Ectopic Pregnancy with Use of Progestin-Only Injectables

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Contraception 92 (2015) 514–522

Review article Ectopic pregnancy with use of progestin-only injectables and contraceptive implants: a systematic review☆,☆☆ ⁎ Rebecca Callahan , Irina Yacobson, Vera Halpern, Kavita Nanda FHI 360; Durham NC 27701 USA Received 21 November 2014; revised 25 August 2015; accepted 29 August 2015

Abstract

Background: 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. Objective: To describe ectopic pregnancy risk associated with use of implants and progestin-only injectable contraceptives through a systematic review of published studies. Data Sources: 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. Study Selection and Extraction: 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. Results: 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. Conclusion: 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. © 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Keywords: Contraception; Ectopic pregnancy; Progestins; Implants; Injectables

1. Introduction data on ectopic pregnancy are sparse; however, case fatality is considerably higher [6–9]. 1.1. Rationale Risk factors for ectopic pregnancy include, but are not Ectopic pregnancies are an important cause of maternal limited to, age, history of pelvic inflammatory disease (PID), morbidity and mortality worldwide. In the United States and smoking, infertility, in vitro fertilization and prior ectopic other developed countries, an estimated 1–2% of all pregnancy [3,10,11]. An estimated half of ectopic pregnan- pregnancies are ectopic [1–3], accounting for 3–5% of cies appear to be caused by delay in transport of a fertilized pregnancy-related deaths [4,5]. In less developed regions, ovum to the uterus due to the damage of the fallopian tubes caused by infection or surgery [12]. It has also been hypothesized that low levels of progestin seen with some ☆ Funding: This review was supported by the Bill & Melinda Gates progestin-only contraceptive methods, while failing to Foundation with additional support from the US Agency for International inhibit ovulation, may impact tubal motility and increase Development under Award No. AID-GPO-A-00-10-00060. the risk of a pregnancy being ectopic [13]. The labels for the ☆☆ Conflicts of Interest: the authors declare no conflicts of interest. ⁎ Corresponding author at: FHI 360, 359 Blackwell Street, Durham, levonorgestrel (LNG)-containing contraceptive implant NC 27701. Tel.: +1-919-544-7040. Jadelle® and the etonogestrel (ENG)-containing implant E-mail address: [email protected] (R. Callahan). Implanon® (and its successor, Nexplanon®) warn that

http://dx.doi.org/10.1016/j.contraception.2015.08.016 0010-7824/© 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). R. Callahan et al. / Contraception 92 (2015) 514–522 515 although the methods lower a woman's absolute risk of PubMed), POPLINE, LILACS and EMBASE published through ectopic pregnancy because they lower the probability of May2015(searchtermslistedinAppendixA).Wealsohand pregnancy, in the case of contraceptive failure, the implants searched reference lists and review articles for relevant studies. may be associated with an increase in the relative proportion Two authors (RC, IY) independently reviewed the search of pregnancies that are ectopic [14,15]. results for studies potentially eligible for inclusion. Articles Women who experience method failure after female tubal considered potentially relevant and published in a language sterilization or while using hormonal or nonhormonal intrauter- other than English were translated by native speakers of the ine device (IUDs) or progestin-only pills (POPs) have been particular language. Two authors (RC, IY) independently reported to have a higher relative risk of ectopic pregnancy read full-text articles to determine eligibility for inclusion, than users of combined oral contraceptives (COCs) or condoms that is, they presented data on pregnancy. For articles where [16–19]. A review of clinical data submitted to the Food and pregnancy site — intrauterine or ectopic — was not Drug Administration for marketing approval of contraceptives reported, we contacted the authors via email to request this found that the proportion of pregnancies that were ectopic ranged information. After the list of eligible studies was established, from 0 out of 27 among users of COCs, to 1 out of 21 among two authors (RC, IY) independently extracted data from the POP users, to 1 out of 2 among users of the LNG IUD [20]. studies using an extraction table developed for the purpose. Several published reviews of ectopic pregnancy risk with the Extracted data included study design, length of follow-up, use of sterilization, IUDs, POPs and emergency contraceptive contraceptive regimen(s), number of women–months and pills (ECPs) have been conducted [13,21–24]; however, no women–years of exposure, number of pregnancies and thorough assessment of the association between progestin-only number of ectopic pregnancies. For articles in which the implants or injectables and ectopic pregnancy has been number of women–years was not reported, it was calculated published. Understanding whether and how ectopic pregnancy by dividing the number of reported women–months by 12. risk varies by these methods is important for both women and The proportion of pregnancies that were ectopic and ectopic providers, especially since common side-effects associated with pregnancy incidence rate per 1000 woman–years was then these methods, including irregular bleeding and lower abdom- calculated for each regimen included in the study. After data inal pain, can also be signs of ectopic pregnancy. extraction was complete, the two authors compared results and resolved any discrepancies. 1.2. Objective 2.3. Risk of bias in individual studies The objective of this review is to describe the risk of ectopic pregnancy among users of progestin-only injectables While the aim of this review is to describe the risk of ectopic and contraceptive implants based on a comprehensive review pregnancy with use of progestin-only injectables and implants, of published research. we do not present a summary estimate of risk for these methods given the wide variation in research design, outcome measures and study populations. We employed a comprehensive search 2. Methods strategy designed to capture all relevant studies in order to qualitatively describe risk. Given our broad inclusion criteria, We conducted this systematic review in accordance with we did not attempt to assess data quality or the risk of bias for all the Preferred Reporting Items for Systematic Reviews and included studies. However, we do report study design and size Meta-Analyses guidelines [25]. foreachincludedstudyin Appendices B1 and B2. 2.1. Eligibility criteria

This review includes all published studies that presented 3. Results pregnancy data with use of any contraceptive implant (marketed or not) and any progestin-only injectable. We included both Oursearchproduced884potentially relevant articles, of comparative analyses as well as single-arm observational which 81 met the eligibility criteria described above (Fig. 1). We studies; however, studies that only presented pregnancy data found 53 studies of progestin contraceptive implants [26–78] for subgroups of women (such as those on hepatic-enzyme and 28 studies of progestin-only injectables [79–106] reporting inducers or those participating in clinical trials of HIV any pregnancies. Most of the studies were prospective cohort prevention drugs) were excluded. We also excluded case reports (n=41) or nonrandomized comparative (n=16) studies; howev- and review articles, although relevant studies from review er, 18 were randomized trials, five were chart reviews and one articles were collected and evaluated for inclusion. was a review of regulatory agency surveillance data (Table 1).

2.2. Search strategy and data extraction 3.1. Implants We searched for studies of contraceptive implants or The implant studies included seven different progestins and a injectables in any language that included pregnancy as an wide variety of regimens (Table 2). Some studies included outcome using the electronic databases MEDLINE (via multiple progestins and multiple regimens. By far, the most 516 R. Callahan et al. / Contraception 92 (2015) 514–522

Papers identified through database Papers identified through hand search of searches published through April 2014 reference lists n=879 n=5

Papers excluded through title/abstract review n=743

Full papers reviewed for eligibility n=141

Papersexcluded: No pregnancy data, n=133 Case reports, n=4

Papers included in review n=81

Fig. 1. Study selection. commonly studied progestin was LNG, with most data coming (MA) and used them for approximately 1 year had an ectopic from studies of the six-rod 5-year implant system, Norplant®, (n= pregnancy incidence rate of 41.6 per 1000 woman–years [61]. 28) containing 216 mg of LNG. For 50 of the 53 implant studies, The high pregnancy and ectopic pregnancy rates observed with location of pregnancy was either reported in the publication or some of these early implants were important reasons why these was obtained through correspondence with the study authors. products never reached the market. Forty-six studies reported woman–months or woman–years of Among five studies of Norplant II, the predecessor to the exposure allowing for calculation of ectopic pregnancy incidence. two-rod LNG-releasing implant Jadelle, that included site of implantation, one reported an ectopic pregnancy at 15 months of 3.1.1. Implants studied but not marketed useinawomanwithahistoryofectopicpregnancy[42] resulting In general, studies of older nonmarketed implants reported in an ectopic pregnancy rate of 2.6 per 1000 woman–years. higher incidence of ectopic pregnancy (Table 2). For example, the ectopic pregnancy incidence rate among women using a 3.1.2. Marketed implants single silastic capsule containing 47 mg of norgestrienone for 6 Twenty-eight studies of Norplant are included in the review, months was 51.8 per 1000 woman–years [57].Womenwho 25 of which reported site of implantation. Among those 25, 14 were implanted with five 30-mg capsules of megestrol acetate (56%) reported no ectopic pregnancies. The ectopic pregnancy incidence rate among the other 11 ranged from 0.1 to 2.9 per 1000 – Table 1 woman years, and the proportion of pregnancies that were Number of published studies of progestin-only implant and injectable ectopic ranged from 3.1% to 100% (Table 2). The highest ectopic contraceptives reporting any pregnancies by study design. incidence rate was reported in a study of 208 Norplant users (345 Study design Implants Injectables woman–years) in New York City [37].Inthatstudy,an (N=53) (N=28) intrauterine pregnancy at month 14 and an ectopic pregnancy at Randomized controlled triala 810 month 24 occurred in women weighing more than 175 lb. Only Nonrandomized comparative cohort studyb 12 4 one other early study of Norplant reported an ectopic incidence of Prospective cohort studyc 30 11 more than 2.0 [45]. In that study, only two pregnancies occurred; d Chart review 23 however, both were ectopic. The remaining nine studies reported Regulatory agency surveillance datae 1 – rates under 1.0 ectopic pregnancies per 1000 W-Y. a – [34,42,47,53,65,71,75,77,79,81,86,87,95,96,100,102 104]. Though fewer in number, studies of other marketed b [33,35,38,51,56–58,61,62,64,74,76,83,94,105,106]. c [26–32,36,37,39,40,44–46,48–50,52,54,55,59,60,63,66,67,69,70, LNG-containing implants including Jadelle (150 mg), Sino- 72,73,78,84,85,88–91,93,97–99,101]. implant (216 mg) and Sino-implant (II) (150 mg) reported d [41,43,80,82,92]. somewhat similar rates of ectopic pregnancy as the Norplant e [68]. studies. Two studies of Jadelle included ectopic pregnancies, R. Callahan et al. / Contraception 92 (2015) 514–522 517

Table 2 Proportion of pregnancies that were ectopic and ectopic pregnancy incidence by implant type and regimen among studies for which pregnancy location is known.a Progestin (dosage) No. of No. of No. of studies % of pregnancies Ectopic pregnancy studiesb women reporting any that were ectopicc incidence per ectopic pregnancies 1000 w-yc Ever-marketed regimens LNG Norplant (6 silastic rods, 216 mg) [26–50] 25 61432 11 3.1–100 0.1–2.9 Jadelle (2 silastic rods, 150 mg) [46,47,78] 3 11391 2 20–33 0.4, d Sino-implant (I) (6 silastic rods, 216 mg) [33,34,65,75,77] 5 22399 1 25 0.8 Sino-implant (II) (2 silastic rods, 150 mg) [34,65–67,69,70,75,77] 8 25425 3 8.3–20 0.2–0.8 ENG Implanon/Nexplanon (single EVA rod, 68 mg) [68,76] 2 205654 1 2.3 d

Regimens studied but never marketed LNG Norplant II Covered Rods (2 silastic rods, 140 mg) [38,42,54,55,72] 5 3023 1 16.7 2.6 3–6 silastic capsules (30 mg each) [62,71] 2 657 1 3 8.3 3-keto-desogestrel Single silastic implants (10, 20, 40 mcg/day) [64] 1 33 1 50 179.2 Single EVA implants (15 & 30 mcg/day) [64] 1170 0 0 MA 4–6 silastic capsules (23–30 mg each) [56,61,62] 3 825 2 7.1–66.7 11.4–41.6 4 MA+1 or 2 LNG silastic capsules (20–30 mg each) [62] 1 244 1 8 3.7 Norgestrienone 1–6 silastic capsules (30–47 mg each) [57,63,71] 3 1131 2 6.2–11.1 4.5–51.8 Nestorone (NES) 3–5 silastic capsules or 1 silastic rod (35mg each) [59] 1 282 0 0 0 Nomegestrol acetate Uniplant (1 silastic rod, 55 mg) [60] 1 1803 0 0 0 Norethindrone (NET) 3–5 silastic capsules or 1 silastic rod (20–40 mg each) [62,74] 2 199 0 0 0 a Site of implantation could not be determined for 3 studies. b Some studies contained more than one progestin and/or regimen. c Among studies that reported any ectopic pregnancies. d Exposure time not reported. one during the fifth year of use resulting in a rate of 0.5 per 1000 3.1.3. Dose effect woman–years [47] and one at 84 months of use (incidence rate Data on the effect of progestin dose on ectopic pregnancy risk could not be calculated) [78]. Two large randomized trials of are limited; however, a couple of studies provide some evidence. Sino-implant (II) did not report pregnancy location; however, In a study in which women received 90- or 120-mg LNG correspondence with authors indicated that all pregnancies were implants, an ectopic pregnancy incidence rate of 8.3 per 1000 intrauterine [75,77]. Postmarketing surveillance studies of women–years was observed for the two groups combined [62], Sino-implant (II) in Kenya and Pakistan following 754 which is considerably higher than even the highest rates observed women reported a single ectopic pregnancy out of five in studies of Norplant or Jadelle, which contain 216 and 150 mg pregnancies occurring within the first year of use resulting in of LNG, respectively. This may be because lower dose implants an ectopic pregnancy rate of 0.8 per 1000 woman–years [69]. have a lower daily release rate and thus are less effective in Pregnancy incidence in studies of the single-rod Implanon/ preventing pregnancy, including ectopic pregnancy. An early Nexplanon (containing 68 mg of ENG) is even lower, with most study comparing silastic and ethylene vinyl acetate (EVA) rods studies reporting zero pregnancies. We found only two studies containing ENG with release rates ranging from 10 to 40 mcg/day of Implanon that reported any pregnancies, one with no ectopic resulted in three pregnancies, including one ectopic, among pregnancies [76] and one reporting five [68]. The latter study womenusingasinglesilasticrodreleasing10or20mcg/day[64]. was a review of surveillance data submitted to Australia's drug 3.2. Injectables regulatory agency, which included 218 unintended pregnancies associated with Implanon use. Only 13 of those pregnancies Two types of progestin-only injectables are included in this were believed to be true method failures, and it is not clear if the review, depot-medroxyprogesterone acetate (DMPA) and five ectopic pregnancies were among that group. Exposure time norethisterone enanthate (NET-EN), in several different dosages was also not captured in these data, so we could not calculate an (Table 3). Many injectable studies did not report pregnancy ectopic pregnancy incidence rate. location. After contacting study authors, we obtained 518 R. Callahan et al. / Contraception 92 (2015) 514–522

Table 3 Proportion of pregnancies that were ectopic and ectopic pregnancy incidence by injectable type and regimen among studies for which pregnancy location is known.a Progestin (dosage) No. of No. of No. of studies % of pregnancies Ectopic pregnancy studiesb women reporting any ectopic that were ectopic incidence per pregnancies 1000 w-y Marketed regimens DMPA 150 mg/3 months [82,87,92,95,96,98–100,102–106] 13 957215 1 1.0 c 104 mg/3 months (subcutaneous) [87] 1 266 0 0 0 NET-EN 200 mg/2 months [88,96,103] 3 1113 0 0 0

Regimens studied but never marketed DMPA 100 mg im/3 months [104] 1 609 0 0 0 NET-EN 200 mg/70–84 days [85] 1 324 1 25.0 3.4 200 mg/3 months [102] 1 832 0 0 0 200 mg/2 months then 200 mg/3 months [100,103] 2 902 0 0 0 20 mg/month [93] 1 203 1 20.0 4.1 a Site of implantation could not be determined for 11 studies. b Some studies contained more than one progestin and/or regimen. c Exposure time not reported. informationonectopicpregnancyfor7of15studiesofNET-EN pregnancies were reported in either the Implanon or Norplant and12of18DMPAstudies. groups after 26,972 and 28,108 women–months of follow Pregnancy rates in the 27 studies of injectable contraceptives up, respectively [107]. Among women not using contracep- were low. Among 10 studies of DMPA for which the pregnancy tion, 1–2% of pregnancies are ectopic. Studies of proges- ratewasreportedorcouldbecalculated, rates ranged from 0.1 to tin-only implants described in this review report higher 1.7 per 100 woman–years [83,87,89,94,96–98,103–106]. proportions of ectopic pregnancies in the event pregnancy Among studies of NET-EN, rates ranged from 0.3 to 6.6 per occurs; however, our review confirms that the absolute risk 100 woman–years [79,81,83,85,88,90,91,93,96,101–103]. of ectopic pregnancy is lower for women using these Only three studies — two of NET-EN and one of DMPA — methods compared with noncontraceptors. The large, multi- reported any ectopic pregnancies. The two associated with country, postmarketing study of Norplant offers a good NET-EN use occurred in studies of nonmarketed regimens: example of this lowered risk. Investigators found an ectopic monthly administration of 20 mg [93] and 200 mg given every pregnancy incidence rate of 0.3 per 1000 woman–years 74 or 80 days [85]. In the former study, the duration of use and among Norplant users compared with a rate of 2.66 among the time of the ectopic pregnancy were not reported. In the latter, women not using contraception. The ectopic pregnancy a total of four pregnancies were documented with one being incidence rate was even higher (9.24 per 1000 woman– ectopic, and the ectopic pregnancy rate was 3.4 per 1000 years) in a subgroup of women not using contraception who woman–years. The ectopic pregnancy occurred approximately were planning pregnancy [35]. In the present review, the 40 days after the second injection in a woman with a history of highest incidence of ectopic pregnancy reported among PID. Finally, four ectopic pregnancies were reported among marketed implants was 2.9 per 1000 woman–years, which is 949,182 users of 150-mg im DMPA in a review of Planned close to that estimated for noncontracepting women (2.1 per Parenthood Federation of America insurance data collected 1000 woman–years [108]); most studies, however, reported between 1994 and 1998 [82]. The pregnancy data from this incidence below 1.0 per 1000 woman–years. review are incomplete, however, as site of implantation is only The only other progestin used in currently marketed documented for 37% of clients between 1997 and 1998 implants (Implanon/Nexplanon) is ENG. Only three studies compared to almost 98% of clients between 1994 and 1995, of implants containing this progestin report any pregnancies; and the review does not report when the four ectopic pregnancies two of these studies were with the marketed product occurred. We did not find any studies of the subcutaneous Implanon including a review of postmarketing surveillance formulation of DMPA reporting ectopic pregnancy. data. While five of the 218 pregnancies reported in that review were ectopic, because of data limitations, it is 4. Discussion unknown how many of them occurred among women who had the device in situ [68]. The exceptionally low number of Contraceptive methods such as LNG or ENG-containing reported failures in the literature makes Implanon/Nexplanon implants are highly effective; in a Cochrane review, no the most effective hormonal contraceptive available. R. Callahan et al. / Contraception 92 (2015) 514–522 519 Because pregnancy is so rare with this method, ectopic both ciliogenesis [12] and ciliary beat frequency [119] in pregnancy is also extremely uncommon. fallopian tube cells in a dose-dependent fashion. It is likely that Compared with studies of implants, fewer injectable studies synthetic progestins affect ciliary development and activity in a report pregnancy location. This may be because very low similar way, although the effect of various progestins may differ incidence of ectopic pregnancy among users of these methods due their dose or structure/activity differences [120]. Current makes it unnecessary to clarify that all reported pregnancies are and future contraceptive development efforts may consider intrauterine. While we cannot be certain that this is the case, the further exploration of the physiological mechanisms underlying fact that only six reports of ectopic pregnancy in three studies ectopic pregnancy risk with specific progestins. existinnearly50yearsofpublished literature on progestin The goal of the present analysis was to review all published injectables supports such an assumption. Furthermore, each of studies of implant and injectable progestin-only contraceptives in the three injectable studies that report ectopic pregnancy have order to describe ectopic pregnancy risk with use of these important limitations, including incomplete data [82],useof methods. To obtain the most comprehensive information, we did very low dose of progestin [93] and a confounding risk factor for not restrict by whether or not the method was ever marketed or by ectopic pregnancy [85]. study design. Formal meta-analysis was not appropriate due to The clinical and epidemiological evidence indicate that the heterogeneous study designs, outcome measures and study LNG-containing implants are more likely to result in an populations in the reviewed studies. One limitation of our review ectopic pregnancy (or any pregnancy) than the ENG implant is that a number of studies, especially of injectables, did not or progestin-only injectables. The type and dose of progestin report pregnancy location, and we cannot be sure that all reported resulting in various levels of ovarian suppression may play a pregnancies were intrauterine. In addition, due to the breadth of role. Implanon/Nexplanon, DMPA and NET-EN more the review, we were unable to thoroughly assess the data quality completely suppress ovulation, thus limiting the potential and risk of bias for each of the 81 studies included in the review. for fertilization and implantation to occur in any location. Certainly, the ectopic pregnancy incidence rates reported in or Studies of Implanon indicate that only 4% of Implanon users calculated from the studies in this review could be influenced by ovulate by the end of the method's 3-year recommended many factors including length of study follow-up, ascertainment duration of use [109]. In contrast, among LNG implant users, of outcomes in individual studies and underlying and unmea- ovulation is suppressed only initially but then resumes in sured confounding risk factors in the studied populations. many. By year 5 of use, more than half of Norplant users Women who choose to use implant or injectable contracep- ovulate regularly [110], and it is estimated that Jadelle use tion can be assured that use of these methods substantially suppresses ovulation in only 45–85% of menstrual cycles reduces their risk of pregnancy and, thus, ectopic pregnancy. [111]. Case studies (not included in this review) reporting The substantial body of research reviewed here shows that ectopic pregnancies in Implanon users who may have lower ectopic pregnancy risk among users of marketed implants and plasma concentration of ENG due to drug interaction with injectables is considerably lower than that of women who are not certain antiretrovirals or other drugs known to induce hepatic using contraception. While women who choose to use enzymes [112–115] and, therefore, do not fully suppress LNG-containing implants, such as Jadelle or Sino-implant (II), ovulation support this theory, as does the higher rate of ectopic and their providers should be aware of potential signs of ectopic pregnancies among users of a lower-dose LNG implants [62]. pregnancy in the small chance that the method should fail, fear While ovulation is more fully suppressed with use of of ectopic pregnancy should not be a deterrent for use or progestin injectables [116], contraceptive failure rates are higher provision of these methods. with DMPA and NET-EN than with implants. This could be Supplementary data to this article can be found online at explained by the fact that, unlike implants, these methods depend http://dx.doi.org/10.1016/j.contraception.2015.08.016. on women's ability to use them correctly, that is, come back for reinjection on time. Nevertheless, in spite of the higher failure Acknowledgements rate, very few reported pregnancies among injectable users are ectopic. Why method failure with use of injectables is less likely This research was made possible through a grant from the to lead to ectopic pregnancy than LNG implants is unknown but Bill & Melinda Gates Foundation and the US Agency for could be related to the particular effects the different progestins International Development, Award No. AID-OAA-A-10- have on target tissues, including the fallopian tubes. 00060. We thank Carol Manion for assistance with the database Research primarily from the field of assisted reproduction search and Dr. Ward Cates and Dr. Laneta Dorflinger for their shows that sex steroids play a crucial role in regulating the careful review of this manuscript. number and activity of ciliated cells in the fallopian tubes, the primary mechanism of gamete and zygote transport [117]. 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