The Impact of Antithrombin Deficiency on Women's Reproductive Health Experiences and Healthcare Decision-Making

Abstract

Background:

Women with inherited antithrombin (AT) deficiency are at high risk for venous thromboembolism (VTE), especially during times of estrogen exposure, but little is known about patient-oriented reproductive decision-making in this population.

Materials and Methods:

Provider-administered survey of women with AT deficiency. Participants were asked to discuss their diagnosis of AT deficiency and questioned about (1) contraception, (2) pregnancies, and (3) menorrhagia, and the impact of their AT deficiency on each reproductive health experience.

Results:

Of 31 women with inherited AT deficiency, 18 (58%) were surveyed, 8 (26%) were unreachable, and 5 (16%) were deceased. Twelve (67%) had a VTE, including two which occurred during pregnancy and five during oral contraceptive (OCP) use. Women reported using OCPs, intrauterine device (IUD), and condoms for contraception. Of five women diagnosed with AT deficiency while taking OCPs, three switched to an IUD, one to condoms, and one used no alternative method. Eighteen women reported 42 total pregnancies, with 33 (79%) resulting in live term birth, 3 (7%) in live preterm birth, and 6 (14%) in spontaneous abortion at a median of 12 weeks. Four (22%) women reported the use of anticoagulation during pregnancy. Eleven (61%) women reported menorrhagia and 4 (36%), while on anticoagulation for VTE events. Ten of 18 women (56%) reported that the diagnosis of AT had affected their reproductive health in some way.

Conclusion:

Women with AT deficiency require careful multidisciplinary management to avoid complications in the setting of contraception and pregnancy. AT deficiency impacts women's reproductive health experiences and patient-oriented reproductive decision-making is key.

Introduction

Antithrombin (AT) deficiency is a rare inherited thrombophilia, with prevalence in the general population between 1 in 500 and 1 in 5000, and is associated with a significantly increased risk for venous thromboembolism (VTE).¹ Women with AT deficiency are at particularly high risk of VTE during periods of estrogen exposure, including use of estrogen-containing oral contraceptives (OCPs) during pregnancy. Women with AT deficiency who use OCPs have an incidence rate ratio of approximately fivefold that of non-AT deficient women, and relative risk of pregnancy-related VTE ranges from 5- to 50-fold.^2
–4 Because of this increased risk, women with AT deficiency are advised to avoid use of estrogen-containing OCPs, and many are treated with prophylactic anticoagulation during pregnancy and immediately postpartum.^5,6

However, despite the significant amount of scientific literature regarding pathophysiology of AT deficiency and risk of VTE in these patients, and the fact that this has led to multiple reproductive health-related management recommendations, there is little published literature regarding women's attitudes and beliefs about contraception, assisted reproduction, and pregnancy and how these attitudes and beliefs affect clinical decision-making in these situations. In this study, we aimed to determine the healthcare and clinical decision-making processes in women with inherited AT deficiency using a patient-centered approach. We describe these women's lifetime reproductive histories, including how their thrombophilia affected their clinical care.

Materials and Methods

Study setting and population

The study was approved by the Mayo Clinic Institutional Review Board. A computerized Mayo Clinic-inherited AT deficiency registry was used to identify all women with a diagnosis of inherited AT deficiency seen at Mayo Clinic for at least one clinical visit at any time before 2016. Women were enrolled in the registry based on a variety of different methods, including (a) measurement of AT activity below the normal range in the setting of a clinical suspicion for AT deficiency (i.e., presentation with a thrombotic event), (b) measurement of AT activity below the normal range in patients with known family history of AT deficiency, (c) confirmatory genetic testing in patients with known family history of AT deficiency, and (d) prior diagnosis of AT deficiency at an outside institution based on presentation with a thrombotic event at a young age and confirmatory testing performed at an outside institution. In the case of newly diagnosed AT deficiency based on clinical suspicion, all patients underwent repeat/confirmatory testing in the absence of factors that could lead to extraneous reduction of AT levels (i.e., liver disease, heparin therapy) to document persistently reduced AT levels. All patients were diagnosed with AT deficiency based on the information above as well as a clinical visit with a hematologist or vascular medicine specialist at our institution. Furthermore, all patients included in the database were then screened by the principal investigator (a hematologist specializing in hemostasis/thrombosis) to confirm the diagnosis based on the combination of clinical, laboratory, and genetic data. Data on demographic and clinical characteristics at the time of diagnosis and during any follow-up visits were abstracted from their Mayo Clinic medical records.

Study design

To our knowledge, there are no validated questionnaires measuring the impact of inherited thrombophilias on women's reproductive health.⁷ We designed a provider-administered questionnaire regarding reproductive health experiences in women with AT deficiency. The questions were chosen for this survey based on consensus between two of the authors regarding which aspects of reproductive health (menorrhagia, pregnancy, etc.) were most likely to impact quality of life in women with AT deficiency. The questions were reviewed and approved by the first, second, and the last authors. The survey is provided as a Supplementary Data (Supplementary Data are available online at www.liebertpub.com/jwh). We attempted to telephone all identified women with AT deficiency to administer the questionnaire. Participants were asked to give verbal consent to participate in the study, and upon providing consent were asked to discuss their diagnosis of AT deficiency (age at diagnosis and VTE history, including diagnosis and treatment) and questioned about multiple aspects of reproductive health. These included (1) any method of contraception they had used during their lifetime, (2) any pregnancies they had experienced and the outcome of each, (3) any use of assisted reproductive technology, and (4) any history of +menorrhagia as well as how their AT diagnosis had impacted each reproductive health experience and how this impact made them feel (open-ended question).

Data analysis

Data were recorded and maintained in a Microsoft Excel spreadsheet. Data were recorded as (a) numeric responses (for questions such as number of pregnancies), (b) coded for yes/no responses (for questions such as presence or absence of a thrombotic event), (c) responses with a discrete set of answer options (such as location of the thrombotic event), or (d) free text for open-ended questions regarding women's self-reported reproductive experiences. Basic analysis was performed using Excel and JMP. Descriptive statistics—including mean (standard deviation), median with ranges (e.g., patient age and number of pregnancies), proportions (e.g., percent of patients choosing each type of contraceptive method; percent of women with pregnancies complicated by postpartum hemorrhage or peripartum thromboembolism)—were the primary method of data analysis. We used a Word Cloud (picture depicting words and phrases used more frequently in larger font size to provide a visual representation of patients' statements⁸) to present data regarding women's self-reported reproductive experiences.

Results

Demographic and clinical characteristics

Of the 31 women with inherited AT deficiency identified from the registry, 18 (58%) were reachable after one to three telephone calls, 8 (26%) were not reachable after three telephone call attempts, and 5 (16%) were deceased. Of the 18 women who were reachable, all provided consent and participated in the survey study. Characteristics of these 18 women are presented in Table 1. Among the 18 women included, the median (range) age at the time of AT deficiency diagnosis was 40 (7–65) years. Genotyping was performed in 8 of 18 women and demonstrated mutations in the AT gene in 6 of 8 women. Twelve of 18 (67%) of women had experienced a VTE, including two VTE, which occurred in the setting of pregnancy (one DVT and one PE), five in the setting of OCP use (one DVT, two PE, one combined DVT/PE, and one dural venous sinus thrombosis), and five unprovoked VTE (one DVT, two PE, one combined DVT/PE, and one hepatic venous thrombosis). Ten of 18 women (56%) reported that the diagnosis of AT deficiency had affected their reproductive health in at least one way.

Table 1.

Clinical Characteristics of Women with AT Deficiency

Patient	Age at diagnosis	History of VTE	Location of VTE	Risk factor for VTE	Contraceptive methods used	No. of pregnancies	Outcome of pregnancies	Menorrhagia	Menorrhagia while on anticoagulation
1	40	Yes	Pulmonary embolism	OCP	OCP	4	1 live term, 1 live preterm, 2 SAB (12, 24 weeks)	Yes	Yes
2	41	Yes	Pulmonary embolism	Unprovoked	None	4	4 live term	Yes	No
3	23	Yes	DVT	OCP	OCP	1	1 live preterm	No
4	60	No			OCP	3	3 live term	No
5	28	No			Condom	0		No
6	46	Yes	DVT and pulmonary embolism	OCP	OCP	2	2 live term	Yes	No
7	16	Yes	Pulmonary embolism	OCP	OCP	2	1 live term, 1 SAB (6 weeks)	Yes	No
8	51	Yes	DVT	OCP	OCP	3	2 live term, 1 SAB (12 weeks)	Yes	No
9	52	Yes	DVT	Unprovoked	OCP	2	2 live term	Yes	No
10	65	Yes	DVT	Pregnancy	None	6	6 live term	No
11	44	Yes	Pulmonary embolism	Unprovoked	OCP	3	3 live term	Yes	Yes
12	30	No			Condom	4	3 live term, 1 SAB (4 weeks)	No
13	15	No			IUD	0		Yes	No
14	45	No			OCP	2	2 live term	Yes	No
15	54	Yes	DVT and pulmonary embolism	Unprovoked	IUD	2	1 live preterm, 1 SAB (unknown)	No
16	20	No			OCP	2	2 live term	No
17	7	Yes	Hepatic venous thrombosis	Unprovoked	IUD, progestin only	0		Yes	Yes
18	9	Yes	Pulmonary embolism	Pregnancy	IUD, OCP	2	2 live term	Yes	Yes

AT, antithrombin; DVT, deep venous thrombosis; IUD, intrauterine device; OCP, oral contraceptive; SAB, spontaneous abortion; VTE, venous thromboembolism.

Contraception use

Contraceptive methods reported by women included OCPs, intrauterine device (IUD), and condoms. Of the five women diagnosed with AT deficiency while taking OCPs, all were recommended to stop OCPs and in some cases switch to another form of contraception. Of these five women, three switched to IUD, one to condoms, and one did not report an alternative method of contraception. Women's thoughts and feelings regarding this are further described in Table 2 and the Figure 1.

FIG. 1.

Word Cloud depicting frequency of women's comments regarding AT deficiency and contraception. AT, antithrombin.

Table 2.

Women's Qualitative Comments Regarding AT Deficiency and Reproductive Health

Regarding contraception

“It was a little scary being young and not knowing other [contraceptive] options.”

“I knew pills weren't an option. I talked to several providers, some were iffy about it and didn't seem to know much. I finally found someone who researched it for me and suggested Mirena. I was happy with the choice.”

“I had a steady partner and knew we had to be careful. IUDs were very new at the time. I figured I didn't have any options for contraception.”

“I was pretty comfortable with the discussion and decisions.”

“I was young and was not worried about it.”

Regarding pregnancy

“I was worried about the higher risk of pregnancy.”

“I wonder in hindsight how knowing my diagnosis would have impacted my pregnancy.”

“I know if I want to get pregnant in the future I need to be on shots.”

“My body never recovered after the pregnancy.”

“My first OBGYN ‘pooh-poohed’ the issue. I knew I had to find someone else. [My next OBGYN] knew it was ‘serious’ and it was a very scary time, but all went well.”

“After the blood clots, we didn't want to have more kids. It was very scary. If it weren't for the AT deficiency we would have had 1 or 2 more.”

“I know [pregnancy] is a higher risk but I would be willing to take it.”

Pregnancy and other reproductive experiences

Fifteen (83%) women reported at least one pregnancy (median [range] number of pregnancies, 2 [1–6]). The total number of pregnancies among all women was 42, with 33 (79%) resulting in live term birth, 3 (7%) in live preterm birth, and 6 (14%) in miscarriage/spontaneous abortion at a median of 12 weeks gestation (range 6–24 weeks). Women's thoughts and feelings regarding their experiences with pregnancy are further described in Table 2 and the Figure 1. Four (22%) women reported the use of anticoagulation during pregnancy. One woman reported use of assisted reproductive technology leading to a successful pregnancy. Eleven (61%) women reported menorrhagia, four (36%) of these while on anticoagulation for VTE events.

Discussion

Disorders of hemostasis and thrombosis are closely associated with women's reproductive health, and the clinical impact of these disorders is seen throughout the full spectrum of a woman's lifetime from menarche to after menopause. As a consequence, many of the healthcare choices women must make throughout their lives are impacted by the presence of these hemostatic disorders. In this patient-oriented study, we sought to explore the impact of inherited AT deficiency on women's reproductive health choices and experiences.

Women often choose to use at least one method of contraception during their reproductive years. Estrogen-containing OCPs are associated with a three- to fivefold increased risk for VTE.⁹ This increased risk approaches multiplicative proportions in combination with inherited thrombophilias such that women with inherited thrombophilias who take estrogen-containing OCPs may have a 20- to 30-fold increased risk for VTE.^10,11 For this reason, current guidelines recommend against the use of estrogen-containing OCPs in women with inherited thrombophilias.¹² However, others have advocated for detailed counseling of these women, with treatment recommendations made on a case-by-case basis.^13,14

While a small study indicated that women with the factor V Leiden polymorphism reported being discouraged from using combined OCPs by their providers and being “emotionally disturbed” by results of positive genetic testing for this thrombophilia, seven, there is limited data in the literature regarding “real-world” contraceptive choices made by women with inherited thrombophilias and the factors which contribute to their choices. We found that 5 of 18 women with AT deficiency had OCP-related VTE events, and all were recommended to stop OCPs and in some cases switch to another form of contraception. However, some women reported lack of awareness of alternative methods of contraception and at least one felt that their healthcare providers were not fully aware of safe alternative methods. This speaks to an opportunity to increase both patient and provider education regarding nonestrogen-containing methods of contraception and the importance of discussing such options with patients when a diagnosis of inherited AT deficiency is made.

Pregnancy is associated with increased risk of both thrombosis (during all of pregnancy and up to 12 weeks postpartum) as well as risk of hemorrhage at the time of delivery.¹⁵ Inherited thrombophilias are associated with increased risk of VTE in pregnancy, and approximately half of women who experience a pregnancy-associated VTE have an inherited thrombophilia.¹⁶ However, formal recommendations for obstetric management of both thrombotic and hematologic disorders are based primarily on expert opinion.^17,18 There is again a paucity of data regarding how women with inherited disorders of hemostasis and thrombosis communicate with their providers and make decisions about obstetric management and how this translates to “real-world” management of these women.

We found that several women who knew of their AT deficiency diagnosis before pregnancy (or after suffering complications in a prior pregnancy) found subsequent pregnancies to be “scary” and/or “high-risk.” Some chose to accept the high risk of subsequent pregnancies, and some chose to avoid further pregnancies. Pregnancy management in AT deficiency is another important area for educational development in both hematology and obstetrics–gynecology, and an opportunity to emphasize the importance of provider–patient communication regarding risks and options for pregnancy in this population. While pregnancy may be “high-risk,” steps should be taken to decrease a patient's fear, and the optimal way to do this may be through increased education and awareness.

A major strength of this study is the unique patient-oriented nature of the study, which allowed for collection of quantitative data (no. of pregnancies, type of contraception, etc.) and also allowed women to discuss and provide commentary on several aspects of their reproductive health that they may not have had the opportunity to discuss in detail with other providers in the past. We believe that this is the first patient-oriented study regarding reproductive health experiences in women with inherited AT deficiency, and in fact one of the few such patient-oriented reproductive health studies in women with any type of thrombophilia. Another strength of the study is the relatively large number of patients with AT deficiency whom we were able to contact (given that AT deficiency is a rare condition and many clinical studies include 10 or fewer women), providing generalizability to other women with AT deficiency.

There are several limitations of this study. First, women self-reported dates and numbers, including age at first VTE event, number of pregnancies, and so on; and for some patients who received much of their medical care at other facilities, there was no way to correlate self-reported data with clinical data available in the electronic medical record. Data regarding type of IUD as well as use of heparin prophylaxis during pregnancy were also missing. Second, since it had been many years since some of the women in the survey had used contraception or been pregnant; patients' self-reported experiences may be prone to recall bias. Finally, this survey-based methodology was quite time-intensive and thus may not be easily expanded in the setting of more common thrombophilias such as factor V Leiden, where a significantly larger number of patients would likely need to be contacted to provide generalizable results.

Conclusions

AT deficiency is an extremely thrombogenic condition, which significantly impacts women's reproductive health experiences. We conducted a patient-oriented survey study of women with AT deficiency and found that their diagnosis had significant impact on several aspects of reproductive health, including contraception use and choice and experiences with pregnancy. Providers in both hematology and obstetrics–gynecology should be aware of such issues and patient concerns, and provider training is essential so that providers are able to educate their patients about safe, appropriate management of reproductive health issues. AT deficiency is a disorder with a wide spectrum of clinical presentations, ranging from asymptomatic genetic carrier status to life-threatening VTE. As such, providers should pursue individualized patient counseling and recommendations for care for women with AT deficiency throughout their reproductive years. There is a significant opportunity for educational initiatives and patient-based outcomes research in this area.

Footnotes

Acknowledgments

This study was supported by funding from a Mayo Clinic Division of Hematology Small Research Grant awarded to the Primary Investigator.

Author Disclosure Statement

No competing financial interests exist.

References

Patnaik

, Mol

. Inherited antithrombin deficiency: A review. Haemophilia, 2008; 14:1229–1239.

Ilonczai

, Olah

, Selmeczi

, et al. Management and outcome of pregnancies in women with antithrombin deficiency: A single-center experience and review of literature. Blood Coagul Fibrinolysis, 2015; 26:798–804.

Rheaume

, Weber

, Durand

, Mahone

. Pregnancy-related venous thromboembolism risk in asymptomatic women with antithrombin deficiency: A systematic review. Obstet Gynecol, 2016; 127:649–656.

Van Boven

, Vandenbroucke

, Briet

, Rosendaal

. Gene-gene and gene-environment interactions determine risk of thrombosis in families with inherited antithrombin deficiency. Blood, 1999; 94:2590–2594.

Centers for Disease Control and Prevention. U.S. selected practice recommendations for contraceptive use, 2013. MMWR, 2013; 62 (RR-05):1–60.

American College of Obstetricians and Gynecologists Women's Health Care Physicians. ACOG Practice Bulletin No. 138: Inherited thrombophilias in pregnancy. Obstet Gynecol, 2013; 122:706–717.

Gartner

, Weber

, Eichinger

. The emotional impact of genetic testing and aspects of counseling prior to prescription of oral contraceptives. Contraception, 2008; 78:392–398.

Viegas

, Wattenberg

, Feinberg

. Participatory visualization with Wordle. IEEE Trans Vis Comput Graph, 2009; 15:1137–1144.

De Bastos

, Stegeman

, Rosendaal

, et al. Combined oral contraceptives: Venous thrombosis. Cochrane Database Syst Rev, 2014; 3:CD010813.

10.

Bergendal

, Persson

, Odeberg

, et al. Association of venous thromboembolism with hormonal contraception and thrombophilic genotypes. Obstet Gynecol, 2014; 124:600–609.

11.

Vandenbroucke

, Koster

, Briet

, et al. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet, 1994; 344:1453–1457.

12.

Centers for Disease Control and Prevention. United States Medical Eligibility Criteria (US MEC) for Contraceptive Use, 2010. Available at: www.cdc.gov/reproductivehealth/unintendedpregnancy/USMEC.htm Accessed March 2, 2016 .

13.

Van Vlijmen

, Veeger

, Middeldorp

, et al. Thrombotic risk during oral contraceptive use and pregnancy in women with factor V Leiden or prothrombin mutation: A rational approach to contraception. Blood, 2011; 118:2055–2061.

14.

Blanco-Molina

. Oral contraception in women with mild thrombophilia: What have we learned recently?. Thromb Res, 2012; 130 Suppl 1:S16–S18.

15.

Kamel

, Navi

, Sriram

, et al. Risk of a thrombotic event after the 6-week postpartum period. N Engl J Med, 2014; 370:1307–1315.

16.

American College of Obstetricians and Gynecologists Women's Health Care Physicians. Obstet Gynecol, 2013; 122:706–717.

17.

Nichols

, Hultin

, James

, et al. von Willebrand disease (VWD): Evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). Haemophilia, 2008; 14:171–232.

18.

Rocca

, Yawn

, StSauver

, et al. History of the Rochester Epidemiology Project: Half a century of medical records linkage in a US Population. Mayo Clinic Proc, 2012; 87:1202–1213.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.02 MB