Attitudes and Practices Regarding Use of Progesterone to Prevent Preterm Births Zsakeba T. Henderson, M.D.,1 Michael L. Power, Ph.D.,2 Vincenzo Berghella, M.D.,3 Eve M. Lackritz, M.D.,1 and Jay Schulkin, Ph.D.2
ABSTRACT
We sought to describe current attitudes and practices of obstetrician-gynecologists regarding use of progesterone and prevention of preterm birth. A self-administered survey was mailed to American College of Obstetricians and Gynecologists Fellows and Junior Fellows in Practice in March to May 2007. The survey consisted of 36 questions, including respondents’ demographic characteristics, preterm birth risk factor knowledge and screening practices, and use of progesterone for the prevention of preterm birth. The response rate was 52% (n ¼ 345); most respondents were general obstetrician-gynecologists (89%). Many (74%) reported recommending or offering progesterone for prevention of preterm birth. Almost all (93%) reported use for the indication of previous spontaneous preterm birth. However, many also reported use for other indications such as dilated/ effaced cervix (37%), short cervix on ultrasound (34%), and cerclage (26%). These results suggest that most obstetricians recommend or offer progesterone to prevent preterm birth for women with a previous spontaneous preterm birth and many also offer it for women with other high-risk obstetric conditions. KEYWORDS: Attitudes and practices, preterm birth, prevention, progesterone
P
reterm birth, the leading cause of neonatal morbidity and mortality in the United States, affects 13% of all births.1 Two randomized placebo-controlled trials2,3 targeting women at risk for subsequent preterm birth have brought new attention to the use of progesterone to prevent preterm birth. The larger trial demonstrated that weekly injections of 17 a-hydroxyprogesterone caproate (17P) significantly reduced (33%) preterm birth < 37 weeks among U.S. women with a history of prior spontaneous preterm birth.3 A subsequent trial showed that among high-risk Brazilian women (with prior preterm birth, prophylactic cervical cerclage, or uterine malformation), daily vaginal proges-
terone reduced preterm birth < 37 weeks by more than 50%.2 Following the publication of these two trials, the American College of Obstetricians and Gynecologists (ACOG) issued a committee opinion to support the use of progesterone to reduce preterm birth among women with a documented history of a previous spontaneous birth at < 37 weeks but also stated that further studies were needed to evaluate the use of progesterone in patients with other high-risk obstetric risk factors.4 In a survey of attendees of the 2004 annual clinical meeting of the Society of Maternal-Fetal Medicine, only 34.8% reported using progesterone to prevent preterm birth.5 Similarly, a larger survey of maternal-fetal
1
Disease Control and Prevention, 4770 Buford Highway, NE, Mailstop K-23, Atlanta GA 30341-3724 (e-mail:
[email protected]). Am J Perinatol. Copyright # by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 5844662. Received: October 8, 2008. Accepted after revision: December 10, 2008. DOI 10.1055/s-0029-1215432. ISSN 0735-1631.
Centers for Disease Control & Prevention, Division of Reproductive Health, Atlanta, Georgia; 2American College of Obstetricians and Gynecologists, Research Department, Washington, District of Columbia; 3Thomas Jefferson University, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Philadelphia, Pennsylvania. Address for correspondence and reprint requests: Zsakeba Henderson, M.D., Division of Reproductive Health, Centers for
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medicine (MFM) specialists conducted 6 months after the 17P trial showed that only 38% of board-certified MFM specialists used progesterone to prevent preterm birth.6 A follow-up to that survey, conducted in 2005, showed that the proportion of physicians that reported progesterone use had significantly increased to 67%.7 However, little is known about the awareness of the progesterone trials by practicing obstetricians who are not MFM specialists and whether they have adopted the use of progesterone to prevent preterm birth since the 2003 ACOG committee opinion regarding progesterone was published. There is also limited information about what risk factors are being used by practicing obstetricians to identify patients at risk for preterm birth, what risk factors are being used to determine who will be offered progesterone therapy, and concerns regarding acceptance of progesterone use into practice. To address these questions and to better understand obstetricians’ screening practices for preterm birth, we surveyed ACOG Fellows and Junior Fellows in Practice to assess their attitudes and practices.
MATERIALS AND METHODS Data were collected through a self-administered mail survey, mailed in March 2007, with two additional mailings in April and May, to 787 members of the ACOG Collaborative Ambulatory Research Network (CARN). Network members are ACOG Fellows or Junior Fellows in Practice who have volunteered to participate in ACOG Research Department surveys and are typically sent four to five surveys per year. The ACOG Research Department maintains membership on an ongoing basis with the goal of constituting a national group of practicing obstetrician-gynecologists reflective of practicing ACOG members as a whole.8,9 The survey consisted of 36 questions and addressed topics including the demographic characteristics of the respondents, the characteristics of the primary practice site and patients, preterm birth risk factor knowledge and screening practices, and knowledge and use of progesterone (of any formulation) to prevent preterm birth. To improve survey comparability, many questions were modeled on the 2005 follow-up survey of MFM specialists.7 Eligible clinicians were those currently in obstetrics practice. A cover letter outlined the purpose and benefits of the study and informed participants that their responses were anonymous and confidential. Response to the survey served as informed consent. Nonrespondents were sent a letter with six key questions to allow us to compare their responses and basic demographic characteristics with those of respondents who answered the same key questions. This research was deemed to be exempt from review by the Institutional Review Board of Georgetown University as research involving the use of educational
tests, survey procedures, interview procedures, or observation of public behavior. Surveys received by June 30, 2007, were included in the analysis. Data were analyzed using a personal computer-based version of SPSS 14.0 (SPSS Inc., Chicago, IL). We computed descriptive statistics for the measures used in secondary analyses. Chi-square tests were used to assess the relationships between selected clinician characteristics and (1) whether respondents recommended or offered progesterone for the prevention of preterm birth and (2) use of progesterone for indications other than a history of prior preterm birth. Selected clinician characteristics included gender, age ( 45 years versus > 45 years), years in clinical practice ( 10 years versus > 10 years), practice type (solo, multispecialty group, obstetrics and gynecology group, university-based, other), specialty (MFM or non-MFM), and the geographic region of practice (Northeast, South, Midwest, and West, U.S. Census Bureau Geographic Terms and Definitions. 2007; http://www.census.gov/popest/geographic/codes02.html. Accessed July 14, 2008.). We also analyzed how concerns regarding progesterone differed among those who reported recommending progesterone compared with those who did not and how concerns varied based on opinions about progesterone efficacy and data supporting its use. To examine differences between MFM specialists and general obstetrician-gynecologists and any changes in practice, we compared the results from this survey with the results from the 2005 follow-up survey of MFM specialists.7 A two-tailed probability of < 0.05 was considered statistically significant.
RESULTS Of the 787 surveys mailed, 318 clinicians did not respond; of those, 105 (33%) returned the letter answering the six key questions. Of the 469 completed surveys, 124 were ineligible (108 did not practice obstetrics, and sixteen did not practice in the United States), resulting in 345 completed surveys and an overall response rate, adjusted for eligibility, of 52% (345/663). Respondents did not differ significantly from nonrespondents in age or gender. Those nonrespondents who returned the letter generally did not differ from respondents in their answers to the six questions; however, they were significantly more likely to report offering or recommending progesterone for prevention of preterm birth (86% versus 74%, p ¼ 0.012). Most respondents (89%) practiced general obstetrics and gynecology as their primary specialty, 8% maternal-fetal medicine, and 2% obstetrics only; 50% were men; and 50% practiced in a private obstetrics and gynecology group. Respondents’ patients were mostly white (mean 59%); about a third of all patients received Medicaid (mean 30%). The median age of respondents
PROGESTERONE TO PREVENT PRETERM BIRTHS/HENDERSON ET AL
Table 1 Respondent Characteristics, by Use of Progesterone* Clinician Demographics
Total (N ¼ 345), n (%)y
Progesterone Users (n ¼ 254), n (%)
Nonusers (n ¼ 91), n (%)
p Valuez
179 (51.9)
119 (46.8)
60 (65.9)
0.002
172 (49.9)
136 (53.5)
36 (39.6)
0.02
146 (42.3) 196 (56.8)
109 (42.9) 143 (56.3)
37 (40.6) 53 (58.2)
0.72
1 (1.1)
0.001
Age (years) > 45 Gender Female Years in clinical practice 10 > 10 Specialty MFM Non-MFM
28 (8.1) 316 (91.9)
33 (13.0) 221 (87.0)
90 (98.9)
Practice-type§ Solo practice
56 (16.2)
29 (11.4)
27 (29.7)
Multispecialty group
38 (11.0)
26 (10.2)
12 (13.2)
University-based Obstetrics-gynecology group
48 (13.9) 174 (50.4)
40 (15.7) 139 (54.7)
8 (8.8) 35 (38.5)
Other
29 (8.3)
20 (7.9)
9 (9.9)
0.001
Geographic region West
81 (23.5)
45 (17.7)
36 (39.5)
Midwest
80 (23.2)
66 (26.0)
14 (15.4)
127 (36.8)
99 (39.0)
28 (30.8)
57 (16.5)
44 (17.3)
13 (14.3)
South Northeast
0.001
*Progesterone users are respondents who reported offering or recommending progesterone. y Percentages may not add up to 100% due to rounding. z Chi-square, comparing progesterone users versus nonusers. § ‘‘Other’’ includes health maintenance organization–based and military practice types. MFM, maternal-fetal medicine.
was 46 (range 31 to 74), with a median age of 40 for female respondents and 52 for male respondents. About half of respondents (51%) had been in practice more than 10 years and most practiced in the South (Table 1). Only 28% of respondents considered their patient population to be at higher than average risk for preterm birth. Almost all (95%) were confident or very confident in their ability to screen for patients who are high risk for preterm birth, and more than half (57%) managed patients at high risk of preterm birth themselves. Prior preterm birth, multiple gestation, and prematurely dilated or effaced cervix were the most frequently reported factors used routinely in practice to screen for patients at high risk of giving birth prematurely (Table 2). Of the almost three-fourths (74%, 254/345) of respondents (hereafter referred to as progesterone users) who recommended or offered progesterone to prevent preterm birth, only 2% stated that patients frequently requested progesterone for this purpose, 35% stated that patients infrequently requested it, and 63% reported that their patients never requested it. Table 1 shows the characteristics of respondents by progesterone use. Use of progesterone was associated with respondent age, gender, specialty, and practice type; progesterone use was more frequent among younger clinicians, female clinicians, MFM specialists, and clinicians in university-
based or obstetrics and gynecology group practices. However, clinician age and gender are confounded in this sample, as the percentage of women entering obstetrics and gynecology has steadily increased in recent decades. After controlling for the association between age and gender, the associations of age and gender with progesterone use were no longer significant. The proportion of progesterone users varied significantly by geographic region, with the West having the lowest proportion of users (Table 1). Table 2 Percentage of Respondents (N ¼ 345) Reporting Various Clinical or Demographic Factors Routinely Used to Screen for Patients at Risk for Preterm Birth Clinical or Demographic Factor
n (%)
Prior preterm birth
344 (99.7)
Multiple gestation
338 (98.0)
Prematurely dilated/effaced cervix > 1 prior preterm birth
319 (92.5) 310 (89.9)
Short cervix on ultrasound
306 (88.7)
Maternal substance abuse
284 (82.3)
Low socioeconomic status
279 (80.9)
Maternal tobacco use
246 (71.3)
Fetal fibronectin test
241 (69.9)
Maternal age < 17 y
240 (69.6)
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Figure 1 Percent of progesterone users (n ¼ 254) who reported offering progesterone for women with a prior spontaneous preterm birth, by gestational age of prior preterm birth.
Nearly all (92%) of progesterone users began recommending progesterone within the past 3 years, although 49% initiated use within the year prior to the survey. Intramuscular administration was preferred (83%), compared with 9% who reported preference for vaginal administration. Most (86%) reported that 50% of their patients declined progesterone, and 35% stated that none of their patients refused it. When asked where they or their patients most often obtained progesterone, 37% said a local compounding pharmacy, 16% home health care services, and 14% mail order. Ninety-three percent (236/254) of progesterone users recommended or offered progesterone for the indication of documented prior spontaneous preterm birth. The indication most frequently reported among this subgroup was any prior spontaneous preterm birth < 37 weeks (42%), and 14% recommended it only if there were additional risk factors (Fig. 1). Fifty-two percent (132/254) recommended progesterone to women without a prior preterm birth for other conditions in the current pregnancy. Among this subgroup, the most common indications for recommending progesterone were prematurely dilated or effaced cervix and short cervix on ultrasound (Fig. 2). Progesterone users who were older (> 45 years) and who were not MFM specialists were more likely to recommend progesterone to women without a prior spontaneous preterm birth, compared with those who were younger (60% versus 45%, p ¼ 0.021) or MFM specialists (55% versus 30%, p ¼ 0.008). Respondents in the Midwest and the South most likely used progesterone for indications other than prior spontaneous preterm birth (Midwest 50%, South 49% versus West 25%, Northeast 25%, p < 0.001). No differences were noted by respondent age, gender, years
in practice, or practice type among those who recommended progesterone for women without a prior preterm birth. Although 55% of all respondents (n ¼ 345) considered prophylactic progesterone for high-risk patients an effective treatment to reduce preterm birth, some were very concerned that it was not easily available (36%) or not covered by insurance (31%), that more data are needed (28%), and that there may be long-term fetal or neonatal effects (27%). The concerns expressed by progesterone users varied significantly from those of nonusers; nonusers were most frequently concerned about the need for more data, and progesterone users were most concerned about lack of availability (Fig. 3). Concerns also varied significantly by how convinced respondents were by clinical trial evidence. Those who were convinced by clinical trial evidence that prophylactic progesterone is effective for patients at high risk of preterm birth (26%) were less likely to be concerned about progesterone safety and efficacy than those (51%) who were only somewhat convinced (p ¼ 0.012). When compared with a recent survey of MFM specialists,7 progesterone use was only slightly higher in our survey (Table 3); however, the most frequently reported indication for use differed significantly. Respondents to the MFM survey were more likely to recommend progesterone for women with a prior spontaneous preterm birth < 34 weeks (41% versus 15.4%, p < 0.001), and respondents to this survey were more likely to report offering progesterone to women with any prior spontaneous preterm birth < 37 weeks (43% versus 30%, p ¼ 0.002). Respondents to this survey were also more likely to recommend progesterone for indications other than a history of prior spontaneous preterm birth
PROGESTERONE TO PREVENT PRETERM BIRTHS/HENDERSON ET AL
Figure 2 Percent of progesterone users (n ¼ 254) who reported offering progesterone for indications other than a prior spontaneous preterm birth. FFN, fetal fibronectin.
(Table 3). In both surveys, intramuscular administration was preferred, and respondents expressed similar concerns about progesterone use.
DISCUSSION In our survey, several key findings emerged. First, nearly three-fourths of respondents recommended or offered progesterone to prevent preterm birth, and most preferred intramuscular administration. Although almost all
progesterone users reported use for a documented history of prior preterm birth, about half reported use for other obstetric indications for women without a prior preterm birth. Last, many concerns were raised about progesterone, but concerns varied significantly by whether respondents recommended or offered progesterone. Data from this survey fill a gap in understanding the attitudes and practices regarding progesterone use to prevent preterm birth among general obstetrician-gynecologists, who make up the majority of respondents to
Figure 3 Concerns regarding progesterone use for prevention of preterm birth among users and nonusers. *Chi-square, p < 0.05. FDA, Food and Drug Administration.
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Table 3 Comparison of Selected Results From this Survey (ACOG 2007) with a 2005 Survey of MFM Specialists SMFM 2005 (N ¼ 572)
ACOG 2007 (N ¼ 345)
Use of progesterone
384 (67%)
254 (74%)
Most frequent indication with prior SPTB
< 34 wk (41%)
< 37 wk (43%)
Use for indications other than prior SPTB
148 (39%)
137 (52%)
p Value* 0.038 < 0.001
Preferred route IM (%)
87
83
0.170
Preferred route vaginal (%)
13
9
0.123
188
91
Need for more data (%)
Concerns of nonusers (very/somewhat concerned), n
97
87
< 0.001
Efficacy (%) Long-term effects (%)
86 77
82 72
0.322 0.438
Safety (%)
56
53
0.615
*Chi-square. SPTB, spontaneous preterm birth; IM, intramuscular; SMFM, survey of maternal-fetal medicine specialists (Ness et al6); ACOG, American College of Obstetricians and Gynecologists.
this survey and who manage a large proportion of pregnancies that result in preterm delivery nationwide. Attitudes and practices reflected in this survey may have been influenced by the first ACOG committee opinion4 published shortly after two progesterone trials in 2003, which advised use of progesterone only for women with a documented history of previous preterm birth < 37 weeks. This is evident in that most respondents use progesterone for this purpose. In contrast, MFM specialists in the prior MFM survey reported more targeted use for women with a history of spontaneous preterm birth at earlier gestational ages.7 The influence of that ACOG committee opinion, however, would not explain the higher use among respondents to this survey of progesterone for other obstetric indications. Additionally, some physicians may have been aware of preliminary results from subsequent trials presented at clinical meetings that suggested the efficacy of progesterone for other indications.10 However, other studies on obstetric practice have suggested that physician practices often do not reflect current evidence and may even contrast clinical trial evidence.11–13 In this survey and in the MFM survey, the concerns of respondents about progesterone were consistent. Those who did not report progesterone use were more concerned than users about every issue except progesterone availability, and they were most concerned about the need for more data, long-term effects, and efficacy. Progesterone users were most concerned about availability and insurance coverage. The increased concerns among those who did not use progesterone are likely why they have yet to adopt this therapy into practice. There are several limitations to this study. The knowledge and practices of respondents may have differed from those of nonrespondents. Respondents did not differ significantly, however, from nonrespondents in age or gender, and data from responses to six key questions returned by 33% of survey nonrespondents
(data not shown) suggest that nonrespondents do not differ substantially from respondents; the higher proportion reporting use of progesterone for prevention of preterm birth may reflect a higher proportion of MFM specialists in that sample. Other studies show that nonresponse bias tends to be less problematic among physicians than other groups.14 Selection bias could have resulted from use of the ACOG CARN for the study sample, which consists of ACOG Fellows who volunteer to take surveys. Previous studies with both CARN and non-CARN ACOG Fellows, however, found no differences in demographic characteristics or response.15 The response rate for this survey was consistent with response rates for previous ACOG surveys, and last, as with all surveys, results were not validated by a review of medical records or other clinical data, and therefore we cannot confirm if reported practice reflects actual practice. Although this survey showed that many U.S. obstetricians have accepted and integrated progesterone into their practices, practitioners in other industrialized nations have been slow to incorporate this therapy. In a recent survey in Australia and New Zealand,16 only 5% of the practicing obstetricians surveyed indicated that they use progesterone for prevention of preterm birth for women with certain high-risk factors (including prior spontaneous preterm birth < 34 weeks, multiple gestation, short cervix on ultrasound, and positive fetal fibronectin). That many U.S. obstetricians have adopted progesterone for prior spontaneous preterm birth as supported by ACOG and clinical trial evidence is not surprising. However, it is a concern that more than half reported use for indications not yet supported by evidence, especially considering the high level of concern in this survey for the need for more data and the relative paucity of evidence to support long-term safety.17,18 A major dilemma for obstetricians is the disparate results from the progesterone trials conducted to date, and increased progesterone use is likely because of the lack of available interventions to prevent preterm birth
PROGESTERONE TO PREVENT PRETERM BIRTHS/HENDERSON ET AL
due to multiple indications. Since this survey was conducted, there have been several additional clinical trials published with conflicting results that have evaluated vaginal progesterone for a history of preterm birth and the use of progesterone for obstetric indications other than a history of preterm birth, including use for a short cervix identified on ultrasound and for twin pregnancies.10,19–21 These are in addition to over 14 ongoing additional trials of progesterone involving women with high-risk pregnancies.22 Clinical acceptance or rejection of progesterone for prevention of preterm birth is still evolving; the ideal formulation of progesterone has yet to be determined, there is still no U.S. Food and Drug Administration approval, and there are lingering concerns about efficacy and safety. Another ACOG committee opinion has also been published since this survey was conducted, which states that further studies are still needed to evaluate the optimal preparation, dosage, route of administration, and other indications for the use of progesterone for the prevention of preterm delivery.23 The results of this survey show that opinions and practices among obstetric providers vary, and until more consistent information is available about the indications for progesterone use and its efficacy and safety, variations in use will likely continue. In general, obstetric decision making is complex, and further studies are needed to better understand obstetrician decision making and how new clinical evidence is adopted into practice. In the meantime, the combined efforts of national clinical and public health organizations to develop and disseminate clinician educational materials, guidelines, and decisionsupport tools may help equip obstetric providers with the necessary information to decide when progesterone use is appropriate.
ACKNOWLEDGMENTS
The authors thank William Callaghan, M.D., M.P.H., and Amen Ness, M.D. for input and advice on survey content.
NOTES
This study was conducted in the United States and was funded by the U.S. Centers for Disease Control and Prevention (CDC); the Collaborative Ambulatory Research Network is supported by Grant #R60 MC 05674 from the Maternal and Child Health Bureau (Title V, Social Security Act), Health Resources and Services Administration, Department of Health and Human Services. Selected data were presented on February 2, 2008 at the 28th Annual Meeting of the Society for Maternal Fetal Medicine in Dallas, Texas and May 6, 2008 at the American College of Obstetricians and Gynecologists Annual Clinical Meeting in New
Orleans, Louisiana. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.
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