosiban) in the treatment of preterm labor: a randomized, double-blind, placebo-controlled trial with tocolytic rescue. Am J Obstet Gynecol. 2000;182:1173-1183.
9. Terrone DA, Rinehart BK, Kimmel ES, May WL, Larmon JE, Morrison JC. A prospective, randomized, controlled trial of high and low maintenance doses of magnesium sulfate for acute tocolysis. Am J Obstet Gynecol. 2000;182:1477-1482.