University of Groningen the Pill and Thrombosis Van Vlijmen, Elizabeth

University of Groningen

The pill and thrombosis van Vlijmen, Elizabeth Femma Willemien

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Download date: 23-09-2021 Chapter1 General introduction and outline of thesis

Introduction

Chapter 1

Introduction

Combined oral contraceptives and venous thromboembolism

The combined oral contraceptive, i.e. the ‘Pill’, was the first medicinal product developed that had to be taken every day on a regular basis by persons not suffering from any disease. Today, world-wide more than 100 million women start the day with taking the ‘Pill’.1 Although the Pill is a safe and highly effective contraceptive method in the vast majority of women, in a small group of women its use is associated with a rare but potentially serious adverse event, i.e. venous thromboembolism (VTE). Up to now, this association has been the topic of many studies, including the studies presented in this thesis, and probably there are many more to follow, as even after the recent 50th anniversary of the Pill this risk still has not been solved.

Combined oral contraceptives

Composition

Combined oral contraceptives (COCs) contain a combination of a synthetic estrogen and a synthetic progestogen. The estrogen component is ethinylestradiol and recently also estradiol, but there are many different types of synthetic progestogens, e.g. levonorgestrel, norethisterone, desogestrel, gestodene, dienogest, drospirenone, norgestimate, etonogestrel, norelgestromin, nomegestrol, chlormadinone, and cyproterone. Initially, the dose of ethinylestradiol was up to 150 micrograms, but since the early seventies the dose is steadily lowered to 35-15 micrograms (so-called sub-50 Pills) that are used today. Also the progestogen doses have decreased substantially. Further, currently several COCs have standard and low-dose versions. Additionally, there are not only oral combined contraceptives, but also non-oral preparations such as a vaginal ring to be applied once a month and a patch to be applied once weekly.

11 Introduction

The reason why there are so many synthetic progestogens is that the initially developed progestagens, besides the desired progestogenic effects, also had androgenic effects. Androgenic properties could result in androgenic side effects like acne, hirsutism, and negative effects on the lipid metabolism. Development therefore focused on progestagens having less androgenic properties.

The consecutive development of new COCs, i.e. with a new synthetic progestogen, is divided into ‘generations‘, and is related to the time point of their market launch. ‘First generation’ is related to the very first COCs, which were approved around 1960. An overview of several generations of COCs with different synthetic progestogens and their first date of introduction is given in Table 1.

Table 1. Combined hormonal contraceptives divided into generations

Type of progestogen Generation Market introduction Ethinylestradiol/norethisterone-containing COC (Modicon©) 1st generation 1960

Ethinylestradiol/levonorgestrel-containing COC (Microgynon 30©) 2nd generation 1974 Ethinylestradiol/norgestimate-containing COC (Cilest©) 2nd generation 1990

Ethinylestradiol/desogestrel-containing COC (Marvelon©) 3rd generation 1984 Ethinylestradiol/gestodene-containing COC (Femodeen©) 3rd generation 1984

Ethinylestradiol/cyproterone-containing COC (Diane 35©) 4th generation 1987 Ethinylestradiol/chlormadinone-containing COC (Madinelle©)a 4th generation 1995 Ethinylestradiol/drospirenone-containing COC (Yasmin©) 4th generation 2000 Ethinylestradiol/etonogestrel-containing vaginal ring (NuvaRing©) 4th generation 2001 Ethinylestradiol/norelgestromin-containing patch (Evra©) 4th generation 2002

Estradiol/dienogest-containing COC (Qlaira©) ‘5th’ generation 2008 Estradiol/nomegestrol-containing COC (Zoely©) ‘5th’ generation 2011

a: ethinylestradiol/chlormadinone-containing COCs are not available in NL

However, as there are now many different preparations, it is suggested not to use these terms any longer, as they lead to confusion. In practice this has already resulted in studies on COCs and thromboembolism with e.g. COCs being catego-

12 Introduction

rized as a ‘3rd generation’, ‘4th generation’ or as a ‘2nd generation’, which makes- the interpretation of clinical results for the individual progestogens such as risk of VTE, challenging.2

History of combined hormonal contraceptives

Around 1920, several Austrian scientists demonstrated the occurrence of temporary contraception by transplantation of ovaries of a pregnant animal into a non- pregnant animal. These experiments were followed by studies in mice showing that extracts of ovaries could inhibit ovulation. These first studies were performed by Ludwig Haberlandt, an Austrian professor of physiology. He is seen as the Grandfather of the ‘Pill’, as he was the first to perform experiments with the goal to obtain contraception by using female sex hormones. His aim was to develop hormonal contraception by mimicking a pregnant state, which would create a ‘temporary hormonal sterilization’. In 1931, he started the production of a hormonal extract ‘Infecundin’ in co-operation with the Hungarian pharmaceutical company Gedeon-Richter. However, he was severely criticized by his colleagues and in the lay public press, who accused him of hindering the unborn life. Despite all opposition, he started the first clinical trials. Unfortunately, he died at an early age and his co-worker Otto Fellner lost his life during World War II, which brought an end to this first initiative.3,4

Although Gabriel Fallopinus already in 1561 mentioned the existence of a ‘corpus luteum’, of which the structure is described by the Dutch anatomist Volcher Coiter in 1573,5 its function in regulating the menstrual cycle remained unknown for long. Only at the end of the nineteenth century scientists in Europe and USA discovered the endocrine function of this temporary existing ‘gland’ after ovulation has taken place. Between 1930-1937, scientists unraveled the action of the corpus luteum hormone as well as its chemical structure, and named the hormone ‘progesterone’.6,7

But at the time, it was still difficult and very expensive to produce sex hormones, as the only way was to process thousands of animal ovaries to retrieve a small amount of sex hormones. In early 1941, the American chemist Russell Marker solved this problem by the discovery of the Mexican wild Yam plant, which contained the plant steroid diosgenin. This plant was said used by Mexican

13 Introduction

women for treatment of menstrual cramps. This phytoestrogen could be used as a source to produce large amounts of progesterone. Carl Djerassi in Mexico and other chemists in the US improved the potency of the ‘Yam’ progesterone by removing the carbon at the 19-position, which led to the first synthetic progestogen ‘norethindrone’. Meantime in Europe, chemists at Schering AG in Germany developed the potent synthetic estrogen ‘ethinylestradiol’. The latter became the estrogen compound in future developed combined oral contraceptives.8

In 1944, disappointed by the negative attitude of politics of academic institutions at the time, the physiologists Gregory Pincus, Hudson Hoagland, Min-Chueh Chang, and John Rock, gynecologist, started the ‘Worchester foundation’, a private research center for experimental biology. With financial support and encouragement of biologist Katharine McCormick and Margaret Sanger of the Planned Parenthood association, they focused on development of oral hormonal contraception.9.10 This collaboration led to a first study in women who received oral natural progesterone. In this first study, a 20-day dose regimen starting at day 5 of the menstrual cycle was chosen as it covers the period in the cycle during which ovulation occurs. Discontinuation after these 20 days would result in a withdrawal bleeding thereby mimicking the normal menstrual bleeding, which could reassure women that they are not pregnant.

In 1956, a first study was performed in women who received a synthetic progestogen and results were published in Science.11 The results indicated that ovulation inhibition could be achieved and that after discontinuation a rapid return to fertility was observed. However, the synthetic progestogen norethindrone used appeared to be contaminated with the estrogen ‘mestranol’. When repeating this study using non-contaminated progestogen, the women reported unwanted irregular (breakthrough) bleeding. Based on these results, it was concluded that the progestogen should be combined with a certain amount of estrogen to keep the endometrium stabilized, which avoids occurrence of breakthrough bleeding. The results of these studies showed the usefulness of combining a progestogen with an estrogen, i.e. the concept of the combined contraceptive pill was born. An additional study in which women used norethindrone 10 mg combined with ethinylestradiol 0.15 mg showed a decrease in risk of pregnancy to 2.4%.12 When in 1957 the pharmaceutical company Searle had submitted an application for approval of this combined oral contraceptive pill, Pincus and Rock strongly contri- buted to convince the US food and drug administration to approve Enovid©.

14 Introduction

This first ‘Pill’, with a huge dose of 150 micrograms mestranol and 10 mg norethy- nodrel, was initially approved for ‘treatment of miscarriages and severe menstrual disorders’, with a patient leaflet mentioning ‘temporary infertility’ as an ‘adverse effect’. But in 1960, the indication of contraception was accepted.13

Mechanism of contraceptive action

Combined oral contraceptives contain an estrogen and a progestogen. The progestogen inhibits ovulation, as it primarily suppresses the production of lutei- nizing hormone (LH), thereby preventing the LH-surge needed to start ovulation. The estrogen component suppresses the production of follicle stimulating hormone (FSH), which will prevent follicular growth and development of a domi- nant follicle. The estrogen component also provides stabilization of the endometrium, which will reduce risk of breakthrough bleeding and it also potentiates the progestogenic activity of the progestogens.10 This potentiating has the advantage that the progestogen dose can be reduced. Initially, a dose regimen was chosen to mimic the menstrual cycle, which included a period of 21 days of tablet intake, followed by a 7-day break in which a withdrawal bleeding occurred due to the drop in hormone levels. Nowadays, several variants are introduced in which the 7-day break is reduced to 4 or even 2 days per month, and recently there are dosage schemes approved in which the ‘Pill’ can be taken continuously for up to 120 days.

Contraceptive efficacy in comparison to other contraceptive methods

Combined oral contraceptives (COCs) are one of the most efficacious contraceptives available. In Europe, combined oral contraceptives are the most frequently used type of birth control; about 85% of women in Western Europe have taken the pill during their fertile life. When taken according to the recommended dose regimen (perfect use), the risk of pregnancy, expressed as the Pearl Index, is only about 0.3% (Pearl Index: the number of failures of a contraceptive method [pregnancies] per 100 woman who use the contraceptive for one year). Only those hormonal contraceptive methods which are not dependent of compliance to regular intake, i.e. progestogen-containing IUDs and implants have an even lower pregnancy risk of around 0.1%, as presented in the table of failure rates based on US figures. However, Pearl Index for typical use (actual use which also includes pregnancies due to non-compliance to the dose regimen) is far lower in Europe than in the US, of which the reason is still not elucidated, although it is suggested that less compliance and the higher BMI of US women may play a role.14,15

15 Introduction

Table 2. Percentage of US women experiencing an unintended pregnancy during the first year of use per contraceptive method

% Women experiencing an unintended pregnancy within the first year of use

Method Typical use1 Perfect use2 No method 85 85 Spermicides 29 18 Diaphragm 16 6 Condom: - female 21 5 - male Combined oral contraceptive 8 0.3 Desogestrel-only pill 8 0.3 Combined hormonal patch (Evra©) 8 0.3 Combined hormonal vaginal ring (NuvaRing©) 8 0.3 Medroxyprogesterone injection (Depo-Provera©)* 3 0.3 Levonorgestrel-containing IUD (Mirena©)* 0.2 0.2 Copper-containing IUD* 0.8 0.6 Etonogestrel containing implant (Implanon©)* 0.05 0.05 Adapted from Trussel J. Contraception 2011;83:397-40414 1: typical use shows how effective the different methods are during actual use (including inconsistent or incorrect use). 2: Pregnancy rates during perfect use show how effective methods can be, where perfect use is defined as following the directions for use. * : LARC’s, long-acting reversible contraception

The social, cultural and economic impact of the approval of the Pill

The introduction of the pill caused an earthquake in the Western world, as it rearranged the relationships between men and women completely. For the first time, women were able to plan their own life, by having the opportunity to decide when to get pregnant and how many children she would have. This meant that she could finish an education, have a job and have a life of her own. Up till then, the fear of unexpected pregnancy before marriage and in marriage, and the frequent state of pregnancy were women’s major burden. So there is a straight line between the introduction of the Pill and the changing in family structure. Initially only married women could have a receipt, but when the Pill became also available to unmarried women, this coincided with the increase in the age at first marriage and the increase in women in professional degree programs.16 Its introduction was the basis of the large positive change up to the economic and social status of the women in the world today.

16 Introduction

At its recent 50th anniversary, the Pill was voted by many as the greatest medical advance of the 20th century, as it enabled women to change their domestic position and plan families around their own careers.

As to the situation in the Netherlands, until the introduction of the ‘Pill’, the Netherlands was prudish society with high birth rates. Contraception was an inde- cent subject, and physicians were ignorant to the subject or didn’t want to have anything to do with it. To sell contraceptives in public was forbidden by law. In 1950, the editors of the ‘Nederlands Tijdschrift voor Geneeskunde’ apologized for having published two articles dealing with different methods for birth control.17,18 With the introduction of the ‘Pill’, a rigorous change in attitude started which was not to be stopped, as in no time a large number of Dutch women started using it. Initially, there was lot of opposition of the church, politicians and doctors, the latter as they were not convinced it would actually work. But in 1963, by wording of the Dutch Bishop Bekkers, the Dutch Catholic church agreed that married couples could decide themselves if they would use the Pill. Within 10 years after its introduction, the Netherlands had highest percentage of Pill users in the world.

Venous thromboembolism

Venous thromboembolism (VTE) is defined as a non-physiologic formation of a thrombus in a vein. In 1846, the German pathologist Virchow hypothesized 3 main mechanisms to cause thrombosis: damage to the vessel wall, stasis of the blood stream, and alterations in the blood composition. The most common location is deep vein thrombosis of the leg and when this thrombus partly deta- ches (embolizes) it can be transported upwards through the right heart into one of the arteries of the lung and cause pulmonary embolism.19,20

VTE is considered a multifactorial disease, based on interactions between genetic and acquired risk factors. In the general population, many risk factors for VTE are present, and often within the same individual, but an interaction of hereditary and acquired risk factors may eventually lead to the development of VTE. Actually, the current view is that the presence of several e.g. more than one risk factors appears to be a requirement for the development of VTE.21-23 There are many factors that contribute to the individual baseline risk of VTE. In this, hereditary thrombophilia and first-degree family history both are established risk factors. The baseline risk

17 Introduction

can be further increased by underlying conditions like malignant disease and obesity, advanced age, and by exogenous risk factors such as surgery, trauma, immobilization, and specifically in women, hormonal exposure due to use of combined oral contraceptives (COCs) hormone replacement therapy, hormonal treatments in assisted reproduction techniques (in vitro fertilization), and the pregnancy-postpartum period.

Risk of venous thromboembolism during combined oral contraceptive use

Since their introduction in 1960, the first case reports appeared in public literature suggesting that COCs are associated with an increased risk of VTE.24,25 Despite an up to 10-fold reduction in dose of both components and the development of new progestogens, this risk, albeit lower, remained.26

Up to 1995, the risk of VTE was assumed attributable to ethinylestradiol (EE), because this component is identical in all COCs, whereas the type of synthetic progestogen included could differ.

Currently, there is consensus that the type of progestogen can influence this estrogen-mediated VTE risk. Such difference in VTE risk became apparent in 1995 with the simultaneous publication of three epidemiological studies in the Lancet, which observed that the use of 3rd-generation COCs (containing the progestogens desogestrel or gestodene) in healthy women and in women with factor V Leiden mutation resulted in a higher VTE risk than the use of 2nd-generation COCs (containing levonorgestrel).26-28 Many other studies followed that further evaluated differences in VTE risk between COCs containing 2nd- and 3rd-generation progestogens.29 In the Netherlands, the results of these studies led to a change in the patient leaflets of all COCs in 1997, by informing that the risk of VTE during use of COCs containing desogestrel- or gestodene-containing COCs (3rd-generation) is 1.5-2 times higher than with levonorgestrel-containing COCs (2nd-generation). Additionally, the Dutch General Practitioners Standard on combined oral contraceptives was changed in 1998 to include a statement that second-generation COCs should be considered first choice.30

Based on the results of the most recent epidemiological studies, lowest risk of VTE is observed during use of COCs containing levonorgestrel and norgestimate

18 Introduction

(both 2nd-generation COCs), or norethisterone (a 1st-generation COC), whereas a higher risk is observed during use of COCs containing desogestrel or gestodene, drospirenone, and cyproterone.32-37 The COC containing cyproterone is approved for hormonal treatment in women with androgen-sensitive acne and hirsutism, but has similar contraceptive properties. Recently, also the transdermal patch containing norelgestromin and ethinylestradiol and the vaginal ring containing etonogestrel and ethinylestradiol were shown to have similarly higher VTE risk.34 The relative risk of VTE of recently introduced COCs containing estradiol instead of ethinylestradiol compared to ethinylestradiol-containing COCs is yet unknown. Nevertheless, the absolute risk of VTE is low: varying between 6-9 cases of VTE per 10.000 years of COC-use in comparison to 2-3 cases of VTE per 10.000 women per year who do not use COCs.33,34 Based on these risk profiles, it is now generally recommended in European guidelines,40 including Dutch guidelines (Nederlands Huisartsen Genoodschap already in 1998)30 to preferentially pres- cribe 2nd-generation COCs to women who start using a COC for the first time.

Recently, a re-evaluation of the risk of VTE during COC-use and during use of non-oral combined hormonal contraceptives has been performed by the Euro- pean Medicines Agency based on all published and unpublished data currently available, including those studies discussed above.2 On the basis of this review, also the COCs containing ethinylestradiol/ norgestimate or ethinylestradiol/ norethisterone have similar VTE risk as noted in women using ethinylestradiol/ levonorgestrel-containing COCs. This re-evaluation subsequently resulted in adap- ting the information in the patient leaflets regarding the risk of VTE of all COCs available in the EU to include the latest VTE risk estimations. The results of this review of VTE risk in different COCs and non-oral combined hormonal contraceptives are shown in Table 3.

19 Introduction

Table 3. Estimated incidence of VTE risk with different combined hormonal contraceptives

RR against Incidence per Generation levonorge- 10.000 women/ strel-COCs per year of use

Non-pregnant non-user 2-3 Ethinylestradiol/levonorgestrel-containing COC (Microgynon 30©) Referentie 5-7 2nd

Ethinylestradiol/norethisterone-containing COC (Modicon©) 1 5-7 1st

Ethinylestradiol/norgestimate-containing COC (Cilest©) 1 5-7 2nd

Ethinylestradiol/desogestrel-containing COC (Marvelon©) 1.5-2 9-12 3rd Ethinylestradiol/gestodene-containing COC (Femodeen©) 1.5-2 9-12 3rd Ethinylestradiol/drospirenone-containing COC (Yasmin©) 1.5-2 9-12 4th Ethinylestradiol/cyproterone-containing COCs (Diane 35©) 1.5-2 9-12 4th Ethinylestradiol/etonogestrel-containing vaginal ring (NuvaRing©) 1-2 6-12 4th Ethinylestradiol/norelgestromin-containing patch (Evra©) 1-2 6-12 4th Ethinylestradiol/chlormadinone-containing COC (Madinelle©)a Unknown Unknown 4th Estradiol/dienogest-containing-COC (Qlaira©) Unknown Unknown 4th Estradiol/nomegestrol-containing COCs (Zoely©) Unknown Unknown ‘5th’

RR: relative risk. a: not available in the Netherlands. Adapted from the ‘Assessment report for combined hormonal contraceptives containing medicinal products’ 16 January 2014, EMA/739865/20132

Risk of VTE also changes with duration of COC-use: VTE risk is highest in the first year following initiation of COC-use and when restarting after a break of at least one month. The risk then reduces over the next year and remains stable thereafter.33,34,38-40 Although the risk is high in the first year of COC-use and then falls, it remains higher than in non-users.

Further, risk of VTE is estrogen-dose dependent; Current low dose (30 microgram ethinylestradiol) has lower risk than COCs containing 50 micrograms or more. Limited data suggest risk of VTE to be slightly lower with COCs containing 20 microgram ethinylestradiol than with COCs containing 30 microgram ethinylestradiol.33

20 Introduction

“Estrogenicity” of combined oral contraceptives

Based on the differences in VTE risk with COCs that have the same estrogen dose but different progestogen type, the prothrombotic effect of COCs is considered not only influenced by the estrogen compound, but is based on the “total estrogenicity” of the specific COC.41 A higher estrogen dose will increase the “total estrogenicity”, but the net estrogenic effect of a COC is also dependent on the anti- estrogenic properties of the synthetic progestogen type. It is assumed that desogestrel- and gestodene-containg COCs (3rd-generation progestogens), but also the more recent COCs containing drospirenone, cyproterone, etonogestrel, norelgestromin (4th-generation COCs), have no or weaker anti-estrogenic activity than levonorgestrel-containing COCs. It is therefore postulated that because these COCs have less or no antagonistic effects on the prothrombotic effect of the estrogen component, the net thrombotic effects will be higher and therefore could result in a higher risk of VTE.

Sex Hormone Binding Globulin (SHBG), produced in the liver, dose-dependently increases after oral intake of EE alone, whereas progestogen intake results in a SHBG decrease, which is dependent on dose and type of progestogen. In view of this, it is postulated that the SHBG increases with increasing estrogenicity, and it was suggested to use SHBG as a surrogate for predicting VTE risk.42

In addition, an association between SHBG levels with a thrombin generation- based APC-resistance test was reported.43 However, others did not share this opinion. Although estrogen intake and more particularly a pregnancy increases SHBG, SHBG is not involved in the clotting cascade, and various metabolic systems also affect the SHBG level.43 However, SHBG, thrombin-based APC resistance tests (APCsr), or any other postulated tests or coagulation factors are as yet not validated as a surrogate endpoint for the clinical outcome of VTE. Some studies have evaluated whether the level of APCsr could be used to explain risk differences observed between users of 2nd or 3rd generation COCs. One study found no association.44 In another study, the large range in APCsr values observed in the plasma samples of women and the small sample sizes resulted in large confidence intervals for the estimated risk. This precluded a meaningful analysis in the female population with respect to the question of whether venous thrombotic risk gradually increased with increasing APCsr.45 This means that it has yet to be demonstrated that such alterations are related to an increase in clinical risk of VTE among COC users, and in particular differences in risks between COCs.

21 Introduction

Biological background of risk of venous thromboembolism during combined oral contraceptive use

The biological background of this association between the use of COCs and the rare adverse event of VTE is complex. The ‘estrogenic’ effect of COCs falls into the category of modifying the blood composition, as its use induces changes in hemostatic balance into a prothrombotic direction by influencing coagulant- and anticoagulant factors and fibrinolysis in Table 4. Results are included which were observed during two months treatment of a 2nd-generation and a 3rd generation COC, with a washout of 2 months between treatments.46

Table 4. Changes in coagulation-, anticoagulation-, and fibrinolytic factors

nd rd 2 generation COCs 3 generation COCs Coagulation factorsa Prothrombin ↑ ↑* Fibrinogen ↑ ↑ Factor V ↓ ↓* Factor VII ↑ ↑* Factor VIII ↑↓ ↑ Factor X ↑ ↑

Anticoagulant systemb Antithrombin ↑↓ ↓

α2-macroglobulin ↑ ↑

α1-antitrypsin ↑ ↑ Protein C inhibitor ↑ ↑ Protein C ↑ ↑*

Protein Stotal and free ↓ ↑* APCsr (aPTT-based assay) ↑↓ ↓* APCsr (EPT-based assay) ↑

Fibrinolytic systemc tPA, antigen, ng/ml ↓ ↓ tPA activity U/ml ↑ ↑ PAI-1 Ag, ng/ml ↓ ↓ PAI-1, act U/ml ↓ ↓ Plasminogen, activity, % ↑ ↑ TAFI Ag, % ↑ ↑*

Significant differences between users of second (2nd gen) and third (3rd gen) generation oral contraceptives (p<0.05). APCsr: activated protein C sensitivity ratio; aPTT: activated partial prothrombin time; ETP: endogenous thrombin potential; PAI: plasminogen activator-inhibitor; TAFI: thrombin-activable fibrinolysis inhibitor; tPA: tissue-type plasminogen activator; Ag: antigen; act: activity; SD: standard deviation. a,47b,48 c,49

22 Introduction

The observed changes are more pronounced during use of 3rd generation COCs than noted during use of 2nd generation COCs, see table above.46-49 It is expected that changes induced by 4th generation COCs will follow the same pattern as noted of 3rd generation COCs. However, in healthy women, these changes in hemostatic variables remain within the normal ranges.21 As stated previously, up to now there are no hemostatic tests that can be used as a validated surrogate for the clinical endpoint of VTE.

Risk of venous thromboembolism during pregnancy and post-partum period

Risk of VTE is substantially higher during pregnancy, especially in the post-partum period, than observed during the use of COCs. In comparison to non-pregnant women, the VTE risk during pregnancy is increased about 9-fold, and up to 50-fold during the postpartum period.50 The main reason of the increased risk of VTE in pregnancy is the hypercoagulable state. This increased coagulation tendency is a physiological adaptation in order to protect the woman at time of delivery from bleeding complications at the placental site of the uterus after placental separation. Like COC-use, a pregnancy is accompanied by changes in sex hormone levels. In comparison to the non-pregnant state, pronounced hemostatic changes are noted, which are presumed due to the huge increase in endogenous estrogen levels already starting from the first trimester in pregnancy; the production of estradiol and estrone is increased 100-fold, and that of estriol a 1000-fold. An accelerated increase of both estradiol and estriol is noted at week 36 of gestation, while at the same time the progesterone level decreases. An increase of coagulation factors, a slight decrease in natural anticoagulants and a decreased fibrinolytic activity are observed. The most pronounced hemostatic changes towards hypercoagulability are noted in the late third trimester, presumably preparing for the upcoming delivery. Initiated by delivery and uterine contractions, activation of blood coagulation occurs, as after placental separation about more than 100 spiral arteries torn from the uterus wall must thrombose. After delivery, fibrinolytic activity rapidly returns to baseline values, while blood coagulation factors mainly normalize during the first 4 to 6 weeks postpartum, although the level of the natural anticoagulant protein S (free fraction) can be decreased for as long as 8 weeks postpartum. Although the increased risk of VTE especially during the postpartum period is firmly established, the exact mechanism of raising sex hormone levels, accompanied with prothrombotic alterations in hemostasis, and the time to return to normal hemostasis is as yet not fully understood.51,52

23 Introduction

Thrombophilia

Inherited thrombophilias are coagulation disorders, leading to a genetic tendency to develop VTE. There are several relevant hereditary thrombophilias identified, which can be divided into rare but severe thrombophilias consisting of a deficiency of the natural anticoagulants protein C, protein S and antithrombin,53-55 of which the prevalence in the general population is about 0.1% each.56-58 These deficiencies increase the risk of VTE more than 10-fold. The absolute risk of VTE in antithrombin-, protein C–, or protein S–deficient persons ranges from 0.7 to 1.7 per 100 person-years. However, these absolute risks are estimated in thrombophilic cohort studies only,59-62 which risks cannot be extrapolated directly to the general population. However, though based on a very low prevalence, some population based case-control studies showed that antithrombin and protein C levels in the deficient range clearly increased risk of VTE 5- and 7-fold.63 However, protein S levels in the deficient range were not associated with an increased VTE risk, except at extremely low level.64

Additionally, mild but more frequent hereditary thrombophilic defects are a mutation in the coagulant factor V Leiden, preventing its inactivation by activated anticoagulant protein C65 and a mutation in prothrombin G20210A, which leads to increased prothrombin, the precursor of thrombin.66 These defects have a prevalence of 5%67 and 2%,68 respectively, in the general Dutch population. Factor V Leiden mutation is the most common thrombophilic defect in the Caucasian population, but far less common or even rare in populations of other ethnic origin. Prothrombin mutation is only prevalent in the Caucasian population.22 In carriers of these mutations, the risk reported in case-control studies is increased about 2-5 fold,66,70 whereas homozygote carriers and persons with double hetero- zygosity for factor V Leiden and prothrombin mutation have further increased VTE risk.71,72 The absolute risk of VTE in factor V Leiden carriers is estimated being 0.15 per 100 person-years.61,69 Nevertheless, in about 50% of families suffering from VTE, no hereditary thrombophilic defects could be identified. It is possible that some further genetic defects will be identified through genome wide association studies, but if so, such defects are expected to have low risk.

24 Introduction

Hereditary thrombophilia and risk of venous thromboembolism during combined oral contraceptive use

The risk of VTE associated with the use of COCs will increase when the woman’s baseline risk is altered. One of the strongest factors that increase baseline risk is the presence of hereditary thrombophilia. Information on the risk of VTE in COC- users who have severe thrombophilic defects (antithrombin-, protein C, or protein S-deficiency) is very limited,60,73 and only evaluated in thrombophilic cohort studies due to the rarity of these thrombophilic defects. In these families, the risk of VTE in COC-users with severe thrombophilias risk increased risk about 10-fold versus non-thrombophilic COC-users; the observed increased absolute risk varied between 4.3 to 27.5 per 100 pill-years of use.

As to the risk of VTE in COC-users who have mild thrombophilic defects, i.e. factor V Leiden or prothrombin 20210A mutation, a large number of case-control studies have evaluated the risk of VTE in COC-users with factor V Leiden and prothrombin-G20210A, which reported odds ratios varying between a 2 and 26-fold increased risk in comparison to matched control groups.29,74-90 Few subgroup-analyses in family cohort studies presented the absolute risk of VTE in COC-users with factor V Leiden or prothrombin mutation, in which the incidence rate varied between 0.48 and 2.0 per 100 pill-years of use.60,73,91,92

Family history and risk of venous thromboembolism during combined hormonal contraceptive use

Several studies have explored the impact of positive family history and currently it is considered an independent risk factor of VTE, regardless of the presence of other risk factors, including hereditary thrombophilia.93 Several case-control studies reported family history to increase the risk of VTE two to three-fold.93-95 Additionally, two studies reported the VTE risk of a positive family history as higher in first-degree female relatives during fertile age than in male relatives of that age.96,97

However, only one study has considered whether also specific characteristics of patients (probands) with VTE could influence the risk of VTE in their relatives.98 Additionally, it was taken into account whether the proband had experienced a

25 Introduction

provoked or unprovoked VTE. Results of this study indicated that relatives of younger patients (<45 years) with either provoked or unprovoked VTE, have much higher risk for VTE than relatives of older patients. An interesting follow-up question would be whether these family-conferred risks could also be hormone- or gender specific. In the study described earlier, gender of the patient with VTE was reported as having no influence on the risk of VTE in their first-degree relatives (OR: 0.96 (95% confidence interval: 0.67-1.38).98 However, no study has yet evaluated whether a female patient with a hormonally-related VTE could be an additional predictor of (hormonally-related) VTE risk in her first-degree female relatives.

Recurrence rate in women with venous thromboembolism associated with combined oral contraceptive use

Several comparative studies evaluated the risk of VTE recurrence in women with COC-associated VTE, in which the recurrence risk varied between 1.8% to 5.6%.99- 103 However, often these women were included as a subgroup, or COC-exposure was combined with exposure to pregnancy and/or hormone replacement, or studies were restricted to women having COC-use as single risk factor.101,103 An additional difficulty is that in several studies not all women discontinued COC-use or categorized COC-associated VTE as unprovoked. The recurrence rate in women with COC-associated VTE who post-VTE have discontinued further COC-use is therefore not firmly established.

Clinical profile of a woman with COC-associated VTE

Up to now, it is not yet fully understood who will develop a COC-associated VTE. Hereditary thrombophilia and first-degree family history, even in the absence of thrombophilia increases the risk of VTE, but studies evaluating the interaction between family history and COC-use are contradictory.104,105 Concomitant presence of other risk factors besides COC-use additionally increases the risk of VTE, like surgery, trauma, immobilization, postpartum period, malignant disease, and obesity. Many of these risk factors are frequently present in COC-users, but only few women actually develop a COC-associated VTE.

26 Introduction

Outline of this thesis

Central theme of this thesis is the association between COC-use and VTE. In this context, the contribution of other risk factors of VTE, including thrombophilia and family history, have been evaluated. Further, comparisons were made against the risk of VTE in women during pregnancy; the condition that is to be prevented by COC-use.

Information on the absolute risk of VTE in COC-users who have thrombophilic defects is limited, whereas this risk in women in combination with other defects was hardly considered in any study. In Chapter 2, we present a thrombophilic family cohort study, in which we assessed the absolute and relative risk of VTE during use of COCs in women with or without protein S-, protein C-, or antithrombin-deficiency and additionally assessed the contribution of other known thrombophilic defects. In Chapter 3 we present a thrombophilic cohort study in which we assessed the absolute and relative risk of first VTE during COC- use and pregnancy-postpartum in women with or without heterozygous, double heterozygous, or homozygous factor V Leiden or prothrombin-G20210A mutation. Furthermore, the absolute risk of VTE during COC use in women with or without mild hereditary thrombophilia was put into the perspective of contraceptive failure of COC and alternative contraceptives.

In Chapter 4, we present a systemic review and meta-analysis of studies, which compared the risk of VTE in COC-users with or without hereditary thrombophilia, in which a case presentation is taken as a starting point.

As shown in cohort studies described in chapter 3 and 4, women from thrombophilic families have an increased risk of venous thromboembolism (VTE), which increases further during combined oral contraceptive use (COCs) and pregnancy. It is unknown whether this additional risk differs between relatives of male and female patients with VTE, and also whether it matters if the female patient had a hormonally-related VTE (during COC-use or pregnancy). In order to explore this question, we performed a large retrospective family cohort study, which is presented in Chapter 5. In a retrospective thrombophilic family cohort of 1005 first-degree female relatives of reproductive age, we compared VTE risk in relatives of female versus male patients, and between relatives of female patients with and without hormonally-related VTE.

27 Introduction

Although COC-use increases the risk of VTE, it is yet not fully understood which woman will develop COC-associated VTE and evidence on recurrence risk varies. In Chapter 6 we present a prospective cohort of 125 consecutive Dutch women with COC-associated VTE who are, according to Dutch General Practitioner (GP) guidelines, was preferentially prescribed levonorgestrel-containing COCs since 1998.29 In this study, we describe clinical characteristics and post-VTE contraception choices, and have prospectively assessed VTE recurrence after discontinuation of further COC-use and thromboprophylaxis in subsequent pregnancies.

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39 40