Copper-containing Intrauterine Devices Research Articles

An in-vivo study of the safety of copper-containing intrauterine devices in 3.0 Tesla magnetic resonance imaging.

The aim of this study is to prospectively evaluate whether women with copper-containing intrauterine devices (Cu-IUD), currently listed as MR conditional, can safely undergo 3.0 Tesla (3T) magnetic resonance imaging (MRI). 73 women, age 18-54years old, with a Cu-IUD who were undergoing MRI for any reason were included consecutively. Pre- and post-MRI standard pelvic ultrasound examinations were completed to determine the appropriate pre- and post-MRI positioning of the Cu-IUD. Displaced IUDs were defined by IUD crossbars not in the fundal portion of the endometrial cavity, a visualized tip in the mid or lower uterus, any part of the device located in the cervical canal or outside of the endometrial canal, a fractured device, or a non-visualized IUD. Additionally, a questionnaire was completed by participants to determine the level of pre- and post-MRI pelvic pain. There were zero observed displaced Cu-IUDs on post-MRI pelvic ultrasounds (p = 0/70, 95% CI 0, .043). Three participants were dropped from the study due to malpositioned IUDs on pre-MRI pelvic ultrasound. Six patients reported new or worsening pelvic pain/discomfort during or after their MRI examination. Our results suggest that performing 3T MRI using a low SAR setting does not cause displacement of Cu-IUDs, with zero out of 70 patients demonstrating IUD displacement.

Comparative analysis of endometrium after using levonorgestrel-releasing intrauterine system and copper intrauterine device

BACKGROUND: To date, the risks of pelvic inflammatory diseases, including chronic endometritis, associated with the use of various intrauterine contraceptives, have remained debatable. AIM: The aim of this study was to conduct a comparative analysis of the endometrial status in women of reproductive age after the use of copper- or levonorgestrel-releasing intrauterine device. MATERIALS AND METHODS: Morphological and immunohistochemical studies of endometrial biopsies obtained by aspiration Pipelle biopsy were performed after intrauterine device extraction in 18 patients who used a copper-containing intrauterine device and in 12 women who used the levonorgestrel-releasing intrauterine device Mirena. Monoclonal mouse antibodies to CD20, CD138, and α-smooth muscle actin (DAKO, Denmark) were used. Criteria for inclusion of patients in the study are reproductive age, use of an intrauterine device for five years, absence of complications associated with the intrauterine device during its use. Exclusion criteria are a history of pelvic inflammatory diseases, sexually transmitted infections, habitual miscarriage, two or more intrauterine interventions. RESULTS: After using a copper-containing intrauterine device, signs of chronic inflammation were found in the endometrium such as cytogenic stroma fibrosis with pronounced infiltration by inflammatory cells, positive expression of CD138 (33.3% of observations), CD20 (88.9% of observations with an average number of 27.4 ± 5.7), α-smooth muscle actin (up to 70% of the cytogenic stroma area), and the presence of lymphatic follicles consisting of B lymphocytes (33.3% of observations). During the use of the levonorgestrel-releasing intrauterine device, decidual transformation of cytogenic stroma cells, as well as secretion and atrophy of the glandular epithelium, were found in the endometrium. CD20-positive cells were detected in five out of 12 cases (41.6% of observations with an average number of 12.8 ± 4.6). Expression of CD138 and α-smooth muscle actin was not detected in any of the cases. CONCLUSIONS: The use of a copper-containing intrauterine device is associated with a high risk of developing chronic endometritis. The absence of signs of chronic inflammation in the endometrium after the use of a levonorgestrel-releasing intrauterine device is probably due to the protective effect of levonorgestrel on the uterine mucosa. Thus, levonorgestrel-releasing intrauterine devices, in comparison with copper-containing intrauterine devices, have a favorable safety profile relative to the endometrium and can be recommended for women of reproductive age, including those who have not given birth.

Prevalence of high-risk HPV and cervical dysplasia in IUD users and controls: a cross sectional study

Objective To examine the prevalence of infections with high-risk human papillomavirus (HPV) and cervical dysplasia, and the clearance rate of HPV infections, in users of different kinds of intrauterine devices (IUDs) and other contraceptive methods. Methods A cross-sectional register-based study including 16,181 women aged 30–49 years participating in the screening programme for cervical cancer in a Swedish County in 2017–2018. Data on contraception from screening records was paired with the HPV test results, cytological and histological follow-up tests and subsequent HPV test. Results There was no difference in the risk of being HPV positive, or histological HSIL+, between users of copper-containing IUDs and women with no reported use of contraception. Use of levonorgestrel intrauterine system and hormonal contraception were associated with higher odds for HPV infection in age-adjusted models (aOR 1.21; 95% CI 1.04–1.41, and aOR 1.41; 95% CI 1.22–1.63, respectively) and for HSIL+ (aOR 1.45; 95% CI 1.02–2.06, and aOR 1.56; 95% CI 1.13–2.16, respectively). No significant differences were found in HPV clearance rates. Conclusions Reported use of levonorgestrel intrauterine system and hormonal contraception, but not use of copper IUD, was associated with a higher prevalence of HPV infections and histological HSIL + compared to no reported use of contraception.

How do thiol disulfide balance and copper-ceruloplasmin levels change in women using copper intrauterine devices?

Objectives We aimed to examine the change in plasma copper (Cu) level and copper transport proteins level before inserting Cu-IUD and after one menstrual cycle and to show the effect of this change on the thiol disulfide balance in women using copper-containing intrauterine device (Cu-IUD). Method Thirty-three reproductive women who admitted to the gynecology clinic and inserted Cu-IUD were examined in this study. Thiol-disulfide homeostasis, plasma Cu and ceruloplasmin levels and ceruloplasmin ferroxidase activity were measured using the blood samples collected just before inserting Cu-IUD and after one menstrual cycle. Results Plasma copper level (p = 0.006), ceruloplasmin (p < 0.001), Ceruloplasmin Ferroxidase (p = 0.005), thiol disulfide homeostasis parameters; native thiol (NT) (p = 0.004), and total thiol (p = 0.003) levels increased significantly. Conclusion After one menstrual cycle in women inserted intrauterine Cu-IUD for contraception, plasma levels of Cu, which is the oxidant molecule, increased significantly. Both plasma ceruloplasmin level and ceruloplasmin ferroxidase activity increased due to elevated Cu levels. This increased oxidant status in the acute period was balanced by the increase in the native thiol level.

In Vitro Carcinogenicity Test of a Copper-Containing Intrauterine Device.

The aim is to study the cellular carcinogenicity of a copper-containing intrauterine device (IUD). So we analyzed the chemical elements of copper-containing IUDs. After that, we used Bhas42 cells in initiation and promotion assays to evaluate the leaching solution that extracted from the copper-containing IUDs at serial dilutions. In the cell carcinogenic experiment, the number of cell foci with malignant transformation was calculated. Although we uncovered no significant differences between the leaching solution at different concentrations and the negative control in the initiation assay, the sample at four concentrations showed significant differences relative to the negative control in the promotion assay (chi-squared test, p < 0.01). Therefore, we preliminarily evaluated that copper-containing IUDs are nongenotoxic carcinogen. Impact statement For the first time, we executed two-stage transformation assays with Bhas42 cells to assess the potential carcinogenicity of a copper-containing intrauterine device (IUD). In this study, we demonstrated that the copper-containing IUD manifested nongenotoxic carcinogenicity, making this the first-ever published report regarding this type of IUD's nongenotoxic carcinogenicity and revealing that its use carries a cancer risk.

Intrauterine device translocation: Case series and management algorithm

Intrauterine devices (IUDs) are the most commonly used long-term contraception due to their 98–99% effectiveness in preventing pregnancy. There are two types of IUD available in Indonesia, a copper-containing IUD and levonorgestrel-releasing IUD. IUD causes chronic inflammatory changes in the endometrium and fallopian tubes that inhibit fertilization and make a hostile environment for implantation. The increased number of endometrial leukocytes is fatal for sperm. In addition, levonorgestrel will inhibit ovulation. The use of an IUD is associated with side effects and complications. The most commonly met complications are IUD expulsion, displacement, translocation, and pregnancy. The average IUD translocation prevalence is 1.3/1000 which mainly occurs during insertion. Translocated IUD may further cause perforation of the bladder or intestines, intestinal obstruction, fistula formation, abscess, adhesion, undesired pregnancy, and chronic pelvic pain. Regardless of the type and location, the WHO recommends removal of the translocated IUD due to its potentially severe complications. Here, we present four cases of IUD translocation at Cipto Mangunkusumo National Hospital from 2020 to 2021, focusing on how to diagnose and the management to remove it.

Feasibility evaluation of a Zn-Cu alloy for intrauterine devices: In vitro and in vivo studies

The comprehensively adopted copper-containing intrauterine devices (Cu-IUDs) present typical adverse effects such as bleeding and pain at the initial stage of post-implantation. The replacement of Cu material is demanded. Zinc and its alloys, the emerging biodegradable materials, exhibited contraceptive effects since 1969. In this work, we evaluated the feasibility of bulk Zn alloys as IUD active material. Using pure Cu and pure Zn as control groups, we investigated the contraceptive performance of Zn-0.5Cu and Zn-1Cu alloys via in vitro and in vivo tests. The results showed that the main corrosion product of Zn-Cu alloys is ZnO from both in vitro and in vivo studies. CaZn2(PO4)2·2H2O is formed atop after long-term immersion in simulated uterine fluid, whereas CaCO3 is generally formed atop after implantation in the rat uterine environment. The cytocompatibility of the Zn-1Cu alloy was significantly higher than that of the pure Zn and pure Cu to the human endometrial epithelial cell lines. Furthermore, the in vivo results showed that the Zn-1Cu alloy presented much improved histocompatibility, least damage and the fastest recovery on endometrium structure in comparison to pure Zn, Zn-0.5Cu and pure Cu. The systematic and comparing studies suggest that Zn-1Cu alloy can be considered as a possible candidate for IUD with great biochemical and biocompatible properties as well as high contraceptive effectiveness. Statement of significanceThe existing adverse effects with the intrinsic properties of copper materials for copper-containing intrauterine devices (Cu-IUD) are of concerns in their employment. Such as burst release of cupric ions (Cu2+) at the initial stage of the Cu-IUD. Zinc and its alloys which have been emerging as a potential biodegradable material exhibited contraceptive effects since 1969. In this study, Zn-1Cu alloys displayed significantly improved biocompatibility with human uterus cells and a decreased inflammatory response within the uterus. Therefore, high antifertility efficacy of the Zn-1Cu alloy was well maintained, while the adverse effects are significantly eased, suggesting that the Zn-1Cu alloy is promising for IUD.

Feasibility evaluation of a Cu-38 Zn alloy for intrauterine devices: In vitro and in vivo studies

The existing adverse effects of copper in copper-containing intrauterine devices (Cu-IUDs) have raised concerns regarding their use. These adverse effects include burst release of cupric ions (Cu2+) at the initial stage and an increasingly rough surface of the Cu-IUDs. In this study, we investigated the use of two copper alloys, Cu-38 Zn and H62 as the new upgrading or alternative material for IUDs. Their corrosive properties were studied in simulated uterine fluid (SUF) by using electrochemical methods, with pure Cu as a control. We studied the in vitro long-term corrosion behaviors in SUF, cytotoxicity to uterine cells (human endometrial epithelial cells and human endometrial stromal cells), in vivo biocompatibility and contraceptive efficacy of pure Cu, H62, and Cu-38 Zn. In the first month, the burst release rate of Cu2+ in the Cu-38 Zn group was significantly lower than those in the pure Cu and H62 groups. The in vitro cytocompatibility Cu-38 Zn was better than that of pure Cu and H62. Moreover, Cu-38 Zn showed improved tissue biocompatibility in vivo experiments. Therefore, the contraceptive efficacy of the Cu-38 Zn is still maintained as high as the pure Cu while the adverse effects are significantly eased, suggesting that Cu-38 Zn can be a suitable potential candidate material for IUDs. Statement of significanceThe existing adverse effects associated with the intrinsic properties of copper materials for copper-containing intrauterine devices (Cu-IUD) are of concern in their employment. Such as, burst release of cupric ions (Cu2+) at the initial stage and an increasingly rough surface of the Cu-IUD. In this work, Cu alloyed with a high amount of bioactive Zn was used for a Cu-IUD. The Cu-38 Zn alloy exhibited reduced burst release of Cu2+ within the first month compared with the pure Cu and H62. Furthermore, the Cu-38 Zn alloy displayed significantly improved biocompatibility and a much smoother surface. Therefore, high antifertility efficacy of the Cu-38 Zn alloy was well maintained, while the adverse effects are significantly eased, suggesting that the Cu-38 Zn alloy is promising for a Cu-IUD.

Dispositif intra-utérin au cuivre (DIUc) : comparaison de la tolérance et de l’efficacité chez des nullipares et des multipares sur 6 mois

IntroductionThe copper-containing intra-uterine device IUD (cIUD) is a non-hormonal, effective, long-acting method of contraception, which is not widely used in nulliparous patients in France. The objectives of the study are to compare the safety of the cIUD by the rate of continuation at 6 months between nulliparous and parous patients, and to assess the complications and side effects at insertion and during follow-up.Material and method This is a multicenter prospective epidemiological study with follow-up for 6 months. The adult patients were included in Nantes from February 2019 to October 2019 during the insertion of a IUD in different centers: the student health service (SUMPPS) (Nantes), the Clotilde de Vautier center in the Clinic Jules Verne (Nantes) and in the gynecological offices of the city of Nantes. ResultsA total of 94 patients were included during the insertion of the cIUD. At 6 months, 77 patients answered the second questionnaire, 49 patients were nulliparous and 28 were parous. The pain on insertion was greater in nulliparous patients with a VAS of 6.5±2.4 (0–10) versus 3.9±2.2 (0–8) for multiparous patients (P<10−4). The 6-month continuation rate for the cIUD was 92.8% for 83.4% for nulliparous patients, and parous patients with no significant difference (P=0.25). Expulsion was the only complication found with 12.2% in nulliparous and 3.5% in parous (P=0.40). Otherwise, 64% of the patients observed heavy bleeding than before without difference with the parity, and 72% of the nulliparous declared to have dysmenorrhea requiring the use of analgesics, against 47% of the parous (P=0.025). The nulliparous were very satisfied or satisfied for 89% in daily life and 96% of them in sex life, without difference compared to parous (97% and 100% respectively). ConclusionThere is no difference in the rate of continuation at 6 months between nulliparous and parous. Nulliparous complained more often of dysmenorrhea in comparison to the period before the cIUD. The satisfaction rates were comparable.

Effects of Copper-Containing Intrauterine Devices on the Endometrium

The use of copper-containing intrauterine devices (Cu-IUDs) is a safe, effective, and long-term contraceptive method. Here, we review the effects of Cu-IUDs on subsequent pregnancy and the morphology, local coagulation function, sensitivity to estrogen and progesterone, cell proliferation, and immune response of the endometrium. Studies on the morphology of endometrium indicate that the use of Cu-IUDs can affect the number and binding capacity of estrogen and progesterone receptors in the endometrium and reduce the response of the endometrium to estrogen and progesterone. The use of Cu-IUDs can also affect the proliferation of endometrial cells, suggesting that the aseptic inflammation caused by Cu-IUDs may differ from chronic infectious or noninfectious inflammation; this highlights that the use of Cu-IUDs provides protection against endometrial proliferative diseases. The use of Cu-IUDs increases local endometrial angiogenesis, bleeding tendency, and fibrinolytic activity, which can result in prolonged menstruation or abnormal uterine bleeding. Additionally, the use of Cu-IUDs can cause the infiltration of numerous lymphocytes, monocytes, macrophages, and other inflammatory cells around the endometrial gland and changes in endometrial immune function, immune cell function, and the number and type of immune molecules. Cu-IUD-induced decidual injury significantly increases the invasiveness of trophoblasts, further affecting the aberrant expression of their growth-, angiogenesis-, and invasion-related factors and improving the formation of the placenta. Moreover, the endometrial damage caused by Cu-IUD placement before embryo transfer can improve both clinical pregnancy and live birth rates; however, specific changes in the immune system after Cu-IUD use as well as its effects on future pregnancies require further investigation.

10% lidocaine spray for pain control during intrauterine device insertion: a randomised, double-blind, placebo-controlled trial

BackgroundVarious medications have been investigated for their efficacy in pain reduction during intrauterine device (IUD) insertion, but there is currently no standard recommendation. This study aimed to investigate the efficacy...

Higher discontinuation rate with a standard-sized compared to a small-sized ‘gold standard’ copper intrauterine device: a case-control review

BackgroundT-shaped intrauterine devices (IUDs) with a copper surface area of 380 mm2 and copper bands on the transverse arms are the most effective types of copper-containing IUDs. A small-sized ‘gold...

Intrauterine Devices: Effective Contraception with Noncontraceptive Benefits for Adolescents.

Although adolescent pregnancy and birth rates have been declining since the early 1990s, the rate of intrauterine device (IUD) use in adolescents remain low. IUDs are a highly effective contraceptive method with a failure rate of less than 1%. There are currently 5 IUDs available and marketed in the United States: the nonhormonal copper-containing IUD (Paragard Copper T380A; Ortho-McNeil) and 4 hormonal levonorgestrel-releasing intrauterine systems (LNG-IUDs). IUDs can be used in adolescents, and the LNG-IUD has many noncontraceptive benefits including the treatment of heavy menstrual bleeding, dysmenorrhea, pelvic pain/endometriosis, and endometrial hyperplasia/endometrial cancer. In addition, the LNG-IUD is an effective tool for suppression of menses.

Risk assessment of copper-containing contraceptives: the impact for women with implanted intrauterine devices during clinical MRI and CT examinations.

To assess the risks for implant users with copper-containing intrauterine devices (IUDs) during MR and CT examinations. A tissue-mimicking phantom suitable for all experiments within this study was developed. Seven different types of copper IUDs were evaluated. Heating and dislocation of each IUD were investigated at two clinically relevant positions in 1.5T and 3T MR scanners. Artifacts in the field of view caused by each tested IUD were determined for clinical MR and CT imaging. No significant heating of any tested IUD was detected during MR measurements. The temperature increase was less than 0.6K for all IUDs. Neither angular deflection nor translation of any IUD was detected. Artifacts in MR images were limited to the very vicinity of the IUDs except for one IUD containing a steel-visualizing element. Streaking artifacts in CT were severe (up to 75.5%) in the slices including the IUD. No significant risk possibly harming the patient was determined during this phantom study, deeming MR examinations safe for women with an implanted copper IUD. Image quality was more impaired for CT than for MR imaging and needs careful consideration during diagnosis. • Risk assessment of copper-containing IUDs with regard to heating, dislocation, and artifacts during MR and CT imaging. • Neither significant heating nor dislocation was determined in MR; image quality was more impaired for CT than for MR imaging and needs careful consideration during diagnosis. • The tested IUDs pose no additional risks for implant users during MR and CT examinations.

Effect of a novel copper-containing intrauterine device material on the endometrial environment in rabbits

Objective(s)This study aimed to determine whether intrauterine placement of a novel composite material [copper (Cu) microparticles, low-density polyethylene, and methyl vinyl silicone rubber (Cu/LDPE/MVQ)] could prevent pregnancy in rabbits, and to evaluate the effects of Cu/LDPE/MVQ on the endometrial environment. Study DesignEighty sexually mature female rabbits were randomly divided into four groups (n=20 each group): control (sham-operated), LDPE/MVQ, Cu/LDPE/MVQ microcomposite, and bare Cu. Ten rabbits from each implant-bearing group were randomly selected for a mating experiment beginning 30 days after insertion. Pregnancy outcomes were observed 15 days after mating. Factors associated with endometrial bleeding and inflammation in the remaining rabbits in each group, and the surface conditions of the implants, were investigated 90 days post-insertion. ResultsThe Cu (0 embryo) and Cu/LDPE/MVQ (0 embryo) groups had significantly fewer embryos than the LDPE/MVQ (1.0±0.6 embryos, p<.05) and sham-operated groups (4.1±1.3 embryos, p<.05). Compared with bare Cu, the Cu/LDPE/MVQ composite material was associated with considerable reductions in injuries and factors associated with abnormal endometrial bleeding and inflammation, such as matrix metalloproteinase 9 (MMP9) and prostaglandin E2 (PGE2). Additionally, the surface of implanted Cu/LDPE/MVQ remained much smoother than that of implanted bare Cu. Conclusion(s)This novel Cu-containing intrauterine device material exhibits a similar effect in prevention of pregnancy with bare copper, and lower levels of inflammatory markers. ImplicationsThis study demonstrates the potential of the novel Cu/LDPE/MVQ microcomposite material as a future substitute for conventional intrauterine device materials.

Antifertility effectiveness of a novel copper-containing intrauterine device material and its influence on the endometrial environment in rats

This study was designed to investigate the antifertility effectiveness of a novel copper-containing intrauterine device material containing a composite of micro-copper (Cu), low-density polyethylene (LDPE), and methyl vinyl silicone rubber (MVQ) and its effects on the endometrial environment in rats. The contraceptive effectiveness was examined 12 days after pregnancy. The pathological changes; factors associated with bleeding, pain, and inflammation in the endometrium; and the surface condition of the implants were investigated after insertion for 90 days. Furthermore, the release rate of copper ions in simulated uterine solution (SUS) was investigated for 270 days. The contraceptive effectiveness was 100% in both the bulk Cu and micro-Cu/LDPE/MVQ groups, and that in the LDPE/MVQ group was 30%. On day 90 after insertion, histopathological observation and the ultrastructural changes in the endometrium showed that the damage caused by bulk Cu was much more severe than that caused by the Cu/LDPE/MVQ microcomposite and that the surface of the latter was much smoother than that of the former. Furthermore, compared with the sham-operated control group, the concentrations of tissue plasminogen activator and prostaglandin E2 were significantly increased 90 days after insertion in all of the experimental groups except for the LDPE/MVQ group (P < 0.05), and the parameters in the Cu/LDPE/MVQ group were significantly lower than those in the Cu group (P < 0.05). In addition, the expression levels of matrix metalloproteinase 9, metalloproteinase 1 tissue inhibitor, plasminogen inhibitor 1, CD34, vascular endothelial growth factor, substance P, and substance P receptor in the endometrium in all of the experimental groups were significantly lower than those in the Cu group 90 days after insertion (P < 0.05). The results of this study indicate that micro-Cu/LDPE/MVQ exhibits satisfactory contraceptive efficacy and causes fewer side effects than Cu.

Retained intrauterine devices in pregnancy.

With typical use, unintended pregnancy rates in the first year after insertion are 0.8% for the copper-containing intrauterine device (IUD) and 0.2% for the levonorgestrel-releasing intrauterine system.[2][1] A systematic review in 2012 found increased rates of spontaneous abortion (48%–77%) and

The effect of depot medroxyprogesterone acetate on postnatal depression: a randomised controlled trial

BackgroundDepot medroxyprogesterone acetate (DMPA) is the most commonly used hormonal contraceptive method in South Africa. It is frequently administered in the immediate postnatal period, yet it is unclear whether it...

Advantages and disadvantages of emergency postcoital contraception

Emergency postcoital contraception (EPC) also known as 'emergency contraception' and 'morning after pill' is an easy way to prevent conceiving and it can be purchased in many countries without any prescription. EPC offers an important chance to prevent an unintended pregnancy when a regular method fails, no method was used, or sex was forced. The currently available options include an estrogen-progestin combination (ethinyl estradiol with levonorgestrel), progestin alone (levonorgestrel), the ulipristal acetate, the antiprogestin synthetic steroid mifepristone (RU-486), estrogen alone (high-dose ethinyl estradiol) and the Copper T intrauterine device (IUD). EPC pills, which may be more accessible than an emergency IUD, reduce the chance that pregnancy will happen after a single act of intercourse by at least 50 percent. The Copper T IUD is the most effective form of emergency contraception with an estimated failure rate of less than 1%. EPC is a simple safe emergency method to reduce the chance of pregnancy and EPC pills do not harm an existing pregnancy. EPC is not suitable for women who cannot take birth control pills, it does not protect against sexually transmitted infections and should not be used as a regular method of birth control. The sooner the pills are taken, the better it is. The effect or the potential of EPC diminishes over time. It may have some temporary side effects such as nausea and vomiting, delay in menses, irregular vaginal bleeding, abdominal pain, headache, dizziness, and fatigue. If these side effects occur, they generally resolve within 24 hours of the pill use. Side effects of the copper-containing IUD are also rare, but may include menstrual cramping or increased menstrual flow.

Interventions for pain with intrauterine device insertion.

Fear of pain during insertion of intrauterine contraception (IUC) is a barrier to use of this method. IUC includes copper-containing intrauterine devices and levonorgestrel-releasing intrauterine systems. Interventions for pain control during IUC insertion include non-steroidal anti-inflammatory drugs (NSAIDs), local cervical anesthetics, and cervical ripening agents such as misoprostol. To review randomized controlled trials (RCTs) of interventions for reducing IUC insertion-related pain We searched for trials in CENTRAL, MEDLINE, EMBASE, POPLINE, ClinicalTrials.gov, and ICTRP. The most recent search was 22 June 2015. We examined reference lists of pertinent articles. For the initial review, we wrote to investigators to find other published or unpublished trials. We included RCTs that evaluated an intervention for preventing IUC insertion-related pain. The comparison could have been a placebo, no intervention, or another active intervention. The primary outcomes were self-reported pain at tenaculum placement, during IUC insertion, and after IUC insertion (up to six hours). Two authors extracted data from eligible trials. For dichotomous variables, we calculated the Mantel-Haenszel odds ratio (OR) with 95% confidence interval (CI). For continuous variables, we computed the mean difference (MD) with 95% CI. In meta-analysis of trials with different measurement scales, we used the standardized mean difference (SMD). We included 33 trials with 5710 participants total; 29 were published from 2010 to 2015. Studies examined lidocaine, misoprostol, NSAIDs, and other interventions. Here we synthesize results from trials with sufficient outcome data and moderate- or high-quality evidence.For lidocaine, meta-analysis showed topical 2% gel had no effect on pain at tenaculum placement (two trials) or on pain during IUC insertion (three trials). Other formulations were effective compared with placebo in individual trials. Mean score for IUC-insertion pain was lower with lidocaine and prilocaine cream (MD -1.96, 95% CI -3.00 to -0.92). Among nulliparous women, topical 4% formulation showed lower scores for IUC-insertion pain assessed within 10 minutes (MD -15.90, 95% CI -22.77 to -9.03) and at 30 minutes later (MD -11.10, 95% CI -19.05 to -3.15). Among parous women, IUC-insertion pain was lower with 10% spray (median 1.00 versus 3.00). Compared with no intervention, pain at tenaculum placement was lower with 1% paracervical block (median 12 versus 28).For misoprostol, meta-analysis showed a higher mean score for IUC insertion compared with placebo (SMD 0.27, 95% CI 0.07 to 0.46; four studies). In meta-analysis, cramping was more likely with misoprostol (OR 2.64, 95% CI 1.46 to 4.76; four studies). A trial with nulliparous women found a higher score for IUC-insertion pain with misoprostol (median 46 versus 34). Pain before leaving the clinic was higher for misoprostol in two trials with nulliparous women (MD 7.60, 95% CI 6.48 to 8.72; medians 35.5 versus 20.5). In one trial with nulliparous women, moderate or severe pain at IUC insertion was less likely with misoprostol (OR 0.30, 95% CI 0.16 to 0.55). In the same trial, the misoprostol group was more likely to rate the experience favorably. Within two trials of misoprostol plus diclofenac, shivering, headache, or abdominal pain were more likely with misoprostol. Participants had no vaginal delivery. One trial showed the misoprostol group less likely to choose or recommend the treatment.Among multiparous women, mean score for IUC-insertion pain was lower for tramadol 50 mg versus naproxen 550 mg (MD -0.63, 95% CI -0.94 to -0.32) and for naproxen versus placebo (MD -1.94, 95% CI -2.35 to -1.53). The naproxen group was less likely than the placebo group to report the insertion experience as unpleasant and not want the medication in the future. An older trial showed repeated doses of naproxen 300 mg led to lower pain scores at one hour (MD -1.04, 95% CI -1.67 to -0.41) and two hours (MD -0.98, 95% CI -1.64 to -0.32) after insertion. Most women were nulliparous and also had lidocaine paracervical block. Nearly all trials used modern IUC. Most effectiveness evidence was of moderate quality, having come from single trials. Lidocaine 2% gel, misoprostol, and most NSAIDs did not help reduce pain. Some lidocaine formulations, tramadol, and naproxen had some effect on reducing IUC insertion-related pain in specific groups. The ineffective interventions do not need further research.