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Depo-Provera and its Effects on Fertility Among Women After Discontinued Use Taylor Brafford, Johnelyn Cadang, Ashley Light, Savannah OSteen, Lauren Stuard-Frederick, Naga Wasserman, and Jazmin Woods University of North Florida

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Introduction Depot Medroxyprogesterone Acetate (DMPA), or Depo-Provera, is considered to be one of the most controversial methods of birth control available for women. This results from the absence of a general consensus among health professionals regarding its use (Davie, 2008). Although DMPA has been noted as a highly effective method in preventing pregnancy, there is concern about 45674859 fertility once DMPA use is discontinued. Using the literature, this review presents a wide range of topics surrounding DMPA, including: defining DMPA, the number of women using DMPA, the composition of DMPA, who is eligible to take DMPA, side effects of DMPA, and studies conducted on DMPA. By exploring these topics in the literature, a better understanding of DMPA and its possible effects on fertility in women age 18-25 can be established.

Number of Women Using Birth Control According to the Centers for Disease Control and Prevention, approximately 62% of women were using contraceptives in 2008 (Mosher, 2010). Over 99% of women between the ages of 15 and 44 who have ever had sexual intercourse have reported the use of some form of birth control (Mosher, 2010). For comparison, 16% of women rely on male condoms and 28% use oral contraceptives (Mosher, 2010). About 2% of women contraceptive users are using the DMPA shot, while 22% of women have used it at some point in their lives (Mosher, 2010). The small percentage of DMPA users is largely due to side effects caused by the shot. One study found that approximately 75% of women who relied on DMPA as their form of birth control stopped its use due to side effects (Mosher, 2010).

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DMPA Defined DMPA is a highly effective contraceptive, given intramuscularly (150 mg/mL) once every three months (Davie, 2008). Contraceptives, also known as birth control and fertility control, refer to methods or devices used to prevent pregnancy. In developing countries, contraceptive use has cut the number of maternal deaths by 44% about 270,000 deaths averted in 2008 but could prevent 73% if the full demand for birth control were met. (Bearinger, L.H., 2011). Other effective birth control methods besides DMPA include barriers such as condoms, diaphragms, and the contraceptive sponge; hormonal contraceptives include oral pills, patches, vaginal rings, and injectable contraceptives such as intrauterine devices (IUDs) (p. 531). DMPA is considered more cost-efficient than the combined oral contraceptive pill. Also, as noted earlier, it proves very effective in preventing pregnancy as it has a 0 to 1 failure rate per 100 women, which is comparable to other forms of contraception, according to the National Prescribing Centre (2006). The National Prescribing Centre suggests that DMPA is as efficient as sterilization, and claims that DMPA could also help reduce unintended pregnancies (2006). Furthermore, DMPA is classified as a long-acting reversible contraception (LARC), as it can take approximately five months for ovulation to return after the last injection (dArcangues and Snow, 1999). One study suggests that 91% of women using DMPA have conceived by 2 years after discontinuation, thus indicating that there is only a delay in fertility, not a loss (Guillebaud, 2004). The delay in fertility consequently affects the number of women utilizing DMPA.

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Composition of DMPA Examining the composition of DMPA could provide helpful information that may further explain the delay in fertility in women. DMPA is prepackaged in both vials and prefilled syringes that contain 1 mL Medroxyprogesterone acetate sterile aqueous suspension 150 mg/mL strength (Depo-Provera Label, 2011). DMPA is available in lower dosages but commonly doctors prescribe Depo-subQ Provera 104, which is injected into the skin instead of the muscle (Depo-Provera Label, 2011). Pfizer uses the following information to outline the components that make up their product:

For the vials, each 1 mL contains: Medroxyprogesterone acetate - 150 mg Polyethylene glycol 3350 - 28.9 mg Polysorbate 80 - 2.41 mg Sodium chloride - 8.68 mg Methylparaben - 1.37 mg Propylparaben - 0.150 mg Water for injection - quantity sufficient

For the prefilled syringes, each 1 mL contains: Medroxyprogesterone acetate - 150 mg Polyethylene glycol 3350 - 28.5 mg Polysorbate 80 - 2.37 mg Sodium chloride - 8.56 mg )

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When needed, the pH of the solution is adjusted with sodium hydroxide and/or hydrochloric acid for both the vials and syringes (Depo-Provera Label, 2011). Not all women may be eligible to take DMPA due to its composition and surrounding side effects.

Side Effects of DMPA Unlike most birth controls, DMPA is injected into the blood stream with a needle. Currently, women must go to their doctors to receive the injection (Otto, Farley, & Caputo, 2010). However, like many other forms of birth control, the actual safety of DMPA use has been under extreme controversy. As noted previously, one study shows a five-month delay in the return of fertility (dArcangues and Snow, 1999), and several other studies have reported six to twelve months of delayed return of fertility. Despite the delays in fertility, no evidence currently exists to support the notion that DMPA causes long-term fertility loss. However, taking a closer look at some of the other side effects and risks might indicate that DMPA could create long-term health concerns, which can ultimately affect fertility in women. These include irregularities in menstruation, loss of bone mineral density (BMD), and increased risk of breast cancer. Some side effects are more serious than others, and women who are considering the injection are encouraged to think about them (Davie, 2008). According to the American Society of Health System Pharmacist, Inc. (2012), some of the less serious side effects include changes in womens periods, weight gain, weakness, tiredness, nervousness, irritability, depression,

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trouble falling and staying asleep, hot flashes, breast pain, stomach and leg cramps, back/joint pain, acne, loss of hair, swelling and itchiness of the vagina, discharge, changes in sexual desire, and cold and flu symptoms. Although this is an extensive list these side effects can usually be found on labels of other birth controls as well. Some of the more serious problems which can occur with DMPA are shortness of breath, severe headache, dizziness, difficulty speaking, crushing chest pain, nausea, change in vision, weakness or numbness, coughing up blood, vomiting, bulging eyes, seizure, yellowing of skin, extreme tiredness, heavier/longer periods, rash, hives, itching, difficulty breathing or swallowing, swelling of hands, difficulty urinating, or frequent urination. Although these are all very serious, they are not as prevalent as decreased BMD. In the study Step count, calcium intake and bone mineral density among women using Depo-Provera, researchers compare the effects of step count and calcium intake on the BMD in women who are using DMPA. The average age of women in this study was 25.6, and most should be at their peak bone mass. When DMPA suppresses ovulation, progesterone production decreases which causes lowered osteoblast and osteoclasts counts. These important cells lead to bone material, which explains why young women who have been using DMPA typically experience a decrease in bone mass (Otto, et al., 2010). Because of this problem with bone density, the Food and Drug Administration (FDA) put a black box warning on DMPA stating that women should only use Depo-Provera contraceptive injection as a long term birth control method (for example, longer than two years) if other birth control methods are inadequate for her (Davie, 2008). Essentially, this means that the FDA renders this injection unsafe for use exceeding two years because of the problems it causes with bone mass. Furthermore, there is concern about an increase in risk for breast cancer.

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Several studies have reported a small increase in breast cancer through the use of DMPA (Pfizer, 2004; Pharmacia, 2004; FPA, 2005). Taking into account all the possible side effects associated with the use Depo-Provera, it may not be suitable for all women.

Who is Eligible to Take DMPA? There are multiple reasons why women can and should take the DMPA shot. If women have a hard time remembering to take the oral contraceptive pill daily, DMPA may be a great alternative in that woman only need one shot every three months (North Carolina Womens Hospital, 2002, p. 1). In addition, it may be used by women with vascular headaches, a history of deep venous thrombosis and women who are breast-feeding (Berkeley University Health Services, 2011). Finally, DMPA only contains the hormone progestin and thus can serve as an alternative birth control method for anyone with a valvular heart disease (Brown University Health Education, n.d.). On the other hand, there are many health risks in taking DMPA, and it is recommended that some women should not receive the shot. According to North Carolina Womens Hospital, You should not take Depo-Provera if you think you are pregnant, want to become pregnant in the next year, have vaginal bleeding without a known reason, have had breast cancer or liver problems, have a history of allergy to Depo-Provera, or have had a history of severe depression (2002, p. 1). As the drug continues to be used and studied, more risks are discovered associated with taking this contraceptive; researchers have found that DMPA may increase the risk of liver tumors and cardiovascular disorders such as phlebitis, strokes, heart attacks, and high blood pressure and continued to say that, For women who smoke, these risks are greater than for

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nonsmokers, and the risks increase with age (Penn State University Health Services, 2005, p. 2). Therefore, if you smoke cigarettes, your risk for the above diseases is increased and it is not recommended you be a candidate for this form of birth control.

Studies Conducted on DMPA Many studies on DMPA collect data on the effect of the shot on BMD. One experiment published in the International Journal of Fitness assesses step count via pedometer and calcium intake to determine the effect on BMD in women age 19-37 years who are taking DMPA. The study found that, while step count did not affect the evaluated right hip, left hip, or lumbar spine, calcium intake was associated with higher BMD and therefore may prove useful in fighting the tendency of DMPA to decrease BMD (Otto, Farley, & Caputo, 2010). Information regarding the effects of DMPA on fertility, however, is not quite as common. According to Davie (2008), DMPA is categorized as a long acting reversible contraception (p. 439), but the question is whether research confirms reversibility of effects in terms of how quickly fertility returns. For most women, ovulation returned in about five months after taking the last DMPA shot, and pregnancy was achieved after two years. Thus, studies show that DMPA effects on fertility are in fact reversible, and fertility is only postponed, not permanently terminated (p. 444). Some research focuses on dose level of the shot, one of which aims to find the lowest effective dose and study the differences in its effects. Participants were randomly and blindly assigned into two groups one received IM DMPA, a 150mg/mL dose, and the other received SC DMPA, a lower 104mg/0.65mL dose. Then, they were routinely tested for return of ovulation for up to twelve months after cessation of the shots. One concern of the growingly popular longterm efficacy birth controls is the reversibility and return of ovulation and fertility. In short, the

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ovulation after the 12-month period, with IM DMPA having a 94.7% return and SC DMPA showing a 97.4% return. However, the earliest observation of an ovulation indicator in an individual was after 15 weeks in the SC DMPA group and only 10 weeks in the IM DMPA group. Also, race and BMI did not appear to affect these rates (John et al., 2004).

Summary of Findings As the literature proves, much still remains unknown about the long-term effects on fertility when using DMPA. Most studies conducted on the use of DMPA show that a delay in fertility does occur after use. However, a clear conclusion about fertility loss has not been identified. Also, statistics show that a smaller percentage of women are using DMPA as a birth control method because of the surrounding side effects, more commonly, a decrease in BMD and irregularities in menstruation. Furthermore, the varying delays in fertility cause concern among women who intend to become pregnant at some point in their lives, thus discouraging the use of DMPA. The purpose of our research will be to address the effect that DMPA has on fertility in women between the ages of 18 and 25 who reside in Duval County and who have never taken any other form of hormonal birth control. Through further research, we hope to identify whether DMPA is a safe method of birth control for women who wish to become pregnant in the future.

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Since our population is essentially every woman in Duval County (N>5,000), this study will include 500 women, ages 18-25, who reside in Duval County, are considering taking birth control, and have signed an informed consent document. Women will be given pamphlets and recruited through OBGYN offices, Planned Parenthood, walk-in clinics, and colleges. All participants will be given condoms along with proper instruction on how to use them, and half of these women (n=250) will be administered DMPA by a physician credentialed to do so. The women must have cyclic menstrual cycles, must not be pregnant at any point in time for the duration of the experiment, and must not have given birth prior to the start of the experiment. Women who have pre-existing, diagnosed fertility issues, previously taken oral contraceptives, or are currently using any hormonal birth control will be excluded from the study. The age, height, weight, and fertility of each participant will be recorded at baseline, monitoring height, weight, and fertility for the length of the study. Race will not be recorded since it has no effect on rate of returned fertility (John et al., 2004). Candidates with a history of illicit drug use within the past 5 years and those taking medications with known side effects on fertility will also be ineligible to participate. In addition, any women with vaginal bleeding for an unknown reason, breast cancer or liver problems, history of severe depression, or history of cardiovascular conditions will not be included in the study. To determine qualifying or disqualifying factors, we will use a confidential survey. Eligible women will be placed into the control group (condoms only) or experimental group (administered DMPA) by means of random assignment. The age range of 18-25 was chosen

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because this is seen as emerging adulthood (Arnett, 2004, p. 20), participants do not require legal guardian consent, and many studies use this range, making results highly comparable. Instrumentation When a woman expresses interest in participating in the study, she will first be given a informed consent and confidential survey, which will gather demographic information (age, address, height, and weight) and any pre-existing conditions which may disqualify the individual. We will also only select those who have never used hormonal birth control. Participants selected for the study will undergo a fertility test before and after the research project, as well as every three months throughout the research project. The outcomes this research project will measure are fertility levels and possible negative effects after one year use of DMPA. Fertility can be tested through several means including observation of cervical mucus and studying family history, or even through ovulation tests. The fertility test that will be used is a simple blood test. It will be done in a clinical setting and sent to a lab for results. The hormones tested for would be Estradiol, Follicle-stimulating hormone (FSH), Luteinizing hormone, and serum progesterone. Estradiol is a form of estrogen, and testing for this would determine ovarian function and quality of eggs. Testing for FSH would reveal information about the womans menstrual cycle and production of eggs. Luteinizing hormone levels establish ovarian hormone production and maturing of the egg in the women. Finally, testing for serum progesterone would show whether ovulation is actually occurring. Design and Procedure

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This study will use a true experimental design, and the participants will be selected using convenience sampling. The 500 women who volunteer to participate will randomly be place into two groups; half of them will be in the experimental group (n=250), and the other half will be placed in the control group (n=250). The women chosen for the study will be females who have never taken any form of hormonal birth control in the past and are not currently doing so. At baseline, each participant will take a simple blood test, which will determine their individual fertility statuses. A qualified nurse will administer the shot to each woman in the experimental group at baseline and every three months thereafter, as directed, for twelve months only (American Society of Health-System Pharmacists, 2010) because the FDA warns not to use DMPA for longer than two years (Davie, 2008). The control group will not receive the shot or any type of birth control but condoms and proper instruction for their use for this one year. One year from baseline, the experimental group will cease DMPA administration, and blood tests for fertility will continue every three months for another full twelve months. Since previous studies show that women regain fertility after about five months, one year should encompass any significant variance in this (dArcangues and Snow, 1999). The independent variable is the birth control method, DMPA or condoms. The dependent variable is the womens fertility status. Data Analysis The data will be reviewed using the Statistical Package for Social Sciences (SPSS). The Independent Sample T Test will be utilized to compare pre and post test fertility measures. The subjects will be screened for fertility every 3 months, for one year on DMPA and for one year after discontinued use. We will use ANOVA to compare the differences in fertility during each 3 month testing.

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American Society of Health System Pharmacist, Inc. (2012). Medroxyprogesterone injection. Retrieved from http://www.nlm.nih.gov/medlineplus/druginfo/meds/a604039.html (48566B)CD)E3AA;FD)!"#$%&'%()*+,-.//*0(1.#(2&'*&'%($/3*(4$/"(-.#(,3-#(-##'5(-.$/+%.(-.#( -2#'-&#5D)$GHI49)J8KL54MK6N)#45MMD Berkeley University Health Services (2011). Depo-Provera for Contraception, (1-2). Retrieved from http://uhs.berkeley.edu/home/healthtopics/PDF%20Handouts/DepoProvera.pdf Brown University Health Education (n.d). Depo-Provera. Retrieved from http://brown.edu/Student_Services/Health_Services/Health_Education/sexual_health/safe r_sex_and_contraceptives/depo_provera.php dArcangues C, Snow R (1999) Injectable contraceptives for women. In: Rabe T, Runnebaum B, eds. Fertility Control: Update and Trends. Springer-Verlag, Berlin: 12149 www.gfmer.ch/Endo/ Course2003/Injectable_contraceptives.htm Davie, L. (2008). Assessing Depo-Provera as a choice for women. Practice Nursing, 19(9), 439448. Retrieved from CINAHL Plus database. Depo-Provera Label. (2011, July). Retrieved from http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedical Products/ucm154784.htm Family Planning Association (2004) Your guide to contraception. Family Planning Association, London.

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Finer, L. (July 22, 2011). Unintended pregnancy in the United States: incidence and disparities, 2006. In Contraception. Retrieved October 17, 2012, from http://www.guttmacher.org/pubs/journals/j.contraception.2011.07.13.pdf Guillebaud J (2004). Contraception today. 5th ed. Taylor and Francis, London. John, J., Caryn, D., Antonia, N., Charlie, W., Frederick R, B., & Daniel R Mishell, J. r. (2004). Original research article: Pharmacokinetics, ovulation suppression and return to ovulation following a lower dose subcutaneous formulation of Depo-Provera. Contraception, 70(1), 11-18. doi:10.1016/j.contraception.2004.01.011 North Carolina Womens Hospital (2002). Information About Depo-Provera, (1-2). Retrieved from http://www.med.unc.edu/nursing/...ed/.../Depo%20Provera%20Information.pdf Mosher, W. (August 2010). Use of Contraception in the United States: 19822008. In Centers for Disease Control and Prevention. Retrieved October 17, 2012, from http://www.cdc.gov/nchs/data/series/sr_23/sr23_029.pdf. Otto, S. M., Farley, R., & Caputo, J. (2010). Step count, calcium intake and bone mineral density among women using depo-provera. International Journal Of Fitness, 6(1), 1-7. Retrieved from EBSCO MegaFile database. Penn State University Health Services (2005). Depo-Provera, (1-2). Retrieved from http://studentaffairs.psu.edu/health/healthTopics/pdf/DepoProveraUHS.pdf Pfizer. (2004). Depo-Provera medroxyprogesterone acetate. Patient information leaflet. Pharmacia Limited, Basildon. Pharmacia (2004) Depo-Provera 150 mg/ml medroxy-progesterone acetate. Instructions for doctors and pharmacists. Pharmacia, Basildon.

!"#$%#&$'"&()(*!)+,-)".."/,-)$*)."&,+0+,1) PubMed Health. (2010, September 1). Medroxyprogesterone Injection. Retrieved from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000283/

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