**4. Injectable contraceptives**

Injection-based methods differ from other methods in the return to fertility since they are irreversible in the short-term, but fertility rates eventually reach those of them [13]. In this group methods one year pregnancy rates range between 72.5–82.9% with median time to pregnancy being 4.5–5 months [1].

**5.2. Physiology**

**5.3. Return to fertility**

IUDs elicit foreign body reactions, which turns the intrauterine milieu lethal for embryos, without significant extrauterine effects. In addition to this, different types of IUDs can alter previous processes through varying degrees: Mucus thickening, glandular atrophy and stromal decidualization in LNG IUDs, spermatozoa decay and toxicity by Copper ions in the uterine cavity, transmission of noxa from the uterine lumen to fallopian tube, etc. [96, 97]. The histological changes were found to be reversible within some months. Unlike OCs, IUDs have

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Fertility is not impaired after IUD removal13. In Diana Mansour's bibliographic review 1 year pregnancy rates for Copper IUDs were 71.2–91.1% for Copper IUDs and 79.1–96.4% for LNG IUDs (median time to pregnancy were 2–3.7 cycles and 4 cycles respectively)1. Currently there is no evidence of a delay in return to fertility after using an IUD [13]; in some studies >50% of women conceived within 3 months after discontinuing it [98]. **Table 1** contains

The history of IUD devices includes some particular case of long-lasting health and reproductive consequences after IUD usage. Despite some previous attempts and projects some decades earlier, it was not until the 1960s that commercial IUDs made their way into the market with the approval of the Lippes Loop and the Safe-t-coil by the FDA in 1966. The **Dalkon shield**, introduced in 1971, attempted to increase the surface of the endometrium in contact with the IUD and to increase retention rate; it included a multifilament tail string encased in Nylon [99]. Several reports associated this IUD with increased infection rates, septic abortions and deaths; apparently the multifilament string could allow vaginal bacteria to access the uterus. Since this IUD was used in many world countries the numbers of women suffering adverse consequences is difficult to estimate. Device sales stopped in 1974 and the company started to recommend device removal if a pregnancy took place, which is now standard practice; women experiencing the adverse events, which includes fertility impairment as sequel, filled many lawsuits and in 1980 the company recommended removal of the Dalkon shield in women who were still wearing them. Distrust and

doubt regarding IUDs lasted for several years after this, especially in the USA [100].

The relationship between IUD usage and pelvic inflammatory disease (PID), a well-known cause of infertility, has been studied extensively for decades [101] and many studies had pitfalls [102]: Sexual habits as a confounding factor, diagnosis bias… The described incidence of pelvic inflammatory disease on IUD users is very low (1.6/1000 person-years) and particularly confined to the first weeks after insertion. Preventive strategies include adequate selection of IUD candidates, prophylactic antibiotic during insertion, careful monitoring and treatment of infections, etc.

Long-term usage is not associated with posterior infertility; several studies have shown pregnancy rates are not delayed in women who used copper IUDs for several years [106]. Zhu et al. performed a study with 1770 Chinese women who had their IUDs removed after a catastrophic earthquake in the Sichuan region and were followed up for two years [103]. 71% women conceived within 1 year after removal and 80% conceived within 2 years. In the multivariate logistic regression analysis age was negatively associated with fertility (OR 0.7548, 95% CI: 0.7148–0.7933), while duration of IUD use (OR 1.0596, CI: 1.0244–1.0960) and previous

not been observed to be associated with follicular phase length [31].

selected studies pertaining return to fertility after contraception.

Depot medroxyprogesterone acetate (DMPA) is the most commonly used injectable, being administered as intramuscular injections every 12 weeks. Product leaflet mentions some pregnancies have occurred 14 weeks after a preceding injection but longer delays are common: the observed mean time to ovulation is 5.3 months and the median time to conception is 10 months after the last injection. About 83% women should conceive within 15 months of the last injection [92].

A large study in over 1000 Thai women remarked that return to fertility and proportions of live births in the offspring of women who used MDPA are similar to those of women using other contraceptive methods (OCs or IUDs): in this study the median delay to conception for MDPA was 5.5 months plus the estimated effect duration of the last injection; this can be compared to 3 months for OCs and 4.5 months for IUD [93].

Intramuscular injections of norethisterone enanthate acts as a contraceptive for 8 weeks; in 11 of 20 women discontinuing this method follicular activity was observed within 90 days of the last injection [94]. The observed median delay to conception is 6 months after the last injection; 14 of 40 women became pregnant within 12 weeks and 31 of 40 after 1 year. Authors remarked the real figures could be higher. The delays in fertility were not correlated with the duration of use.

Intramuscular injections of estradiol cypionate and medroxyprogesterone acetate (Cyclofem®) are administered every month. 1.4% women became pregnant at the end of the first month (since the first missed injection), 52.9% after 6 months and 82.9% after 9 months. Pregnancy outcomes were favorable: 51 (94.4%) pregnancies ended in a live birth [95].
