Abnormal Uterine Bleeding In Premenopausal Women Taking Oral Anticoagulation After Mechanical Valve Replacement.

Varuna Varma, Amrit Gupta*, Nirmal Gupta Department of Cardiovascular and Thoracic surgery and *Department of Maternal and Reproductive Health Sanjay Gandhi Post graduate Institute of Medical Sciences, Lucknow. UP. India. 226014 Corresponding author: Amrit Gupta Associated Professor, Department of Maternity and Reproductive Health. Sanjay Gandhi Post graduate Institute of Medical Sciences, Lucknow. UP. India. 226014. Objective: To analyse the causes of Abnormal Uterine Bleeding (AUB) in females following valve replacement surgeries and to design efficient methods for its early recognition, prevention and treatment. Design: Prospective observational study Setting: Sanjay Gandhi Post graduate Institute of Medical Sciences, Lucknow. India Patients: Women of all age group with prosthetic valve replacement on Acitrom (Acenocoumarol) therapy. From July 2009 through September 2010.

Results: One-hundred eighty-nine valve placement were performed by a single surgeon in 123 patients during one year period (July 2009 to September 2010). Of these thirty-five women were identified with abnormal uterine bleeding with prosthetic valve replacement on anticoagulants investigated for the presence of an underlying pathology. In our study the median age was 32.8 years. The commonest compliant was mennorrhagia which was seen in (Numbers) 64.8% women. In (numbers) 88.5% women organic aetiology was found which was reproductive in origin and represented the majority. International normalized ratio (INR) (n=24) 68.5% women were in therapeutic INR range, whilst in (Numbers) 11.4% had increased (outside the therapeutic range) INR. After commencing on progesterone (Norethisterone) menstrual bleeding was reoprtedly decreased at 3and 6 months. In (N) 8% women who presented with adnexal mass and haemorrhagic ovarian cyst , hormonal therapy showed reduction in volume and size by approximately 75% within 6months. Conclusion: Oral anticoagulants should be given very cautiously in women especially in their reproductive age group after valve replacement heart surgery. Hormonal medications that mainly potentiate the effects of oral anticoagulants should be avoided. Abrupt discontinuation of anticoagulants and use of procoagulants is not advisable in order to control AUB endangering patient lives to prevent peripheral/neural thrombo-embolic episodes or severe valve dysfunction without treating other causes menstrual abnormalities.

Keywords: Oral anticoagulation, Abnormal uterine bleeding

Introduction Replacement of a diseased heart valve/s with a prosthetic valve exchanges the native disease for potential prosthesisrelated complications which mandates life-long use of oral anticoagulation treatment (OAT) to prevention of venous /arterial thrombo-embolism/stroke / Atrial fibrillation or valve dysfunction. [1] Bleeding complications during mandatory anticoagulation treatment are not uncommon and can be life threatening. These hemorrhagic complications usually occur abruptly, are difficult to predict, and limit their therapeutic benefit. Women, who are taking anticoagulants, are vulnerable for increased menstrual bleeding and in the abdominal cavity at the time of their ovulation, which is a potentially life-threatening complication due to increased INR levels. Abnormal uterine bleeding (AUB) is defined as any alteration in the pattern or volume of menstrual blood flow that constitutes a major clinical problem that affects approximately 25 30% of women with a gynecological problem. [1,2] [4] A reported risk for major bleed of 0.8% per patient per year for heart valve patients has seen , while the incidence for minor bleed is about ten times greater than that for major bleeding. However, a specific cause is identified in [5] only 50% of the affected women. AUB may be the result of local pathologies such as uterine fibroids, polyps, [6-7] adenomyosis, endometriosis, infection, or carcinoma, systemic disorders such as inherited clotting deficiency [8-9] thrombocytopenia, chronic liver failure, or hypothyroidism [10] metabolic syndrome such as polycystic ovarian syndrome (PCOS) and other iatrogenic factors such as the use of intrauterine contraceptive devices [11] and oral anticoagulation therapy. Combination of long-term oral anticoagulation and abnormal uterine bleeding can be challenging because of the absolute need of stable and relatively higher INR and at the same time reduction of oral anticoagulation dosages in the events of excessive and persistent uterine bleeding in women. Any management strategy, either stopping or continuing oral anticoagulation or even instituting often required hormonal therapies could work as a double edged sword due to significant alterations in INR levels caused by hormone-drug interactions. Very little is published in the literature about the risk profile of patients on mandatory long-term oral anticoagulation for maintaining higher levels of INR (as compared to patients with deep vein thrombosis) in patients with mechanical heart valves and associated AUB. There is only a single published report from India on this subject in the English literature. [27] We have therefore, performed the following prospective observational study to highlight clinical challenges associated with the malady and management options practicable in predominantly rural and semi-urban Indian scenarios. Objectives: 1. To analyze the cause of abnormal uterine bleeding in women who are placed on life long oral anticoagulation therapy after elective valve replacement heart surgery using mechanical prosthetic heart valves. 2. To identify and recommend effective methods for its early recognition, prevention and treatments suitable in Indian conditions.

Material and Methods Informed verbal consent was obtained from all patients whose data is being used to collate this study. Study Design and Patients This is a prospective observational study, which was carried out at Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, from July 2009 to September 2010 in 35 women in reproductive age group (15 and 40 year) with a clinically relevant abnormal uterine bleeding event whilst receiving anticoagulation therapy after replacement of their native valve by mechanical prosthesis. Study Inclusion criteria Women who have undergone an elective single or multiple valve replacement surgery either Aortic (AVR) or Mitral (MVR) or combined aortic and mitral valve replacement (DVR) with mechanical valve prosthesis. Study Exclusion criteria 1. Patients with known hemorrhagic disorders 2. Contraindications for treatment with Coumadin derivatives

3. 4.

Reconstructive replacement with bioprosthesis AUB like oligomenorrhea, amenorrhea were excluded from the study

Anticoagulation treatment Anticoagulation regimen has a defined range of INRs, AVR (2.0-2.5), MVR (2.5-3.0) and DVR (3.0-3.5) using oral anticoagulation with a vitamin K antagonist (VKA). Dosing and follow-up recalls are individualized for patient in question. Any clinical relevant bleeding event was recorded as an event requiring medical evaluation or surgical treatment. Special emphasis was placed on meticulous recording of all values of INR on every patient visit along with documentation of any complications occurring during the follow-up. Patients were given documentation cards for life-long at our department mentioning its current INR value, patients original dose, advised dose and its duration. The treating surgeon checked patients reports once 2-4 weeks interval. Any abnormal uterine bleeding complication were recorded and admitted immediately for a expert examination and consultation by an institutional gynecologist (Corresponding author: Dr. Amrit Gupta). Initial assessment The detailed history and clinical examination of these women was carried out and recorded on a detailed questionnaire and clinical evaluation sheet. A detailed questionnaire included a history and elaborate clinical evaluation Paps smear and high vaginal swab was taken during the initial local examination, if indicated. Laboratory tests: Taking a detailed history for bleeding from other sites howsoever minor, paternal consanguinity as well as family history of bleeding tendencies appeared as a very strong predictor for inherited coagulation defects in patients with menorrhagia. Patients with preoperative menorrhagia without a discernable cause, therefore, would have required evaluation for the congenital coagulation disorders. 1. 2. 3. Results In our prospective observation of 35 women in the reproductive age group (25-40 years), (N) 74.28% were operated for mitral valve, (N) 17.14% and (N) 8.57% for double valve and aortic valve replacement respectively. Cause of abnormal uterine bleeding was found to be organic in (N) 88.57%. Of these (N) 58.06% were reproductive in origin and iatrogenic (N) 9.67%. Genital tuberculosis was observed in (N) 19.35 % of women. Incidence of tubercular ovarian cyst observed was (N) 25.80%. All women were divided into two groups according to their INR status Group A (normal INR) and Group B (abnormal INR). Of these (N) 68.57% women were in Group A and (N) 31.42% women in Group B. All patients (100%) in Group A had an underlying uterine pathology as compared to patients in Group B where only (N) 11.43% were underlying cause for abnormal uterine bleeding was not identified and hence noted to be suffering with Dysfunctional Uterine Bleeding (DUB). (Fig1). A battery of investigation was done to screen patients for their infection, hematological evaluation, liver and kidney function test, hormonal and coagulation profile. Subsequently screening for tuberculosis was done by microscopy and culture of menstrual blood collected on Day-1 of menstrual period A detailed ultrasound of pelvic region was done to evaluate for any uterine or adnexal pathologies.

30 25 20 15 10 5 0 With Uterine pathology Without uterine pathology Group A(Normal INR) Group B(Raised INR)

Fig 1: This Bar diagram shows us the distribution between both the groups according to the presence /absence of any underlying uterine cause.

30 25 20 15 10 5 0 Total number of Number of patients valvular heart patients under Therapeutic INR range AVR(2.0-2.5) Total number of patients above Therapeutic INR range(>6) Number of patients below Therapeutic INR range(<2)

MVR(2.5-3.5)

DVR(3.0-3.5)

Fig 2: Amongst total number of patients for valvular heart replacement surgery maximum 54.28% underwent MVR using mechanical prosthesis who were bleeding under the therapeutic range of INR values between 3.0 3.8(+/- 3). Range of hemoglobin in patients AUB Hemoglobin level ranging between 9 to 12g/dl in (N) 65.71% in patients with AUB had their INR within the therapeutic range for their valve surgeries. In contrast, patients with low hemoglobin (6 to 9g/dl) were found to be INR beyond therapeutic range (range). INR 10 H e m o g l o b i n l e v e l s 8 6 4 2 0 0 2 4 6 8 10 12 14

Fig 3: This scattered diagram shows the degree of severity between the level of INR and Hemoglobin.

Discussion Approximately 2530% of women with a gynecological problem are affected with menorrhagia. [2, 3] Menstrual disorders in the form of menorrhagia constitute a major clinical problem that affects a large number of women during their reproductive life. Although uterine bleeding associated with anticoagulant therapy is not uncommon. This is particularly so in patients who are on oral anticoagulation for the prevention of valve thrombosis and systemic thromboembolic complications after mechanical prosthesis as a replacement for diseased valves. [26] Varieties of other options such as; temporary withdrawal or reduction in oral anticoagulation dosage, hormonal or non-hormonal drug therapies, endometrial ablation, hysteroscopic resection and hysterectomy are available for treating AUB in women depending up on its cause, womens age, parity and obviously the intractability. However these options become limited in women on oral anticoagulation with mechanical heart valves in their reproductive age. In developing countries rheumatic heart valve disease is still a common ailment in rural and semi-urban population particularly in young (reproductive age). All such women require life-long oral anticoagulation medication to prevent stroke, peripheral embolic episodes or valve thrombosis resulting into severe debilitating morbidities or fatal outcomes in most instances. Although, these risks can be obviated by valve repair or giving a choice of bioprosthetic insertion at the time of their first surgery in young women (wishing to complete their families) even in with rheumatic valve disease but with a definite risk of reoperation due to repair or structural valve degeneration over a period of time. Our institution caters in large population of this kind situated in one of the largest yet underdeveloped state in the northern part of India. In one year period from July 2009 to September 2010 in 35 women were encountered in reproductive age (15 and 40 year, mean=32.8years 3.4months) with a clinically relevant abnormal uterine bleeding event whilst receiving anticoagulation therapy following replacement of their native valve by a single or multiple mechanical prosthesis. This incidence is considerably more as compared to the women on oral anticoagulants (for other causes) with abnormal uterine bleeding in reproductive age group [12] with the prevalence ranging from 9% to 30% [13] The reported frequency of AUB was signicantly higher reporting as menorrhagia as the main presenting complaint 30% without an underlying pathology but was lesser in our observation (n=4) 11.42 % (P < 0.01)[12] without an underlying intra uterine pathology. These four patients with AUB had increased INR without any underlying uterine cause and were successfully treated with Progestin (pills, patches, and rings). It was observed that the risk of major bleeding was increased when the INR exceeds 4.5 and rises steeply and exponentially above after the INR crosses 6.0 or more [14] necessitating gradual meticulous dosage management of oral anticoagulation. Recommendation that evolves from managing these patients in this manner confirms that in careful exclusion of intra-uterine cause can obviate the need for much more invasive or hormonal drug therapies in these women and can not be a reason to discontinue anticoagulation therapy. [15] Management of AUB caused by hormonally responsive intrauterine pathologies was done by a progestin or danazol with increased frequency of INR assessments. Inordinately increased INRs were managed by low dose intramuscular vitamin K injection and omission of 1or 2 doses of short acting oral anticoagulant drug (Acitrom). Blood products such as fresh frozen plasma were not used and packed RBCs were used exceptionally in emergent situations such as, when the patients hemoglobin was lesser than 7.0 g/dl or had to undergo emergency hysterectomy due to massive concealed intra-abdominal bleeding caused by rupture of hemorrhagic ovarian cyst. There is evidence of increased risk of AUB associated with the fluctuating levels of INR. [16] Incidence of INR fluctuation in even very well managed patients has been reported to be 10 to 17 per 100 patient-years. [17-23] In our observations only 11 (31%) patients had fluctuating INR and remaining 24 (69%) had maintained INR levels within the desired therapeutic ranges for their valve condition. This could be effect of the socioeconomic patient characteristic or an important variable of increased incidence or uterine as well as pulmonary Kochs is another major problem in patients of our region requiring additional anti-Kochs treatment that results in unpredictable fluctuations of INR levels due to its effect on liver metabolism through its microsomal activation pathways. Six (17%) were treated successfully with anti-Kochs treatment for 9 months for genital tuberculosis. Two (6%) patients with large tubo-ovarian mass were placed on hormonal therapy had reduction in the volume and size of cyst within 6

months of therapy and only 1 patient (3%) with multiple large uterine fibroids that has completed her family failed to respond to conservative treatment underwent vaginal hysterectomy. In premenopausal patients with AUB intrabdominal hemorrhage can be caused by corpus luteal cyst rupture. This can be a cause for an abrupt hemorrhagic shock and severe anemia in patients with mechanical valves on oral anticoagulation. [24] Of the total 6, one patient underwent emergency unilateral salpingo-oophorectomy for life threatening intra-abdominal hemorrhage encountered in our observation other 5 (14%) were treated successfully with hormonal therapy albeit with increased frequency of INR assessments. AUB caused by dysfunctional uterine bleeding (DUB) without any underlying anatomic or uterine pathologies should be attributed to coagulopathy unless proved otherwise. [25] In our observation these patients responded well to hormonal therapy by Progestin only pills, which not only prevented bleeding caused by monthly ovulation (follicular rupture) but also prevented bleeding into the ovary and within the pelvic region. We therefore, recommend that unless premenopausal women with DUB on oral anticoagulation for mechanical heart valves (unless particularly keen on having pregnancy) can be recommended to take low dose birth control pills to prevent morbidity (anemia, pelvic inflammatory disease) caused by DUB and follicle rupture. Management of mandatory oral anticoagulation therapy in all patients after mechanical heart valve poses a special challenge in premenopausal women due to their specific needs. This becomes more complicated rural and semiurban illiterate patients in lower or lower middle-class. Lack of specialist in different locations presents an additional challenge for the cardiac surgeons and their units. Close cooperation between gynecologists and treating surgeons along with intense preoperative workup of patients and counseling of patients, their families help a great deal in improving their quality of their family and sexual lives. Prevention strategy 1. All patients undergoing operation for mechanical valve replacement surgery that entails mandatory lifelong oral anticoagulation in reproductive age group should ideally undergo a detailed preoperative pelvic ultrasound to rule out any underlying cause of uterine or adnexal pathologies. 2. More frequent INR assessments and high index of suspicion for concealed uterine or ovarian pathologies is the key in the event of any abnormal drop in hemoglobin.

Conclusions Oral Anticoagulants should be used very cautiously in women in reproductive age group after valvular heart surgery after using mechanical prosthesis. Increased INR shouldnt always be incriminated for abnormal uterine bleeding without excluding out other underlying causes. Since these patients are at an high risk of thromboembolic episodes or valve dysfunction, balance between the bleeding risk before the start of anticoagulant treatment and benefits of the therapy should be carefully evaluated whilst placing these patients on pro-coagulant medications or abrupt discontinuation of oral anticoagulants for the control of excessive uterine bleeding endangering their lives.

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