Return to fertility after subcutaneous depot medroxyprogesterone acetate: a narrative review

Abstract

Background

This narrative review examines the time to return to fertility after discontinuation of subcutaneous depot medroxyprogesterone acetate (DMPA SC) 104 mg among women of reproductive age.

Methods

The review was conducted using multiple data sources including PubMed, CINAHL, Web of Science, The Cochrane Library, Google Scholar, Ovid Medline, EMBASE, POPLINE, Global Health/EBSCO, Scopus, WHO Global Index Medicus, International Clinical Trials Registry Platform (ICTRP), Global Index Medicus – WHO, African Index Medicus (AIM), ScienceDirect, Public Library of Science (PLOS), BioMed Central, Dryad and JSTOR. Search terms included DMPA, SC-DMPA, depot medroxyprogesterone acetate, ovulation, pregnancy, Depo Provera, return to ovulation, fertility, return to fertility, subcutaneous and SubQ. We included studies that used the standard and not experimental dosing of DMPA SC.

Results

Four of the 31 articles met the inclusion criteria. The trials compared DMPA SC 104 mg with intramuscular DMPA (DMPA IM) at various dosages and routes. Follow-up varied from 7.5 to 18 months after the last injection. Median time to ovulation for DMPA SC was 212 days and was not statistically significantly different from DMPA IM 150 mg (183 days). There were no differences in time to ovulation by region, body mass index or age. No studies reported on time to pregnancy, effect of duration or frequency of dosing.

Conclusions

Median time to ovulation for DMPA SC 104 mg of 212 days was similar to that of DMPA IM 150 mg of 183 days, suggesting that choice of formulation (SC vs IM) does not impact the timeline for return to fertility.

WHAT IS ALREADY KNOWN ON THIS TOPIC

• The return of fertility after depot medroxyprogesterone acetate (DMPA) is often delayed by several months compared with other methods. Some recent studies suggest that return to fertility may be longer with ovulation delays of up to 12 months after expiry of the last dose of subcutaneous depot medroxyprogesterone acetate (DMPA SC) 104 mg necessitating changes in patient product information by the manufacturer and some countries. The objective of this review was to summarise the evidence regarding return to fertility after discontinuation of DMPA SC 104 mg.

WHAT THIS STUDY ADDS

• The research question addressed by this review synthesises the existing literature on how long it takes for ovulation and/or pregnancy to occur after discontinuation of DMPA SC. It also reviews the effect, if any, of body mass index (BMI), geographical region, dosage, frequency of use and duration of use on return to fertility after discontinuing DMPA SC. Finally, it compares return to fertility after discontinuation of DMPA SC versus intramuscular DMPA (DMPA IM).

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

• This review reports that time to ovulation was not different for DMPA SC and DMPA IM. There were no studies on time to pregnancy or on effect of duration and frequency of use. However, there was no effect of BMI or geographical region. The findings were limited by small sample sizes and heterogenous comparison groups using non-standard dosing, route and frequency of DMPA SC or IM. There is a need for future prospective trials with larger sample sizes and recommended doses in multiple settings.

Background

Women using or desiring hormonal contraception including subcutaneous depot medroxyprogesterone acetate (DMPA SC) often express concern about its effect on fertility after discontinuation.¹ The WHO 2016 Selected Practice Recommendations for Contraceptive Use indicate that except for male and female sterilisation, all other methods of contraception are reversible, usually with prompt return to fertility on method discontinuation, except the injectable contraceptives DMPA and norethisterone enanthate (NET-EN).² This publication further states that the median delay in return to fertility for DMPA is 10 months from the date of the last injection, regardless of the duration of its use. Similar recommendations were stated in the 2015 WHO Medical Eligibility Criteria for Contraceptive Use.³ However, these recommendations were generally derived from studies on intramuscular DMPA 150 mg IM (DMPA IM) and not necessarily DMPA SC 104 mg (DMPA SC). Similarly, according to guidelines from the 2022 Family Planning: A Global Handbook for Providers, the return of fertility after cessation of progestogen-only injectables is often delayed. “Fertility takes an average of about 4 months longer to return for depot medroxyprogesterone acetate (DMPA) and 1 month longer for NET-EN compared with most other methods.”⁴ This is potentially due to long-term suppression of reproductive physiology, and therefore delayed return of fertility, ovulation and subsequent pregnancy.

Some of the recent studies on DMPA SC suggest that return to fertility may be longer, with ovulation delays of up to 12 months after expiry of the last dose.⁵ This caution has informed some of the changes in the manufacturer’s product information, which has consequently been adopted by some countries.

The objective of this review was therefore to summarise the published evidence regarding the return to fertility after the administration of DMPA SC to inform decisions as to whether the statements in WHO normative guidelines require revision.

Methods

This review employed a narrative approach chosen for its effectiveness in evaluating and summarising potential heterogeneous literature. Although vulnerable to bias, a narrative review was most appropriate due to its flexibility to allow for judgements of varied literature. Other strict review methods would have limited eligible articles in this understudied area and potentially yielded no or very limited findings.

Protocol development

The review was conducted using multiple data sources including PubMed, CINAHL, Web of Science, The Cochrane Library, Google Scholar and Ovid Medline, EMBASE, POPLINE, Global Health/EBSCO, Scopus, WHO Global Index Medicus, International Clinical Trials Registry Platform (ICTRP), Global Index Medicus – WHO, African Index Medicus (AIM), ScienceDirect, Public Library of Science (PLOS), BioMed Central, Dryad and JSTOR.

Search strategy

Search terms included 'DMPA', 'SC-DMPA', 'depo medroxyprogesterone acetate', 'return to ovulation', 'pregnancy', 'Depo Provera', 'ovulation', 'fertility', 'return to fertility', subcutaneous' and 'SubQ'.

We hand-searched the citations of the included publications to identify additional articles. We also examined review articles and their reference lists for eligible articles. Searches were restricted to articles written in or translatable in the English language, which were published and peer reviewed. Selected articles based on computer simulations or testing a novel statistical method were also included. Grey literature/unpublished studies, conference abstracts, letters to the editor, opinion pieces or advertising claims or recommendations from the manufacturer or regulatory authorities were excluded. A search was conducted from January to April 2024 and included the period from 1960 up to January 2024.

Eligible studies

We included prospective and retrospective randomised and non-randomised controlled trials, observational studies, and comparative and non-comparative studies. Studies were eligible if they used the standard dosing of DMPA SC and not experimental dosing, and if participants received the intervention (104 mg DMPA SC) and any comparison including 150 mg DMPA IM used 3-monthly and were followed up to determine return to fertility as measured by ovulation or pregnancy. The condition or domain studied was defined as return to fertility after discontinuation of DMPA SC from the time of the last injection in line with the WHO definition. Return to fertility was estimated as the average or range of time until laboratory and/or imaging confirmed ovulation or pregnancy.

Study population

The study population included all women of reproductive age and excluded women who were ineligible for administration of DMPA SC or DMPA IM as per the individual studies. Return to fertility after experimental non-standard DMPA IM comparisons was also excluded. Studies in which women received the standard dose but at intervals longer than the recommended 3 months were additionally excluded.

Intervention and control

The intervention or exposure in this review was use of at least one dose of SC DMPA 104 mg every 3 months prior to discontinuation, because a single dose provides up to 13 weeks of contraception. Studies on comparative experimental dosages and frequencies were included only if they involved DMPA 104 mg SC and data were presented only for the DMPA SC 104 mg arm. For the comparator or control, all options were considered including no comparison group, different dosing regimens of DMPA SC or different dosing regimens of DMPA IM as long as they had the outcome of interest. Data on DMPA IM were only presented if the IM DMPA was standard at 150 mg, given intramuscularly and compared with DMPA SC at standard dosage of 104 mg and at a frequency of every 3 months. Thus, only outcomes of standard dosages of DMPA SC or DMPA IM are considered and reported in this review.

Study outcomes

The main outcomes of interest included the mean/median time to ovulation (as a proxy marker for return to fertility) or to pregnancy after discontinuation of DMPA SC. Return to fertility was defined by evidence of ovulation described as progesterone levels >4.7 ng/mL and/or transvaginal ultrasound scan showing rupture of a dominant follicle or pregnancy. The proportion that ovulated by a certain time was also considered an outcome in eligible studies. However, it was noted that this outcome may not accurately convey the exact point of return to fertility. The time of discontinuation was defined as per the WHO Handbook and Selected Practice Recommendations⁶ as the ‘date from last injection’ and not the time from when the effect wears off in the body for DMPA, that is, 13 weeks or 3 months after the last injection. We finally estimated these key primary outcomes: mean (SD/median/range) time to pregnancy or proportions pregnant after the last dose or injection of DMPA SC and mean (SD/median/range) time to ovulation or proportions who ovulated after the last dose or injection of DMPA SC. Secondary outcomes were the effect of body mass index (BMI) on time to pregnancy or ovulation, effect of frequency and duration of use on time to pregnancy or ovulation, and time to pregnancy or ovulation or proportions pregnant or who ovulated after discontinuation of DMPA SC 104 mg versus 150 mg DMPA IM. The measure of effect for the primary outcome was the mean/median (and range or SD) or proportions measuring time to return to fertility, ovulation or pregnancy.

Data extraction

Study Selection: Two reviewers (AO, LM) conducted searches of predefined terms on the identified databases. The two reviewers independently reviewed each record’s title and abstract to see whether it met the inclusion criteria, then conducted a full-text review. Data extraction was independently conducted by the two authors including but not limited to: author contact information; funding source; type and length of exposure; average time to return of fertility; operationalisation of return to fertility; type of determination (if multiple outcomes reported); methods; population demographics (including mean age, BMI and ethnicity); interventions and comparison groups; and outcomes.

Risk of bias (quality) assessment

Risk of bias assessment was not conducted due to the observational descriptive nature of this narrative review. However, duration of follow-up and attrition rates were reported.

Analysis of subgroups or subsets

Where data were available, subgroup analyses were conducted to describe variations in age or age group, BMI, dosage of DMPA SC, and geography or region.

Patient and public involvement statement

This was a narrative review of published literature and not newly developed research. Therefore, there was no need for patients’ priorities, experience and preferences. Patients were equally not involved in the design, recruitment to and conduct of the review.

Results

Of the 31 articles that underwent full-text review (figure 1), four studies met the inclusion criteria (table 1).⁵,⁸ Of the 27 ineligible studies, two evaluated non-standard doses and dose intervals,^{9 10} two did not include DMPA SC,^{11 12} two had no data on return to fertility,^{13 14} eleven had other aspects of DMPA SC,¹⁵,²⁴ three reported on contraceptives generally,²⁵,²⁷ while the remaining seven were either guidelines or review articles.²⁸,³⁴ The sample size of all included studies ranged from 24⁶ to 101⁵ participants, but 9–63 participants were specific for DMPA SC. Studies were conducted in Brazil, Chile, Santo Domingo, Dominican Republic, the Americas including the United States, and Asia. None of the study subjects were from Africa. The racial background of participants included White, Asian, African American and biracial women. For all the studies, the participants’ BMI range was from 18 to 46.7 kg/m² and the age range was from 18 to 40 years. The studies were randomised clinical trials that compared DMPA SC 104 mg with DMPA IM at various dosages and routes of administration. Only one study compared the standard dosing of DMPA SC (104 mg/0.65 mL) with DMPA IM.⁶ Two of the studies evaluated a single dose of DMPA SC while two others evaluated two doses of DMPA SC given 3 months apart.^{5 8} All eligible studies measured the time to ovulation or proportions of those who ovulated as an outcome. None of these studies evaluated time to pregnancy or proportions of pregnant women after discontinuation of DMPA SC 104 mg.

Figure 1. Screening and eligibility of studies on return to fertility after subcutaneous depot medroxyprogesterone acetate (DMPA SC). DMPA IM, intramuscular DMPA.

Table 1. Time to ovulation after discontinuation of subcutaneous depot medroxyprogesterone acetate: summary of findings from included studies.

Author, study, objective	Study design, population, setting, region (n)	DMPA as intervention	Control	Dosing (single/multiple/mixed)	Time to ovulation	Comments
Taylor et al, 20225 To estimate the risk of ovulation after single (n=15) or two (n=9) doses of DMPA 104 mg SC at 3-month intervals, investigational subcutaneous regimens of DMPA IM, single 45, 75, 105, 150 or 300 mg	Secondary analysis of two contemporary PK and PD studies in Chile, Dominican Republic, Brazil and the USA n=101 BMI 18–34 kg/m2 Age 22–40 years Follow-up for a minimum of 7.5 months, until ovulation and maximum of 18 months Serum progesterone concentrations were measured weekly starting 12 weeks after each injection	DMPA SC 104 mg as a single dose or two doses, 3 months apart	No standardised control or comparator	Mixed, single or two doses of DMPA SC 104 mg	None (0/15) ovulated during 7.5 months of follow-up 1/9 (11%) ovulated within 9 months of their second injection The probability of ovulation within 4 months of last dose of DMPA SC 104 was 1.5% (Weibull, 1.3%; 95% bootstrap CI 0.5 to 2.3)	Marker of ovulation was serum progesterone ≥4.7 ng/mL (and follicular rupture for second study) 35.6% White, 64.4% Black or biracial; and median BMI 26.6 (range 18.1–33.9) Age median 34 (range 22–40) Completed follow-up 94%
Halpern et al, 20218 To evaluate the PK and PD of MPA following two doses of DMPA SC 104 given 3 months apart (n=9) compared with single subcutaneous injection in the abdomen of 150 or 300 mg DMPA IM	Clinical trial - partially randomised, multicentre, parallel-group in Santo Domingo, Dominican Republic, USA n=42 Age 18–40 years BMI 18–35 kg/m2 95.2 .% biracial Monitored for minimum 7.5 months after treatment initiation, until ovulation or for 12 months, whichever was earlier Serum progesterone and oestrogen were measured on days 0 (baseline), 7 and 14; then every 2 weeks until week 12; then approximately weekly until return of ovulation, or through month 12, whichever was earlier	DMPA SC 104 mg two doses, 3 months apart	No standardised control or comparator	Multiple, two doses DMPA SC 104 mg	No ovulations 7.5 months after initiation of treatment The estimated probability of ovulation at months 12 since the initiation of treatment was 11%	Ovulation defined at progesterone ≥4.7 ng/mL Elevated progesterone, oestrogen, TVS for follicular growth not used to modify primary definition of ovulation but to more accurately characterise ovarian function 38/42 evaluable, 1 data excluded/censored Median age 34 (range 25–39) years
Halpern et al, 20217 To identify the lowest dose of DMPA IM (45, 75 or 105 mg) that, when administered off-label subcutaneously, suppressed ovulation and had a PK profile consistent with a 4-month contraceptive effect of DMPA 104 mg SC (n=15)	Randomised, partially blinded, multicentre, parallel-group study Brazil, Dominican Republic, Chile n=60, n=15 each for either single 45, 75 or 105 mg of DMPA IM given SC and DMPA SC 104 mg Age 18–40 years BMI 18–35 kg/m2 Monitored until ovulation or 7.5 months (224 days) after the injection, whichever was earlier Serum MPA levels were measured on days 1, 3, 7, 10, 14, 21, 28, 35, 42; then at weeks 8, 10, 12, 13, 15, 17, 19, 21, 23, 25, 26, 28, 30 and 32	DMPA SC 104 mg single dose	No standardised control or comparator	Single dose	No (0/15) ovulation until 7.5 months after injection	Ovulation marker was single elevated progesterone ≥4.7 ng/mL with/without rupture of the lead follicle on TVS Completed follow-up n=54/60, 90%, three censored in 75 mg group due to detectable MPA at baseline and one due to prohibited medication Median age 33 (range 22–40) years Median BMI 26.9 kg/m2
Jain et al, 20046 Efficacy and duration of ovulation suppression, and return to ovulation at 12 months following a single injection of either DMPA SC 104 mg or DMPA IM 150 mg. Additional objectives were to determine influence of BMI and ethnicity Data on 24 women given DMPA SC 104 mg from a separate PK study conducted in Singapore is discussed for comparison	Prospective, evaluated, blinded RCT in Los Angeles, USA and Singapore n=82 Age 18–40 years BMI 18–46.7 kg/m2 Los Angeles 39 DMPA SC 104 mg 19 IM DMPA 150 mg Singapore 24 DMPA SC 104 mg only Los Angeles, races: DMPA SC 33% African American and 66% White DMPA IM 15.8% African American and 84.2% White Singapore, races: 100% Asian Serum MPA measurements were made on the day of dosing and then 11 other times during the first cycle, 11 times from post injection days 80–106 and then once per week from cycles 2–12 unless the subject ovulated	DMPA SC (104 mg/0.65 mL)	Single IM DMPA (150 mg/mL)	Single dose	No statistically significant difference between DMPA SC 104 mg and DMPA IM 150 mg regarding: Median time to return of ovulation from last injection for: DMPA SC 104 mg 212 days, about 7 months after last injection DMPA IM 150 mg 183 days, about 6.1 months after last injection Mean time to return of ovulation from last injection for DMPA SC 104 mg 219 (±55) days SD, about 7.3 months after last injection DMPA IM 150 mg 180 (±60.5) days, about 6 months after last injection Minimum time to return of ovulation from last injection for: DMPA SC 104 mg 106 days, about 3.5 months after last injection DMPA IM 150 mg 70 days, about 2.3 months after last injection Maximum time to return of ovulation from last injection for: DMPA SC 104 mg 358 days, about 11.9 months after last injection DMPA IM 150 mg 315 days, about 10.5 months after last injection Cumulative rate of ovulation at the end of 12 months after last injection 38/39=97.4% (38/39) DMPA SC 18/19=94.7% (18/19) DMPA IM No data on Singapore study	Ovulation defined primarily by serum progesterone concentrations >4.7 ng/mL and confirmed by urinary pregnanediol-3-glucuronide levels that were three times the mean baseline level for at least three consecutive urine samples All other secondary biomarkers supporting information for ovulation assessment. Mean (SD) age Los Angeles SC 33.8 (5.5), IM 36.5 (3.7) Singapore SC 33.8 (4.3) Mean (SD) BMI Los Angeles SC 28.7 (6.3), IM 30.5 (5.6) Singapore SC 22.4 (3.0) Not affected by BMI or race Ovulation suppressed in overweight and obese individuals

BMI, body mass index; DMPA, depot medroxyprogesterone acetate; IM, intramuscular; MPA, medroxyprogesterone acetate; PD, pharmacodynamics ; PK, pharmacokinetics ; RCT, randomised clinical trial; SC, subcutaneous; TVS, transvaginal sonography.

Duration of follow-up varied, with the shortest duration being 7.5 months after the last injection of DMPA SC (equivalent to 4.5 months after expiry of the last dose)^{5 7} and the longest duration being 18 months (equivalent to 12 months after expiry of the last dose).⁵ The follow-up period was measured from the time of last injection in three studies⁵,⁷ and in one study from first injection rather than last injection despite two dosages of DMPA SC being administered.⁸ Notably, no study measured the follow-up period from time of expiry of last dose.

In all studies, the marker of ovulation was progesterone levels ≥4.7 ng/mL. However, other studies included transvaginal ultrasound demonstration of rupture of dominant follicle and/or urinary pregnanediol-3-glucuronide as an additional marker of ovulation.^{6 7}

The estimated time to ovulation from last injection of DMPA SC 104 mg was 212 days (approximately 7 months) after that last injection. This was not statistically significantly different from the time to ovulation following administration of DMPA IM 150 mg, which was 183 days (approximately 6.1 months) after the last injection. The mean and minimum time to return to ovulation following DMPA SC 104 mg was 219 (±55) days (approximately 7.3 months) after last injection and 106 days (approximately 3.5 months) after last injection, respectively. This mean and minimum time to return to ovulation was not different from DMPA 150 mg IM of 180 (±60.5) days (approximately 6 months) after last injection. Finally, the maximum time to return of ovulation from last injection following DMPA SC 104 mg was 358 days (approximately 11.9 months) after last injection and not different from DMPA IM 150 mg of 315 days (approximately 10.5 months) after last injection.

Although the proportions that ovulated within a time period are non-specific, the cumulative rate of ovulation at the end of 12 months after last injection was 97.4% for DMPA SC 104 mg and not different from DMPA IM at 94.7%. The probability of ovulation within 9 months of the second injection of DMPA SC was 11%. While one study provided the above data, the remaining studies reported no ovulation after 7.5 months of follow-up. No significant differences in time to ovulation were observed after discontinuation of DMPA SC 104 mg when analysed by region, BMI or age range. Additionally, no studies reported on the effects of duration and frequency of dosing.

Discussion

In this narrative review, there were no ovulations 7.5 months after a single injection and only 1/9 (11%) 9 months after two injections of DMPA SC 104 mg. The median time to ovulation was 212 days (approximately 7 months) and 97.4% ovulated 12 months after last injection of DMPA SC 104 mg. Notably, this finding was not different from that of DMPA 150 mg IM for which the median time to ovulation was 180 days (approximately 6 months) and 94.7% ovulated 12 months after last injection. There were no studies on time to pregnancy or on effect of duration and frequency of use. The few studies on effect of BMI reported similar pharmacokinetic profiles. This review indicates that although DMPA SC and DMPA IM users may experience a longer delay in the return to fertility, the cumulative return to fertility is relatively high at 12 months, with most women ovulating within this time. Additionally, the proportions of those who ovulated by the 12th month were similar for DMPA IM and DMPA SC users. From this narrative review, women who use or are considering the use of DMPA SC and DMPA IM and have important concerns regarding possible effects on future fertility are to be informed of the similarity in return to fertility for both products. Further, there is a need to understand that the return to fertility as measured by ovulation does not equate to time to pregnancy. This is because of the additional factors that contribute to fertility that may not have been standardised or evaluated in these studies.

Conclusions

Based on the available evidence, the WHO has updated the language on return to fertility in the Selected Practice Recommendations for Contraceptive Use Fourth Edition as follows: “All other methods (apart from male and female sterilisation) are reversible, usually with a prompt return to fertility on discontinuation, with the exception of the injectable contraceptives depot medroxyprogesterone acetate (DMPA) and norethisterone enanthate (NET-EN). Users should be informed that there can be a delay of up to 1 year in the return to ovulation after discontinuation.”³⁵ These recommendations should be applied equally for DMPA IM and SC with regard to information and counselling regarding return to fertility. Future studies should use time of last injection rather than expected date of next injection to estimate return to fertility after DMPA SC. Additionally, future studies should consider head-to-head randomised trials comparing the primary outcomes over a longer period of time, in diverse populations using larger sample sizes, standard dosing, route and frequency of DMPA SC or IM.

The lead author is not a staff member of WHO. Some of the co authors are WHO staff. The author alone is responsible for the views expressed in this publication and they do not necessarily represent the views, decisions or policies of the World Health Organization.