All included studies either used the intramuscular DMPA formulation or did not specify the type of DMPA used; unspecified DMPA was assumed to be the intramuscular formulation because this was the first formulation of DMPA developed.
The 24 studies included 61 comparisons between DMPA users and users of other methods. Forty-two of the 61 comparisons were between DMPA users and women using nonhormonal controls, such as the copper intrauterine device (Cu-IUD), or women using any type of nonhormonal method (withdrawal, barrier, fertility awareness-based, abstinence, and sometimes including Cu-IUD). Ten of the 61 comparisons included women using combined hormonal methods, referring to combined estrogen and progestin-containing pills, patches, or vaginal rings. Five comparisons included women using a mix of non-DMPA methods, and four comparisons included women using other progestin-only methods (implant or levonorgestrel intrauterine system) (Figure 2).
For the internal validity quality assessment, risk of bias was rated as “low” for zero of 61 comparisons, “moderate” for 19 of 61, and “high” for 42 of 61 comparisons (Appendix 5, http://links.lww.com/AOG/B253). The most common reasons for rating a study as having a high risk of bias were not controlling for major confounding variables or having high (greater than 50%) overall loss to follow-up, high differential loss to follow-up by contraceptive method group, or high risk of selection bias. Reasons for rating a study as having a moderate risk of bias included having loss to follow-up between 20% and 50%, not controlling for minor confounding variables, or having potential recall bias (Appendices 6–8, available online at http://links.lww.com/AOG/B253).
For external validity quality assessment, generalizability was rated as “good” in ten studies, “fair” in 14 studies, and “poor” in zero studies (Appendices 6–8, http://links.lww.com/AOG/B253). Two factors downgraded the study to “fair”: 1) either intentionally21–23 or unintentionally15,24–28 excluding women of obese body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) or 2) being conducted in a country other than the United States21–23,25–35 or from a small subpopulation in the United States,36 making the study population less generalizable to the U.S. primary care population.
Sixteen articles describing fourteen studies reported on weight- or body composition-related outcomes among DMPA injectable contraceptive users compared with their comparison group. There were nine prospective cohort studies and five retrospective cohort studies (Figure 1). Most of these studies reported either weight change, change in BMI, or both. Five studies15,21,24,29,37 measured body composition with the widely used dual-energy X-ray absorptiometry technique and reported on changes in total body or central fat mass; two studies reported on perceived or self-reported weight change.38,39 All but one study36 compared outcomes of DMPA-users to outcomes of nonhormonal method users (Figure 2). Six of the studies had moderate risk of bias, and eight had high risk of bias (Appendix 5, http://links.lww.com/AOG/B253). The articles by Berenson et al38 and Berenson and Rahman37 are from the same study; Berenson et al present the patient-reported subjective data, and Berenson and Rahman present the objective measurements. In this review, we referenced these as one study with multiple outcome measures. The articles by Dos Santos from 2014 to 2016 had partially overlapping study participants and different rates lost to follow-up, so we referenced them as two separate studies.21,22
Among the six studies with moderate risk of bias, five reported objective weight or BMI outcomes and three reported on body composition. Risk of bias was rated as “moderate” most frequently for attrition greater than 20% or not controlling for potential confounding by activity level or diet (Appendix 6, http://links.lww.com/AOG/B253); these are two lifestyle variables that can correspond to both contraceptive method choice and to weight gain. Four studies15,23–25 found DMPA users had statistically significant increases in weight, BMI, or body fat mass compared with Cu-IUD or other nonhormonal method users, and two studies21,22 found no statistically significant difference in change in BMI or body fat between DMPA and Cu-IUD users. The study by Batista et al found that DMPA users and Cu-IUD users had similar mean weight at baseline (62 kg vs 61 kg, respectively, P=.54), but at 1-year follow-up, DMPA users had statistically significantly higher mean weight than Cu-IUD users (DMPA 65 kg vs Cu-IUD 62 kg, P<.001).23 Clark et al found that new DMPA users had gained approximately 2.6 kg at 1 year, whereas nonhormonal method users had gained less than 0.1 kg (P<.03)24; at 2.5 years, DMPA users had gained a total mean of 6.1 kg, whereas nonhormonal method users gained, as reported in the article, “virtually no weight” (P<.03). Modesto et al25 found that new DMPA users gained 1.3 kg over 1 year, whereas Cu-IUD users gained 0.2 kg (P<.001). Modesto's 10-year follow-up found that DMPA users who had remained in the study and continued using DMPA for the entire period had gained 6.6 kg, whereas Cu-IUD users had gained 4.9 kg (P=.04); however, the 10-year data are at high risk of bias owing to a 79–90% loss to follow-up.25 Dos Santos et al found no statistically significant differences in change of BMI at 1 year between DMPA and Cu-IUD users.21,22
With respect to body composition, Bonny et al found that DMPA users had a total body fat increase of 10.3% over 6 months, whereas nonhormonal method users had a total body fat decrease of 0.7% (P=.04).15 Clark et al similarly found a statistically significant increase in fat mass, along with an increase in central-to-peripheral fat mass ratio, in DMPA users over 2.5 years compared with no change in nonhormonal method users; duration of DMPA use was the strongest predictor of these outcomes.24 Dos Santos et al found no statistically significant difference between groups in total body fat over 1 year.21
Of the eight studies examining weight-related outcomes that had high risk of bias, seven reported on objective weight or BMI measurements, two reported on subjective or perceived weight gain, and two additionally reported on body composition. Among the studies reporting objective measurements, three found that DMPA users had statistically significantly greater increases in weight or BMI from baseline compared with their comparison group, in follow-up durations ranging from 2 to 5 years.26,36,37 Three studies found equivalent increases from baseline between groups, in follow-up durations ranging from 1 to 10 years.27–29,40 One study found outcomes differed by baseline BMI: DMPA users in the baseline normal- and overweight-BMI groups gained more weight over 3 years than Cu-IUD users, but differences in weight gain were not found between DMPA and Cu-IUD users in those who had baseline obese BMI.30
Among the two studies that measured subjective weight gain, both found a statistically significantly greater perceived weight gain in DMPA users compared with nonhormonal method users, with Nault et al reporting a 75% sensitivity and 84% specificity for true weight gain.38,39
The study of body composition by Dal'Ava et al29 found that DMPA users had a statistically significant increase in central body fat compared with Cu-IUD users (P=.04) over 1 year. Similarly, Berenson and Rahman37 found that DMPA users had increased central-to-peripheral fat ratio compared with nonhormonal method users over a 3-year follow-up (P<.01). For total body fat measurements, Dal'Ava et al found no statistically significant difference between groups at 1 year, whereas Berenson and Rahman found that DMPA users had statistically significantly increased fat mass compared with nonhormonal method users over a 3-year follow-up (P<.01).29,37
Notably, six of the studies with high risk of bias received their bias rating because of potential selection bias. For example, the studies by Pantoja et al,30 Bahamondes et al,26 and Taneepanichskul et al27,28 retrospectively sampled only the DMPA and other contraceptive method users who had used their method continuously for at least 3, 5, and 10 years, respectively. Excluding users who discontinued their method earlier, which for DMPA users could have been due to weight gain, could have resulted in an underestimate of true weight gain in the DMPA user group (Appendix 6, http://links.lww.com/AOG/B253).
Four studies (Berenson et al,38 Civic et al,41 Brown et al,42 and Ott et al43) reported on depressed or negative mood, nervousness, “well-being,” or mood swings in DMPA users compared with control groups. All four studies were prospective cohort studies rated as having a high risk of bias for inadequately controlling for major confounding variables such as relationship status or relationship satisfaction, life stressors, or financial or socioeconomic instability; the study by Civic et al41 additionally had a risk of selection bias owing to a 60% loss to follow-up or method discontinuation over 3 years (Appendix 7, http://links.lww.com/AOG/B253). Comparisons were made between DMPA and nonhormonal methods, combined hormonal contraceptives, and a mixed group of non-DMPA methods. Berenson et al38 and Civic et al41 used standardized measurement instruments, whereas Brown et al42 and Ott et al43 used investigator-designed instruments that had not been validated.
The study by Berenson et al38 followed new contraceptive method users for 2 years and found no statistically significant difference in nervousness or depressive symptoms, comparing users of DMPA to users of nonhormonal methods. In contrast, Civic et al41 found that DMPA users had 44% greater adjusted odds of having increased depressive symptoms compared with nonusers of DMPA (as measured by a difference of 10 or more points on the Community Epidemiology Survey—Depression Scale) (P=.047; 95% CI 1.00–2.07). Brown et al42 found that both DMPA and combined oral contraceptive users had statistically significant greater overall “negative well-being” than nonhormonal method users, measured over three menstrual cycles. Ott et al43 found that DMPA users compared with combined oral contraceptive and other non-DMPA users had more “negative mood,” with statistical significance that had unclear clinical significance (maximum absolute difference 0.22 points on an index range of 3–15 points).
Among the two studies that reported on mood swings for DMPA users compared with nonhormonal method users, Berenson et al38 found DMPA users had decreased odds of mood swings (adjusted odds ratio [aOR]=0.66; 95% CI 0.45–0.97), whereas Brown et al42 found no statistically significant difference.
Four studies examined low sexual interest or loss of libido in DMPA users compared with control groups; two of these were prospective cohort studies (Berenson et al38 and Ott et al43) and two were cross-sectional studies (Boozalis et al44 and Schaffir et al45). Boozalis et al44 was rated as having a moderate risk of bias for not controlling for potential confounding by relationship satisfaction; the studies by Berenson et al38 and Ott et al43 were rated as having a high risk of bias for additionally not controlling for potential confounding by relationship status and life stressors. Berenson et al38 also had a high risk of bias owing to a high loss to follow-up or discontinuation of 55–61% at 2 years (no data were reported for their 1-year follow-up when attrition was less than 50%). The study by Schaffir et al45 was rated as having a high risk of bias because of potential selection bias, because participants had to have been using their method for an average of 4–5 years without an interest in changing methods (Appendix 7, http://links.lww.com/AOG/B253).
Boozalis et al44 conducted a follow-up phone interview at 6 months of method use among participants from a large prospective cohort study. They found DMPA users had greater odds of reporting lack of interest in having sex for several months in the previous 6 months compared with Cu-IUD users (aOR=2.61; 95% CI 1.47–4.61). A subgroup of these participants additionally had baseline interviews from the time of method initiation. In this group, the 6-month estimates were adjusted for lack of interest in having sex at baseline, with the resulting aOR no longer statistically significant (aOR=1.99; 95% CI 0.79–5.05), suggesting that the initial findings could be attributed to lower baseline interest in sex among the DMPA initiators.44
Berenson et al38 used a symptom checklist to assess loss of libido and dyspareunia in DMPA, combined oral contraceptive, and nonhormonal method users over 2 years. Users of DMPA had greater odds of loss of libido compared with nonhormonal method users (aOR=2.24; 95% CI 1.50–3.34), whereas combined oral contraceptive users had similar odds compared with nonhormonal method users (aOR=0.84; 95% CI 0.56–1.26).38 There was no statistically significant difference in odds of dyspareunia in DMPA users compared with nonhormonal method users.
Ott et al43 used a 5-point Likert-type scale to ask participants daily whether they were interested in having sex. Weekly mean sexual interest scores were not statistically significantly different between DMPA and combined oral contraceptive users.
Finally, Schaffir et al45 used the validated Female Sexual Function Index questionnaire in a cross-sectional analysis and found that DMPA users and combined oral contraceptive users had no statistically significant difference in scores of desire (index range 0–6: DMPA 3.8 vs combined oral contraceptive 4.2, P=.27), arousal (index range 0–6: DMPA 4.8 vs combined oral contraceptive 5.0, P=.46), and total Female Sexual Function Index scores (index range 0–36: DMPA 28.8 vs combined oral contraceptive 30.1, P=.28).
The single study reporting on menstrual symptoms was a prospective cohort study (Berenson et al38) that used a symptom checklist at visits every 6 months for 2 years. It was at high risk of bias owing to loss to follow-up (55–61% attrition at 2 years). At 2 years, DMPA compared with nonhormonal method users had greater odds of reporting continuous bleeding longer than 20 days (aOR=13.37; 95% CI 5.35–33.38), greater odds of reporting intermenstrual bleeding (aOR=3.61; 95% CI 2.22–5.90), greater odds of reporting missed periods (aOR=96.90; 95% CI 53.81–174.47), and lower odds of reporting cramping (aOR=0.35; 95% CI 0.24–0.51).
Various other potential side effects were assessed by single studies. In Berenson et al's38 prospective cohort study, DMPA users had statistically significant lower odds of bloating (aOR=0.48; 95% CI 0.34–0.69) and greater odds of loss of energy (aOR=1.55; 95% CI 1.10–2.18), but equivalent odds of mastalgia, acne, scalp hair loss, hirsutism, and headache compared with nonhormonal method users. Ziaei et al's31 prospective cohort study compared new DMPA users to withdrawal users and found that urinary tract infection cumulative incidence over a 3-month period was 5% compared with 0.5%, respectively (P=.018). Users of DMPA were also statistically more likely to experience urologic symptoms (P<.001), including urinary frequency (22% in DMPA users vs 1.5% in withdrawal users) and urinary incontinence (7.5% in DMPA users vs 1% in withdrawal users). This study was at moderate risk of bias: although it matched participants on age, gravidity, and socioeconomic and educational status at baseline, it did not account for potential confounding by frequency of sexual activity (Appendix 8, http://links.lww.com/AOG/B253).
Three case–control studies examined whether DMPA protected against cancers; two studies were rated as having a moderate risk of bias (Cuevas et al,33 Wilailak et al35), and one was rated as having a high risk of bias (Silpisornkosol et al34). Notably, the search terms for cancer were broad to include all cancer types, but the studies that resulted and ultimately were included were of genitourinary tract cancers only.
Cuevas et al33 and Wilailak et al35 examined history of DMPA use among patients hospitalized for treatment of epithelial ovarian cancer and those in control groups hospitalized in a similar timeframe with nongynecologic diagnoses, matched on age, hospital, and year of interview. Cuevas et al33 found no difference in odds of ovarian cancer among those with history of DMPA use compared with never-users (aOR=1.07; 95% CI 0.6–1.8). Wilailak et al,35 however, found that those with history of DMPA use had 39% lower odds of epithelial ovarian cancer compared with never-users (aOR=0.61; 95% CI 0.44–0.85). Odds of epithelial ovarian cancer were even lower in those with history of DMPA use for more than 3 years compared with never-users (aOR=0.17; 95% CI 0.07–0.39).
Silpisornkosol et al34 used a similar matched case–control study design and examined history of DMPA use in endometrial cancer patients compared with those in a control group. They found that history of DMPA use was associated with 79% lower odds of endometrial cancer compared with never-users (aOR=0.21; 95% CI 0.06–0.79). Notably, they excluded women who had first used DMPA in the year before the cancer diagnosis, as they were thought likely to have been prescribed DMPA for symptoms related to the yet-undiagnosed endometrial cancer.
All three case–control studies collected DMPA use history retrospectively and were therefore subject to recall bias, as gynecologic cancer patients may report previous exposure to hormones differently than patients without a history of gynecologic cancer. An additional weakness of the Silpisornkosol et al34 study is that they did not account for potential confounding by history of obesity, which is an important risk factor for endometrial cancer and might also be related to DMPA use (Appendix 8, http://links.lww.com/AOG/B253).
Bahamondes et al's32 case–control study examined the effects of DMPA on tubal infertility. This study retrospectively collected data on history of DMPA use. It was rated as having a moderate risk of bias owing to potential recall bias. Those with a history of DMPA use had lower odds of infertility caused by tubal obstruction compared with never-users of DMPA (aOR=0.35; 95% CI 0.1–0.8).32 Barrier contraceptive users and combined oral contraceptive users had even lower odds (aOR=0.16; 95% CI 0.1–0.5; aOR=0.27; 95% CI 0.2–0.3, respectively) compared with never-users of barrier and combined oral contraceptive methods. When considering only those with secondary tubal infertility (ie, tubal infertility after having had at least one live birth), the protective effects of DMPA and barrier method use were no longer statistically significant whereas the protective effect of combined oral contraceptives persisted, suggesting the protective effects of DMPA may apply only to primary tubal infertility (ie, tubal infertility in those who have never had a live birth).
We synthesized the evidence on DMPA-related side effects and health benefits to improve the quality of contraceptive counseling.3,19 Our findings suggest an association between DMPA use and weight gain, including increased body fat mass, and support an association with irregular bleeding and amenorrhea. Inconsistent evidence exists for an association between DMPA use and mood or libido changes. Limited evidence suggests an association between DMPA use and decreased risk of cancers and tubal infertility.
Our systematic review found no eligible randomized controlled trials. Although randomizing women to contraceptive methods can present ethical and logistical challenges,46 it may be possible in some cases47,48 and would enhance the quality of evidence. Notably, the prospective cohort studies included in this review had a moderate or high risk of bias, highlighting the need for improved methodology for nonrandomized studies. Providers should recognize that the lack of data indicating the statistical significance of a specific side effect does not preclude individual patients from experiencing that side effect. Conversely, recognized side effects are not experienced universally, and some identified side effects could be a result of residual confounding. By being transparent about the evidence's complexity and limitations, providers can build trust with patients and support their contraceptive decision making in a patient-centered and evidence-based manner.
The existing evidence on weight and body composition has moderate to high risk of bias but suggests weight gain ranging from 1.3 to 3 kg among DMPA users over 1 year, compared with 0.1–1.1 kg weight gain in the nonhormonal method comparison groups.23–25 Likewise, there are statistically significantly greater increases in total body or central fat mass among DMPA users compared nonhormonal method users.15,21,24,29,37 A 2016 Cochrane review similarly concluded that the quality of evidence regarding weight is low; they reported a possible increase in weight gain of less than 2 kg at 6 or 12 months in progestin-only users compared with nonhormonal users.49 The Cochrane review excluded24,37–39 or did not consider23,26 five studies that we included, which unanimously showed a statistically significant increase in weight gain in DMPA users compared with their nonuser counterparts.
Whether weight gain differs between baseline obese and nonobese DMPA users was addressed in two of our review's studies, both of which found greater weight gain in baseline nonobese DMPA users.30,37 Given the heterogeneity and limitations of these findings, higher-quality studies are needed to better understand the relationship between DMPA use and weight gain, and the influence of baseline weight.
Our findings were inconclusive on whether DMPA use affects mood, sexual interest, and libido. Studies were limited by inability to address important potential confounders such as life stressors, relationship status, and relationship satisfaction.50,51 Two studies by Skovlund et al, published after our publication timeframe, found positive associations between hormonal contraceptive methods and, assessed separately, risk of depression and suicide, but findings were subject to residual confounding.52,53
A recent review by Worly et al,54 which included descriptive studies and those without a comparison group, found that concerns for depression in users of DMPA were unfounded, except possibly in postpartum women. Future prospective studies with appropriate comparison groups, validated instruments, and attention to important confounding variables are needed to assess this important aspect of contraceptive users' lives.55
Few studies evaluated menstrual changes, despite it being one of the most prominently perceived side effects of DMPA.18 Findings of prolonged bleeding, amenorrhea, spotting, and decreases in cramping were consistent with commonly-cited side effects of DMPA.18 Women may perceive menstrual side effects positively or negatively, and these perceptions should be explored in contraceptive counseling.
Few studies evaluated the protective effect of DMPA use on cancer risk. The included case–control studies suggest that DMPA may reduce risk of endometrial and ovarian cancers. A recent retrospective cohort study by Mørch et al,56 published after our publication timeframe, found a positive association between hormonal contraceptive methods and breast cancer, but found no association for DMPA users specifically.
Other potential side effects, such as acne, scalp hair loss, headache, hirsutism, loss of energy, and mastalgia, may be important to women's contraceptive decision-making and are understudied areas. Furthermore, none of the eligible studies evaluated return to fertility after discontinuing DMPA. A 2011 review on return to fertility similarly found no DMPA studies that met their inclusion criteria.57
Patient-centered counseling should incorporate the available evidence while acknowledging its limitations and recognizing the value of women's lived experience of contraceptive use.
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