
==== Front
Medicine (Baltimore)
Medicine (Baltimore)
MD
Medicine
0025-7974
1536-5964
Lippincott Williams & Wilkins Hagerstown, MD

39252281
MD-D-23-09163
00068
10.1097/MD.0000000000039448
3
5600
Research Article
Observational Study
Perinatal outcomes with a copper intrauterine device in situ after 28 gestational weeks: A retrospective study of sole center in southeast China
Chen Xiuying MD, PhD chenxiuying2007@zju.edu.cn
a
https://orcid.org/0000-0002-9526-2278
Zhao Baihui MD ab*
a Department of Obstetrics and Gynecology, Center for reproductive Medicine, The Fourth Affiliated Hospital of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, Zhejiang, China
b School of Medicine, Women’s Hospital, Zhejiang University, Hangzhou, Zhejiang, China.
* Correspondence: The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang 322300, China; Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, China (e-mail: zhaobh@zju.edu.cn).
06 9 2024
06 9 2024
103 36 e3944818 10 2023
02 8 2024
05 8 2024
Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal.

The purpose of this study was to investigate the pregnancy outcomes with a copper intrauterine device (IUD) in situ after 28 gestational weeks and the association between pregnancy with copper IUDs and neonatal congenital malformations. This retrospective study had compared the singleton pregnancies with the copper IUDs in situ and without after 28 gestational weeks in 1 delivery center of southeast China. The main exposure was a copper IUD in uterine cavity with pregnancy. The pregnant outcomes as preterm birth, premature rupture of membranes, infections were observed and compared. We had also compared neonatal congenital malformations in 2 groups. The statistical analysis was carried out using R (version 4.0.4; R Development Core Team) statistical software. Association between IUD use or duration of IUD use and adverse pregnancy outcomes were estimated using logistic model. Two-tailed P value < .05 was deemed statistically significant. A total of 148 pregnant women were included in our study, 74 with copper IUDs in situ were categorized into case group and 74 without IUDs during pregnancy into control group. No significant difference of maternal age, BMI, birth weight and gender were observed between 2 groups. In case group, the rates of preterm premature rupture of membranes (37.8%) and spontaneous preterm birth (23.0%) were significantly high compared to control group. Odds ratios of premature rupture of membranes and spontaneous preterm birth were 2.86 and 5.22 respectively. Women of elder age (≥35 years) in case group were more likely to experience premature rupture of membranes. The rates of neonatal congenital malformation were 10.8% (8/74) in case group and 1.4% (1/74) in control group respectively. We had found that pregnancy with copper IUD in situ increased the risk of premature rupture of membranes and spontaneous preterm birth after 28 gestation weeks, the risk of spontaneous preterm birth increased 5.22 times. Pregnancy with IUD in situ may be at increased risk of infection and neonatal malformation.

copper intrauterine device
neonatal congenital malformation
pregnancy
preterm delivery
preterm premature rupture of the membranes
OPEN-ACCESSTRUE
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pmc 1. Introduction

When properly situated, the copper intra-uterine devices (IUDs) are the most widely used and reliable forms of reversible contraception.[1] The effectiveness of copper IUDs can be comparable with permanent contraception. The approved duration of copper IUDs from Food and Drug Administration was varied from 3 to 10 years depending on the ingredient used. Available data support contraceptive effectiveness of the copper IUDs for up to 12 years.[2] In China, currently available copper IUDs are licensed for duration of 8 to 10 years. Contraception with copper IUDs is highly effective, long acting, and can rapidly reverse after removal. Since 2015, the World Health Organization (WHO) and many regional and national guidelines have recommended copper IUDs to be one of the primary long-acting reversible contraceptive methods for nulliparous women to reduce unplanned pregnancy.[3,4]

Unplanned pregnancies as a contraceptive failure of copper IUDs are rare. With typical-use, the failure rate for copper IUDs ranged from 0.2% to 1.0%.[5] The cumulative failure rate for copper IUDs at 10 years ranged from 2.2 to 7.2 pregnancies per 100 women.[6] Previous study showed that pregnancy with IUDs in situ increased risks of preterm delivery, spontaneous abortion and septic abortion,[7] but has no maternal toxicity. Besides, Schaeffer et al[5] reported women with IUD lower prevalence of maternal hypertension or preeclampsia during pregnancy. Unfortunately, limited data was existed regarding neonatal outcomes, which was of great significance for the public health.[8,9]

As early as 1981, Barlow et al found that IUDs in rodents would release embryotoxic agents which could threat embryo development, malformation in fetal brain and liver.[6,8,10] When intrauterine pregnancy is detected in a patient with IUD, evaluations is performed with ultrasonographic examination to determine the exact locations of pregnancy and IUD. Detailed counseling about risks and outcomes of intrauterine pregnancy with an IUD should be given to patients. When the pregnant woman decides to continue her pregnancy, the IUDs were removed if strings were visible, according to the WHO recommends.[11] A 2012 systematic review had found an increased risk of preterm birth, spontaneous abortion with IUDs retained and early IUD removal appeared to improve pregnancy outcomes.[7] More recently, based on National Inpatient Sample database of the United States of American, researchers also had found that pregnancy with IUD in situ had an increased risk of spontaneous and induced abortions, and preterm deliveries.[5] Reports of perinatal outcomes about Chinese pregnant women with copper IUD in situ is rare. As a result, most pregnancies with IUD in uterus will remove the IUD during the 1st and 2nd-trimester. Purpose of this retrospective study was to observe the perinatal outcomes after 28 gestational weeks (3rd trimester) in Chinese women with copper IUDs in situ, and the association between copper IUD and fetal anomaly.

2. Materials and methods

This retrospective comparative study had recruited those patients who experienced accidental singleton pregnancy with the copper IUD in situ and had surpassed 28 gestational weeks from March 2006 to March 2018 in Women’s Hospital of Zhejiang in China. We had searched the same database of singleton pregnancy without using IUDs contemporaneously and had randomly sampled one of the matched gestational weeks, age and body mass index (BMI) as control. Medical records of cases and controls were directly recruited by using hospital patient database. This study was approved by the Ethics Committees of Women’ hospital, School of Medicine Zhejiang University and Approval number 20170193.

Pregnant women with the following situations were ruled out: multiple pregnancy; premature rupture of membranes before 28 gestational weeks; maternal medical disorders before 28 weeks (e.g. hypertension, heart disease, asthma, diabetes and thyroid disease); pregnancy woman with a history of neonatal congenital malformation, fetal or neonatal death; previous history of preterm delivery and incompletion of perinatal outcomes in cases or controls.

The statistical analysis was carried out using R (version 4.0.4; R Development Core Team, New Jersey) statistical software. The normality of the distribution of continuous variables was presented as mean ± SD and analyzed with Shapiro–Wilk test. Since the data were non-normally distributed, medians (quartile range) were reported for continuous variables. Categorical variables were presented as numbers and percentages (%). A chi-squared test was used to analysis categorical variables, and a Wilcoxon rank sum test was used for the analysis of non-normally distributed continuous variables. Association between IUD use or duration of IUD use and adverse pregnancy outcomes were estimated using logistic model. And we included 2 multivariate adjusted models using covariates collected. In model a, we adjusted for age and BMI. In model b, we additionally adjusted for birth weight, history of abortion, parity. Then we conducted a stratified analysis according to age, and further adjusted the model using BMI, birth weight. Two-tailed P value < .05 was deemed statistically significant.

3. Results

A total of 148 pregnancy women were included in our study, 74 with copper IUD in situ were categorized into case group and 74 without IUD during pregnancy into control group. No significant difference of maternal age, BMI, history of abortion, birth weight, gender and gestational weeks at birth were observed between 2 groups. There were more primiparas in control group. Maternal pregnancy outcomes of placenta previa and abruption, hypertension, iatrogenic preterm birth in 2 groups were no statistical difference. There were 28 (37.8%) of case group and 13 (17.6%) of control group encountered premature rupture of membranes. The spontaneous preterm birth rate was 23% and 5.4% respectively. Six of case group had experienced infection of puerperal or neonatal. Significant increased incidence of premature rupture of membranes, spontaneous preterm birth and infection were observed in case group. The rates of neonatal congenital malformations were 10.8% (8/74) in case group and 1.4% (1/74) in control group respectively. Only 1 fetal cardiovascular malformation observed in control group, the others were in the case group, including 3 fetal cardiovascular malformation, 3 fetal surface deformity and 2 other fetal malformations. There was statistically significant difference in the rate of neonatal congenital malformations between 2 groups (P = .033; Table 1). The IUD were used >9 years in 6 of 8 cases. One neonatal death occurred in IUD group due to low birth weight combined with respiratory distress syndrome. Demographic characteristics, pregnancy details of the patients and distribution of the complications are shown in Table 1.

Table 1 Characteristics of IUD users and non-users.

	Overall (n = 148)	IUD (n = 74)	None (n = 74)	P	
Age (median, yr)	32.36 ± 5.67	32.69 ± 5.78	32.04 ± 5.57	.488	
BMI	26.92 ± 3.02	26.88 ± 3.27	26.95 ± 2.80	.905	
Birth weight* (%)				.174	
 Low birth weight (<2500 g)	34 (23.1)	21 (28.8)	13 (17.6)		
 Normal birth weight (2500~4000 g)	106 (72.1)	50 (68.5)	56 (75.7)		
 Fetal macrosomia (>4000 g)	7 (4.8)	2 (2.7)	5 (6.7)		
Neonatal gender (%)				1	
 Male	85 (58.2)	42 (58.3)	43 (58.1)		
 Female	61 (41.8)	30 (41.7)	31 (41.9)		
Gestational week at birth (median, wk)	38.0 (36.0, 39.0)	38.00 (35.8, 39.0)	38.0 (37.0, 39.0)	.242	
History of abortion (%)				.616	
 0	59 (40.4)	27 (37.5)	32 (43.3)		
 1	57 (39.0)	31 (43.1)	26 (35.1)		
 ≥2	30 (20.6)	14 (19.4)	16 (21.6)		
Parity (%)					
 0	24 (16.4)	4 (5.6)	20 (27.0)	.001	
 ≥1	122 (83.6)	68 (94.4)	54 (73.0)		
Placental abruption* (%)	5 (3.4)	2 (2.7)	3 (4.1)	1	
Placenta previa* (%)	4 (2.7)	1 (1.4)	3 (4.1)	.620	
Hypertension of pregnancy (%)	12 (8.1)	6 (8.1)	6 (8.1)	1	
Preterm premature rupture of membranes (%)	41 (27.7)	28 (37.8)	13 (17.6)	.010	
Spontaneous preterm birth (%)	21 (14.2)	17 (23.0)	4 (5.4)	.005	
Iatrogenic preterm birth (%)	14 (9.5)	4 (5.4)	10 (13.5)	.160	
Infection (%)	6 (4.1)	6 (8.1)	0 (0.0)	.028	
 Puerperal*	3 (2.0)	3 (4.1)	0 (0.0)	.245	
 Neonatal*	5 (3.4)	5 (6.8)	0 (0.0)	.058	
Neonatal malformation (%)	9 (6.1)	8 (10.8)	1 (1.4)	.033	
 Cardiovascular*	4 (2.7)	3 (4.1)	1 (1.4)	.620	
 Surface deformity*	3 (2.0)	3 (4.1)	0 (0.0)	.245	
 Other*	2 (1.4)	2 (2.7)	0 (0.0)	.497	
BMI = body mass index, IUD = intrauterine device.

* 1≤T<5, using correction for continuity.

Odds ratios of premature rupture of membranes and spontaneous preterm birth were 2.86 (1.36, 6.27) and 5.22 (1.81, 18.92) respectively. IUD women of elder age (≥35 years) were more likely to experience premature rupture of membranes (odds ratios 5.78), while IUD women of younger age (<35 years) were more likely to experience spontaneous preterm birth (odds ratios 6.32; Table 2).

Table 2 Odds ratios and 95% confidence intervals for the association between IUD use and adverse pregnancy outcome.

Odds ratios	Premature rupture of membranes	Spontaneous preterm birth	Iatrogenic preterm birth	
All	2.86 (1.36, 6.27)	5.22 (1.81, 18.92)	0.37 (0.10, 1.15)	
<35 yr	2.00 (0.80, 5.22)	6.32 (1.54, 42.96)	1.02 (0.12,8.85)	
≥35 yr	5.78 (1.57, 28.09)	4.11 (0.89, 29.45)	0.19 (0.03, 0.84)	
IUD = intra-uterine device.

4. Discussion

During the period of 1-child policy in mainland of China, postpartum insertion of an IUD was a standard care package for women with 1 child,[9] this might contribute to high level of acceptance of IUDs in China. Despite the high percentage of effectiveness, pregnancy in the presence of copper IUD could occur, and cumulative pregnancy rates were 1.4 to 1.6 at 7 years for the copper-releasing IUD.[12,13] Although some women were encountered pregnancy with IUDs in situ, the majority of them had selected abortion for fear adverse pregnant outcomes due to IUD. Some studies had investigated the associations between adverse perinatal outcomes and pregnancy with a copper IUD. Recently the published review by Brahmi et al[7] demonstrated that pregnancies with an IUD in situ were at risks for adverse pregnancy outcomes, including miscarriage, septic abortion, chorioamnionitis, and preterm delivery compared with the general obstetric population. Ozgu-Erdinc et al[14] had found the combined risk of adverse pregnancy outcomes (miscarriage, intrauterine fetal death, intrauterine growth retardation, preterm birth and preterm premature rupture of membranes) in the retained IUD group was reported about 63.3%. Previous studies have analyzed the effects of IUD on the entire pregnancy process. Our study demonstrated that the rate of spontaneous preterm birth reached 23.0% in pregnancy with a copper IUD in situ although it had surpassed 28 weeks of gestation, and the Odds ratios was 5.22 compared to normal pregnancy. Obstetrician should pay attention to pregnancy with IUDs even though it had exceeded 28 gestational weeks for 28% experienced premature rupture of membranes and 23% threatened by spontaneous preterm birth, screening for pathogenic microorganism in the reproductive tract and use of prenatal glucocorticoids should be considered. The results of stratified analysis also had found that pregnancy women aged beyond 35 years in IUD group were more likely to experience premature rupture of membranes, this should be taken into account in following treatments.

Our study demonstrated that a copper IUD in situ after 28 gestational weeks had increased the rate of neonatal congenital malformations (P = .033). And we still don’t know if pregnancy with a copper IUD in the uterus will affect neonate’s growth.

Neonatal congenital malformations found in the IUD group includes neonatal subependymal cysts, patent foramen ovale, ventricular septal defect with patent ductus arteriosus, solitary kidney, neonatal skin tag, tetralogy of Fallot and cleft lip. The rate of neonatal congenital malformations was higher in the case group compared to the control group, which was similar to previous study.[15] Histopathologic reports of specimens coming from 7 IUD pregnancies at the 1st-trimester and 2nd-trimester pregnancy showed that fetus with normal body developmental without pathological alterations or malformations, chorionic plates had regular arborization and vascularization, and the placenta had normal villi.[16] Besides, they also found 1 in 3 carried to term cases had major lip defect. Retained IUD was thought to be the possible risk factor for the lip lesion. Though, data were still insufficient to draw conclusions on any associations between pregnancy with an IUD in situ and risk of neonatal congenital malformations. We had observed the years of IUD use in the women who had a congenital malformation neonate. We had found that 2 of them had used the IUD for 1 to 3 years, and 6 of them for >9 years. Further research for more cases or meta-analysis could take into consideration for observing the association between duration of IUD use and neonatal congenital malformation. We also had found that pregnancy with a copper IUD in situ did not increase the risk of low birth weight and neonatal intrauterine infection.

Consistent with previous study,[7] our study demonstrated that pregnancies with a copper IUD in situ were associated with preterm delivery, which was more than twice as the worldwide preterm livebirths (11.1%).[11] In our study, preterm premature rupture of membranes (PPROM) had contributed 80.9% (17/21) of preterm birth in the women with a copper IUD in situ. While in normal pregnancy, Only one third of premature birth was caused by PPROM or related to PPROM.[17,18] The rest was due to maternal or fetal problems as medical indication (e.g. preeclampsia, placental presentation, placental abruption, fetal growth restriction, and multiple pregnancies).

Finally, we had found the infection rate of the IUD group was significantly increased in IUD group. Previous study had suggested that pregnancy with IUD was at a higher risk of chorioamnionitis and intraamniotic infection than normal pregnancy.[17] We had classified puerperal and fetal infections, there were no significant difference between 2 groups severally. The relatively small sample size of our study may have contributed to the difference.

We believe that our study is valuable for the clinical consultation of this extremely rare condition. There are several limitations in our study. As the study is a retrospective study, we rely on medical records for reporting of data, so some outcomes of interest may be potentially underreported. The study has a relatively small sample size, because of the rare incidence of pregnancy with copper IUD and most of them had chosen termination of unplanned pregnancy or experienced miscarriage. So, the studies may be underpowered to detect the significant differences between groups. Moreover, lack the neonate follow-up cases due to the limit of the conditions.

Thus, more researches are needed for drawing a conclusion on the association between pregnancy with a copper IUD and neonatal outcomes. Well-designed prospective study of the pregnancy with a copper IUD in situ and an offspring follow-up could lead to a better understanding of the adverse outcomes of a copper IUD.

5. Conclusion

We had found that pregnancy with a copper IUD in situ increased the risk of premature rupture of membranes and spontaneous preterm birth after 28 gestation weeks, the risk of spontaneous preterm birth increased 5.22 times. Pregnancy with IUD in situ may be at increased risk of infection and neonatal malformation. The influence of IUD on the neonatal growth and development is still unknow, more researches are needed to clarify the association between pregnancy with a copper IUD and the neonatal congenital malformations.

Acknowledgments

I would thank to Mrs. Lili Cao for helping with data collection.

Author contributions

Conceptualization: Xiuying Chen, Baihui Zhao.

Data curation: Xiuying Chen.

Formal analysis: Xiuying Chen.

Investigation: Xiuying Chen

Methodology: Xiuying Chen.

Software: Xiuying Chen.

Supervision: Baihui Zhao.

Topic design, manuscript edit and revise: Baihui Zhao.

Writing – original draft: Xiuying Chen.

Writing – review & editing: Baihui Zhao.

Abbreviations:

BMI body mass index

IUD intra-uterine device

PPROM premature rupture of membranes

This work was supported by the Public Welfare of Science and Technology Plan Projects of Yiwu (grant number: 2016-S-12).

The authors have no conflicts of interest to disclose.

All data generated or analyzed during this study are included in this published article [and its supplementary information files].

How to cite this article: Chen X, Zhao B. Perinatal outcomes with a copper intrauterine device in situ after 28 gestational weeks: A retrospective study of sole center in southeast China. Medicine 2024;103:36(e39448).
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