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Progestogen-only contraceptive use among breastfeeding women: A system- atic review

Sharon J. Phillips, Naomi K. Tepper, Nathalie Kapp, Kavita Nanda, Marleen Temmerman, Kathryn M. Curtis

PII: S0010-7824(15)00585-5 DOI: doi: 10.1016/j.contraception.2015.09.010 Reference: CON 8613

To appear in: Contraception

Received date: 7 May 2015 Revised date: 20 September 2015 Accepted date: 21 September 2015

Please cite this article as: Phillips Sharon J., Tepper Naomi K., Kapp Nathalie, Nanda Kavita, Temmerman Marleen, Curtis Kathryn M., Progestogen-only contracep- tive use among breastfeeding women: A systematic review, Contraception (2015), doi: 10.1016/j.contraception.2015.09.010

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Progestogen-only contraceptive use among breastfeeding women:

A systematic review

Sharon J. Phillips1, Naomi K. Tepper2, Nathalie Kapp3, Kavita Nanda4, Marleen Temmerman1, Kathryn M. Curtis2

1Department of Reproductive Health and Research, World Health Organization, Geneva, Switzerland (prior affiliation) 2Division of Reproductive Health, US Centers for Disease Control and Prevention, Atlanta, GA, USA 3Independent reproductive health consultant, Paris, France 4FHI 360, Durham, NC, USA

The findings and conclusions in this report are those of the authors and do not necessarily represent the officialACCEPTED position of the World MANUSCRIPT Health Organization or US Centers for Disease Control and Prevention.

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ABSTRACT Background: Postpartum women need effective contraception. Concerns have been raised that use of progestogen-only contraceptives may affect breastfeeding performance and infant health outcomes. Objectives: We investigated the clinical outcomes of breastfeeding duration, initiation of supplemental feeding, and weaning, as well as infant outcomes including infant growth, health and development among breastfeeding women using progestogen-only contraceptives compared with breastfeeding women not using progestogen-only contraceptives. Search Strategy: We searched the PubMed database for all articles published from database inception through December 2014. Selection Criteria: We included primary research studies of breastfeeding women of any age or parity who received progestogen-only contraceptives (POCs), including progestogen-only pills, injectables, implants, or hormonal intrauterine devices (IUDs). The main outcomes were breastfeeding performance (as measured by initiation, continuation, frequency and exclusivity of breastfeeding) and infant health (as measured by growth, development or adverse health effects). Results: Forty-nine articles reporting on 47 different studies were identified that investigated the use of POCs in breastfeeding women and reported clinically-relevant outcomes of infantACCEPTED growth, health or breastfeeding MANUSCRIPT performance. Studies ranged from poor to fair methodological quality and generally failed to show negative effects of the use of POCs on breastfeeding outcomes or on infant growth or development. One randomized controlled trial (RCT) raises concerns that immediate insertion of the levonorgestrel IUD postpartum may be associated with poorer breast-feeding performance when compared with delayed insertion, although two other RCTs evaluating early etonogestrel implants compared with delayed initiation of implants or depot medroxyprogesterone acetate failed to find such an association. Conclusion:

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The preponderance of evidence fails to demonstrate adverse breastfeeding outcomes or negative health outcomes in infants such as restricted growth, health problems, or impaired development. Evidence newly added to this review was largely consistent with previous evidence.

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1. Introduction

The benefits of breastfeeding for both women and their infants are considerable [1-3]. The World Health Organization (WHO) recommends infants breastfeed exclusively during the first months of life [4]. Although women breastfeeding exclusively and on demand are unlikely to conceive before six weeks postpartum, many women discontinue fully breastfeeding before that time and are at risk of repeat pregnancy [5]. Because birth spacing has demonstrated health benefits for women and infants, early initiation of contraception in the postpartum period may improve outcomes. Progestogen-only and progesterone contraceptives have been in use for years; however, their dosages and formulations have changed over time. Methods available include progestogen-only pills, progestogen and progesterone implants, injectables, progesterone rings, and progestogen-releasing intrauterine devices. They are highly effective when used as directed [6]. The use of progestogen-only methods of contraception (POCs) during the period of lactation has raised concerns for negative effects [7]. Progestogens could interfere with lactogenesis, especially immediately postpartum, [8] and have been shown to be transferred to breast milk [9]. Animal data suggest that progesterone receptors are common in the developing rat forebrain [10]. It is therefore possible that POCs may affect infant health or development [11]. The large loading dose of progestogens found in the injectable depot medroxyprogesterone acetate (DMPA) has been particularly called into question [12]. This systematicACCEPTED review was conducted MANUSCRIPT for the WHO's Medical Eligibility Criteria for Contraceptive Use (MEC) [13] and examines the effects of POCs on outcomes such as breastfeeding performance and infant growth, development and health. It updates a previous review from 2010 [14].

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2. Methods

We followed PRISMA (Preferred Reporting Items for Systematic Reviews and Meta- Analyses) guidelines for the conduct of systematic reviews. [15] 2.1 Key questions We identified two key questions of interest: 1) Among breastfeeding women and their infants, was the use of POCs associated with a difference in breastfeeding or infant outcomes, compared with non-use of POCs? 2) Among breastfeeding women and their infants, was initiation of POCs before six weeks postpartum associated with a difference in breastfeeding or infant outcomes, compared initiation of POCs at six weeks or later? 2.2 Search strategy We searched Pubmed for relevant articles in all languages published or in press from database inception through December 15, 2014 (See Appendix I). We searched reference lists of relevant articles for additional citations of interest. We did not consider unpublished studies, abstracts, or dissertations. We had previously contacted one author for clarification regarding allocation between treatment groups [16] and contacted another for clarification of method of analysis and measures of association of interest [17]. 2.3 Study selection We included primary reports of studies of breastfeeding women who received POCs (oral, injectable, implantable or hormonal intrauterine devices [IUDs]), as well as progesterone pellets. Studies assessingACCEPTED progesterone vaginal MANUSCRIPT rings (PVRs) [18] were excluded as they were reviewed separately [19]. The main outcomes were breastfeeding performance and infant health. Studies that reported solely on self-perceived ability to breastfeed (without any reporting on duration of breastfeeding), breastfeeding episodes, milk composition, or milk quantity were excluded. Studies that did not specify when contraceptives were initiated were also excluded. Studies that compared use of POCs with use of another type of hormonal contraceptive were considered indirect evidence. We included trials, cohort, and case-control studies, and excluded cross-sectional and non-comparative studies.

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2.4 Study quality assessment Two authors assessed the quality of each study (SP and NT) using the United States Preventive Services Task Force evidence grading system [20]. 2.5 Data synthesis We used a standard data abstraction template to systematically assess and summarize the evidence. Because many studies and recommendations separate results by the use of contraception before and after six weeks postpartum, we structured this report similarly. Summary odds ratios were not calculated, given the heterogeneity of interventions, results, and non-quantifiable outcomes reported.

3. Results

The literature search yielded 848 articles; 771 were excluded on title and abstract review and 28 were excluded after full-text review, leaving 49 reports meeting inclusion criteria. Since this review was last updated in 2008 [14], four new randomized controlled trials (RCTs) [21-24] and five new observational studies were published [17, 25-28], and an additional five observational studies that were not included in the 2008 review were identified [29-33], for a total of eight reports of RCTs and 41 reports of non-randomized clinical trials or observational studies for review (Table 1). These 49 articles reported on 47 different studies investigating the use of POCs in breastfeeding women and reported clinically relevant outcomes of infant growth, health or breastfeeding performance.

Results for Key QuestionACCEPTED One, then for Key MANUSCRIPT Question Two, are presented by study design and by time of contraceptive initiation: less than six weeks or greater than or equal to six weeks postpartum. Newly identified studies are presented first, followed by a brief summary of findings from the previous review. Non-randomized clinical trials are presented together with observational data.

3.1 Key Question One, Initiation at less than six weeks postpartum: Lactation performance

3.1.1 Randomized clinical trials

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Four RCTs [22, 34-36] investigated POC initiation within 6 weeks postpartum. A new RCT provides indirect evidence: this trial randomized 127 women planning to breastfeed to either POPs or combined oral contraceptives (COCs), started two weeks postpartum [22]. No difference was noted between groups in breastfeeding continuation or supplementation over six months.

Three RCTs were included in the previous review. In one, fewer levonorgestrel (LNG) IUD users were breastfeeding than copper (Cu) IUD users at 75 days; this difference disappeared at six months [35]. Mean duration of breastfeeding was similar. Another investigating the use of norethindrone compared with placebo found no difference between groups in breastfeeding initiation [34]. A third found no difference in breastfeeding outcomes over 12 weeks between women who received injectable norethisterone enanthate (NET-EN) or placebo [36].

3.1.2 Non-randomized clinical trials and observational studies

3.1.2.1 Injectables In 11 non-randomized clinical trials and observational studies, four of which are newly included since the last review [17, 26, 28, 32], progestogen-only injectables (POIs) (either DMPA or NET-EN) were initiated in the first six weeks postpartum; most of these found either no effect on breastfeeding outcomes or improved outcomes among DMPA users. In one new prospective cohort study women initiated DMPA or a non-hormonal method postpartum;ACCEPTED no difference in breastfeeding MANUSCRIPT frequency or continuation was observed at six weeks or three or six months [28]. A second prospective cohort study found that women who initiated DMPA after 72 hours were more likely to exclusively breastfeed at three months than those who either did not initiate or initiated early [17]. No differences emerged in exclusive breastfeeding to six months for those who did not initiate DMPA compared with those who initiated by three or six months. A third retrospective cohort study found no significant differences in duration or continuation of breastfeeding through six weeks between women who initiated DMPA before five days postpartum compared with those who did not [26]. The fourth new study prospectively investigated the use of DMPA compared with use of other contraceptive methods [32].

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Most of the women studied received DMPA within the first three months postpartum. Those who received DMPA were more likely to be fully breastfeeding at three and six months postpartum, and were more likely to continue breastfeeding through 12 and 18 months. Of women who received DMPA in the first three months, 35% were still breastfeeding at 12 months compared with 67% of those who received DMPA after three months.

The remaining studies were included previously. One found that no women using NET- EN, DMPA, or non-hormonal methods supplemented breastfeeding in the 6-month study period [37]. Another found that women using DMPA breastfed for longer than a historical control group, although no difference was noted compared with IUD users [38]. Two other studies similarly found longer duration of breastfeeding among women using DMPA compared with non-hormonal methods [39, 40]. Another found that NET-EN and (presumably non-hormonal) IUD users had no difference in time to first supplementary feeding, but infants of IUD users weaned earlier [41]. Mothers who received either DMPA or a nonhormonal method at hospital discharge had no differences in breastfeeding exclusivity, supplementation, or duration [42]. Finally, when DMPA initiated at hospital discharge was compared with non-hormonal method use, no differences were found in breastfeeding at two or six weeks, although fewer DMPA users were breastfeeding at four weeks [43].

3.1.2.2 POPs ACCEPTED MANUSCRIPT Eight observational studies assessed the use of POPs in the first six weeks postpartum; all were included in the previous review and found either no differences between POP users and non-users or improved breastfeeding outcomes with POP use. In a non-randomized trial, POP users initiated breastfeeding earlier than placebo users.[44]. Other studies found no difference in breastfeeding duration for POP users compared with historical controls [38] or compared with non-hormonal users [40, 45], while two found longer breastfeeding duration among POP users compared with historical controls [46] or IUD users [47]. Finally, two studies found less supplementation among POP users than non- hormonal users [48, 49].

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3.1.2.3 Implants Five observational studies, all in the previous review, largely found no difference in outcomes when assessing the impact of implants in the first six weeks postpartum. Women using a norethindrone implant were more likely to supplement breastfeeding at 3 months than those using condoms, but no differences were noted at any other time through six months nor in the mean duration of breastfeeding [50]. Two studies found no difference in supplementation comparing LNG implant with IUD users [41, 51]; one of these also found no difference in breastfeeding duration [51]. Users of nomegestrol implants compared with IUD users similarly had no difference in time of weaning or breastfeeding rates through 12 months [52]. Finally, breastfeeding duration did not differ between users of an etonogestrel (ETG) implant compared with Cu-IUD users over three years [53, 54].

3.1.2.4 Multiple POCs One study, included previously, assessed users of the LNG implant or POPs (analyzed together) and found no differences in breastfeeding initiation or exclusivity, although at one of three time points POC users were less likely to be breastfeeding than non- hormonal users [43].

3.1.2.5 Non-orally available progestogens Progesterone, unlike progestogens, is not absorbable orally; therefore, use during breastfeeding is believed to be safe for a neonate. As it is absorbed by the mother, it could impact breastfeeding.ACCEPTED Two studies examinedMANUSCRIPT the use of progesterone pellets in the first six weeks postpartum; both were included in the previous review. Neither showed an impact on continuation of breastfeeding at six [55] or six and twelve months [56], compared with Cu-IUD use.

3.2 Initiation at  6 weeks postpartum: Lactation performance

One RCT and 13 observational studies (four newly identified [25, 27, 29, 31]) evaluated the use of POCs initiated six or more weeks postpartum. None of these reported negative impacts on breastfeeding outcomes among POC users compared with non-users, with the

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exception of one observational study that found the average age of supplementation was younger among POP users compared with IUD users [31].

3.2.1 RCTs

One RCT, previously reviewed, found no difference between Cu-IUD and LNG-IUD users in duration of breastfeeding or supplementation at six to eight weeks postpartum [57].

3.2.2 Observational studies

3.2.2.1 Injectables Three observational studies (one new) were identified. The new study did not find supplementation among infants of mothers receiving injectables nor among those who received no method [37]. Among the studies included in the previous review, one found no difference between DMPA and non-hormonal users in breastfeeding discontinuation or initiation of complementary foods [58]. Another found no difference in breastfeeding duration within study sites between DMPA or NET-EN users, compared with non- hormonal method users, although differences were seen between sites [59, 60].

3.2.2.2 POPs Four studies (one new) assessed the impact of POPs on breastfeeding outcomes. In the new study, a non-randomized trial [31], women used POPs, a Cu-IUD plus placebo pill, or one of several ACCEPTEDcombined hormonal methods. MANUSCRIPT The average age of supplementation was lower in the POP group compared with the IUD group (11.2 vs 15 weeks), although statistical comparisons were not reported. Among the studies included in the prior review, one found no difference in complementary feeding or breastfeeding continuation up to 24 weeks when comparing POP users with non-hormonal users [58]. Two others found no difference in breastfeeding duration between POP and non-hormonal users [59- 61].

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3.2.2.3 Implants and hormonal IUDs Six studies, two of which are new, assessed the impact of implant or hormonal IUD use on breastfeeding outcomes; none found differences between groups. One new study assessed the effect of both the ETG implant and the LNG-IUD compared with Cu-IUD and found no differences between groups in mean duration of breastfeeding at 6 months [25]. The other new study included LNG implant and Cu-IUD users and found no difference in the percentage fully breastfeeding at months six or 12 and no difference in breastfeeding duration [29].

In one of the previously reviewed studies, women who received a norethindrone implant were similar to condom users in supplementation and breastfeeding continuation to eight months [50]. In three studies of women who initiated the LNG implant, similar duration of breastfeeding was seen among both hormonal and non-hormonal users [59-63].

3.2.2.4 Multiple progestogen-only methods

3.2.2.5 Non-orally available progestogens Three studies, none new, assessed the impact of non-orally available progestogens (progesterone pellets and nesterone or elcometrine implants) on breastfeeding outcomes. In two of these, breastfeedingACCEPTED duration was MANUSCRIPT similar between women using progesterone pellets [55] or a nesterone implant [64], compared with Cu-IUD. Elcometrine implant users had a higher rate of breastfeeding at three and six months and similar rates at nine to 12 months compared with Cu-IUD users [65].

3.3 Initiation less than six weeks postpartum: Infant outcomes Thirty-seven studies (four randomized controlled trials, 32 observational studies, and one cohort study with a nested RCT) were identified, including many of the studies previously described. Although some studies found differences in growth, health or

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development at some individual time points, most demonstrated no adverse impact of POCs.

3.3.1 Randomized controlled trials

Three trials were identified. One of these studies is new and provides indirect evidence; the other two were included in the previous review. In the new study women initiated either POPs or COCs at two weeks postpartum; no differences emerged in infant weight, length, or head circumference through eight weeks [22]. In a study of POPs or placebo no differences were reported for infant weight gain at 14 days [34]. Similarly infants of LNG-IUD users had similar weight, height and health through 12 months compared with Cu-IUD users [35].

3.3.2 Observational studies

3.3.2.1 Injectables Seven observational studies, three newly identified [28, 30, 33], assessed infant outcomes after initiation of POIs; all either found no detrimental effect or a protective effect of injectables on infant growth and health. A new cohort study of 250 women found no differences in infant growth or reports of illness up to six months when comparing users of DMPA initiated within 10 days postpartum with users of non-hormonal methods [28]. Another newly identified cohort study found no difference in infant weight gain up to 46 months between ACCEPTEDinfants whose mothers had MANUSCRIPT been exposed to DMPA at various time points and those who did not receive DMPA prior to nine months postpartum [33]. No significant differences were found between groups in infant infections, although a subgroup that received DMPA within 2 days postpartum had a 75% higher incidence than the other groups (statistics not reported). Another cohort study included infants who were exposed to DMPA during breastfeeding (but not during their mother's pregnancy), during both pregnancy and breastfeeding, or not at all [30]. Infants who were exposed only during breastfeeding were no more likely than the unexposed to have a height or weight over two standard deviations below the mean. Infants exposed to DMPA during breastfeeding (including those exposed during pregnancy) were more likely to have short

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stature; this difference was no longer significant after adjusting for socioeconomic factors and no effect on weight was seen. Follow-up period was unspecified.

The remaining four studies were included in the previous review. In one, infant weight gain was the same for NET-EN, DMPA, and Cu-IUD users up to month three, after which weight gain was greater in both the DMPA and NET-EN groups [37]. No physical, mental, or radiological differences were seen through 18 months. Another study found no effect of maternal DMPA use on infant weight, development or health compared with non-hormonal method use through three to six years of follow-up [39]. One child death was reported in the non-hormonal group, none in the DMPA group. In another study, infants had no adverse effects with maternal NET-EN use through 30 months of age when compared with non-hormonal method use; specific outcomes were not provided [40]. The fourth study found no difference in growth or development among infants of NET-EN users compared with infants of Cu-IUD users over 12 months [41].

3.3.2.2 POPs Six observational studies or non-randomized trials, none new in this review, assessed infant outcomes associated with POP use; most found no adverse effects. In one study, infants of women using POPs had greater weight increase than placebo users at day 14 [44]. Another study found no difference in urinary FSH, LH or testosterone among male infants of POP users compared with users of no method at four weeks [66]. Another study found no adverseACCEPTED effects of POPs up MANUSCRIPT to an average of 4.5 years of age, compared with infants of women who used the lactational amenorrhea method (LAM) or the IUD (presumably non-hormonal) [40]. Two studies found no growth differences between infants of mothers using POPs compared with non-hormonal users [48, 49]; one of these also found no difference in hospitalizations [48], while the other found more frequent minor illnesses and greater mortality (3 vs 0 deaths) among children of mothers who used non-hormonal methods [49]. Finally, infants of desogestrel users had temporary breast enlargement (2 infants), and perceived increased sweating (1 infant), compared with no adverse effects among infants of Cu-IUD users [47]. Follow-up through 2.5 years revealed no clinically relevant effects of desogestrel on the growth or health of the infants.

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3.3.2.3 Implants Eight studies that assessed the impact of implants were included, none of which are new; generally no adverse effects were reported. In one study infant weight was no different between norethindrone implant and barrier method users [50]. Another found no health or serum immunoglobulin differences between infants of LNG implant and non-hormonal users [67] and another found no differences in mean FSH, LH or testosterone [66]. One study found slower weight gain in infants of LNG implant users up to three months, compared with Cu-IUD users. This difference disappeared at four to six months, however length increased less among infants of LNG users compared with Cu-IUD users [51]. No differences in morbidity were reported. In another study infant lengths did not differ and weight was greater among infants of LNG implant users [68], and in a third no differences were found between implant users and non-hormonal users in growth or development [41]. A study of the nomegestrol implant compared with Cu-IUD found no difference in growth or health; greater infant mortality was seen in the implant group (six deaths from gastroenteritis, seizures, and pneumonia, compared with one death from gastroenteritis in the Cu-IUD group) but was not statistically significant [52]. Finally, a study of ETG implants compared with the Cu-IUD found no differences in infant growth, adverse events, respiratory or skin disorders, or developmental scores [53, 54].

3.3.2.4 Non-orally available progestogens Two studies reported no difference in infant growth or health comparing progesterone pellet users with ACCEPTEDplacebo or Cu-IUD users MANUSCRIPT[55, 56].

3.4 Initiation at  6 weeks: Infant outcomes

Most of the studies described above also reported on infant outcomes. The majority found no significant differences between infants of POC users and non-hormonal method users, although differences in both directions were noted in some comparisons.

3.4.1 Randomized controlled trials

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Two RCTs (neither new) investigated the effect of POC initiation after six weeks postpartum. In both, no differences in infant growth or development were seen between users of the LNG-IUD compared with the Cu-IUD through one year [57] or between users of POPs or DMPA compared with non-hormonal method users through 24 weeks [58].

3.4.2 Observational studies

3.4.2.1 Injectables Three observational studies (none new) assessed the impact of maternal use of POIs initiated at six weeks postpartum or later; none are new. One found increased weight gain among infants of DMPA and NET-EN users compared with non-hormonal users, and also found no physical, mental, or radiological differences over 18 months [37]. Another similarly found no difference in mean weight between DMPA users and non- hormonal users through 24 months [58]. Another study showed more weight gain among infants of DMPA and NET-EN users at some time-points (three and 12 months) and no difference at others (six and nine months). The majority of comparisons in developmental tests were similar, although some tests favored non-hormonal methods and others favored DMPA or NET-EN [59, 60].

3.4.2.2 POPs Four studies, one new [31], assessed the impact of POPs. The new study found no difference in infantACCEPTED growth between those whoseMANUSCRIPT mothers used a POP compared with those whose mothers used an IUD plus placebo pill up to 32 weeks [31]. In the other three studies, one found smaller increase in arm circumference at two sites among infants of POP users compared with non-hormonal users but found no difference for other growth measures nor for the majority of developmental test results [59, 60]. The second found no differences in infant weight gain over six months when comparing infants of POC users with those of users of multiple other hormonal and non-hormonal methods [61]. The third found no difference in infant growth (length, weight, arm circumference) among infants of women using POPs compared with those using non-hormonal methods [58]

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3.4.2.3 Implants/Hormonal IUDs Six studies, two new [25, 29], assessed infants whose mothers initiated progestogen-only implants or hormonal IUDs. In one new study women initiated the ETG implant or LNG-IUD six weeks postpartum; no difference was found in infant weight or height through six months, although infants in the implant group had less increase in tibial length than infants in the Cu-IUD group [25]. The other found no differences over 12 months in infant weight between users of the implant and users of the Cu-IUD initiated at eight weeks [29].

The remaining four studies were included previously. In one, infants of women who used a norethindrone implant had no differences in weight gain compared with those who used non-hormonal implants [50]. Likewise infants of LNG implant users had similar growth and development compared with non-hormonal users, although a few differences were noted in some of the multiple developmental tests [59, 60]. In two studies of LNG implant use compared with non-hormonal methods, no differences were noted between groups in infant weight gain [61, 63], although in one of the studies a higher incidence of respiratory infections and skin conditions was noted among infants whose mothers used an LNG implant [63]; more urologic and neurological conditions occurred among infants of Cu-IUD users.

3.4.2.4 Multiple progestogen-onlyACCEPTED methods MANUSCRIPT One study (not new) included infants of mothers using various POCs and found that infant growth was generally the same between POC and non-hormonal users [69].

3.4.2.5 Non-orally available progestogens Three studies reported on infant outcomes of mothers using non-orally available progestogens, none new. Infant growth was no different in users of nesterone pellets compared with non-hormonal methods [64]; neither infant growth nor health was different between users of progesterone pellets and users of non-hormonal methods [55].

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Similarly there was no difference in infant growth or development between infants of users of nesterone implants and Cu-IUD users [65].

3.5 Key Question Two: Early versus delayed initiation In total, eight studies address the effect of initiation of POCs before six weeks postpartum compared with later initiation, of which five are new [17, 21, 23, 24, 33]. The majority found no effect on breastfeeding or infant outcomes, although one RCT found that more women continued breastfeeding at six months in the later initiation group [23] and another found more infections in infants of DMPA users [33].

3.5.1 Breastfeeding outcomes: RCTs and Observational Studies

Six of the studies assessed breastfeeding outcomes when POCs were initiated early or late postpartum (three RCTs, three observational). All three RCTs and one of the observational studies are new. One RCT compared women using ETG implants immediately postpartum versus DMPA initiated at six weeks [21]. No differences were seen between groups in the percentage of women exclusively breastfeeding at six or 12 weeks. Another RCT compared post-placental placement of LNG-IUD with delayed placement at six to eight weeks and found no difference in breastfeeding initiation between groups, or in breastfeeding continuation at six to eight weeks; women in the delayed group were more likely to be breastfeeding at six months [23]. A final study compared womenACCEPTED randomly assigned to the MANUSCRIPT ETG implant either one to three days postpartum or at four to eight weeks postpartum and found no significant difference in breastfeeding outcomes [24].

One new observational study found that women who initiated DMPA after 72 hours postpartum were more likely to be breastfeeding at three months than those who initiated before 72 hours or who did not use DMPA [17]. In the other observational studies, norethindrone implant initiated early compared with delayed was not associated with differences in supplementary feeding or continuation of breastfeeding [50], and women

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who initiated progesterone pellets later were more likely to be supplementing breastfeeding than those who initiated early [55].

3.5.2 Infant outcomes: Observational studies

No RCTs and four observational studies (one new [33]) were identified for infant outcomes. The new study found that women who received DMPA within 48 hours postpartum reported a higher incidence of infectious diseases in their infants than those who initiated DMPA later or not at all [33].

Among previously included studies, early versus delayed DMPA or NET-EN was not associated with any differences in growth, development or health [37], nor was early versus delayed norethindrone associated with growth differences [50]. Use of progesterone pellets was not associated with any differences in growth, development or health [55].

4. Discussion

Overall, evidence from 49 articles reporting on 47 studies on use of POCs during breastfeeding is of poor to fair methodological quality. Of the 14 studies that were newly included in this review, four were older studies [30-33] of poor quality and one was published in 1999 and of fair quality [29]. None of these older studies showed any negative effect of use of POCs on breastfeeding or infant outcomes. Of the nine studies that were publishedACCEPTED since the last review, fourMANUSCRIPT were RCTs. One of the four trials suggested that early, compared with delayed, postpartum initiation of the LNG-IUD was associated with shorter breastfeeding duration and less breastfeeding exclusivity at six months [23]. However, two other RCTs found no differences [21, 24]. The fourth new trial provides indirect evidence demonstrating no difference in outcomes between POPs compared with COCs [22]. Among the newly identified observational studies, findings were generally consistent with the observational studies in the previous review, with no adverse effects noted on breastfeeding or infant outcomes.

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Exogenous administration of POCs could theoretically inhibit breastfeeding [70]; however, the evidence in this review does not generally support a negative impact on breastfeeding outcomes. Studies examining the initiation of POCs among postpartum women overall demonstrated no adverse effects on measures of breastfeeding success, such as duration of breastfeeding or time to supplementation, although a few reported differences in both positive and negative directions at individual time points. The preponderance of the evidence points towards no deleterious impact of POCs on breastfeeding success, although further study is warranted to examine the impact of immediate postpartum placement of the LNG-IUD.

Theoretical concerns also have been raised regarding the impact of exposure to progestogens on neonates, particularly in the first six weeks of life [12]. Studies identified in this review showed no consistent adverse effects of exposure to progestogens through breast milk on infant health outcomes such as growth, development and health through the first few years of life. We identified no data to inform a conclusion on longer-term effects and any such effects remain unknown.

The PVR was not addressed in this review. A recent review concluded that PVR use among breastfeeding women did not affect breastfeeding performance or infant growth during the first year postpartum [19].

Our ability to drawACCEPTED firm conclusions is limited MANUSCRIPT as most studies are observational, have lacked clear definitions of breastfeeding patterns, and failed to control for potential confounders [71]. Many did not provide information key to determining their quality and did not perform tests of significance. Some were not informative to our cutoff point of six weeks as participants initiated both before six weeks and after. Initiation before six weeks ranged from immediately postpartum to nearly 42 days.

In 2014, the WHO Expert Working Group reviewed this evidence to evaluate medical eligibility criteria for the use of POCs among breastfeeding women. All of the above studies were reviewed with the exception of one, which was identified after the meeting

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and found no deleterious effects of POCs [28]. The findings of this systematic review were incorporated into the recent update of the MEC [72].

5. Conclusion

Consistent evidence by multiple measures of successful breastfeeding, largely from fair or poor quality observational studies, suggests that POCs, when used by lactating women, do not compromise a woman's ability to breastfeed. Evidence that POCs do not adversely affect infant growth, health or development during the first year postpartum is generally consistent across observational and randomized studies. Further research is necessary to determine any effects on child health or development beyond the first year. Evidence newly added to this review is largely consistent with the previous evidence.

Acknowledgements

The authors would like to acknowledge the contributions of Mary Lyn Gaffield, Roger Chou, and the Guidelines Development Group for the Medical Eligibility for Contraceptive Use. This review was supported by the World Health Organization, the US Centers for Disease Control and Prevention, and FHI360.

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References

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[35] Heikkila M, Luukkainen T. Duration of breast-feeding and development of children after insertion of a levonorgestrel-releasing intrauterine contraceptive device. Contraception. 1982;25:279-92. [36] Lawrie TA, Hofmeyr GJ, De Jager M, Berk M, Paiker J, Viljoen E. A double-blind randomised placebo controlled trial of postnatal norethisterone enanthate: the effect on postnatal depression and serum hormones. Br J Obstet Gynaecol. 1998;105:1082-90. [37] Karim M, Ammar R, el-Mahgoub S, el-Ganzoury B, Fikri F, Abdou I. Injected progestogen and lactation. British medical journal. 1971;1:200-3. [38] Guiloff E, Ibarra-Polo A, Zañartu J, Toscanini C, Mischler TW, Gómez-Rogers C. Effect of contraception on lactation. Am J Obstet Gynecol. 1974;118:42-5. [39] Jimenez J, Ochoa M, Soler MP, Portales P. Long-term follow-up of children breast-fed by mothers receiving depot-medroxyprogesterone acetate. Contraception. 1984;30:523-33. [40] Zacharias S, Aguilera E, Assenzo JR, Zañartu J. Effects of hormonal and nonhormonal contraceptives on lactation and incidence of pregnancy. Contraception. 1986;33:203-13. [41] Shaaban MM. Contraception with progestogens and progesterone during lactation. J Steroid Biochem Mol Biol. 1991;40:705-10. [42] Hannon PR, Duggan AK, Serwint JR, Vogelhut JW, Witter F, DeAngelis C. The influence of medroxyprogesterone on the duration of breast-feeding in mothers in an urban community. Archives of pediatrics & adolescent medicine. 1997;151:490-6. [43] Halderman LD, Nelson AL. Impact of early postpartum administration of progestin-only hormonal contraceptives compared with nonhormonal contraceptives on short-term breast-feeding patterns. Am J Obstet Gynecol. 2002;186:1250-6. [44] Kamal I, Hefnawi F, Ghoneim M, Abdallah M, Abdel Razek S. Clinical, biochemical, and experimental studies on lactation. V. Clinical effects of steroids on the initiation of lactation. Am J Obstet Gynecol. 1970;108:655-8. [45] West CP. The acceptability of a progestagen-only contraceptive during breast- feeding. Contraception. 1983;27:563-9. [46] Zañartu J, AguileraACCEPTED E, Munoz-Pinto G.MANUSCRIPT Maintenance of lactation by means of continuous low-dose progestogen given post-partum as a contraceptive. Contraception. 1976;13:313-8. [47] Bjarnadottir RI, Gottfredsdottir H, Sigurdardottir K, Geirsson RT, Dieben TO. Comparative study of the effects of a progestogen-only pill containing desogestrel and an intrauterine contraceptive device in lactating women. BJOG. 2001;108:1174- 80. [48] McCann MF, Moggia AV, Higgins JE, Potts M, Becker C. The effects of a progestin-only oral contraceptive (levonorgestrel 0.03 mg) on breast-feeding. Contraception. 1989;40:635-48. [49] Moggia AV, Harris GS, Dunson TR, et al. A comparative study of a progestin-only oral contraceptive versus non-hormonal methods in lactating women in Buenos Aires, Argentina. Contraception. 1991;44:31-43.

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[50] Seth U, Yadava HS, Agarwal N, Laumas KR, Hingorani V. Effect of a subdermal silastic implant containing norethindrone acetate on human lactation. Contraception. 1977;16:383-98. [51] Shaaban MM, Salem HT, Abdullah KA. Influence of levonorgestrel contraceptive implants, NORPLANT, initiated early postpartum upon lactation and infant growth. Contraception. 1985;32:623-35. [52] Abdel-Aleem H, Abol-Oyoun el SM, Shaaban MM, et al. The use of nomegestrol acetate subdermal contraceptive implant, uniplant, during lactation. Contraception. 1996;54:281-6. [53] Reinprayoon D, Taneepanichskul S, Bunyavejchevin S, et al. Effects of the etonogestrel-releasing contraceptive implant (Implanon on parameters of breastfeeding compared to those of an intrauterine device. Contraception. 2000;62:239-46. [54] Taneepanichskul S, Reinprayoon D, Thaithumyanon P, Praisuwanna P, Tosukhowong P, Dieben T. Effects of the etonogestrel-releasing implant Implanon and a nonmedicated intrauterine device on the growth of breast-fed infants. Contraception. 2006;73:368-71. [55] Diaz S, Peralta O, Juez G, et al. Fertility regulation in nursing women. VI. Contraceptive effectiveness of a subdermal progesterone implant. Contraception. 1984;30:311-25. [56] Croxatto HB, DÌaz S, Peralta O, et al. Fertility regulation in nursing women. II. Comparative performance of progesterone implants versus placebo and copper T. Am J Obstet Gynecol. 1982;144:201-8. [57] Shaamash AH, Sayed GH, Hussien MM, Shaaban MM. A comparative study of the levonorgestrel-releasing intrauterine system Mirena versus the Copper T380A intrauterine device during lactation: breast-feeding performance, infant growth and infant development. Contraception. 2005;72:346-51. [58] Tankeyoon M, Dusitsin N, Chalapati S, et al. Effects of hormonal contraceptives on milk volume and infant growth. WHO Special Programme of Research, Development and Research Training in Human Reproduction Task force on oral contraceptives. Contraception. 1984;30:505-22. [59] Progestogen-onlyACCEPTED contraceptives during MANUSCRIPT lactation: I. Infant growth. World Health Organization Task force for Epidemiological Research on Reproductive Health; Special Programme of Research, Development and Research Training in Human Reproduction. Contraception. 1994;50:35-53. [60] Progestogen-only contraceptives during lactation: II. Infant development. World Health Organization, Task Force for Epidemiological Research on Reproductive Health; Special Programme of Research, Development, and Research Training in Human Reproduction. Contraception. 1994;50:55-68. [61] Díaz S, Zepeda A, Maturana X, et al. Fertility regulation in nursing women. IX. Contraceptive performance, duration of lactation, infant growth, and bleeding patterns during use of progesterone vaginal rings, progestin-only pills, Norplant implants, and Copper T 380-A intrauterine devices. Contraception. 1997;56:223-32. [62] Díaz S, Herreros C, Juez G, et al. Fertility regulation in nursing women: VII. Influence of Norplant levonorgestrel implants upon lactation and infant growth. Contraception. 1985;32:53-74.

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[63] Schiappacasse V, Díaz S, Zepeda A, Alvarado R, Herreros C. Health and growth of infants breastfed by Norplant contraceptive implants users: a six-year follow-up study. Contraception. 2002;66:57-65. [64] Massai MR, Díaz S, Quinteros E, et al. Contraceptive efficacy and clinical performance of Nestorone implants in postpartum women. Contraception. 2001;64:369-76. [65] Coutinho EM, Athayde C, Dantas C, Hirsch C, Barbosa I. Use of a single implant of elcometrine (ST-1435), a nonorally active progestin, as a long acting contraceptive for postpartum nursing women. Contraception. 1999;59:115-22. [66] Shikary ZK, Betrabet SS, Toddywala WS, Patel DM, Datey S, Saxena BN. Pharmacodynamic effects of levonorgestrel (LNG) administered either orally or subdermally to early postpartum lactating mothers on the urinary levels of follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone (T) in their breast-fed male infants. Contraception. 1986;34:403-12. [67] Abdulla KA, Elwan SI, Salem HS, Shaaban MM. Effect of early postpartum use of the contraceptive implants, Norplant, on the serum levels of immunoglobulins of the mothers and their breastfed infants. Contraception. 1985;32:261-6. [68] Affandi B, Karmadibrata S, Prihartono J, Lubis F, Samil RS. Effect of Norplant on mothers and infants in the postpartum period. Advances in contraception. 1986;2:371-80. [69] Baheiraei A, Ardsetani N, Ghazizadeh S. Effects of progestogen-only contraceptives on breast-feeding and infant growth. International journal of gynaecology and obstetrics. 2001;74:203-5. [70] Brownell EA, Fernandez ID, Howard CR, et al. A systematic review of early postpartum medroxyprogesterone receipt and early breastfeeding cessation: evaluating the methodological rigor of the evidence. Breastfeeding medicine. 2012;7:10-8. [71] Thulier D, Mercer J. Variables associated with breastfeeding duration. Journal of obstetric, gynecologic, and neonatal nursing. 2009;38:259-68. [72] World Health Organization. Medical Eligibility Criteria for Contraceptive Use. Geneva, Switzerland: WHO, 2015. ACCEPTED MANUSCRIPT

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Table 1 Table abbreviations ACOG: American College of Obstetrics and Gynecology BF: Breastfeeding CEBRE: Center for the Study of Reproductive Biology COC: Combined oral contraceptive Cu-IUD: Copper IUD DMPA: Depot medroxy-progesterone acetate ETG: Etonogestrel FAPESP: Fundação de Amparo à Pesquisa do Estado de São Paulo LNG: Levonorgestrel LNG-IUD: Levonorgestrel IUD NET: Norethisterone NET-EN: Norethisterone Enanthate NH: Non-hormonal POP: Progestogen-only pill PP: Postpartum PVR: Progesterone vaginal ring TL: Tubal ligation

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Author, Study Interventio Outcomes Results Strengths/weaknes Qualit Year, design, ns Follow-up ses y source of Location, duration gradin support Population g/ , Key questi on Kamal, 1969 Non- 6-10 weeks Breastfeeding Breastfeeding outcomes Strengths Level [31] randomize PP: performance --Avg age of supplementation 11.2 --Double blinded II-1 d clinical POP (0.5 mg (age of wks POP group, 15 wks placebo poor Not stated trial lynestrenol) supplementati (statistics not reported) Weaknesses on) --No statistical Key Newly Egypt IUD + Infant outcomes analysis reported for Questi identified placebo Infant growth --No relation between growth curve comparisons of on 1 N=120 (growth and method used interest postpartum 2 kinds of curve, percent --High, but not women COCs, 1 weight clearly reported, (data CIC (not increase) loss to follow-up available reported --Number of on 50) here) Follow-up 32 participants/group weeks not reported Allocation not reported Kamal, 1970 Non- 2 days PP: Breastfeeding Breastfeeding outcomes Strengths: Level [44] randomize performance --Lactation initiation earlier (3 vs. 5 --Included II-1 d clinical 10= Placebo (initiation of days) in POP than placebo group primiparas poor Not stated trial 10= POP lactation) (lynestrenol Infant outcomes Weaknesses: Key Egypt 500 mcg) Infant growth --Greatest weight increase in POP- --Nonrandomized Questi 10= COC (weight) exposed infants --Small sample size on 1 N=40 (results not --Short follow up primiparou presented) Follow-up 14 --No statistical s and 10= EE days comparisons multiparou (results not s women, presented) ages 20-37 Karim, 1971 Prospective 7days PP: Breastfeeding Breastfeeding outcomes Weaknesses: Level [37] cohort performance --No breastfeeding supplementation --Percent follow- up II-2, 68= NET- (supplementat reported up to six months in any of infants not poor Not stated Egypt EN (200 ion) groups reported mg) --No standardized Key N=331 51= DMPA Infant growth Infant outcomes techniques to Questi women (150 mg) and health --After 3rd month, infant weight measure health and on 1 after 100= ACCEPTED(weight, gain per MANUSCRIPT month higher in all POC specifics of health and 2 normal Nonhormon physical groups than in non-hormonal outcomes not delivery als exam, controls; weight gain in hormonal reported dentition, groups equivalent 42 days PP: mentality, --No physical, mental, or radiologic 57= NET- walking, differences in infants between EN radiographs) groups 55= DMPA Follow-up 18 months Guiloff et al., Cohort 1-2 days PP: Breastfeeding Breastfeeding outcomes Weaknesses: Level 1974 [38] performance Mean lactation duration (presented --Unclear if II-2 Chile 80= DMPA (mean as mean months with 95% CI) prospective or poor Population (250 mg IM duration of DMPA 1-2 days PP: 6.7 (5.2-8.7) retrospective council, N=696 q 6 months) lactation) Historical control: 4.8 (4.1-5.3) --Historical control Key Warner- multiparou 30 days PP: DMPA 30 days PP: 9.3 (6.0-10.0) --Historical Questi Lambert s women, 33= DMPA Follow-up 12 Chlormadione acetate 30 days PP: recollection of on 1 Research ages 16-40 54= months 7.5 months (4.7-9.7) duration of lactation Institute Chlormadio Quingestanol acetate 30 days PP:

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Historical ne acetate 4.2 (2.8-5.6) control was (250 mg IM IUD 30 days PP: 7.7 (6.8-8.9) composed q 3 months) Historical control: 5.3 (4.8-5.8) of the past 81= lactation Quingestano history of a l acetate subset of (300 mcg) women 81= IUD enrolled in Other the study participants who were used COCs still (results not breastfeedi reported ng at 30 here) days

Giner- RCT ≤14 hours Breastfeeding Breastfeeding outcomes Weaknesses: Level Velasquez,et PP: performance No difference between groups in --Methods poorly I, al., 1976 [34] Mexico (initiation) breastfeeding initiation (statistics described poor 12= NET not reported) --Small sample size Not stated N=20 (350 mcg) Infant growth --Follow-up and Key healthy 8= Placebo (weight) Infant outcomes exclusions not Questi women, No difference between groups in described on 1 ages 18-36 Follow-up 14 weight gain (average 493 g days placebo, 441 g NET, difference not significant) Zanartu et Prospective First 30 days Breastfeeding Breastfeeding outcomes Strengths: Level al., 1976 [32] cohort PP: performance 3rd month/6th month PP: 94% --High percentage II-2, N=133 (exclusive and /80% DMPA group fully with follow-up poor CEBRE, N=406 DMPA partial breastfeeding; fewer in non-DMPA (406/500 with at University of fully 30-90 days lactation group (p<0.001) least 18 months Key Chile breastfeedi PP: status at 3, 6, follow-up) Questi Medical ng women N= 206 12, 18 12th/18th month PP: 42%/10% still Weaknesses: on 1 School using DMPA 30- months) breastfeeding; fewer in non-DMPA --Unclear if non- DMPA 90 days PP group (p<0.001) DMPA users were Newly with at 91-180 days Follow-up 18 using other identified least 18 PP: months Of those who rec'd DMPA up to 90 hormonal or non- months N= 67 days PP, 35 % still breastfeeding at hormonal follow-up, DMPA 12 months (vs 64% who rec'd after contraceptives 173 90 days, no statistics) --No separate controls (DMPA 150 analysis by DMPA or 250-300 dose; minimal mg) analysis by timing; ACCEPTED MANUSCRIPTno statistical N=173 no analysis for indirect DMPA (& comparison either --Wide range in received timing of DMPA education administration about --No statistical breastfeedin analyses g or no intervention) Zanartu, et Non- 3rd to 10th Breastfeeding Breastfeeding outcomes Weaknesses: Level al.,1976 [46] randomize week PP: performance At 3 months: --Historical control II-1, d clinical (duration) 98% Chlormadione still --Wide variation in poor Ayerst trial 100= breastfeeding timing of Chlormadio Follow-up 18 76% NH still breastfeeding contraceptive Key Chile ne acetate- months At 6 months: initiation Questi 0.6 mg 80% (POP) and 56% (NH) still --Loss-to follow-up on 1 N=100 breastfeeding not reported healthy 173= NH At 12 months: --Statistical analyses

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women, (historical 42% (POP) and 0% (NH) still not reported for all ages 19-42 control; breastfeeding (p<0.001) outcomes of interest some inert IUD, some no method) Seth et al., Cohort 6 days PP: Breastfeeding Breastfeeding outcomes Weaknesses: Level 1977 [50] performance Still breastfeeding at 8 months --Small sample size II-2, India 23= Implant (continued 80% NH, 56.6% early, 66.6% --Methods poorly poor WHO (40 mg breastfeeding delayed, difference not significant described N=50 norethindron at 8 months, 3 month supplementation --Baseline Key healthy, e acetate) supplementati Early implant 56.4%, controls 40% characteristics not Questi women, (early) on rates) (p<.05), other times, NS described on 1 ages 20-40 Infant outcomes --Percent follow-up and 2 6 weeks PP: Infant growth No differences between groups in not reported 12= Implant (weight) weight (delayed) 15= NH Follow-up 11 (Condoms/g months el) Croxatto et Cohort 30-35 days Breastfeeding Breastfeeding outcomes Weaknesses: Level al., 1982 [56] PP: performance Fully breastfeeding: No sig --Little description II-2, Chile (fully, difference between groups at 3, 6 or of intercurrent fair Population 84= partially, or 9 months illnesses (or their Council and N= 439 Progesterone not Breastfeeding at 6 months assessment) Key Canadian healthy pellets (100 breastfeeding 51.2% progesterone 58.3% IUD --High rates of Questi International women mg) at follow-up Breastfeeding at 12 months discontinuation/ on 1 Development who did 130= visits) 10.7% progesterone 17.6% IUD termination from Research not hold Placebo (p<.05) study/ loss to Center jobs, ages injectable Infant growth Infant outcomes follow-up in all 18-35 125= Cu (weight) No differences in infant weight groups T200 IUD gain among groups (4515 g Infant health progesterone, 4633 placebo, 4801 (reports of IUD, not statistically significant) or intercurrent health (no statistics reported) illness)

Follow-up 12 months Dahlberg Retrospecti Some time Infant growth Infant outcomes Strengths: Level 1982 [33] ve cohort in 1st 9 (weight) Weight gain --Subgroup data II-2, months PP: No difference between groups at presented with poor No funding Thailand Infant health any time point in follow-up, different amounts of 210= Some (incidence of regardless of length of exposure DMPA exposure Key Newly N= 331 exposureACCEPTED to infectious Health MANUSCRIPT Weaknesses: Questi identified infants DMPA diseases No difference in average numbers --Data obtained on 1 born at 121= No leading to of infectious diseases reported per solely through and 2 Thai exposure to clinic visits) year between groups (although record review hospital DMPA subgroup who received DMPA at 2 --Statistical analysis between Follow-up up days PP had 75% higher incidence not reported 1977-1979 to 46 months than other groups, statistics not --Analytical reported) methods not clearly described --Timing of exposure to DMPA not clear --Wide variation in when DMPA was given postpartum Heikkila and RCT (with 32-56 days Breastfeeding Breastfeeding outcomes Weaknesses: Level Luukkainen, change to PP: performance Breastfeeding continuation 75 days --Allocation I, poor 1982 [35] protocol (duration, post-insertion: 79% in IUD group, concealment and partway 30= LNG time to 56% LNG 30 group, p<0.05 randomization Key

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Population through (10 mcg/d supplementati (results for LNG-10 not reported) sequence ill- Questi Council, trial) IUD) on Breastfeeding continuation 6 described on 1 US Agency 40= LNG months post-insertion: no --Mid-way through for Finland (30 mcg/d Infant growth difference among 3 groups trial, added lower- International IUD) (height, Median duration of breastfeeding dose IUD and Development N=110 40= Copper weight) 141days LNG-10; 154 days LNG- changed allocation , Ford women IUD 30; scheme Foundation Infant 197 days Cu-IUD --Copper IUD group development (difference significant) younger and less (time of Mean duration: no significant parous walking, tooth difference --Illnesses not eruption) Supplementation: no significant recorded or assessed difference systematically Infant health Infant outcomes (infectious Growth and development diseases) No differences in height, weight, time of walking, tooth eruption Follow-up 12 Health months No differences between groups in respiratory/middle ear infections West et al., Cohort Up to 8 Breastfeeding Breastfeeding outcomes: Weaknesses Level 1983 [45] weeks performance At 3 months: 62% POP, 62% NH --Follow-up by II-2, Scotland postpartum: (duration, still breastfeeding postal survey poor Medical 84= supplementati At 5 months: 51% POP, 53% NH --No statistical Research N=227 Norethistero on) still breastfeeding (statistics not analysis Key Council healthy ne 0.35 mg reported) --Unclear when Questi women, (76% by methods were on 1 fully week 4) initiated breastfeedi 29= ng (data Combined available oral on 203) contraceptiv e 89= Nonhormon al

Diaz et al., Cohort 30 days PP: Breastfeeding Breastfeeding outcomes: Strengths Level 1984 [55] performance No difference in breastfeeding --Clear description II-2, Chile 84= (exclusivity at status at 6 months between those of methods and poor Instituto Progesterone 6 months and initiated at 30 or 60 days analysis Bioquinico N=653 pellets continuation) postpartum and their contemporary Weaknesses: Key Beta, WHO, healthy (100mg) controls; however those who --Women lost to Questi International women 125= CuACCEPTED Infant growth initiated MANUSCRIPT at day 60 were more likely follow-up or on 1 Development after T200 IUD (weight gain to supplement at month 6 than discontinuing their and 2 Research normal 130= at 6 months) those initiating at day 30 (68% method not reported Centre of pregnancy, Placebo and health exclusive vs 53% exclusive, --Statistical analyses Canada, 18-35 injection (how assessed statistics not reported) not presented for Population years not defined) Infant outcomes outcomes of interest Council 60 days PP: Weight gain --No control for 193= Follow-up 6 No difference between groups confounding Progesterone months Health --Unclear how pellets No negative effects of progesterone infant health was 121= Cu on infant health assessed T200 IUD Jimenez et Retrospecti 2nd month Breastfeeding Breastfeeding outcomes: Weaknesses: Level al., 1984 [39] ve cohort - PP: performance Median lactation duration: 21 --Primary study not II-2, follow-up (reported months DMPA vs. 13 months NH published poor Upjohn to 128= DMPA duration of (p<0.05) --Some outcomes unpublishe (150mg q 3 lactation) Infant outcomes relied on Key d primary months) Growth retrospective self- Questi study 142= Infant growth No difference between groups in report on 1

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Nonhormon (weight, arm height; weight different between --Groups dissimilar Chile al circumference groups but no difference when (mothers in DMPA , head adjusted for confounders group older, of N=270 circumference Health higher parity Women ) 1 death in control group and their (accidental), 0 in DMPA group children Infant health Development exposed to (respiratory No differences between groups in contracepti infections, psychomotor development, on during diarrheal milestones, health problems, infant lactation, disease, height or physical exam 3-6 years hospital prior admissions, mortality)

Infant development (standardized physical exam, interview, record review, and psychomotor scale) Tankeyoon, Prospective 6 weeks PP Breastfeeding Breastfeeding outcomes: Strengths: Level et al., 1984 cohort with (+/- 3 days): performance No differences in complementary --Multi-cultural and II-2, [58] nested (use of feeding or discontinuation of multi-centre with poor RCT 59= DMPA complementar breastfeeding between groups nested double WHO 111= y food, Infant outcomes blinded RCT Key Hungary Nonhormon discontinuatio No differences in mean weight or Weaknesses: Questi Thailand al (barriers, n due to rate of growth between --No power on 1 sterilization, perceived contraceptive groups calculation N=341 IUD) inadequate --No details of experience Pill-users milk supply) method d breast- (randomized switching/discontin feeding ): Infant growth uation women, 85= (weight, --No attempt to ages 20-35, POP length, arm control analysis for parity 2-4, 86= circumference confounders after COC (results ) healthy not reported term here) Follow-up 24 delivery ACCEPTEDweeks MANUSCRIPT Abdulla et Cohort 30-39 days Infant health Infant outcomes Weaknesses: Level al., 1985 [67] Egypt PP: (occurrence of No infants had significant illnesses --Selection and II-2, significant assessment poor Rockefeller N=20 10= LNG illnesses; No significant differences between procedures not Foundation healthy implant serum IgA, groups in infant serum specified Key women 10= IgG, IgM) immunoglobulins --Small sample size Questi after Barriers/ with no power on 1 singleton, nothing Follow-up 6 calculations term months --Percent follow-up delivery not reported (mean age 29) Shaaban et Cohort 30-42 days Breastfeeding Breastfeeding outcomes Weaknesses: Level al., 1985 [51] PP: performance No differences in number --No adjustment of II-2, Egypt (frequency, breastfeeding episodes/day or for possible poor Rockefeller 50= LNG supplementati number supplemental feeds confounders Foundation N=150 implant on) Infant outcomes --Differences at Key healthy, 50= Cu Growth baseline between Questi

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multiparou T380 IUD Infant growth Slower weight gain in Norplant groups on 1 s, breast- 50= (weight, group to 3 months (but >50%ile); --Unclear how feeding- Barriers/not length) no differences at 4-6 months; infant morbidity experience hing slower length increase in Norplant was measured d women Infant health group from months 3-6 (but (mean age (illness) >50%ile) 29) after Health normal, Follow-up 6 No differences in infant morbidity term months delivery Shikary et Cohort 4 weeks PP: Infant health Infant outcomes Weaknesses: Level al., 1986 [66] (daily 4-hour No significant differences in mean --Small sample size II-2, India 9 = POP urine samples FSH, LH and testosterone area with no power fair WHO, (LNG 30 tested for under the curve between the groups calculations Population N=29 mcg) FSH, LH, --Short follow-up Key Council women 10=LNG testosterone) Questi after term implant on 1 delivery of 10= No Follow-up 15 male method weeks infants, ages 20-35 Zacharias et Prospective 3 to 6 weeks Breastfeeding Breastfeeding outcomes Strengths: Level al., 1986 [40] cohort PP: performance Mean duration: --Survival analysis II-2, (duration) 17 months LAM techniques poor UpJohn, Chile 143= LAM 21 months IUD Weaknesses: Ayerst 109= Cu T Infant growth 30 DMPA --Measures for Key N=665 IUD and 22 POP (p<.03 for pairwise growth and Questi women, (presumably development comparison with DMPA) development not on 1 after term non- (not specified) Infant outcomes provided deliveries hormonal) Growth/development --Statistical 228= DMPA Follow-up of No adverse effects of progestogens comparisons not 185= POP children to a (not specified) performed (0.6 mg median age of --No attempt to clogestone 4.5 years control analysis for acetate) confounders --Baseline differences between groups --Infants with "signs of inadequate nutrition" discontinued from study and not ACCEPTED MANUSCRIPTreported on Affandi et Cohort 4-6 weeks Infant growth Infant outcomes Weaknesses: Level al., 1986 [68] PP: (weight, Infants in LNG group gained --Limited II-2, Indonesia length) significantly more weight than the description of poor Population 60= LNG IUD group. No differences in statistical analysis Council N= 120 implant Follow-up 6 length between groups. (Statistical and no attempt to Key women months comparisons, p values not control for Questi after term, 60= Copper provided) confounders on 1 healthy IUD --Baseline delivery, differences between planning to groups breastfeed --Percent follow-up ≥6 months not reported McCann et Cohort 1 week PP: Breastfeeding Breastfeeding outcomes Strength: Level al., 1989 [48] performance Median age of initiation of --Survival analysis II-2, Argentina 250= LNG (continuation, supplementation 5.4 for LNG vs. performed poor USAID, (30 mcg) supplementati 4.6 months for NH users (p<.05); Weaknesses: Family N=500 on) also significantly different on --Only enrolled Key Health healthy 250= NH survival analysis older, multiparous Questi

32 ACCEPTED MANUSCRIPT

International, multiparou methods Infant growth NH users three times more likely to women on 1 Wyeth s women, (54% IUD) (weight, discontinue breastfeeding during --High loss to Pharmaceuti after term length, head study period than LNG users (22 vs follow-up (55% at 9 cals delivery circumference 7, p value not reported) months) with prior , growth Infant outcomes --Statistical analysis breast- velocity) No differences between groups in not reported on all feeding infant growth on any measure outcomes of interest experience, Follow-up 9 --Infant health ages 30-35 months outcomes collected but not reported

Moggia et Cohort 1 week PP: Breastfeeding Breastfeeding outcomes: Weaknesses: Level al., 1991 [49] 250= performance More frequent supplementary --No primiparous II-2, Argentina Norgestrel (supplementat feeding in NH group at month 2 women fair Family 75 mcg ion) and 3 (p<.05), otherwise no --Baseline Health N=500 difference; no difference in number differences between Key International healthy 250= NH Infant growth of women supplementing at any groups (birthweight Questi women methods (weight, time lower in POP on 1 with (75% IUD) length, head Infant outcomes group) experience circumference Growth --High loss to breast- ) No difference in infant growth follow-up (15% feeding, Health POC, 13% NH after term Infant health No differences between groups in LTFU over 6 delivery, (hospitalizatio hospitalizations. Minor illnesses months) ages 18-35 ns, minor more common in NH group (91 (483 in illnesses, NH, 60 POC, p<.01); 3 infant final mortality) deaths in NH group, 0 in POP analysis) group Follow-up 6 months Shaaban, Cohort 5th to 7th Breastfeeding Breastfeeding outcomes Weaknesses: Level 1991 [41] week performance No differences in timing or type of --Methodology II-2, Egypt postpartum: (age of supplementation poorly-described poor WHO, 120= LNG supplementati IUD users weaned earliest, --Baseline Population Phase 1: implant on, age of followed by LNG implant and characteristics not Key Council, 360 120= NET- weaning) NET-EN (statistics not reported) described Questi Rockefeller healthy EN Infant outcomes --Statistical analyses on 1 Foundation women and injectable Infant growth Growth not reported for their 120= IUD (weight, arm No differences in infant growth outcomes of interest infants circumference Development --Percent lost to , skinfold No difference in attainment of follow-up not Phase 2: thickness) milestones reported PVR and ACCEPTED MANUSCRIPT Cu-IUD, Infant results not development discussed (attainment of here milestones)

Follow-up 12 months Pardthaisong Cohort During Infant growth Infant outcomes Strengths: Level , 1992 [30] lactation (weight, Growth --Clear description II-2, Thailand (any time, height) Relative risk for score below -2Z of methodology poor Ford 77% on growth chart (no exposure as --Appropriate Foundation N=3231 initiated Length of reference): analytical methods Key WHO infants between follow-up for 1.1 (0.9-1.2) lactational exposure Weaknesses: Questi FHI with months 1-3) lactationally- only (no prenatal exposure); 1.2 --Baseline on 1 varying exposed (1.0-1.3, p<0.05) any lactational differences noted levels of 857= DMPA infants exposure (including some with between DMPA pre-natal only during unclear prenatal exposure); RR 1.1 (0.9- users and non-users and lactation 1.4) for any lactational exposure --Unclear length of

33 ACCEPTED MANUSCRIPT

lactational (not when adjusted for potential follow-up DMPA pregnancy) confounders --Timing and exposure/ 1215= amount of exposure non- DMPA to DMPA unclear exposure during --Unexposed may lactation, have been using some also other hormonal during methods pregnancy 1167= No DMPA WHO, 1994 Cohort 6-8 weeks Breastfeeding Breastfeeding outcomes: Strengths: Level [59, 60] PP: performance Frequency and duration of --Large cohort, II-2, Egypt, (frequency, breastfeeding differed between multi-cultural and fair WHO Iran, 475= POP duration sites, but not between contraceptive multi-centre Thailand, (LNG or exclusive groups within a site --Standardized Key Kenya, lynestrenol) breastfeeding) Infant outcomes assessment of Questi Chile, 541= DMPA Growth development on 1 Hungary 121= NET- Infant growth One site had larger wt increase in --Confounders EN (weight, arm NET-EN grp (6, 12 mo) and assessed and N=2466 453= LNG circumference DMPA grp (3 mo) compared to NH controlled for in married implant , skinfold grp analysis women, 876= NH thickness) Smaller increase in arm Weaknesses: after term (IUD, circumference at two sites for POP --Large differences delivery barriers, Infant health group (3 mo and 3,12 mo) between sites for and their sterilization) (mortality) Development breastfeeding infants 247 comparisons; 32 showed performance and Infant significant differences: in 20, infant outcomes development infants in progesterone-only grps --Percent lost to (age passed passed tests at earlier ages, and in follow-up not standard 12, they passed at later ages. reported developmenta Mortality l test) No significant differences within sites by method Follow-up 12 months Abdel- Cohort 2nd PP Breastfeeding Breastfeeding outcomes Strengths: Level Aleem et al., month: performance No significant differences between --Assessment of II-2, 1996 [52] Egypt (frequency of groups in breastfeeding frequency, infants was blinded fair 120= breastfeeding, continuation or exclusivity to contraceptive South-to- N=242 Nomegestrol % group Key South healthy, implant breastfeeding Infant outcomes --Power calculations Questi Cooperation exclusively 120= Cu- at all and Growth presented on 1 in breastfeedi IUD ACCEPTEDexclusively at No differences MANUSCRIPT in infant growth Weaknesses: Reproductive ng women different time Health --Underpowered to Health and their periods) No significant differences in health. look at infant health term 7 infants died: 6 in implant group outcomes infants Infant growth (4 gastroenteritis, 1 seizures, 1 --Percent follow-up (mean age (weight, arm pneumonia), 1 (gastroenteritis) in not reported 26) circumference IUD group (not significant, p>.05) --Baseline , skinfold differences between thickness) groups

Infant health (frequency of diarrhea, fever, cough, and mortality)

Follow-up 12 months Hannon et Cohort At the time Breastfeeding Breastfeeding outcomes Strengths: Level

34 ACCEPTED MANUSCRIPT

al., 1997 [42] of hospital performance No difference in duration of Sample selection/ II-2, USA discharge: (breastfeeding lactation (median 10.14 weeks for methods clearly poor National continuation DMPA vs., 6.57 weeks in described Institutes of N= 103 45= DMPA and nonhormonal users, p=.19) Power calculations Key Health and women 150 mg exclusivity) performed Questi Thomas consecutiv No difference in time to Weaknesses: on 1 Wilson e, term 52= NH Follow-up 16 supplementation with formula -Limited duration of Sanitorium deliveries (unspecified weeks follow-up with ability ) -No infant outcomes to follow- -Baseline up by differences between telephone groups (DMPA younger, unmarried) Diaz et al., Cohort 57 +/- 3 Breastfeeding Breastfeeding outcomes Weaknesses: Level 1997 [61] with days PP: performance No difference between groups for Historical control II-2, historical (duration of mean and total duration of fair WHO, control 117= POP any and breastfeeding Population (lynestrenol) exclusive Infant outcomes Key council, Chile 187= breastfeeding) No differences in growth between Questi CONRAD Progesterone groups on 1 N=662 vaginal ring Infant growth cohabitatin 120= LNG (weight) g parous implant (1-3) 122= Follow-up 6 women Copper IUD months after term 236= NH delivery, (LAM) ages 18-38 Lawrie et al., RCT <48 hours Breastfeeding Breastfeeding outcomes Strengths: Level 1998 [36] PP: performance No difference between groups in --Clear description I, South (duration of continuation rates at 6 or 12 weeks of methods fair Schering Africa 85= NET- any --Enrolled women Ltd, Iris EN breastfeeding, regardless of Key Ellen Hodges N=166 84= placebo exclusive or past/current Questi Trust of the immediate partial) breastfeeding on 1 University of postpartum All women experience the women additionally Maternal Weaknesses: Witwatersran >19 years used a NH depression --Small sample size d, South method (not reported --Breastfeeding African here) outcomes were Medical secondary Research Council, South ACCEPTED MANUSCRIPT African Institute for Medical Research Coutinho et Prospective 6 weeks PP: Breastfeeding Breastfeeding outcomes Strengths: Level al., 1999 [65] cohort performance Higher rates in implant group (95- --Power calculation II-2, 66=Elcometr (any 76%) vs. IUD (84-57%) at 3, 6 mos performed fair Rockefeller Brazil ine implant breastfeeding (p<.05), no differences at 9, 12 mos --Standardized Foundation 69=Cu-IUD at follow-up Infant outcomes outcomes used and Key N=135 time points) Growth described Questi women, No differences between groups on 1 18-35 after Infant growth Development Weaknesses: term health (weight, arm No differences in age met --No control for delivery circumference developmental milestones potential planning to , skin-fold confounders breastfeed thickness) for 6 mo and their Infant

35 ACCEPTED MANUSCRIPT

infants development (age meeting standard milestones, using developmenta l tests)

Follow-up 12 months Diaz et al, Prospective 57 +/- 3 Breastfeeding Breastfeeding outcomes Strengths: Level 1999 [29] cohort days PP performance Fully breastfeeding month 6: 93% --Clearly described II-2, (any or LNG, 86% IUD (no difference); methods fair Population Chile 29= LNG exclusive Fully breastfeeding month 12: 4% Weaknesses: Council implant breastfeeding LNG, 10% IUD (no difference) -- Key N= 108 51=Cu-IUD up to 6 mos, Duration of lactation 15 mos LNG, Breastfeeding/Infant Questi Newly breastfeedi 28=PVR no milk 14 mos IUD (no difference) outcomes were on 1 identified ng women (results not supplementati Infant outcomes secondary planning to reported on at 12 mos) Growth --Length of follow- continue to here) No difference between LNG and up unclear breastfeed Infant growth Cu-IUD groups at months 1, 6, or --Loss to follow-up (weight) 12 not specified

Follow-up minimum 12 months Bjarnadóttir Cohort 28-56 days Breastfeeding Breastfeeding outcomes: Strengths: Level et al., 2001 PP: performance No difference in BF continuation at --Power calculations II-2, [47] Iceland (any cycle 4 (5-6 mos PP), but at end provided fair 42= breastfeeding cycle 7 (8 to 9 mos PP), 78% in --Clearly described Organon N=83 Desogestrel- desogestrel compared with 59% in methods Key multiparou 75mg Infant growth IUD group were still breastfeeding --Long-term follow- Questi s women 41= Cu375 (length, (statistics not reported) up of exposed on 1 with prior IUD weight, head Infant outcomes infants experience circumference Growth Weaknesses: breast- ) No differences --Wide variation in feeding, Health timing of after term Infant health Temporary breast enlargement in 2 contraceptive delivery, (intercurrent infants, increased sweating in 1 initiation ages 18-40 illness, infant in desogestrel group; no hospitalizatio occurrences in IUD group. No ns) other differences in health

ACCEPTEDFollow-up 2.5 MANUSCRIPT years Baheiraei et Prospective 6 weeks PP: Infant growth Infant outcomes Weaknesses: Level al., 2001 [69] cohort (weight, Growth --Contraceptive II-2, 51= length, head No differences in weight or length use/switching or poor Not stated Iran Progestogen circumference at any time; mean head formulations are not -only ) circumference change 1.42 cm stated Key N=140 (DMPA; (progestogen-only) vs. 1.19 (NH) at --Separate estimates Questi women, POP) Follow-up 26 10-13 weeks (p<0.05). No for different on 1 after 89= NH weeks differences at other time points methods not healthy (IUD, presented term condom, --Percent lost to delivery sterilization) follow-up not reported

Massai et al., Prospective 55-60 days Lactation Breastfeeding outcomes Strengths: Level 2001 [64] cohort PP: performance No difference in breastfeeding --Describes II-2, episodes per day or length of contraceptive fair US Agency Chile 100= Infant growth breastfeeding (273 days implant vs. switching and

36 ACCEPTED MANUSCRIPT

for Nesterone (weight gain) 263 IUD) discontinuation Key International N=200 implant Infant outcomes Weaknesses: Questi Development cohabitatin 100= Follow-up 1 Growth --High on 1 / UN g women, Copper IUD year No differences discontinuation Population after term (17% in NES group Fund delivery; and 22% in IUD age 18-38 group) Halderman Cohort Prior to Breastfeeding Breastfeeding outcomes Weaknesses: Level and Nelson discharge performance No difference in breastfeeding --Short follow-up II-2, 2002 [43] USA from (initiation, initiation --No infant poor hospital: continuation, Any breastfeeding at 4 weeks: outcomes National N=319 supplementati 83.1% NH, 76.7% POC (p= .022 --Aggregate data for Key Institutes of women, 102= DMPA on) Any breastfeeding at 2, 6 weeks: methods other than Questi Health primarily 79= LNG No difference DMPA on 1 Hispanic, implant or Follow-up 6 Exclusivity, supplementation: No --Differences ages 16-49 POP weeks difference at any time between groups at 138= NH baseline (DMPA younger, less parous, less experienced with breastfeeding) Schiappacass Prospective 55 +/- 3 Breastfeeding Breastfeeding outcomes Strengths Level e, 2002 [63] cohort days PP: performance No differences in mean and total --Information on II-2, from 2 (duration) duration; at 12th month, LNG contraceptive fair (Some data previous 220= LNG group had fewer fully breastfeeding switching and originally studies implant Infant growth Infant outcomes discontinuation Key reported in 222= (weight, Growth --Long-term follow Questi Diaz 1985 Chile Copper IUD height) and No differences up on 1 [62] and as health Health --Adjusted for part of WHO N=442 Higher incidence of respiratory potential 1994 [59, cohabitatin Follow-up 6 infection (colds, bronchitis; 44.3 vs. confounders 60]) g parous years 37.7/100 infant months, p<.0001) --Power calculation (1-3) and skin conditions (diaper, for infant growth WHO women allergic and bacterial dermatitis, --Blinded after term prurigo) in LNG group. Higher assessment of health delivery, incidence of urogenital disease (0.4 --Verification with ages 18-35 vs. 0.2) and psychomotor hospital records impairment (23 vs. 12) in IUD Weaknesses: group. --High loss to f/u Hospitalizations greater in LNG over time (14% of group (1% vs. 0.4%, p<.05) among implant group and breastfeeding infants; but higher in 21% of IUD group) IUD group overall (1.7% vs. 0.6%) --No power ACCEPTEDRates forMANUSCRIPT other illnesses similar; 1 calculations for death in Norplant group at 7 health outcomes months for acute diarrhea and --Confounders for septicemia skin disease not assessed --Data from infants from different time periods --Pollution levels in Santiago may limit generalizability Shaamash et RCT 6-8 weeks Breastfeeding Breastfeeding outcomes Strengths: Level al., 2005 [57] PP: performance No differences in breastfeeding --Randomized I, Egypt (duration, # duration (149 vs. 160 days for --Adequate fair Schering 163= LNG- episodes/day, LNG-IUD vs. Cu-IUD) or allocation N=320 IUD exclusivity) exclusivity concealment Key women 157= Infant outcomes --Sample size Questi after term Copper IUD Infant growth Growth calculations on 1 delivery (weight, No differences --Standardized

37 ACCEPTED MANUSCRIPT

length, skin- Development infant development fold No differences tests thickness) and Weaknesses: development --Enrolment and (age passing exclusion criteria standard not stated developmenta --Intent-to-treat l tests) analysis and percent loss-to-follow-up Follow-up 1 not reported year --Infant health outcomes collected but not reported Taneepanich Prospective 28-56 days Breastfeeding Breastfeeding outcomes Strengths: Level skul et al., cohort PP: performance Mean duration of breastfeeding: --Long-term follow- II-2, 2006 [54] (duration) 421 d (Implant) vs. 423 d (IUD), up of infants to fair Reinprayoon Thailand 42= NS childhood et al., 2000 Etonogestrel Infant/ child Infant outcomes Weaknesses: Key [53] N=80 implant growth Growth --No information on Questi women 38= Copper (length, No differences between contraceptive on 1 Organon after term IUD weight) and contraceptive groups for length, switching or deliveries, development weight, or head circumference discontinuation ages 18-40 Health --Methods to assess years Infant health (no statistical comparisons psychomotor (intercurrent reported) development not illness) 10/42 implant infants reported stated skin/appendages disorders vs. 6/38 --Infant illness by Follow-up 3 IUD infants; 17/42 implant infants maternal report only years reported respiratory system --Response rate for disorders vs. 10/38 IUD infants; study inclusion not 3/42 implant infants reported GI stated disorders vs. 5/38 IUD infants; 2/42 --Sample size implant infants reported chosen based on neonatal/infancy disorders vs. 2/38 WHO IUD infants recommendations No differences reported in adverse for toxicology, not events or psychomotor for breastfeeding or development ( >60% infants in both health outcomes groups had resp. disorders, and >30% in both groups had skin disorders) Brito et al., RCT (open 24-48 hours Breastfeeding Breastfeeding outcomes Strengths: Level 2009 [21] label) following performance No difference in exclusive --Randomization I, fair delivery:ACCEPTED (duration of breastfeeding MANUSCRIPT between groups at 6 methods appropriate FAPESP Brazil 20= exclusive weeks or 12 weeks: (6 wks 95% --Allocation Key CNPq Etonorgestre breastfeeding) ETG, 85% DMPA; 12 wks 85% concealment Questi N= 40 l implant ETG, 75% DMPA) appropriate on 2 Newly women (ETG) Infant growth Infant outcomes --Methods clearly identified with BMI (weight) Growth described < 30, ages 6 weeks PP: No differences at 6 or 12 wks Weaknesses: 18-35 20=150 mg Maternal --Short follow-up years DMPA health --Small sample size (outcomes not with no power reported here) calculations

Follow-up 12 weeks Chen et al, RCT (open Immediate Breastfeeding Breastfeeding outcomes: Strengths: Level 2011 [23] label) post- performance Initiation --Randomization I, fair placental: (initiation, 32/50 (post-placental); 27/46 methods appropriate Anonymous United 50= LNG- duration) (delayed) p=.59 --Allocation Key foundation States IUD Duration concealment Questi

38 ACCEPTED MANUSCRIPT

Follow-up 6 5 wks (post-placental); 8.5 wks appropriate on 2 Newly N=96 6-8 weeks months (delayed) p=0.06 --Methods clearly identified women PP Any breastfeeding at 6 months described interested (delayed): 3/50 post-placental, 11/46 delayed Weaknesses in 46=LNG- p=0.02 --6 members of postpartum IUD Exclusive breastfeeding at 6 delayed group got IUD months interim DMPA prior 1/50 post-placental, 6/46 delayed to LNG-IUD p=0.05 placement --Short follow-up --Very low rates breastfeeding in both groups may limit generalizability Gurtcheff et RCT (open Insertion at Breastfeeding Breastfeeding outcomes Strengths: Level al., 2011 [24] label) 1-3 days PP: performance Mean time to lactogenesis stage II --Randomization I, Fair (time to 64 hrs (early); 65 hrs (standard) methods appropriate National United 35= ETG lactogenesis Lactation failure --Allocation Key Center for States implant stage II, 1/34 early, 0/35 standard, risk concealment Questi Research (early) lactation difference 0.03 (early vs standard) appropriate on 2 Resources N=69 4-8 weeks failure, Formula supplementation --Methods clearly peripartum PP formula No difference between groups at 2 described Newly women 34= ETG supplementati wks, 4-8 wks, 3 mos, or 6 mos --Power calculations identified desiring implant on) presented ETG (standard) Weaknesses: implant Follow-up 6 --32% (11/34) months women randomized to standard insertion did not receive implant; as a result analyses are per- protocol Costa et al., Cohort 6 weeks PP: Breastfeeding Breastfeeding outcomes Strengths: Level 2012 [27] performance Exclusive: --Included II-2, Brazil 28=POCs (exclusive and Mean duration 137 days NH, 113 primiparas fair FAPESP (DMPA, total days POC (p=0.143) --Clear description N=82 POP, LNG- breastfeeding Total (any breastfeeding): of methods Key Newly postpartum IUD) duration) 183 days NH, 183 days POC Weaknesses: Questi identified women 54=NH (p=0.383) --No separate on 1 (Barrier, Follow-up 6 analysis of different LAM, TL, months POCs Cu-IUD) --Breastfeeding ACCEPTED MANUSCRIPToutcomes were secondary outcomes

39 ACCEPTED MANUSCRIPT

Espey et al., RCT 2 weeks PP: Breastfeeding Breastfeeding outcomes: Strengths: Level 2012 [22] (double performance No difference in continuation at 8 --Included I, fair blinded) 64 =COC (breastfeeding weeks (64% COC, 63.5% POP) or primiparas (0.35 mg continuation over six months (survival analysis); --Randomization Key ACOG US ethinyl at 8 wks, 6 no difference in supplementation at methods appropriate Questi contraceptive estradiol, 1 months; 8 weeks (percents not reported) --Allocation on 1 grant and N=127 mg supplementati concealment University of women norethindron on at 8 weeks) Infant outcomes appropriate New Mexico aged 15- e) Growth --Methods clearly 45, 65 =POP Infant growth No difference through 8 weeks described Newly planning to (norethindro (weight, --Double-blinded identified BF and use ne 0.35 mg length, head --Minimal method oral norethindron circumference switching contracepti e) ) --Loss to follow-up ves similar between Follow-up 6 groups months for Weaknesses breastfeeding --Small sample size outcomes, 2 --Short follow-up months for for infant outcomes infant outcomes Matias et al, Cohort By 72 h Breastfeeding Breastfeeding outcomes: Strengths: Level 2012 [17] By 1 month performance Women initiating DMPA after 72H --Clearly described II-2, Peru PP: (exclusive PP had higher odds of exclusive methodology fair NIH, Fogarty 19= DMPA breastfeeding breastfeeding at 3 mos than those --Appropriate International n=117 By 3 months at 3 months who initiated before 72h or those analytic methods Key Center, postpartum PP: and 6 months who did not initiate at all (adj OR Weaknesses: Questi NICHD, UC women 41= DMPA postpartum) 6.1, CI 1.7-21.4 - unpublished data) --Unclear when on 1 Davis planning to By 6 months within the time and 2 exclusively PP: Follow-up 6 DMPA initiation by 1 month PP: frame method was Newly breastfeed 45= DMPA months Mo DMPA Non- p started identified s users users --Unclear what PP exclusivel exclusivel methods, if any, y BF (%) y BF (%) non-were used by 3 79 71 N S non-DMPA users 6 44 33 N S

DMPA initiation by 3 months PP: Mos DMPA Non-users p PP users exclusively exclusively BF (%) ACCEPTED MANUSCRIPTBF (%) 3 85 65 Sig 6 38 33 NS

DMPA initiation by 6 months PP: Mos DMPA Non-users p PP users exclusively exclusively BF (%) BF (%) 3 78 68 NS 6 29 40 NS

Multivariate model: DMPA use by 3 months associated with adj RR of exclusive BF at 3 months 1.35 (1.1- 1.66) Brownell et Cohort 1st 5 days Breastfeeding Breastfeeding outcomes: Strengths Level al 2013 [26] (retrospecti PP: performance Median duration --Power analysis II-2, ve) (continuation) DMPA 30 days, no DMPA 41 days done (but post-hoc) fair No funding 68= DMPA (HR 1.14, non-significant) --DMPA exposure

40 ACCEPTED MANUSCRIPT

US 115= No Continuation at 2 week verified through Key Newly DMPA No difference between groups on hospital records Questi identified N=183 survival curve (p=0.24) --Survival analysis on 1 women Continuation at 6 weeks methodology who No difference between groups (HR Weaknesses initiated 1.22, p=0.42) --Few women in BF either group Insufficient events after 6 weeks to continued BF after 6 draw conclusions weeks --Unclear if women in non-DMPA group were exposed after 5 days to either DMPA or to other contraceptives Bahamondes Prospective Day 42 PP: Breastfeeding Breastfeeding outcomes: Strengths: Level et al 2013 cohort 10= COC performance No significant difference among --Frequent data II-2, [25] 10= ETG (duration, # groups in continued breastfeeding collection poor Brazil implant episodes/day) at 6 months (data not shown) --Clearly described FAPESP, 10= LNG- Significantly more breastfeeding methodology Key Conselho N= 40 IUD Infant growth episodes day 4 of study in ETG vs Weaknesses: Questi Nacional de multiparou 10= Cu-IUD (weight, Cu-IUD; otherwise no difference --Short follow-up on 1 Pesquisa s women height, tibial (data not shown) (other than BF with prior length) Infant outcomes duration measure) Newly BF No significant difference in weight --Small sample size identified experience Infant salivary or height change from day 42-63; with no power deuterium significant difference in increase in calculations (data not tibial length (0.6 cm vs 1.3 cm) in reported presented) ETG vs Cu-IUD, otherwise no significant difference Follow-up 3 weeks (growth outcomes); 6 months (breastfeeding outcomes) Singhal et al, Prospective Day 3-10 Breastfeeding Breastfeeding outcomes: Strengths Level 2014 [28] cohort PP: performance No significant difference between --Included II-2, 150= DMPA (duration, # groups in frequency/continued primiparas poor India (only 100 episodes/day) breastfeeding at 6 weeks or 3 or 6 --DMPA exposure Not stated with full months verified Key N= 250 follow-up) Infant growth Infant outcomes Questi women 100= NHACCEPTED (weight, No significant MANUSCRIPT differences between Weaknesses on 1 Newly who length) groups in weight or length gain at --High LTFU and identified initiated any time point no information BF Infant health No significant differences between provided on DMPA (episodes of groups in illnesses users who failed to diarrhea, URI, provide 6 months fever, rash) follow-up (50/150) --Comparison group Follow-up 6 poorly described; months unclear which non- hormonal methods were used --No power calculations reported

41