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Obstetrics & Gynecology:
doi: 10.1097/01.AOG.0000278597.40292.32
Original Research

Thrombophilia and the Obstetric Patient

Cleary-Goldman, Jane MD1; Bettes, Barbara PhD2; Robinson, Julian N. MD3; Norwitz, Errol MD, PhD4; Schulkin, Jay PhD2

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Author Information

From 1the Department of Obstetrics and Gynecology, Mount Sinai School of Medicine, New York, New York; 2Department of Research, American College of Obstetricians and Gynecologists, Washington, DC; 3Division of Maternal Fetal Medicine, Brigham and Women's Hospital, Harvard Medical School, Massachusetts; and 4Division of Maternal Fetal Medicine, Yale Medical School, New Haven, Connecticut.

Supported in part by a grant from Health Resources and Services Administration/Maternal and Child Health Bureau.

Corresponding author: Jane Cleary-Goldman, MD, Carnegie Hill Imaging for Women, 70 East 90th Street, New York, NY 10128; e-mail: jcgoldman@mfmnyc.com.

Financial Disclosure The authors have no potential conflicts of interest to disclose.

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Abstract

OBJECTIVE: To examine how practicing obstetricians evaluate and manage thrombophilias in selected clinical situations.

METHODS: A questionnaire investigating knowledge and practice patterns pertaining to thrombophilia was mailed to 300 randomly selected American College of Obstetricians and Gynecologists Fellows and Junior Fellows in February 2005.

RESULTS: Approximately 50% (151) of questionnaires were returned. Statistical analysis focused on the 104 responding obstetricians. The majority (greater than 70%) know which thrombophilias are inherited and which are acquired. More than 50% send an inherited thrombophilia panel and antiphospholipid antibodies on patients with a history of fetal demise, intrauterine growth restriction (less than 5th percentile), abruption, and severe preeclampsia. Ninety-two percent test patients with recurrent miscarriages for antiphospholipid antibodies. Despite no clear evidence, 80% also test these patients for inherited thrombophilias. The majority intervene with either thromboprophylaxis or low-dose aspirin when managing patients at risk for thromboembolism. Seventy percent use low-molecular-weight (fractionated) heparin for patients requiring therapeutic anticoagulation, while 62% also use it for prophylactic anticoagulation. Thirty-eight percent of physicians using low-molecular-weight (fractionated) heparin monitor anti-factor Xa levels. The majority (56%) felt their residency training with regard to thrombophilia was barely adequate. Only 8% felt their training was comprehensive, while 36% felt it was adequate.

CONCLUSION: Most responding obstetricians do not manage thrombophilia patients according to expert opinion. Despite the fact that often there is no clear evidence for treatment, many physicians are inclined to intervene in patients at risk for thromboembolism. Educational endeavors are needed to guide obstetricians caring for patients at risk for thromboembolism.

LEVEL OF EVIDENCE: III

It is well established that many inherited thrombophilias are associated with thromboembolism. Likewise, the antiphospholipid antibody syndrome (acquired thrombophilia) is associated with thromboembolism in addition to adverse pregnancy outcomes, such as recurrent early pregnancy failure, placental insufficiency, severe preeclampsia, and intrauterine fetal demise.1,2 The association between obstetric complications and inherited thrombophilias, such as factor V Leiden mutation, prothrombin G20210A mutation, antithrombin III deficiency, protein S deficiency, and protein C deficiency is less clear. Studies suggest that certain thrombophilias such as factor V Leiden mutation and prothrombin G20219A mutation are a risk factor for late pregnancy loss.3–5 However, the evidence is conflicting concerning the association between inherited thrombophilias and other pregnancy complications.6–8

In clinical practice, the management of an obstetric patient with an inherited thrombophilia or an obstetric history which could be associated with a thrombophilia is complicated. No large randomized controlled studies guide the management of these patients. Rather, management is predominantly based on small studies and expert opinion which can lead to controversy.9–11 The purpose of this study was to examine how contemporary obstetricians evaluate and manage thrombophilias in specific clinical scenarios.

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MATERIALS AND METHODS

In February 2005, prevalidated questionnaires were mailed to 300 American College of Obstetricians and Gynecologists (ACOG) Fellows and Junior Fellows. This survey recorded demographic details, professional experience, didactic knowledge of thrombophilia, and an evaluation of training. Participants consisted of a computer-generated random sample of ACOG fellows. Those fellows who had received a questionnaire from our group in the past year were removed from the pool before generating the random sample to minimize the effects of questionnaire exhaustion on our response rate. As is our usual practice in survey research, nonrespondents received up to 3 additional mailings. Questionnaires returned by July 1, 2005, were included in this study.

The majority of questions in the demographic section and all of the questions in the knowledge, practice style, and education sections offered a range of multiple-choice answers. There were 10 questions on demographic information relating to characteristics of the individual and his/her practice. Three questions focused on knowledge about thrombophilias. Eight questions related to management style. Five clinical scenarios were presented of a pregnant woman with 1) asymptomatic factor V Leiden mutation, 2) history of thromboembolism of unknown etiology while on oral contraceptive pills, 3) antiphospholipid antibody syndrome with recurrent miscarriage, 4) recurrent miscarriage of unknown etiology, and 5) family history of thromboembolism without a thrombophilia. A copy of the questionnaire is available on request.

The data were analyzed using a personal computer–based software package (SPSS 11.5; SPSS Inc, Chicago, IL). Descriptive statistics were computed for measures used in secondary analyses. Group differences in responses on continuous measures were assessed using independent sample t tests. Categorical data were assessed using the χ2 test. Data were analyzed for group differences using sex and age as between-subject factors. Each factor was evaluated separately. Institutional review board exemption from the Columbia University Medical Center New York, New York, had been obtained.

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RESULTS

Of the 300 questionnaires, 151 (50.3%) were returned. Of the 151 respondents, 47 (31.1%) do not practice obstetrics. Those who do practice obstetrics were approximately 10 years younger (X=43.6 years), on average, than those who do not (X=54.8 years; F [1,148]=37.52, P<.001). The two groups had equal proportions of men and women, and there was no difference between the two groups on the region of the country in which they practice.

Data analyses were limited to those 104 respondents who practice obstetrics. Sixty percent were women (62 of 104), while 40% were men (42 of 104). For the year 2004, the respondents' mean number of deliveries was 119.07±63.62 (range 0 to 300). The median number of deliveries was 110. Eighty-two percent (85 of 104) were board-certified in obstetrics and gynecology, while 18% (19 of 104) stated that they were in residency. The mean age of those that had completed residency was 45.02± 9.61 years, and the mean number of years since completing residency was 13.50±9.51 years.

The majority of practitioners (53%) who were not in residency were in group practice. Fourteen percent were in solo practice, 11% were in faculty practice, 7% were in a multi-specialty group, and 3% worked for a health maintenance organization.

Seven percent of respondents indicated that they were maternal–fetal medicine specialists. The number of maternal–fetal medicine specialists was not large enough to make comparisons between maternal–fetal medicine and non–maternal–fetal medicine practice patterns. Omitting maternal–fetal medicine specialists from analysis would reduce the number of respondents by approximately 7%, which would have an impact on the strength of our conclusions.

The management of thrombophilia requires knowledge of issues particular to this type of pregnancy. The majority (greater than 70%) knew which thrombophilias were inherited and which were acquired (Table 1). More than 50% knew that the antiphospholipid antibody syndrome is diagnosed by specific clinical features along with certain antiphospholipid antibodies (lupus anticoagulant and high titer anticardiolipin antibodies). Fewer than anticipated (20%) knew that antithrombin III deficiency is the most thrombogenic inherited thrombophilia, with a greater than 50% risk of venous thromboembolic event during pregnancy.9 Thirty-six percent chose factor V Leiden mutation, 18% stated that they did not know, 9% selected prothrombin G20210A mutation, 9% selected the antiphospholipid antibody syndrome, 5% selected the methyleneterahydrofolate reductase gene mutation, 4% chose protein S deficiency, and 1% selected protein C deficiency.

Table 1
Table 1
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With regard to an inherited thrombophilia work-up, the majority (98%) test for factor V Leiden mutation, lupus anticoagulant, and anticardiolipin antibodies (Table 2). While 57% send methylenetetrahydrofolate reductase gene mutation C677T and 27% send methylenetetrahydrofolate reductase gene mutation 1298C, only 43% send fasting homocysteine levels. The mean number of investigations reported was 7.8±2.06, with a range of 1 to 12. Men and women did not differ on the number of investigations they reported ordering.

Table 2
Table 2
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In certain clinical scenarios, obstetricians may consider testing patients for inherited or acquired thrombophilia or both. Table 3 describes situations in which physicians test patients for inherited thrombophilias and for the antiphospholipid antibody syndrome. Figure 1 describes how the respondents would manage the five clinical scenarios described above in clinical practice.

Table 3
Table 3
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Fig. 1
Fig. 1
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Physicians were asked several questions about the management of patients requiring anticoagulation. For patients requiring therapeutic anticoagulation during pregnancy, 22% use unfractionated heparin, 70% use low-molecular-weight (fractionated) heparin, and 8% do not manage patients on anticoagulation during pregnancy. For patients requiring prophylactic anticoagulation during pregnancy, 30% use unfractionated heparin, 62% use low-molecular-weight (fractionated) heparin, and 8% do not manage patients on anticoagulation during pregnancy.

For patients on unfractionated heparin, 10% monitor the level of anticoagulation using clinical signs such as bleeding gums and bruising, 77% monitor activated partial thromboplastin time levels every 2.99±1.96 weeks, 1% use anti-factor Xa levels, and 13% stated they do not manage patients on unfractionated heparin during pregnancy. For patients requiring low-molecular-weight (fractionated) heparin during pregnancy, 39% monitor the level of anticoagulation using clinical criteria such as bleeding gums and bruising, 10% monitor activated partial thromboplastin time levels every 3.22±1.92 weeks, 38% follow anti-factor Xa levels every 3.88±2.51 weeks, and 13% do not manage these patients. Seventy-seven percent of respondents monitor platelet levels if patients are on therapeutic unfractionated heparin or low-molecular-weight heparin during pregnancy while 23% do not. Six percent monitor the platelets every week, 13% monitor them every two weeks, 44% monitor them once per month, 6% monitor them every 6 weeks, 23% monitor them every trimester, and 8% do not manage these patients. Table 4 describes how responding obstetricians would manage a patient on therapeutic anticoagulation with low-molecular-weight (fractionated) heparin around the time of delivery.

Table 4
Table 4
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The majority (56%) of practicing obstetricians felt their residency training with regard to thrombophilia was barely adequate to nonexistent. Only 8% felt their training was comprehensive, while 36% felt their training was adequate.

Physicians were asked to indicate how they stay informed about advances in thrombophilia and pregnancy. American College of Obstetricians and Gynecologists' publications were selected most frequently (78%) as an important source of information, followed by journals (58%), continuing medical education programs (50%), literature/Internet searches (31%), and text books (26%).

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DISCUSSION

The management of the obstetric patient with an inherited thrombophilia is complex. Many women who have an underlying thrombophilia are healthy, while there are others who do not have a known thrombophilia but experience many medical and obstetric complications. Risk for thromboembolism and for adverse pregnancy outcomes seems to derive from an interplay of medical and obstetric history, family history, and genetic and environmental factors. In addition, current treatment, prophylactic or therapeutic anticoagulation, is not without risks such as bleeding, decreased platelets, and possible osteopenia/osteoporosis, and it has not been studied in large-scale randomized and controlled studies.

Taking care of the obstetric patient with thrombophilia or an obstetric history that could be associated with thrombophilia is controversial due to the fact that there are no clear guidelines directing all aspects of management. There is only one ACOG Practice Bulletin on the subject and it concentrates on the antiphospholipid antibody syndrome.1 Two “High-Risk Pregnancy Series: an Expert's View” articles from Obstetrics & Gynecology address inherited thrombophilias and the antiphospholipid antibody syndrome in pregnancy.9,10 Nonetheless, many questions regarding management are not well elucidated in these texts, such as when to start and the frequency of fetal surveillance. The majority of practicing obstetricians rely on ACOG to guide their clinical practices on these topics.

There are areas of management where respondents are consistent with the advice of the experts. The majority (greater than 50%) test for inherited thrombophilias and for the antiphospholipid antibody syndrome in patients who have had a history of intrauterine fetal demise, abruption, severe intrauterine growth restriction, and severe preeclampsia. For the most part, they also test patients for the most common thrombophilias (factor V Leiden, prothrombin gene mutation, antithrombin activity level, protein C activity level, and protein S activity level). Likewise, they test patients for the antiphospholipid antibody syndrome (Table 2). Very few practitioners test patients for thrombophilias which have even more uncertain effects (protein Z level, B-fibrinogen-455 G-A polymorphism, apolipoprotein B R3500Q and E2/E3/E4, factor XIII V 34L, GPIIIa L33P, HFE C282Y, and the extended antiphospholipid antibody panel). However, fewer than the anticipated number of practitioners test patients for fasting homocysteine levels and 4G/4G plasminogen activator inhibitor-1 polymorphism, which experts suggest are included in a thrombophilia work-up. It was also interesting to note that, while 57% send methylenetetrahydrofolate reductase gene mutation C677T and 27% send methylenetetrahydrofolate reductase gene mutation 1298C, 43% also send fasting homocysteine levels.

Figure 1 indicates how practicing obstetricians would manage five clinical situations involving a patient with thrombophilia or a history that could potentially increase the risk for thromboembolism. With the exception of case 3, which involved the antiphospholipid antibody syndrome, fewer than 50% would manage the clinical scenario as the experts would suggest.1,2,9,10 This likely reflects the fact that there are no clear management guidelines.

Except for case 3, there are no studies supporting treatment of the pregnant woman with either anticoagulation or low-dose aspirin therapy. Nonetheless, 66% in case 1, 46% in case 2, 42% in case 4, and 94% in case 5 would treat with either low-dose aspirin, prophylactic or therapeutic anticoagulation, or a combination of low-dose aspirin and anticoagulation with or without steroids. Our study is consistent with a Canadian Survey on the management of thrombophilia in pregnancy from 2002 which also suggests that physicians in an uncertain clinical situation are inclined to intervene rather than observe despite no clear evidence to support the practice.12

It is interesting to note that, depending on the question, as many as 13% of respondents stated that they do not manage these types of patients in routine clinical practice. We suspect that this reflects the fact that this is a confusing subject without clear guidelines. The survey also indicates that many of the respondents felt their training was not adequate with regard to thrombophilias and that they are depending on ACOG to provide clear guidelines. Educational efforts are needed to help practicing obstetricians manage patients with or at risk of thrombophilia. While one option would be to send all of these patients to a specialist in high-risk pregnancies, this is not practical due to the fact that thrombophilias are relatively common and due to the fact that specialists may not be available in all areas of the country.

One limitation of this study is the relatively small sample size. It should be noted that this was intended as a study to provide a snapshot of current knowledge and practices of obstetricians with regard to thrombophilias to inform future research and continuing education efforts. The overall response rate was within the range of response rates experienced by our group (approximately 50%), and power analyses from previous ACOG survey studies have suggested that the minimum number of responses needed to ensure significant effect sizes is approximately 100.13 In view of the fact that the major statistical criteria were met, we can safely conclude that further investigations are needed to establish how comfortable practicing obstetricians are managing patients with thrombophilia. The optimal strategy of how to better educate contemporary obstetricians about this elusive subject also needs to be determined.

In summary, large randomized studies would be optimal to elucidate the management of patients with inherited thrombophilias and patients with a history of previous adverse pregnancy outcomes. Such studies may not be practical for ethical reasons. Until the uncertainties surrounding the management of thrombophilias are resolved, educational resources should be devoted to helping practicing obstetricians mange these patients. The American College of Obstetricians and Gynecologists may be the ideal organization to effect this change.

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REFERENCES

1. Antiphospholipid syndrome. ACOG Practice Bulletin No. 68. American College of Obstetricians and Gynecologists. Obstet Gynecol 2005;106:1113–21.

2. American College of Obstetricians and Gynecologists. Thromboembolism in pregnancy. ACOG Practice Bulletin No. 19. Washington, DC: ACOG; 2000.

3. Grandone E, Brancaccio V, Colaizzo D, Scianname N, Pavon G, Di Minno G, et al. Preventing adverse obstetric outcomes in women with genetic thrombophilia. Fertil Steril 2002;78:371–5.

4. Ridker PM, Miletich JP, Buring JE, Ariyo AA, Price DT, Manson JE, et al. Factor V Leiden mutation as a risk factor for recurrent pregnancy loss. Ann Intern Med 1998;128:1000–3.

5. Sarig G, Younis J, Hoffman R, Lanir N, Blumenfeld Z, Brenner B. Thrombophilia is common in women with idiopathic pregnancy loss and is associated with late pregnancy wastage. Fertil Steril 2002;77:342–7.

6. Dekker GA, de Vries JI, Doelitzsch PM, Huijgens PC, von Blomberg BM, Jakobs C, et al. Underlying disorders associated with severe early-onset preeclampsia. Am J Obstet Gynecol 1995;173:1042–8.

7. Dizon-Townson D, Miller C, Sibai B, Spong CY, Thom E, Wendel G, et al. The relationship of factor V Leiden mutation and pregnancy outcomes for mother and fetus. Obstet Gynecol 2005;106:517–24.

8. Kupferminc MJ, Eldor A, Steinman N, Many A, Bar-Am A, Jaffa A, et al. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 1999;340:9–13.

9. Lockwood CJ. Inherited thrombophilias in pregnant patients: detection and treatment paradigm. Obstet Gynecol 2002;99:333–41.

10. Branch DW, Khamashta MA. Antiphospholipid syndrome: obstetric diagnosis, management, and controversies. Obstet Gynecol 2003;101:1333–44.

11. Paidas MJ, Ku DW, Langhoff-Roos J, Arkel YS. Inherited thrombophilias and adverse pregnancy outcomes: screening and management. Semin Perinatol 2005;29:150–63.

12. Rodger MA, Carrier M, Keely E, Karovitch A, Nimrod C, Walker M, et al. The management of thrombophilia during pregnancy: a Canadian survey. J Obstet Gynaecol Can 2002;24:946–52.

13. Wilkins-Haug L, Hill L, Schmidt L, Holzman GB, Schulkin J. Genetics in obstetricians' offices: a survey study. Obstet Gynecol 1999;93:642–47.

Cited By:

This article has been cited 2 time(s).

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Screening and treatment for heritable thrombophilia in pregnancy failure: inconsistencies among UK early pregnancy units
Norrie, G; Farquharson, RG; Greaves, M
British Journal of Haematology, 144(2): 241-244.
10.1111/j.1365-2141.2008.07444.x
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Obstetrics & Gynecology
Factor V Leiden Homozygous Genotype and Pregnancy Outcomes
Biron-Andréani, C; Bauters, A; Le Cam-Duchez, V; Delahousse, B; Lequerrec, A; Dutrillaux, F; Boinot, C; Saladin-Thiron, C; Polack, B; Gruel, Y; Morange, P; on behalf of the PROCARE-GEHT Group,
Obstetrics & Gynecology, 114(6): 1249-1253.
10.1097/AOG.0b013e3181c2243d
PDF (167) | CrossRef
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© 2007 The American College of Obstetricians and Gynecologists

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