REVIEW ARTICLES

Prescrierea contraceptivelor în diverse afecţiuni: diabet zaharat, boli cardiovasculare, hipertensiune arterială, boli hematologice şi renale

 Prescription of contraception in various medical conditions: diabetes mellitus, cardiovascular diseases, hypertension heart disease, hematological and renal diseases

First published: 10 aprilie 2020

Editorial Group: MEDICHUB MEDIA

DOI: 10.26416/OBSGIN.68.2.2020.3692

Abstract

Research and educational efforts to choose contraceptives for women with medical conditions are limited. Contraceptive and family planning counseling should start early in life, and the choice of contraceptive method should take into consideration the impact of an (unplanned) pregnancy on maternal-associated disease, the risks and benefits of the contraceptive type, the patient’s age, the existing risk factors associated with her medical pathology, and the patient’s preferences. Data from studies suggest a lack of interest regarding the use of contraception in women with known chronic conditions. The medical conditions may influence the women’s birth control methods, and the prescription of contraception in various medical conditions may be a challenge. This paper is a minireview about contraceptive use in various medical conditions: diabetes mellitus, cardiovascular diseases, hypertension heart disease, hematological and renal diseases.
 

Keywords
contraceptive, medical conditions, diabetes mellitus, cardiovascular disease and hypertension heart disease, hematological and renal diseases

Rezumat

Eforturile de cercetare şi educaţie care vizează administrarea contraceptivelor la femeile cu afecţiuni medicale sunt limitate. Contracepţia şi planificarea familială trebuie să înceapă devreme, iar alegerea metodelor contraceptive trebuie să ţină cont de impactul unei sarcini (neplanificate) asupra bolii materne asociate, de riscurile şi beneficiile tipului de contraceptive, de vârsta pacientei, de factorii de risc asociaţi patologiei medicale şi de preferinţele pacientei. Studiile arată un dezinteres pentru alegerea unui mijloc de contracepţie al femeilor care prezintă afecţiuni cronice. Bolile asociate influenţează metodele de regularizare ale sarcinilor, iar prescrierea contracepţiei la pacientele cu diverse afecţiuni reprezintă o alegere dificilă. Această lucrare este un minireview despre utilizarea contraceptivelor în diferite patologii medicale asociate: diabet zaharat, boli cardiovasculare, hipertensiunea arterială, boli hematologice şi renale.
 

Research and educational efforts to choose contraceptives for women with medical conditions are limited. Much of the current evidence in healthy or sick women indicates that the use of most contraceptive methods does not cause a significant increase in health risks. In fact, pregnancy often represents a higher risk of morbidity or mortality factor in women of childbearing age, between 15 and 49 years old, with medical problems. Therefore, it is essential to ensure that women are offered the most effective methods of contraception, in order to maintain their health(1). Among factors to consider when choosing a contraceptive method, the patient’s age (over or under 35 years old) and the patient’s associated profile must also be taken into account. Additionally, risk factors such as smoking, alcohol, obesity and physical inactivity are also important in choosing the most appropriate contraceptive method. For instance, estroprogestive oral contraception containing less than 50 mcg of ethinylestradiol is safe in women over the age of 35 years old who are healthy, non-smoking and have a normal weight(2). Recent literature data suggest a lack of interest regarding the use of contraception in women with known chronic conditions. Therefore, contraception is scarcely used by diabetic women (71.2%), by women suffering from connective tissue disorders (68.5%) and by hypertensive women (65.3%). By contrast, only 26.3% of women with heart disease fail to use contraceptives(3), knowing that they have a contraindication to a pregnancy.

This work is a minireview about the contraceptive use in various medical conditions: diabetes mellitus, cardiovascular diseases, hypertension heart disease, hematological and renal diseases.

Contraceptives and diabetes(4,5)

Diabetes mellitus – the most common metabolic disorder – is a global public health concern. Given the negative interrelationship in both directions between pregnancy and diabetes, it is preferable to schedule conception and pregnancy when diabetes is biologically and clinically balanced, because chronic hyperglycemia can have negative effects on embryogenesis. Thus, it is vital for a diabetic woman to use a safe and effective contraception method. Women with diabetes without complications can choose from the full range of contraceptive methods, including hormonal contraception or intrauterine devices. Women with vascular, neurological or renal diabetic complica­tions may need specialized advice to assess the risk-benefit ratio, particularly with respect to estroprogesterone contraception. Estroprogestative contraceptive is also unlikely to be suitable for women with risk factors such as smoking, obesity or hypertension due to the increased risk of venous thromboembolism, myocardial infarction, stroke and death(6).

We must keep in mind that for diabetic women there are challenges in choosing a method of contraception, due to the metabolic, vascular and, at the same time, the infectious risk that appears after several years of disease. In patients under the age of 35 years old, who were recently diagnosed with diabetes without complications, the low-dose estroprogestative pill used for a short period did not cause complications. The method of hormonal oral contraception containing estrogen has negative effects on carbohydrate metabolism, while intrauterine devices have a risk of infection(7). A recent review emphasized that estroprogestative contraceptives containing less than 35 µg of ethinylestradiol did not alter blood glucose concentrations and insulin secretion(8). Also, contraception must be different in patients with insulin-dependent diabetes compared to those who are not receiving insulin, in patients who are multiparous compared to those who are primiparous, and in patients with controlled diabetes compared to those who do not control their blood sugar levels. The patient’s age is also important when prescribing contraception and also whether she is in a stable relationship or has occasional sex. A Cochrane review from 2013 was inconclusive in determining whether hormonal contraception affected carbohydrate and lipid metabolism and the long-term complications in women with diabetes mellitus(9). Diabetics may also opt for local contraception, but its effectiveness is lower when compared to the main contraceptive methods, such as intrauterine devices or pills.

Intrauterine devices (IUD). During acute hyperglycemic phase, the phagocytic activity of leukocytes is diminished. This causes a decrease in local defense, thus the risk of infection increases for IUD carriers. Data from literature have shown that intrauterine devices are well tolerated by diabetic women. The rule is that diabetes should be controlled and intrauterine devices should be strictly supervised(10). In case of metrorrhagia or profuse leukorrhea, a careful assessment must be done to deter­mine the cause of these symptoms and to decide whether it is needed to remove the intrauterine device. The effectiveness of intrauterine devices for diabetics does not differ from that of intrauterine carriers without diabetes. Levonorgestrel-releasing intrauterine system are optimal devices for women with diabetes, since the plasma concentration of progestin is going to be low and unable to influence carbohydrate metabolism. When implanting the intrauterine device, attention must be paid to the presence of asepsis and antisepsis. If hormonal oral contraception has many risks for the diabetic woman, intrauterine contraception can be considered a viable alternative option. The risk of infection can be avoided by strictly following all the rules of inserting the intrauterine device, avoiding an infection or correctly treating a potential genital infection(11).

Hormonal contraception. We must keep in mind that the administration of hormonal contraceptives in a diabetic patient poses serious problems, and the following aspects should be known by the gynecologist when dealing with contraceptives for diabetes. Large amounts of synthetic estrogen produce a decrease in carbohydrate tolerance. However, a low-dose of ethinylestradiol has limited effects on carbohydrate metabolism. Progestogens with antiandrogenic properties (derived from norsteroids, medroxyprogesterone acetate and chlormadinone acetate, cyproterone acetate and dienogest) disrupt carbohydrate metabolism. Levonorgestrel causes a moderate increase in glycemic response, inducing hyperglycemia and marked hyperinsulinism. The effect of progestogens, as well as of estrogens, depends on their concentration. A mini-dose of estrogens (that contain a third generation of oral pills), also of non-androgenic progestogen, appears to alter carbohydrate metabolism the least. Nevertheless, these products contain ethylestradiol, which has negative vascular effects. Thus, we must be careful if the diabetic patient already has vascular changes(8). Third-generation progestines (desogestrel, gestodene, norgestimate) have a reduced action on carbohydrate metabolism, unlike first-generation progestogens (norethindrone, lynestrenol, ethynodiol diacetate and norethisterone) and second-generation progestogens (levonorgestrel and norgestrel), which are androgenic and act on carbohydrate metabolism. Therefore, it would be advisable to prescribe a third-generation mini-dose of estroprogestin pill or a mini-pill.

Local methods. In case of patients with diabetes, local methods are widely used. These are “ecological” methods, but they also have low effectiveness.

Surgical sterilization. If the diabetic woman is over 40 years old or has diabetes with vascular or renal complications and an absolute contraindication to pregnancy, surgical sterilization is an important method to consider(12).

Contraception for patients
with cardiovascular diseases

Pregnancy in a patient with a preexistent heart condi­tion represents an increased risk factor for maternal morbidity and mortality. During pregnancy, there are several adap­tive changes that occur in a woman’s cardio­vascular system to meet the metabolic requirements of both the mother and the fetus. Circulating blood volume increases, while systemic resistance decreases, which leads to increased resting heart rate and cardiac output. These changes lead to decompensation in women with preexisting serious heart disease (e.g., patients with tight aortic stenosis). Heart disease remains the leading indirect cause of maternal death in the U.S.(13) We must keep in mind that therapeutic abortion or abortion on request also pose certain risks. This requires ensuring safe contraception and planning a pregnancy when cardiac balance allows. The improvements in treatments for heart disease have increased the number of female patients living to puberty or fertility age. Contraception is highly recommended, especially in women with complex congenital heart disease. Ensuring an effective contraception for patients with heart disease is difficult due to the side effects of contraceptives, in particular the risk of infection and negative effects on the cardiovascular system. Contraception must be done in close collaboration with the cardiologist, who knows the type of heart disease, its evolution and staging, and the risk of infectious, thromboembolic and hypertensive implications. Contraception in women with heart disease requiring long-life anticoagulation (mechanical valves prostheses, pulmonary hypertension) is difficult to prescribe due to the increased risk of valvular thrombosis, which is commonly managed using vitamin K antagonists (warfarin). In these women, the cardiovascular and thrombogenic risks of (unplanned) pregnancy often outweigh the inherent risks of most contraceptive methods. The major requirements of modern contraceptives – namely efficacy, acceptability and lack of risks – cannot all be reached in a cardiac patient(7).

Local contraception. This type of contraception involves risks for the cardiovascular system and also a minor risk of infection. Both mechanical and chemical contraceptives can be used: condoms, sponges, diaphragms, spermicides. We just have to keep in mind that their effectiveness is low and sometimes the couple’s lack of acceptability is due to the fact that they do not protect against sexually transmitted diseases.

Intrauterine devices: banded copper containing intrauterine device (Copper-T®) and levonogestrel-releasing intrauterine system (Mirena®). This modern and effective method of contraception should be used for women with heart disease, but only in selected cases. Intrauterine devices are not recommended for a cardiac patient with risk of cardiovascular infections (most commonly, endocarditis) due to the risks of an acute cardiac episode that could lead to decompensation of the patient. The possible conditions that can get complicated by endocarditis are: persistence of the arterial canal, VSD (ventricular septal defect) communications, acquired valvular diseases (aortic and mitral stenosis, mitral aortic insufficiency), congenital disease, and valvular prostheses. Women taking life-long anticoagulant treatment cannot use intrauterine devices because of the risk of bleeding. If all conditions are satisfied to avoid infection (absence of preexisting genital infections, preexisting cervix, lack of pathogenic microbial flora etc.) at the time of insertion, and the woman is closely monitored, then the intrauterine device can be used successfully in cardiac women. The insertion of an intrauterine device should be preceded by the use of protective antibiotics (ampicillin 2 g and gentamicin 80 mg, given intravenously one hour before IUCD insertion)(14). Levonogestrel-releasing intrauterine system is therefore indicated in these women, due a reduction in vaginal blood loss; although being on anticoagulants, it may increase the tendency to irregular bleeding patterns. However, there may be an interaction between warfarin and levonorgestrel in high doses.

Combined estroprogestative pill. The use of estroprogestative pills is contraindicated because their negative side effects affect the cardiovascular system (thromboembolic risk, hydrosaline retention, coagulation disorders, pulmonary hypertension and rhythm disorders). According to some studies, estroprogestative pills with a low concentration of estrogen can be used in stage I cardiopathies.

Progesterone-only pill (mini-pills). Microprogestative pills whose side effects on the cardiovascular system are minimal are the most useful. Desogestrel (Cerazette®) is the single progesterone-only pill recommended in women with (severe) cardiac disease(15). Other types of hormonal methods can be used, but only containing progestins. The disadvantage of this type of contraception is its low acceptability due to menstrual disorders(16).

Subdermal implants can be used for longer periods (years).

Tubal ligation and tubal stents are considered irreversible forms of sterilization. Finally, emergency contraception may be considered for unprotected sexual intercourse. These are considered safe methods in women with heart disease(17).

Contraception in women
at high cardiovascular risk
and hypertension heart disease

It is well known that the risk of thrombosis and thromboembolic disease is increased by oral estroprogestative contraceptives which increase prothrombin and decrease antithrombin III levels(13). The risk of cardiovascular events caused by hypertension is also known. In the early 2000s, authors have demonstrated the association between anovulatory cycles and menstrual irregularities caused by estrogen deficiency in perimenopausal women, which are associated with increased risk of coronary atherosclerosis and adverse cardiovascular events(18,19). Several authors have demonstrated the effect of oral contraceptive pills on the preexisting lipid profile. Endrikat et al. (2002) have reported that patients using a dose of 20 g EE/100 g LNG oral contraceptive had reductions in high-density lipoprotein cholesterol (HDL-C) and small increases in low-density lipoprotein cholesterol (LDL-C) and triglycerides, as compared to those using 30 g EE/150 g LNG oral contraceptive(20). When using progestin-only pills administered continuously, no changes in LDL-C or apolipoprotein-B were found(21). Numerous studies have confirmed the effect of combined hormonal pill with estrogen and progesterone, especially those containing first- and second-generation progestins, on the increase in blood pressure in normotensive women(22). The use of oral contraceptives with drospirenone, which has an antialdosterone effect, led to lower blood pressure.

It seems that the prevalence of hypertension in the female population, especially in the fertile population, has increased, as evidenced by the large number of cases of preeclampsia and pre-pregnancy hypertension. Nowadays, hypertension is considered a complex disease, caused by the interaction of external and behavioral factors (including oral contraception) with genetic predisposition(23). Unfortunately, hypertensive disease is highly underestimated, especially in young patients in their fertile period.

Large epidemiological studies have shown that the long-term use of estrogen-containing oral contraceptives induces an increase in blood pressure and suddenly increases the risk of high blood pressure. The susceptibility to the hypertensive effects of oral contraceptives is exacerbated in the presence of risk factors such as age, family history of high blood pressure, preexisting ocular or kidney disease, parity and obesity. High blood pressure in combined-pill users usually develops in the first 6 months of use and occasionally is delayed up to 6 years(24).

The use of third-generation estroprogestative contraceptives, however, appears to have fewer cardiovascular side effects(25).

Therefore, in case of women with hypertension, the recommended contraceptive methods are local methods and intrauterine devices. However, progestational drugs, macroprogestins (medroxyprogesterone acetate) and continuous doses of microdose pills (mini-pill, progesterone-only pill) can also be used(26). Normodose progestins (progesterone, 17-alpha-hydroxy-progesterone derivatives) should only be used under strict supervision of the lipid profile and blood pressure changes.

Contraception in hematological diseases

Anemias. These conditions are common in young women with high fertility potential. Iron deficiency anemia is a common problem among women of childbearing age, especially when metrorrhagia appears. During menstruation, women need to consume three times higher amounts of iron than men.

Both estrogen and progestogen or progesterone-only pills can be used in women with anemia. The hypothesized effects of estroprogestins on folate metabolism and vitamin B12 could not be clearly demonstrated. Moreover, estrogen pills decrease the intensity of the menstrual cycle, leading to a decrease in iron loss during this period, thus having a potentially beneficial effect(1). It is recommended to investigate the cause of anemia and metrorrhagia before the administration of such treatments.

Intrauterine devices should be used with caution due to repeated bleeding that can lead to anemia, even in women without preexisting conditions. In patients with anemia, intrauterine devices are not the first-choice methods. An assessment of red blood cells count and hemoglobin level should be performed 6-12 months after the insertion of an intrauterine device, even in women without preexisting anemia, and especially in those with anemia(27).

Using a levonogestrel-releasing intrauterine system would decrease the flow of the menstrual cycle until it stops.

Malignant hematological diseases
(leukemias, lymphomas, Hodgkin’s disease)

For such pathologies, contraception is absolutely necessary due to the teratogenic risk of chemotherapy and radiotherapy treatment. Contraception with estrogen-combined pills and local contraception are recommended. Intrauterine devices are contraindicated in women who use therapies for spinal cord aplasia, due to their hemor­rhagic and infectious risks. Because of the teratogenic risk of chemotherapy, the contraception will be recommended two years after stopping the chemotherapy for malignant hematological diseases(28).

In case of radiotherapy exclusively, contraception must be prescribed for another 6-12 months after its termination. It should also be mentioned that radiotherapy and chemotherapy lead to decreased fertility, and thus local contraception can be successfully used.

Contraception in kidney disease

Kidney diseases, due to their multitude, as well as their consequences in women during the reproductive period, make it necessary to choose an effective and risk-free contraceptive method. The most common kidney diseases include: chronic interstitial nephropathy, hypertension of renal origin, chronic glomerular nephropathy, systemic lupus erythematosus with renal involvement, drug intoxications, and kidney pathologies that can lead to kidney failure. Nowadays, the number of young women with renal dialysis and kidney transplantation who use contraception and are planning a pregnancy has increased considerably.

Intrauterine devices. These are considered elective contraceptive methods in patients with renal conditions. Both intrauterine devices with copper or progesterone- releasing intrauterine system can be used. Care must be taken for women receiving treatment with corticosteroids or immunosuppressants, for which there is a higher risk of infection, and the effectiveness of the intrauterine device is lower.

Combined pills. Estrogen pills are contraindicated in kidney disease, due to the risk of high blood pressure and edema complications.

Pill. Progestin (microdose progestogens) contraception can be used in these cases.

These are particularly useful because of their minimal vascular and metabolic risk. Their known drawbacks are amenorrhea and menometrorrhagia. The high benefits-to-disadvantages ratio makes this type of pill to be used in many situations. It is considered that microdose progestogens are not free of metabolic risks, particularly on carbohydrate metabolism or blood pressure regulation systems, which is why their use by women with kidney disease and/or kidney failure should be made with caution(29).

Local contraceptives. This type of contraception has no systemic effects, but they have a low acceptability. Young women undergoing kidney dialysis need contraceptive protection, because either pregnancy or curettage can have detrimental effects for them. Normodose progestogens, which also cause a decrease in menstrual flow, are the most commonly used type of progestogen. Intrauterine devices cannot be used in these women, due to bleeding and exacerbation of preexisting anemia. Also, estrogrogestans should not be used, due to their metabolic and vascular risks, while micropill progestogen contraceptives cannot be used because of their bleeding risks(30).

Conclusions

Contraceptive counseling should start early, and the choice of contraceptive method must be based on the impact of an (unplanned) pregnancy, the risks and benefits of the contraceptive type, the patient’s age, the existing risk factors associated with her medical pathology, and the patient’s preferences. Family planning is a delicate, sometimes difficult issue, that carries many ethical, moral and medical dilemmas.

Combined oral contraceptives increase the risk of thrombosis and hypertension, and alter the lipid profile (HDL cholesterol and triglycerides). Combined oral contraceptives are not recommended for women with heart disease (especially for those at high venous or arterial thrombotic risk), ischemic heart disease, or high blood pressure. Contraception in diabetics must be well individualized, according to the type and duration of diabetes, and the existence of vascular, renal or ocular complications. In such cases, clinical and paraclinical follow-up must be performed with the utmost rigor. Overall, women with chronic conditions have a higher risk of complications during pregnancy, therefore it is important to use an optimal method of contraception and to avoid a therapeutic abortion, which has much higher maternal risks.   n

 

Conflict of interests: The authors declare no conflict of interests.

Bibliografie

1. Chen M, Culwell K. Contraception for Women with Medical Problems in Glob. libr. Women’s Med. 2015; Available at: https://www.glowm.com/section_view/heading/ContraceptionforWomenWithMedicalProblems/item/381
2. Use of hormonal contraception in women with coexisting medical conditions: ACOG 2019. Available at: https://www.acog.org/clinical/clinical-guidance/practice-bulletin/articles/2019/02/use-of-hormonal-contraception-in-women-with-coexisting-medical-conditions
3. Alexopoulos AS, Blair R, Peters AL. Management of Preexisting Diabetes in Pregnancy: A Review. JAMA. 2019; 14;321(18):1811-1819.
4. Chasan-Taber L, Willett WC, Stampfer MJ, Hunter DJ, Colditz GA, Spiegelman D, Manson JE. A prospective study of oral contraceptives and NIDDM among U.S. women. Diabetes Care. 1997 Mar; 20(3):330-335.
5. Kim C, Siscovick DS, Sidney S, Lewis CE, Kiefe CI, Koepsell TD. Oral contraceptive use and association with glucose, insulin, anddiabetes in young adult women: the CARDIA study. Coronary Artery Risk Development in Young Adults. Diabetes Care. 2002; 25: 1027–32.
6. Robinson A, Nwolise C, Shawe J. Contraception for women with diabetes: challenges and solutions. Open Access J Contracept. 2016; 7: 11–18. 
7. Nojomi M, Morrovatdar N, Davoudi F, Hosseini S. Contraceptives use by Iranian women with hypertension, diabetes or obesity. East Mediterr Health J. 2013; 19 (7): 638-643.
8. Gourdy P. Diabetes and oral contraception. Best Pract Res Clin Endocrinol Metab. 2013; 27(1):67-76.
9. Visser J, Snel M, Van Vliet HA. Hormonal versus non-hormonal contraceptives in women with diabetes mellitus type 1 and 2. Cochrane Database Syst Rev. 2013; 28(3):CD003990.
10. Goldstuck ND, Steyn PS. The intrauterine device in women with diabetes mellitus type I and II: a systematic review. ISRN Obstet Gynecol. 2013 Dec 11; 814062.
11. Shawe J, Smith P, Stephenson J. Use of contraception by women with type 1 or type 2 diabetes mellitus: ‘it’s funny that nobody really spoke to me about it’. Eur J Contracept Reprod Health Care. 2011; 16(5):350–358. 
12. Kjos SL, Peters RK, Xiang A, Thomas D, Schaefer U, Buchanan TA. Contraception and the risk of type 2 diabetes mellitus in Latina women with prior gestational diabetes mellitus. JAMA. 1998 Aug 12; 280(6):533-8.
13. Adam D, Jakes AD, Coad F, Nelson-Piercy C. A review of contraceptive methods for women with heart disease. The Obstetrician & Gynecologist. 2018; 20: 21-9. 
14. Roos-Hesselink JW, Cornette J, Sliwa K, Pieper PG, Veldtman GR, Johnson MR. Contraception and cardiovascular disease. Eur Heart J. 2015 Jul 14; 36(27):1728-34, 1734a-1734b.
15. Wald RM, Sermer M Colman JM. Pregnancy and contraception in young women with congenital heart disease: General considerations. Paediatr Child Health. 2011; 16:e25–e29.
16. Baumgartner H, Bonhoeffer P, De Groot NM, de Haan F, Deanfield JE, Galie N, Gatzoulis MA, Gohlke-Baerwolf C, Kaemmerer H, Kilner P, Meijboom F, Mulder BJ, Oechslin E, Oliver JM, Serraf A, Szatmari A, Thaulow E, Vouhe PR, Walma E; Task Force on the Management of Grown-up Congenital Heart Disease of the European Society of Cardiology (ESC); Association for European Pediatric Cardiology (AEPC); ESC Committee for Practice Guidelines (CPG). ESC Guidelines for the management of grown-up congenital heart disease (new version 2010). Eur Heart J. 2010 Dec; 31 (23): 2915-2957. 
17. Ouyang P, Michos ED, Karas RH. Hormone replacement therapy and the cardiovascular system: lessons learned and unanswered questions. J Am Coll Cardiol. 2006; 47: 1741–53.
18. Bairey Merz CN, Johnson BD, Sharaf BL, Bittner V, Berga SL, Braunstein GD, Hodgson TK, Matthews KA, Pepine CJ, Reis SE, Reichek N, Rogers WJ, Pohost GM, Kelsey SF, Sopko G; WISE Study Group. Hypoestrogenemia of hypothalamic origin and coronary artery disease in premenopausal women: a report from the NHLBI-sponsored WISE study. J Am Coll Cardiol. 2003; 5, 41(3):413-419.
19. Solomon CG, Hu FB, Dunaif A, Rich-Edwards JE, Stampfer MJ, Willett WC, Speizer FE, Manson JE. Menstrual cycle irregularity and risk for future cardiovascular disease. J Clin Endocrinol Metab. 2002 May; 87(5):2013-2017. 
20. Endrikat J, Klipping C, Cronin M, Gerlinger C, Ruebig A, Schmidt W, Düsterberg B. An open label, comparative study of the effects of a dose-reduced oral contraceptive containing 20 microg ethinyl estradiol and 100 microgrames levonorgestrel on hemostatic, lipids, and carbohydrate metabolism variables. Contraception. 2002; 65(3):215-21.
21. Barkfeldt J, Virkkunen A, Dieben T. The effects of two progestogenonly pills containing either desogestrel (75 g/day) or levonorgestrel (30 g/day) on lipid metabolism. Contraception. 2001; 64: 295–299.
22. Chasan-Taber L, Willett WC, Manson JE, Spiegelman D, Hunter DJ, Curhan G, Colditz GA, Stampfer MJ. Prospective study of oral contraceptives and hypertension among women in the United States. Circulation. 1996; 1, 94(3):483-489. 
23. Wei W, Li Y, Chen F, Chen C, Sun T, Sun Z, Wu Y, Zhou J, Ba L. Dyslipidaemia, combined oral contraceptives use and their interaction on the risk of hypertension in Chinese women. J Hum Hypertens. 2011; 25: 364-371. 
24. Oparil S. Hypertension and oral contraceptives. J Cardiovasc Med. 1981; 6(4):381, 384-387.
25. Shufelt CL, Bairey Merz CN. Contraceptive hormone use and cardiovascular disease. J Am Coll Cardiol. 2009; 53: 221-231. 
26. Hussain SF. Progestogen-only pills and high blood pressure: is there an association? A literature review. Contraception. 2004; 69 (2): 89-97. 
27. Neinstein  LS, Katz B. Patients with hematologic disorders need careful birth control counseling. Contracept Technol Update. 1985; 6 (3): 43-46.
28. Jain R, Muralidhar S. Contraceptive Methods: Needs, Options and Utilization. J Obstet Gynaecol India. 2011; 61 (6): 626–634. 
29. Attini R, Cabiddu G, Montersino B, Gammaro L, Gernone G, Moroni G, Santoro D, Spotti D, Masturzo B, Gazzani IB,  Menato G, Donvito V, Paoletti AM, Piccoli GB . Contraception in chronic kidney disease: a best practice position statement by the Kidney and Pregnancy Group of the Italian Society of Nephrology. Journal of Nephrology. 2020 Mar 12; doi /10.1007/s40620-020-00717-0. 
30. Wiles K, Nelson-Piercy C. Contraception in patients with kidney disease.in Oxford textbook of clinical nephrology, 4th ed, 2018. Oxford University press, DOI: 10.1093/med/9780199592548.003.0293.