SMFM Papers. The intrauterine device (IUD) is the. Pregnancy outcome in women with. with an intrauterine contraceptive device.

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1 Pregnancy outcome in women with an intrauterine contraceptive device Hadas Ganer, BA; Amalia Levy, PhD; Iris Ohel, MD; Eyal Sheiner, MD, PhD OBJECTIVE: To investigate pregnancy outcome in patients who conceived with an intrauterine contraceptive device. STUDY DESIGN: A retrospective study comparing the pregnancy outcome of women with retained intrauterine device, patients after intrauterine device removal in early pregnancy, and pregnancies without an intrauterine device (n 141,191) was performed. RESULTS: A significant linear association was documented among the 3 groups and adverse outcomes such as preterm delivery (18.4% in the retained intrauterine device, 14.4 % in removed intrauterine device, and 7.3% in the no-intrauterine device group; P.001) and chorioamnionitis (7.1% in the retained intrauterine device, 4.1% in removed intrauterine device and 0.7% in the no-intrauterine device group; P.001). The presence of retained or removed intrauterine device was found as an independent risk factor for both preterm delivery and chorioamnionitis in multivariable models. CONCLUSION: Women conceiving with an intrauterine device are at increased risk for adverse obstetric outcomes, whereas the risk is higher for pregnancies with retained intrauterine device compared with early intrauterine device removal. Key words: chorioamnionitis, intrauterine device, low birthweight, obstetric outcome, premature labor Cite this article as: Ganer H, Levy A, Ohel I, et al. Pregnancy outcome in women with an intrauterine contraceptive device. Am J Obstet Gynecol 2009;201:381.e1-5. The intrauterine device () is the second most popular contraceptive method worldwide, after sterilization. The estimation is that 15% of the world s women of reproductive age (160 million women) use it. 1 It provides at least 5 years of protection 2 with % effectiveness in preventing pregnancy. 1 The presence of the device in the uterine causes local release of prostaglandins and leukocytes from the endometrium (and progesterone from the proper devices), which in turn creates a hostile environment for the oocyte and sperm, From the Faculty of Health Sciences, Joyce and Irving Goldman Medical School (Mrs Ganer), and the Departments of Epidemiology and Health Services Evaluation (Dr Levy) and Obstetrics and Gynecology (Drs Ohel and Sheiner), Soroka University Medical Center, Ben Gurion University of the Negev, Be er-sheva, Israel. Presented at the 29th Annual Meeting of the Society for Fetal-Maternal Medicine, San Diego, CA, Jan , Received Feb. 26, 2009; revised May 19, 2009; accepted June 11, Reprints not available from the authors /$ Published by Mosby, Inc. doi: /j.ajog whereas the copper has an independent spermatocytic effect. 3-5 Despite the high percentage of effectiveness noted so far, pregnancy in the presence of an can occur, and involves several complications. One of the most noted complications is ectopic pregnancy. 6-8 Further complications of pregnancy in the presence of an include premature labor and abortion, 9 which have also been studied in women who had the device removed at the beginning of their pregnancy. 10 A comprehensive research regarding these complications included 201 women who conceived with s, which were removed in 81 patients. 10 This study found a significant difference in the combined rate of preterm labor and miscarriages amomg the groups, whereas in the group of women who had their s left, 48.4% had an abortion, as opposed to 29.6% in the group of women who had the device removed. In another study, 11 the birthweight of newborn infants born in pregnancies with s was found to be low in contrast to pregnancies in which the was removed before conceiving. This study examined 5700 pregnancies, from which 289 pregnancies were unplanned and the had been removed. A higher rate of low birthweights was noted in this group, as the average birthweight in this group was lower in comparison to pregnancies with no s (3.27 kg and 3.47 kg, respectively). No differences were found in relation to congenital malformations among the groups of woman with s, women who had it removed, and women with no. 12 Later evidence points to a rise in the incidence of cleft lip in pregnancies with s, 13 although this was reported based on a small series of 10 pregnancies with s. A number of different trials were conducted regarding the specific variables associated with the presence of an that cause such complications. 14 Dislocation of the device was found to be an important factor affecting the course of pregnancy, 15 a phenomenon most common in the first years after the insertion of an. The World Health Organization has a recommendation protocol regarding the sequence of actions to be taken in the event of a pregnancy in the presence of an. 16 This protocol includes ruling out ectopic pregnancy and a recommendation to remove the if the string is visible and the device can easily be removed through the cervix. This recommendation is based mainly on articles from the 1970s and 1980s, whereas the most up-to-date article by which the OCTOBER 2009 American Journal of Obstetrics & Gynecology 381.e1

2 protocol is supported includes a research group of only 10 women. 16 In light of the limited research of pregnancies with s, the need arises for a research with a large series of pregnancies, which will supply an up-to-date conclusion regarding obstetric complications that occur in the presence of and the incidence of complications after removal of the device at the beginning of the pregnancy. We hypothesized that the highest risk for adverse perinatal outcomes (such as chorioamnionitis and preterm delivery) would be found for the retained group, moderate risk would be found for removed, and the lowest risk for the no- group. MATERIALS AND METHODS A population-based study comparing all pregnancies of woman with an, after at the beginning of the pregnancy, and without was conducted. Deliveries occurred during the years at the Soroka University Medical Center, which serves the entire population in the southern region of Israel. Data were collected from the computerized perinatal database. The information was recorded directly after delivery by an obstetrician. Attribution of the study groups was based on ICD9 coding: ICD9 code v45.51 for deliveries of women with retained ; ICD9 code z97.71 for deliveries of women who had it removed at the beginning of their pregnancy (removal of is basically performed during the first trimester on diagnosis of pregnancy), and a control group of deliveries of women with no. Coding is performed after careful evaluation of the medical prenatal care records, as well as the routine hospital documents. Only 4 skilled medical secretaries examined the information routinely before entering it into the database. These procedures ensure the completeness and accuracy of the database, which was previously validated with an excellent kappa of 90%. 17 The hospitalization documents of women with s were retrieved from the Soroka hospital archives to gather information regarding the type of and its duration of usage, which is not included in the computerized database. All pregnancies of at least 22 weeks of gestation were included, although nulligravid deliveries were excluded from the analysis (because no cases of were noted among these patients). Deliveries of woman with no prenatal care and multiple gestations were also excluded from the analysis. Clinical characteristics were noted: maternal age, number of pregnancies, parity and gestational age. The following obstetric risk factors were examined: fertility treatments, hypertensive disorders (defined as mild-to-severe preeclampsia or chronic hypertension), gestational, and pregestational diabetes mellitus. The following labor characteristics and perinatal outcomes were assessed: intrauterine growth restriction (IUGR), malpresentation, premature rupture of membranes (PROM), labor induction, placental abruption, placenta previa, meconium-stained amniotic fluid, mode of delivery, Apgar score at 1 and 5 minutes, birthweight, congenital malformations, tubal ligation, perinatal mortality, and chorioamnionitis. Chorioamnionitis was defined clinically, as the presence of uterine tenderness and/or purulent or malodorous amniotic fluid with any 2 of the following: antepartum temperature of more than 37.8 C (100.4 F), maternal tachycardia ( 120 beats/min), maternal leucocytosis ( 18,000 cells/mm 3 ), or fetal tachycardia ( 160 beats/min). 18 The local ethics institutional board approved this study. Statistical analysis was preformed by using the SPSS package (SPSS, Inc., Chicago, IL). Statistical significance was calculated by using the 2 test, Fisher exact test or the linear by linear test for differences in qualitative variables, and the t test for differences in continuous variables. The linear by linear association 2 (or the Mantel-Haenszel test for linear association) is an ordinal measure of significance, which is preferred when testing the significance of linear relationship between ordinal variables. 19 Multivariable categorical logistic regression models were constructed to control for confounders. Women with, after removal and without included in the models as dummy variables, while women without were the reference group. Odds ratios (OR) and their 95% confidence intervals (CI) were computed. A P.05 was considered statistically significant. The sample size was calculated according to an of 5% and a power of 80% in regard to preterm labor and low birthweight, which occur at a rate of 7-10% in the general population. To receive statistically significant results a sample of 90 pregnancies is required, so that the sample in this study and is adequate for investigating the research s objectives. RESULTS Of 141,483 singleton gestations that occurred during the 19-year period of the study, 292 were of women who conceived with an, which was removed in 194 women during early pregnancy. All s were copper-based devises. Clinical characteristics of women differed between the 2 groups as noted in Table 1. Table 2 summarizes obstetric risk factors among the 3 groups. Gestational diabetes was found to be more prevalent in the group as compared with patients with or without. Likewise, previous cesarean delivery was more common in both the group and the group as compared with patients without. A significant linear association was documented among the 3 groups and adverse outcomes, including PROM, placental abruption, placenta previa, preterm delivery, cesarean delivery, Apgar scores lower than 7 at 5 minutes, low birthweights, congenital malformations, and chorioamnionitis (Table 3). There were 21 cases of malformations in the groups, which were all structural. No chromosomal anomalies were noted. The malformations consisted of 65% cardiac malformations (including patent foramen ovale, patent ductus arteriosus, tricuspid regurgitation, ventricular septal defect, and atrial septal defect), 18% genitourinary malformations (undescended testis and hydronephrosis), 12% digital anomalies (such as syndactily), and 5% others (club foot). 381.e2 American Journal of Obstetrics & Gynecology OCTOBER 2009

3 SMFM Papers TABLE 1 Clinical characteristics of women with, after and without By using a multiple logistic regression model controlling for confounders of maternal age and parity, usage and removal were both found to be independent risk factors for preterm delivery 37 weeks (Table 4). While controlling for PROM and gestational age, both usage and removal were found to be independent risk factors for chorioamnionitis (Table 4). (n 141,191) P Mean maternal age (y SD) Number of pregnancies % 54.1% 58.3% % 45.9% 41.7% Parity % 67.5% 68.1% % 32.5% 31.9% Mean gestational age (wk SD), intrauterine device; SD, standard deviation. TABLE 2 Obstetric risk factors of women with, after and without (n 141,191) P Fertility treatments 0% 1.0% 1.0%.600 Hypertensive disorders 4.1% 6.2% 5.2%.720 Mild preeclampsia 2.0% 3.1% 2.8%.870 Severe preeclampsia 0% 0.5% 0.8%.590 Chronic hypertension 2.0% 3.1% 1.9%.500 Diabetic disorders 3.1% 13.4% 7.3%.001 Gestational diabetes 3.1% 11.9% 5.8%.001 Diabetes mellitus 0% 1.5% 1.5%.480 Polyhydramnions 4.1% 5.2% 4.6%.900 Oligohydramnions 1.0% 2.6% 2.0%.670 Previous cesarean delivery 19.4% 21.6% 15.4%.020 Recurrent abortions 4.1% 6.4% 6.4%.270, intrauterine device. COMMENT The major finding of our populationbased study was that conceiving with an is a significant risk factor for adverse maternal and perinatal outcomes. Moreover, a significant linear-by-linear association exists between (1) a retained throughout pregnancy, (2) an that was removed during early pregnancy, and (3) no, regarding critical outcomes such as preterm delivery and chorioamnionitis. s retained and removed were found to be independent risk factors for both preterm delivery and chorioamnionitis, whereas the risk was higher for pregnancies with retained as compared with early. It can be speculated that the mechanism of chorioamnionitis is a reactive inflammation caused by the presence of a foreign body the, that may also evolve a secondary infection. Therefore, the removal of the device in early pregnancy reduces the risk for chorioamnionitis and preterm delivery, but does not fully diminish it in comparison to pregnancies with no such exposure. Previous studies 9-11 have found similar adverse obstetric outcomes in women carrying an, for example, preterm delivery, low birthweight, and chorioamnionitis. Nevertheless, these studies were relatively small. Our study design allows for the investigation of obstetric parameters that have not been previously examined in large study groups. Moreover, unlike most other studies, we have included a control group of pregnancies with no usage, for comparison to pregnancies with s and pregnancies in which the was removed. When we include a comparison group of pregnancies with no usage, a higher rate of adverse outcomes was demonstrated for the group vs normal pregnancies. This stands in contrast to previous studies, 20 in which removal was found to reduce rates of preterm delivery when compared with retained s, and bears significant clinical importance as to counseling and management of such pregnancies. Because s are inserted in multipara women in Israel, the cases of deliveries of women with s were only found in multigravida deliveries. Therefore, nulligravida deliveries were excluded. Likewise, lack of prenatal care and multigestational deliveries were excluded, because such variables are risk factors of obstetric complications. Our study has several inherent weaknesses, because of its retrospective design. Because the removal of s is not performed in a hospital but rather in outpatient settings, we did not have data OCTOBER 2009 American Journal of Obstetrics & Gynecology 381.e3

4 TABLE 3 Pregnancy and labor complications and outcome of patients with, after and without (n 141,191) P linear by linear IUGR 1.0% 0.5% 1.7%.254 Bleeding during second trimester 0% 0.5% 0.1%.179 Malpresentation 8.2% 8.8% 4.9%.008 PROM 10.2% 7.7% 5.7%.021 Perinatal mortality 1.0% 1.5% 1.2%.952 Placental abruption 4.1% 2.1% 0.7%.001 Placenta previa 4.1% 0.5% 0.5%.001 Average gestational age (wk SD) Preterm delivery ( 37 wks) 18.4% 14.4% 7.3%.001 Induction of labor 23.5% 25.8% 23%.528 Cesarean delivery 31.6% 20.6% 12.8%.001 Apgar at 1 min 5 2.1% 4.1% 1.8%.103 Apgar at 5 min 5 1% 0% 0.3%.470 Apgar at 1 min 7 3.5% 7.3% 3.5%.336 Apgar at 5 min 7 3.1% 0% 0.5%.026 Average birthweight (kg SD) Birthweight 2.5 kg 11.2% 13.4% 6.7%.001 Birthweight 1.5 kg 5.1% 3.6% 1.1%.001 Malformations 10.2% 5.7% 5.1%.041 Chorioamnionitis 7.1% 4.1% 0.7%.001 Uterine rupture 0% 0% 0.1%.691 Tubal ligation 13.3% 4.1% 1.9%.001 Postpartum hemorrhage 1.0% 0.5% 0.5%.582, intrauterine device; IUGR, intrauterine growth restriction; PROM, premature rupture of membranes; SD, standard deviation. TABLE 4 Multiple logistic regression models of risk factors for preterm delivery and choriamninitis a Model OR 95% CI P PTD Maternal age Parity usage Choriamnionitis PROM Gestational age usage CI, confidence interval;, intrauterine device; OR, odds ratio; PROM, premature rupture of membranes; PTD, preterm delivery. a The models also included the year of delivery. regarding the exact gestational age at removal of the and whether it affected the rate of preterm birth or other outcomes. It would seem possible that early removal might prove to be substantially less risky than late removal and at some late gestational age removal is no safer than leaving the device in place. This point deserves further attention when planning future prospective studies to formulate accurate recommendations in cases of pregnancies diagnosed in women who have an. Another issue is the length of use of an before conceiving. Hospitalization documents of patients from the group and removal group were retrieved and examined for information regarding the 381.e4 American Journal of Obstetrics & Gynecology OCTOBER 2009

5 SMFM Papers length of use before conceiving. Unfortunately, such information was not located in most files, thereby raising the need for further investigation regarding the influence of such variables on the adverse outcomes demonstrated. The rate of gestational diabetes and previous cesarean deliveries was significantly higher in the group (Table 2), whereas diabetes mellitus was equally prevelant in all 3 groups. This raises the question as to whether these risk factors are in fact the reason the was removed once the pregnancy was confirmed. Although the removal of was performed during the first trimester of pregnancy, whereas gestational diabetes is diagnosed only after 24 weeks (when the diagnostic glucose tolerance test is performed), it is not likely that diabetes was the indication for the. It is also not probable that efficacy is reduced in women with a scared uterus caused by the malpositioning of the device or a high expulsive rate, although there is scarce data on this topic. Nevertheless, one study 21 showed no statistically significant differences in expulsion rates or other pertinent event rates among women with previous cesarean deliveries. In conclusion, women conceiving with an should be informed regarding these outcomes, because reduces the risk for adverse obstetric outcomes, but does not eliminate it. Careful surveillance of high-risk pregnancies is warranted, as well as neonatal surveillance in the case of preterm and chorioamnionitic deliveries. f REFERENCES 1. Maurice J. The intrauterine device () worth singing about. Progress in Reproductive Health Research, World Health Organization 2002; 60: Rowe PJ, Boccard S, Farley TMM, Peregoudov S. Long-term reversible contraception twelve years of experience with the TCu380A and TCu220C. Contraception 1997;56: Mechanisms of the contraceptive action of hormonal methods and intrauterine devices (s). Family Health International Keller S. s block fertilization. Network Family Health International 1996;16 5. Stanford J, Mikolajczyk R. Mechanisms of action of intrauterine devices: update and estimation of postfertilization effects. Am J Obstet Gynecol 2002;187: Sivin I. s and ectopic pregnancy. Contraception 1995; 52: Skjeldestad FE, Hammervold R, Peterson DR. Outcomes of pregnancy with an in situ - a population based case-control study. Adv Contracept 1988; Furlong LA. Ectopic pregnancy risk when contraception fails. J Reprod Med 2002; 47: Rollnik JD, Lück HJ, Giersig C. Two cases of abortion and premature birth after removal of a levonorgestrel-releasing intrauterine system. Eur J Contracept Reprod Health Care 2002;7: Alvior GT Jr. Pregnancy outcome with removal of intrauterine device. Obstet Gynecol 1973;41: Pill, users run no increased risk of ectopics, malformation, miscarriage in planned pregnancies. Fam Plann Perspect 1980;12: Simpson JL. Do contraceptive methods pose fetal risks? Res Front Fertil Regul 1985; 3: Fulcheri E, di Capua E, Ragni N. Pregnancy despite : adverse effects on pregnancy evolution and fetus. Contraception 2003; 68: Dunn JS Jr, Zerbe MJ, Bloomquist JL, Ellerkman RM, Bent AE. Ectopic complicating pregnancy. J Reprod Med 2002;47: Inal M, Ertopçu K, Ozelmas I. The evaluation of 318 intrauterine pregnancy cases with an intrauterine device. Eur J Contracept Reprod Health Care 2005;10: Selected practice recommendations for contraceptive use, 2nd ed. Geneva, Switzerland: World Health Organization; Ofir K, Sheiner E, Levy A, Katz M, Mazor M. Uterine rupture: differences between a scarred and an unscarred uterus. Am J Obstet Gynecol 2004;191: Ramsey PS, Lieman JM, Brumfield CG, Carlo W. Chorioamnionitis increases neonatal morbidity in pregnancies complicated by preterm premature rupture of membranes. Am J Obstet Gynecol 2005;192: Agresti A. Introduction to categorical data analysis. NewYork: John Wiley; 1996: Hnat M, Vu J, Mcintire D. Pregnancy outcomes in women with intrauterine device contraceptive failure. Am J Obstet Gynecol 2005;193:s Chi IC, Balogh S. Interval insertion of intrauterine device in women with previous cesarean section. Contraception 1984;30: OCTOBER 2009 American Journal of Obstetrics & Gynecology 381.e5