Multinational comparative clinical trial of long-acting injectable contraceptives: Norethisterone enanthate given in two dosage regimens and depot-medroxyprogesterone acetate. Final report: Who special programme of research, development and research training in human reproduction*

There is limited evidence on the impact of the use of progestin-only hormonal contraception (POC) on weight change. We conducted a secondary analysis of prospective weight change among women enrolled in the Evidence for Contraceptive options and HIV Outcomes (ECHO) trial.

The ECHO trial was conducted at 12 sites in eSwatini, Kenya, South Africa and Zambia between December 2015 and October 2018. HIV negative, women aged 16–35 years, desiring contraception, were randomised (1:1:1) to either 3-monthly intramuscular depot medroxyprogesterone acetate (DMPA-IM), levonorgestrel (LNG) implant or copper intrauterine device (IUD). Follow-up was up to 18 months. Weight (kg) was measured at baseline and study exit. Analysis was performed as intention to treat (ITT) and time on continuous contraceptive use. The primary outcome of this secondary analysis is weight change from study enrolment to the final visit at study month 12–18. The ECHO trial is registered with ClinicalTrials.gov, NCT02550067.

7829 women were randomly assigned to DMPA-IM (n = 2609), copper IUD (n = 2607) or LNG implant (n = 2613). The ITT population included 7014 women 2293 DMPA-IM group, 2372 copper IUD group and 2349 LNG group) who were not lost to follow-up, pregnant on study, or missing weight data. The mean weight increased in all groups but was significantly different in magnitude: 3.5 kg (SD = 6.3), 2.4 kg (SD = 5.9) and 1.5 kg (SD = 5.7) in the DMPA-IM, LNG implant and copper IUD groups, respectively. Comparative differences between groups were (2.02 kg (95% CI, 1.68, 2.36, p < 0.001) for DMPA-IM versus copper IUD, 0.87 kg (0.53,1.20 p < 0.001) for LNG implant compared to copper IUD and 1.16 kg (0.82, 1.50, p < 0.001) for DMPA-IM compared with LNG implant. Results for continuous contraceptive use were similar.

We found differences in weight gain between POC users compared to the non-hormonal copper IUD group over 12–18 months of use. Women using POCs should be counselled about this potential side effect when choosing a contraceptive method.

Access to safe and effective contraceptive choices is a reproductive right and contributes tremendously to improvements in maternal and child health. Progestin-only injectables, particularly intramuscularly injected depot medroxyprogesterone acetate (DMPA-IM), have received increased attention given findings suggesting a potential association with increased HIV risk. For women at high risk of HIV, the World Health Organization's Medical eligibility criteria for contraceptive use currently aggregate recommendations for all progestin-only injectables, including DMPA-IM, subcutaneously injected DMPA (DMPA-SC) and intramuscularly injected norethindrone/ norethisterone enanthate (NET-EN), except in the case of some drug interactions. We considered whether published data indicate differences or similarities between these injectables relevant to risk of acquiring HIV. In vitro data confirm different biological activities of these distinct progestins, including that MPA, and not NET, binds and activates the glucocorticoid receptor resulting in different biological effects relevant to immune function. Limited clinical data suggest changes in immunologic activity following DMPA-IM and NET-EN initiation, but interstudy variation and study design differences diminish ability to determine clinical relevance and the degree to which DMPA-IM and NET-EN could act differentially. The highest-quality epidemiologic studies suggest a potential 40% increase in HIV incidence in users of DMPA-IM relative to women not using hormonal contraception but no significant increase in risk in users of NET-EN. In our opinion, most of the available biologic activity and epidemiologic data indicate that DMPA and NET-EN are likely to act differently, and data remain too limited to evaluate differences between DMPA-IM and DMPA-SC.

Fournir des lignes directrices aux fournisseurs de soins quant à l’utilisation de modes de contraception pour la prévention de la grossesse et quant à la promotion d’une sexualité saine.

Orientation des praticiens canadiens en ce qui concerne l’efficacité globale, le mécanisme d’action, les indications, les contre-indications, les avantages n’étant pas liés à la contraception, les effets indésirables, les risques et le protocole de mise en œuvre des modes de contraception abordés; planification familiale dans le contexte de la santé sexuelle et du bien-être général; méthodes de counseling en matière de contraception; et accessibilité et disponibilité des modes de contraception abordés au Canada.

La littérature publiée a été récupérée par l’intermédiaire de recherches menées dans MEDLINE et The Cochrane Library entre janvier 1994 et janvier 2015 au moyen d’un vocabulaire contrôlé (p. ex. contraception, sexuality, sexual health) et de mots clés (p. ex. contraception, family planning, hormonal contraception, emergency contraception) appropriés. Les résultats ont été restreints aux analyses systématiques, aux études observationnelles et aux essais comparatifs randomisés / essais cliniques comparatifs publiés en anglais entre janvier 1994 et janvier 2015. Les recherches ont été mises à jour de façon régulière et intégrées à la directive clinique jusqu’en juin 2015. La littérature grise (non publiée) a été identifiée par l’intermédiaire de recherches menées dans les sites Web d’organismes s’intéressant à l’évaluation des technologies dans le domaine de la santé et d’organismes connexes, dans des collections de directives cliniques, dans des registres d’essais cliniques et auprès de sociétés de spécialité médicale nationales et internationales.

La qualité des résultats a été évaluée au moyen des critères décrits dans le rapport du Groupe d’étude canadien sur les soins de santé préventifs (Tableau 1).

Déclarations sommaires

• 15.

  Les implants de progestatif comptent des taux d’échec aussi faibles que ceux de la contraception permanente. (II-2)

• 16.

  L’insertion d’un implant immédiatement à la suite d’un accouchement ou d’un avortement constitue une façon efficace d’abaisser les taux de nouvelle grossesse chez les adolescentes et de nouvel avortement. (II-2)

• 17.

  Les perturbations du cycle menstruel constituent l’effet indésirable le plus courant des modes de contraception à progestatif seul. (II-2) L’aménorrhée est très courante dans le cadre de l’utilisation d’acétate de médroxyprogestérone-retard et d’implants de progestatif. (II-2)

• 18.

  L’utilisation de progestatifs administrés selon des doses contraceptives ne semble pas accroître le risque de thromboembolie veineuse, d’infarctus du myocarde ou d’accident vasculaire cérébral. (II-2)

• 19.

  L’efficacité des implants de progestatif (ou de l’acétate de médroxyprogestérone) n’est pas amoindrie chez les femmes obèses ou présentant une surcharge pondérale. (II-2)

• 20.

  La constatation d’un gain pondéral précoce dans le cadre de l’utilisation d’acétate de médroxyprogestérone-retard permet de prédire la poursuite du gain pondéral. (II-2)

• 21.

  L’utilisation d’acétate de médroxyprogestérone-retard est associée à un délai quant à la reprise de l’ovulation. (II-2)

• 22.

  L’utilisation d’acétate de médroxyprogestérone-retard est associée à une baisse de la densité minérale osseuse. Cette baisse atteint sa rapidité maximale au cours des deux premières années d’utilisation et semble être largement réversible à la suite de l’abandon du traitement à l’acétate de médroxyprogestérone-retard. (I) Nous ne disposons pas de données probantes solides indiquant que l’utilisation d’acétate de médroxyprogestérone-retard cause l’ostéoporose (II-2) ou qu’elle entraîne une hausse du risque de fracture. (II-2)

• 23.

  Il n’a pas été démontré que l’utilisation de préparations à progestatif seul entraîne une baisse de la production de lait maternel. (I) Les petites quantités d’hormones stéroïdiennes sécrétées dans le lait maternel n’exercent pas un effet indésirable sur la croissance et le développement du nouveau-né. (II-2)

• 24.

  L’utilisation d’acétate de médroxyprogestérone-retard est associée à une baisse des risques de cancer de l’endomètre et de cancer de l’ovaire. (II-2)

Recommandations

• 12.

  Le recours à des modes de contraception à progestatif seul devrait être envisagé chez les femmes qui présentent des troubles médicaux dans le cadre desquels la prise d’œstrogènes est contre-indiquée ou moins souhaitable, comme dans le cas des femmes qui ont récemment connu un accouchement, qui allaitent ou qui fument et qui sont âgées de plus de 35 ans. (III-A)

• 13.

  Aucune restriction ne devrait être imposée quant à l’utilisation d’acétate de médroxyprogestérone-retard (y compris en ce qui a trait à la durée d’utilisation) chez les femmes en âge de procréer qui sont autrement admissibles à l’utilisation de ce mode de contraception. Les risques et les avantages globaux de la poursuite de l’utilisation d’acétate de médroxyprogestérone-retard devraient faire l’objet de discussions avec les utilisatrices à intervalles réguliers tout au long du traitement. (III-A)

• 14.

  Des services de counseling traitant des perturbations du cycle menstruel devraient être offerts avant la mise en œuvre d’un mode de contraception à progestatif seul. (I-A)

• 15.

  Les fournisseurs de soins devraient aviser leurs patientes des effets potentiels de l’acétate de médroxyprogestérone-retard sur la densité minérale osseuse et leur offrir des conseils en matière de « santé osseuse » (y compris en ce qui concerne la supplémentation en calcium et en vitamine D, l’abandon du tabagisme, la pratique d’exercices de port de poids et l’atténuation de la consommation d’alcool et de caféine). (III-A)

• 16.

  En présence de saignements prolongés et/ou fréquents chez des utilisatrices de contraceptifs à progestatif seul, la présence d’une grossesse, d’une infection transmissible sexuellement ou d’une pathologie génitale devrait être écartée. (III-B)

• 17.

  La possibilité d’une grossesse ectopique doit être écartée lorsqu’une grossesse en vient à se manifester chez une femme qui utilise un mode de contraception à progestatif seul. (III-A)

To provide guidelines for health care providers on the use of contraceptive methods to prevent pregnancy and on the promotion of healthy sexuality.

Overall efficacy of cited contraceptive methods, assessing reduction in pregnancy rate, safety, ease of use, and side effects; the effect of cited contraceptive methods on sexual health and general well-being; and the relative cost and availability of cited contraceptive methods in Canada.

Published literature was retrieved through searches of Medline and The Cochrane Database from January 1994 to January 2015 using appropriate controlled vocabulary (e.g., contraception, sexuality, sexual health) and key words (e.g., contraception, family planning, hormonal contraception, emergency contraception). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies published in English from January 1994 to January 2015. Searches were updated on a regular basis in incorporated in the guideline to June 2015. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies.

The quality of the evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1).

Summary Statements

• 15.

  Progestin implants have failure rates as low as permanent contraception. (II-2)

• 16.

  The use of a progestin implant immediately postpartum and post-abortion is an effective way of decreasing repeat pregnancy in adolescents and repeat abortions. (II-2)

• 17.

  The most common side effect of progestin-only contraceptive methods is menstrual cycle disturbances. (II-2) Amenorrhea is very common with depot medroxyprogesterone acetate and progestin implant use. (II-2)

• 18.

  The use of progestins given at contraceptive doses does not appear to increase the risk of venous thromboembolism, myocardial infarction, or stroke. (II-2)

• 19.

  The efficacy of progestin implants or depot medroxyprogesterone acetate is not decreased in overweight and obese women. (II-2)

• 20.

  Early weight gain with depot medroxyprogesterone acetate use is predictive of continued weight gain. (II-2)

• 21.

  Depot medroxyprogesterone acetate use is associated with a delay in resumption of ovulation. (II-2)

• 22.

  The use of depot medroxyprogesterone acetate (DMPA) is associated with a decrease in bone mineral density. This decrease is most rapid in the first 2 years of use and appears to be largely reversible once DMPA is discontinued. (I) There is no strong evidence that the use of DMPA causes osteoporosis (II-2) or increases the risk of fracture. (II-2)

• 23.

  The use of progestin-only preparations has not been shown to decrease breast milk production. (I) The small amounts of steroid hormones secreted in breast milk do not have an adverse effect on infant growth and development. (II-2)

• 24.

  Depot medroxyprogesterone acetate use is associated with a decreased risk of endometrial and ovarian cancer. (II-2)

Recommendations

• 12.

  Progestin-only methods of contraception should be considered in women with medical conditions where estrogen is contraindicated or less appropriate, such as women who are recently postpartum, breastfeeding, or in smokers over age 35. (III-A)

• 13.

  There should be no restriction on the use of depot medroxy-progesterone acetate (DMPA), including duration of use, among women of reproductive age who are otherwise eligible to use the method. The overall risks and benefits of continuing DMPA use should be discussed with DMPA users at regular intervals throughout the course of treatment. (III-A)

• 14.

  Counselling regarding menstrual cycle disturbances should be done prior to initiating a progestin-only method of contraception. (I-A)

• 15.

  Health care providers should inform patients of the potential effects of depot medroxyprogesterone acetate on bone mineral density and counsel them on “bone health,” including calcium and vitamin D supplementation, smoking cessation, weight-bearing exercise, and decreased alcohol and caffeine consumption. (III-A)

• 16.

  If prolonged and/or frequent bleeding occurs in users of progestin-only contraceptives, pregnancy, sexually transmitted infection, and genital pathology should be ruled out. (III-B)

• 17.

  Ectopic pregnancy should be ruled out if a pregnancy occurs in a woman using a progestin-only method of contraception. (III-A)

Use of contraception lowers a woman's risk of experiencing an ectopic pregnancy. In the case of method failure, however, progestin-only contraceptives may be more likely to result in ectopic pregnancies than some other methods such as combined hormonal and barrier contraceptives.

To describe ectopic pregnancy risk associated with use of implants and progestin-only injectable contraceptives through a systematic review of published studies.

We searched electronic databases for articles in any language published through May 2015 describing studies of progestin-only injectables and implants. We also searched bibliographies and review articles for additional studies.

Studies that reported any pregnancies were included in the review. Independent data extraction was performed by two authors based on predefined data fields, and where possible, we calculated the proportion of pregnancies that were ectopic and the ectopic pregnancy incidence rate per 1000 woman–years.

Fifty-three studies of implants and 28 studies of injectables were identified; 79% reported pregnancy location. The proportion of ectopic pregnancy ranged from 0 to 100% with an incidence of 0–2.9 per 1000 woman–years in studies of marketed levonorgestrel implants. Studies of etonogestrel implants and the injectables, depot-medroxyprogesterone acetate and norethisterone enanthate, reported few ectopic pregnancies.

Progestin-only contraceptive implants and injectables protect against ectopic pregnancy by being highly effective in preventing pregnancy overall; however, the absolute risk of ectopic pregnancy varies by type of progestin. Risk of ectopic pregnancy should not be a deterrent for use or provision of these methods.

Progestin-only contraceptive injectables and implants are highly effective, longer-acting contraceptive methods that can be used by most women in most circumstances. Globally, 6% of women using modern contraception use injectables and 1% use implants. Injectables are the predominant contraceptive method used in sub-Saharan Africa, and account for 43% of modern contraceptive methods used. A lower-dose, subcutaneous formulation of the most widely used injectable, depot-medroxyprogesterone acetate, has been developed. Implants have the highest effectiveness of any contraceptive method. Commodity cost, which historically limited implant availability in low-resource countries, was markedly lowered between 2012 and 2013. Changes in menstrual bleeding patterns are extremely common with both methods, and a main cause of discontinuation. Advice from normative bodies differs on progestin-only contraceptive use by breastfeeding women 0–6 weeks postpartum. Whether these methods are associated with HIV acquisition is a controversial issue, with important implications for sub-Saharan Africa, which has a disproportionate burden of both human immunodeficiency virus (HIV) and maternal mortality.