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Two physicians discuss the pros and cons of universal assessment for ob/gyns and their patients.
By Sonia S. Hassan, MD
Dr. Hassan is Associate Dean for Maternal, Perinatal, and Child Health and Professor, Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology at Wayne State University School of Medicine, Detroit, Michigan.
In 1960, the United States ranked twelfth in the world in infant mortality; this ranking has fallen steadily to forty-third.1 Preterm birth (PTB)-related deaths are one of the leading causes of this infant mortality rate.2, 3 In 2005, 12.9 million births worldwide were preterm.4 In 2011, the rate of PTB in the United States was 11.7% (463,361 babies per year).5,6
The challenge for providers and researchers has been, first, to predict who will deliver prematurely, and second, to implement an intervention that will prevent PTB. A sonographic short cervix diagnosed by transvaginal ultrasound (TVUS) is the most powerful predictor of PTB. Fifty percent of women with a cervical length <15 mm will deliver <32 weeks.6, 7 TVUS provides the most accurate and reproducible cervical length measurement with no associated risks; it is widely accepted by patients. Yet implementation of a program in which all pregnant women undergo cervical length measurement requires the availability of an intervention that can prevent PTB.
Vaginal progesterone for prevention of PTB and neonatal complications
Two randomized clinical trials have demonstrated that vaginal progesterone reduces the rate of PTB in women with a sonographic short cervix.8,9 A randomized clinical trial investigating the use of vaginal progesterone to prevent PTD (<34 weeks) in women with a short cervix (<15 mm) reported a 44% reduction in risk of PTB (19.2% vs 34.4%; relative risk [RR], 0.56; 95% confidence interval [CI], 0.36-0.86).8 In 2011, a randomized clinical trial9 demonstrated that administration of vaginal progesterone to women with a short cervix (10 mm-20 mm) was associated with:
--a 45% decrease in the rate of PTB at <33 weeks (primary endpoint), a 38% decrease in the rate of PTB at < 35 weeks, and a 50% decrease in the rate of PTB at <28 weeks’ gestation;
--a 61% decrease in the rate of respiratory distress syndrome (RDS); and
--a decrease in the rate of composite neonatal morbidity.
A meta-analysis of individual patient data from 5 randomized clinical trials revealed that in addition to reducing the rate of PTB and respiratory distress syndrome, administration of vaginal progesterone to women with a short cervix was associated with a reduction in the rate of mechanical ventilation, admission to neonatal intensive care units (NICUs), and composite neonatal morbidity/mortality.10
Impact and implications for the healthcare system
The potential impact of the use of vaginal progesterone in women with a short cervix can be surmised from the estimate that 11 patients need to be treated to prevent 1 PTB <35 weeks, and that 9 patients need to be treated to prevent 1 PTB before 34 weeks’ gestation. Furthermore, 15 patients need to be treated to prevent 1 episode of respiratory distress syndrome.10
Estimates indicate that 141 pregnant women from the general population need to be screened with TVUS (treating those with a cervical length ≤25 mm with vaginal progesterone) to prevent 1 case of PTB <33 weeks.9,10
Cost-effectiveness analysis studies have demonstrated that the preterm prevention strategy of implementing universal cervical length risk assessment with TVUS and using vaginal progesterone is cost-effective.11-13 Werner and colleagues12 have estimated that for every 100,000 women screened, there is a cost savings of more than $19 million annually. In the United States, the total annual cost savings is estimated to be $500 million, based on the 2011 population.
Numerous institutions now employ universal TVUS cervical length risk assessment. Delaying implementation at other centers will result in patients missing the opportunity for treatment. This is similar to what happened with antenatal steroids, for which efficacy was demonstrated in 1972.14 Not until 1994, however, were they widely adopted for use in women at risk of PTB.15
Delaying universal sonographic cervical length risk assessment would result in the ethical problem of having an intervention for a diagnosis that we are not seeking in all patients. Vaginal progesterone’s efficacy has been demonstrated in women with and without a prior PTB; hence, all patients need to be assessed for cervical length. As obstetricians, we are becoming obligated to provide pregnant women with the knowledge about the length of their cervices. Therefore, this critical question must be considered: When there is a treatment available to prevent PTB for those with a sonographic short cervix, doesn’t every woman have a right to know her cervical length? The answer is yes.
1. United Nations, Department of Economic and Social Affairs, Population Division, Population Estimates and Projections Section. World Population Prospects, the 2010 Revision. http://esa.un.org/wpp/Excel-Data/mortality.htm. Updated June 2011. Accessed April 18, 2013.
2. MacDorman MF, Mathews TJ. Behind international rankings of infant mortality: how the United States compares with Europe. NCHS Data Brief. 2009:1-8.
3. MacDorman MF. Race and ethnic disparities in fetal mortality, preterm birth, and infant mortality in the United States: an overview. Semin Perinatol. 2011;35:200-208.
4. Beck S, Wojdyla D, Say L, et al. The worldwide incidence of preterm birth: a systematic review of maternal mortality and morbidity. Bull World Health Organ. 2010;88:31-38.
5. Hamilton BE, Hoyert DL, Martin JA, Strobino DM, Guyer B. Annual summary of vital statistics: 2010-2011. Pediatrics. 2013;131:548-558.
6. Heath VC, Southall TR, Souka AP, Elisseou A, Nicolaides KH. Cervical length at 23 weeks of gestation: prediction of spontaneous preterm delivery. Ultrasound Obstet Gynecol. 1998;12:312-317.
7. Hassan SS, Romero R, Berry SM, et al. Patients with an ultrasonographic cervical length < or = 15 mm have nearly a 50% risk of early spontaneous preterm delivery. Am J Obstet Gynecol. 2000;182:1458-1467.
8. Fonseca EB, Celik E, Parra M, Singh M, Nicolaides KH. Progesterone and the risk of preterm birth among women with a short cervix. N Engl J Med. 2007;357:462-469.
9. Hassan SS, Romero R, Vidyadhari D, et al. Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol. 2011;38:18-31.
10. Romero R, Nicolaides K, Conde-Agudelo A, et al. Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and metaanalysis of individual patient data. Am J Obstet Gynecol. 2012;206:124. e1-19.
11. Cahill AG, Odibo AO, Caughey AB, et al. Universal cervical length screening and treatment with vaginal progesterone to prevent preterm birth: a decision and economic analysis. Am J Obstet Gynecol. 2010;202:548. e1-8.
12. Werner EF, Han CS, Pettker CM, et al. Universal cervical length screening to prevent preterm birth: a cost-effectiveness analysis. Ultrasound Obstet Gynecol. 2011;38:32-37.
13. Page J, Emerson J, Cahill A, et al. The impact of cervical length on the cost-effectiveness of vaginal progesterone as a preterm birth intervention. Am J Obstet Gynecol. 2013;208(Suppl 1):S66.
14. Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics. 1972;50:515-525.
15. The effect of antenatal steroids for fetal maturation on perinatal outcomes. National Institutes of Health Consensus Statement. 1994;12(2):1-24.
NEXT: PRAGMATIC ISSUES ARGUE AGAINST SCREENING >>
By Patrick S. Ramsey, MD, MSPH
Dr. Ramsey is an ACOG Young Physician-at-Large and District XI-Junior Fellow Advisor, Medical Director, Maternal Transport Service, San Antonio Methodist Hospital System, and Adjunct Associate Professor of OB/GYN in the Uniformed Services University of the Health Sciences & University of Texas School of Public Health, San Antonio.
Cervical length screening has emerged as an important clinical tool to assess PTB risk. Iams et al demonstrated an inverse relationship between cervical length and PTB risk, creating immense enthusiasm for cervical length screening as a potential tool for screening women at risk.1 However, a sine qua non attribute of a screening test is the availability of an effective intervention.
Several recent studies have proposed progesterone for PTB prevention in women with short cervices.2-4 In a double-blind, placebo-controlled trial of 413 women with cervical length <15 mm, Fonseca et al demonstrated that micronized progesterone was effective in preventing PTB at <34 weeks’ gestation.2 Hassan et al and colleagues conducted a double-masked, placebo-controlled multicenter trial of 465 women with cervical lengths of 10 mm to 20 mm. They noted significant reduction in the PTB rate at <33 weeks and neonatal morbidity among women treated with progesterone gel.3 In contrast, Grobman and colleagues, in a multicenter double-masked, placebo-controlled trial of 657 nulliparous women, failed to demonstrate benefit of 17-alpha hydroxyprogesterone caproate to prevent PTB at <37 weeks in women with cervical lengths <30 mm.4 The mixed success of these trials has prompted some to advocate for universal cervical length screening. Significant pragmatic issues strongly argue against such a practice.
First, these trials were executed with uniform recruitment criteria, standardized cervical length screening, compliance assessments, and follow-up visits. While consistent management protocols were used within the trials, the protocols varied between them.2-4 In addition, the trials differed in gestational age (16 weeks-25 weeks) at which cervical length screening was done, progesterone intervention employed, and cervical length intervention threshold. Therefore, the basis for universal cervical length screening is weak. A similar historic situation was universal screening and treatment of bacterial vaginosis (BV). Initial trials using variable BV definitions and treatment regimens, largely in high-risk populations, suggested benefit for PTB prevention. Universal screening and treatment of a low-risk population was also prematurely advocated and later abandoned because of lack of efficacy in subsequent large randomized trials.
Another screening test principle is cost-effectiveness. The previously mentioned trials required screening massive numbers of women to identify the small proportion of women with short cervices (Hassan n=32,091, Fonseca n=24,620, and Grobman n=15,435), raising the issue of cost-effectiveness of universal screening.2-4 A 2010 economic analysis concluded that universal sonographic screening for short cervix and vaginal progesterone treatment appeared to be cost-effective and yielded the greatest reduction in PTB at <34 weeks compared with alternatives.5
This simplistic analysis did not account for costs and untoward outcomes related to unnecessary treatment of women with interventions such as cerclage, antibiotics, and tocolytics. This is particularly important for 60% of women with a short cervices who ultimately do not deliver preterm. Hassan’s data suggested that 14 women would require treatment to prevent 1 preterm birth at <33 weeks and 22 women would require treatment to prevent 1 case of respiratory distress syndrome.3 While these numbers seem favorable, they are a product of the rigorous environment of randomized trials.
Universal cervical length assessment in the general population with ill-defined screening protocols, variable cervical length screening techniques, non-standardized progesterone regimens, and varied alternative interventions in practice will dramatically reduce any benefit and significantly increase medical expenditures.
The 2013 Cochrane Review “Cervical assessment by ultrasound for preventing preterm delivery” concluded, “Currently, there is insufficient evidence to recommend routine screening of asymptomatic or symptomatic pregnant women with transvaginal ultrasound cervical length.”6 Thus, universal cervical length screening should not be supported at this time based on the available literature.
1. Iams JD, Goldenberg RL, Meis PJ, et al. The length of the cervix and the risk of spontaneous premature delivery. National Institute of Child Health and Human Development Maternal Fetal Medicine Unit Network. N Engl J Med. 1996;334(9):567-572.
2. Fonseca EB, Celik E, Parra M, Singh M, Nicolaides KH; Fetal Medicine Foundation Second Trimester Screening Group. Progesterone and the risk of preterm birth among women with a short cervix. N Engl J Med. 2007;357(5):462-469.
3. Hassan SS, Romero R, Vidyadhari D, et al; PREGNANT Trial. Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol. 2011;38:18-31.
4. Grobman WA, Thom EA, Spong CY, et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units (MFMU) Network. 17 alpha-hydroxyprogesterone caproate to prevent prematurity in nulliparas with cervical length less than 30 mm. Am J Obstet Gynecol. 2012; 207:390.e1-8.
5. Cahill AG, Odibo AO, Caughey AB, et al. Universal cervical length screening and treatment with vaginal progesterone to prevent preterm birth: a decision and economic analysis. Am J Obstet Gynecol. 2010; 202:548.e1-8.
6. Berghella V, Baxter JK, Hendrix NW. Cervical assessment by ultrasound for preventing preterm delivery. Cochrane Database Syst Rev. 2013;1:CD007235.