Pregnancy outcomes of women with a congenital unicornuate uterus after IVF–embryo transfer

Accepted Manuscript Title: Pregnancy outcomes of women with a congenital unicornuate uterus after IVF–embryo transfer Author: Xihong Li, Yan Ouyang, Yan Yi, Ge Lin, Guangxiu Lu, Fei Gong PII: DOI: Reference:

S1472-6483(17)30372-3 http://dx.doi.org/doi: 10.1016/j.rbmo.2017.07.015 RBMO 1801

To appear in:

Reproductive BioMedicine Online

Received date: Revised date: Accepted date:

31-3-2017 30-6-2017 25-7-2017

Please cite this article as: Xihong Li, Yan Ouyang, Yan Yi, Ge Lin, Guangxiu Lu, Fei Gong, Pregnancy outcomes of women with a congenital unicornuate uterus after IVF–embryo transfer, Reproductive BioMedicine Online (2017), http://dx.doi.org/doi: 10.1016/j.rbmo.2017.07.015. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Short title: Pregnancy outcomes of unicornuate uteri

Pregnancy outcomes of women with a congenital unicornuate uterus after IVF–embryo transfer Xihong Li a,*,1,, Yan Ouyang

a,b,1

, Yan Yi c, Ge Lin

, Guangxiu Lu

a,b

, Fei Gong

a,b

a,b

Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha City, Hunan 410078, China; b Institute of Reproductive and Stem Cell Engineering, Central South University, Changsha City, Hunan 410078, China; c Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15260, USA * Corresponding authors: E-mail addresses: [email protected] (Xihong Lee); [email protected] (Fei Gong). 1 These authors contributed equally to this work. a

Key message In this study, we investigated the pregnancy outcomes of unicornuate uteri with a large sample size. We found that the presence of a unicornuate uterus was associated with an increased risk of early pregnancy loss, premature delivery, perinatal mortality, low birthweight and low live birth rate.

Abstract Unicornuate uteri are caused by non-development of one Müllerian duct. The objective of this study was to investigate pregnancy outcomes of singleton and/or twin pregnancies in women with unicornuate uterus after IVF–embryo transfer (IVF–ET). The study group comprised 238 patients with a unicornuate uterus and the control group 818 patients with normal uterus. Compared with pregnancies with normal uterine morphology, a unicornuate uterus was associated with an increased risk of early pregnancy loss [adjusted odds ratio (aOR) 1.88, 95% confidence interval (CI) 1.25–2.83; P = 0.002], premature delivery (aOR 2.11, 95% CI 1.45–3.07; P < 0.001), perinatal mortality (aOR 3.35, 95% CI 1.89–5.94; P < 0.001), low birthweight (LBW, aOR 1.43, 95% CI 1.04–1.79; P = 0.005) and very low birthweight (VLBW, aOR 2.58, 95% CI 1.53–4.34; P < 0.001). Additionally, significantly lower rates of term delivery (aOR 0.43, 95% CI 0.31–0.58; P < 0.001) and live birth (aOR 0.53, 95% CI 0.37–0.76; P < 0.001) were observed. These findings indicate that the presence of

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unicornuate uterus is associated with significantly increased risk of some adverse pregnancy outcomes compared with pregnancies with a normal uterus in women who undergo IVF–ET. Keywords: 3D ultrasonography, IVF, miscarriage, pregnancy outcome, unicornuate uterus

Xihong Li is Associate Professor and Director of the Imaging Department of the Reproductive and Genetic Hospital of Citic-Xiangya. She is adept at diagnosing pelvic lesions such as early ectopic pregnancy, endometrium lesions, genital malformation and tubal diseases and is mainly engaged in gynaecological and prenatal diagnosis at present.

Introduction Congenital uterine malformations result from elongation, fusion and absorption disorders of the bilateral Müllerian ducts at approximately 6 to 18 weeks of embryogenesis. Their prevalence in the general population is estimated to be 4.3–6.7% (Chan et al., 2011; Grimbizis et al., 2001; Saravelos et al., 2008), with an estimated prevalence of 8.0–13.3% (Chan et al., 2011; Jayaprakasan et al., 2011) in infertile patients. A combination of two-dimensional (2D) ultrasound, hysteroscopy and/or laparoscopy is the most widely used method for the traditional diagnosis of Müllerian anomalies (Rackow and Arici, 2007). With the rapid development of volume ultrasound, three-dimensional (3D) ultrasound has been recognized recently as another gold standard for the diagnosis of Müllerian anomalies (Ghi et al., 2009; Salim et al., 2003; Woelfer et al., 2001). It can provide

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highly reliable, objective and precise measurable information for the anatomy of the cervix, the uterine cavity, the uterine wall, the external contour of the uterus and for associated pelvic pathology, which is the absolute advantage in differential diagnosis between different classes (Grimbizis et al., 2013, 2016; Jaslow and Kutteh, 2013). Unicornuate uteri account for 5.0–13.0% of all Müllerian anomalies (Akar et al., 2005; Lin et al., 2002) and are caused by non-development of one Müllerian duct. A rudimentary horn is present in 74–90% of unicornuate uterine patients. According to the European Society of Human Reproduction and Embryology (ESHRE) and the European Society for Gynaecological Endoscopy (ESGE) classification system, there are two subclasses of the unicornuate uterus, depending on the presence or not of a functional rudimentary cavity, either communicating or non-communicating (Grimbizis et al., 2013, 2016). Although normal pregnancies can occur in some patients with a clinically asymptomatic unicornuate uterus (Sugaya, 2010), unicornuate uteri are related to miscarriage, premature delivery, low birthweight, perinatal mortality and other complications similar to other uterine anomalies (Andrews and Jones, 1982; Venetis et al., 2014). The aim of this study was to investigate the pregnancy outcomes of singleton and/or twin pregnancies in women with a unicornuate uterus after IVF–embryo transfer (IVF–ET). To the best of our knowledge, this study is the largest series to describe unicornuate uteri following IVF treatment at a single reproductive centre to date.

Materials and methods Patients We performed a retrospective analysis to determine the relationship between congenital unicornuate uteri and pregnancy outcomes. All patients in this study underwent a systematic examination to identify the causes of infertility, and evaluation of maternal uterine anatomy by 3D-transvaginal ultrasonography (TVS) was performed as a routine step. The diagnosis of a unicornuate uterus was based on the ESHRE/ESGE classification system, and it was defined as the unilateral uterine development with incompletely formed contralateral part or absent (Grimbizis et al., 2013, 2016). If uterine malformation was suspected in a patient during ultrasound examination, hysterosalpingography, hysteroscopy and/or laparoscopy were then used to confirm the diagnosis. Immunological, genetic, endocrine and blood tests were also routinely arranged.

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All infertile outpatients with a unicornuate uterus from January 2012 to December 2014 were recruited. Because the number of outpatients with a normal uterus was very large over the same time period, we selected patients during the middle 3 months (January 2013 to March 2013). All enrolled outpatients had IVF indications, and qualifying individuals underwent IVF cycles. Only pregnant women younger than 40 years of age, with a body mass index (BMI) between 18 and 28 and with both ovaries detected were recruited. Patients with donor oocytes, preimplantation genetic diagnosis (PGD)/preimplantation genetic screening (PGS), parental chromosomal abnormalities, spontaneous/selective reduction, triplet pregnancies, induced labour for congenital fetal structural or chromosomal abnormalities and uterine fibroids or polyps distorting the endometrial cavity were excluded from this analysis. All patients who successfully achieved pregnancy were enrolled. Two hundred and thirty-eight patients with a unicornuate uterus were finally chosen as the study group, and 818 patients with a normal uterus were selected as the control group (Figure 1). The diagnosis of normal uterus was also according to the ESHRE/ESGE classification system and the definition was a ‘uterus having either straight or curved interostial line, with an internal indentation at the fundal midline not exceeding 50% of the uterine wall thickness’ (Grimbizis et al., 2013, 2016). Written informed consent was obtained from all participants. This study was approved by the Ethics Committee of the Reproductive and Genetic Hospital of CITIC-Xiangya (date of approval: 19 January 2016; reference number: LL-SC-2016-008; Changsha, China).

IVF procedure and embryo transfer In the fresh cycles, all patients underwent conventional control ovarian hyperstimulation (COH). COH was performed using long or short protocols with gonadotrophin-releasing hormone (GnRH) agonists (Ferring Pharmaceuticals, Switzerland) and recombinant FSH (rFSH; Gonal F, Merck-Serono, Geneva, Switzerland). Human chorionic gonadotrophin (HCG; Profasi, Merck-Serono) was administered when three or more follicles measuring at least 18 mm in diameter were observed on the ultrasound. Oocyte retrieval was performed by TVS 34–36 h after HCG injection. Fertilization was achieved using either standard IVF or intracytoplasmic sperm injection (ICSI), depending on the couple’s cause of infertility. The frozen embryo transfer (FET) protocols were previously described by Veleva et al. (2009). Freezing and thawing were performed with 1,2-propanediol and sucrose as cryoprotectants according to the recommendations of the freezing and thawing kits (Vitrolife Sweden AB). Natural cycles were performed only in women who had spontaneous

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ovulation. Hormone replacement treatment (HRT) was performed in women with amenorrhoea or irregular menstrual cycles. The embryo morphology was scored according to Hardarson et al. (2001). An embryo with at least seven blastomeres of grades 1 and 2 on day 3 and a blastocyst on day 5 were defined as good quality. One to three embryos with good quality were transferred at the day 3 or day 5 stage.

Outcome measures The serum -HCG levels were measured 14 and 12 days after the transfer of day 3 embryos and blastocysts respectively, and TVS was performed 4 weeks after embryo transfer (ET). Clinical pregnancy was diagnosed if gestational sacs were observed, and viable pregnancy was confirmed when a fetal heartbeat was detected. All patients were tracked until the end of the pregnancy. The pregnancy and perinatal outcomes were defined as follows: early pregnancy loss referred to miscarriages that occurred before 10 gestational weeks; late miscarriage referred to miscarriages that occurred after at least 10 but before 20 gestational weeks; an ectopic pregnancy was a pregnancy with an extrauterine gestational sac observed on the ultrasound scan or by laparoscopy; preterm delivery referred to childbirth at least 20 but before 37 gestational weeks; very preterm birth (VPB) referred to childbirth greater than or equal to 20 but before 32 gestational weeks and term delivery was delivery at greater than or equal to 37 but before 42 gestational weeks (Zegers-Hochschild et al., 2009). Additionally, a live birth was defined as the delivery of a live infant after 20 weeks of gestation who survived for at least 7 days (Ozgur et al., 2015). A stillbirth was defined as the delivery of a deceased infant at or after 20 weeks of gestation. Perinatal mortality included mortality in live-born infants within the first 7 days and stillborn infants at 20 weeks of gestation or later. Low birthweight (LBW) was defined as a birthweight <2500 g; a very low birthweight (VLBW) was a birthweight <1500 g (Zegers-Hochschild et al., 2009). The gestational age was determined by subtracting the date of ET from the date of birth plus an additional 17 and 19 days for day 3 embryo and blastocyst transfers, respectively. The pregnancy and obstetric outcomes were followed up by telephone call or fax using a form predesigned by a specified team at our centre.

Statistical analysis SPSS version 17.0 software (SPSS, Inc., Chicago, IL, USA) was used to perform the statistical analyses. Descriptive statistics were presented as the means ± standard deviations (SDs) and as percentages for the enumerated

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data. Differences in the means between groups were analysed using Student’s t-test. The chi-squared test or Fisher’s exact test was used to determine statistical significance between percentages. A P-value < 0.05 was considered significant. Multiple logistic regression analyses were used to better estimate the relationships between the unicornuate uterus and adverse pregnancy outcomes by adjusting for potentially confounding effects.

Results From January 2012 to December 2014, uterine malformations were found in 6960 of 53,428 infertile patients (13.0%, 6960/53,428). Five hundred and sixty patients (1.0%, 560/53,428) were diagnosed with a unicornuate uterus, including 443 with a rudimentary uterine horn (79.1%, 443/560); a rudimentary horn hysterectomy was performed in three of these patients. Of the 455 patients who received IVF treatment, ET was cancelled in 12 cases, and clinical pregnancies were diagnosed in 290 cases (65.5%, 290/443). After excluding 43 cases of spontaneous/selective reduction of twins to singleton, six cases of triplet pregnancies, two cases of induced labour for fetal congenital abnormalities and one case of lost to follow-up, we analysed the data from 238 patients with a unicornuate uterus. Among the 2240 patients with a normal uterus, 1484 cases received IVF treatment, and ET was cancelled in 50 cases. Clinical pregnancies were diagnosed in 929 cases (64.8%, 929/1434). After excluding three cases of PGD/PGS, one case of donor oocytes, 82 cases of spontaneous/selective reduction of twins to singleton, 16 cases of triplet pregnancies, six cases of induced labour for fetal congenital abnormalities and three cases of lost to follow-up, we included 818 patients with a normal uterus as the control group (Figure 1).

Patient characteristics The unicornuate group and the control group were statistically similar with respect to maternal age (MA), BMI, previous miscarriage, infertility type, insemination methods, transfer cycle, number of retrieved oocytes and endometrial (EM) thickness on transfer day. However, infertility duration (P = 0.011), cause of infertility (P = 0.002), FSH (P < 0.001), number of transferred embryos (P < 0.001) and 14-day HCG (P = 0.042) were significantly different between these two groups (Table 1). Regarding singleton pregnancies, the BMI, previous miscarriage, transfer cycle, number of retrieved oocytes, EM thickness on the transfer day, infertility type and 14-day HCG were statistically similar between the two groups; however, the MA (P = 0.028), FSH (P < 0.001), infertility duration

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(P = 0.011), number of transferred embryos (P < 0.001), cause of infertility (P = 0.005) and insemination methods (P < 0.001) were significantly different. Regarding twin pregnancies, with the exception of the insemination methods (P < 0.001), all other characteristics were similar between the two groups (Table 1).

Pregnancy and obstetric outcomes in unicornuate and control groups Compared with the control group, the unicornuate group had significantly higher rates of early pregnancy loss (18.1% versus 10.5%; P = 0.002), premature delivery (23.9% versus 15.0%; P = 0.001), perinatal mortality (9.0% versus 3.3%; P < 0.001), LBW (32.5% versus 22.9%; P = 0.003) and VLBW (10.3% versus 4.4%; P < 0.001); the term delivery rate (54.2% versus 71.6%; P < 0.001), the live birth rate (74.4% versus 84.4%; P < 0.001), the gestational age at delivery (37.1 ± 3.5 versus 38.0 ± 3.0; P = 0.002) and the live birthweight (2683.0 ± 810.0 versus 2918.0 ± 732.0; P < 0.001) were significantly lower. The rates of late miscarriage (0.8% versus 0.4%, P = 0.363), ectopic pregnancy (2.9% versus 2.4%, P = 0.670) and Caesarean section (82.9% versus 78.6%, P = 0.194) were all higher in the unicornuate group than those in the control group, but the differences were not statistically significant (Table 2). After adjustment for the infertility duration, cause of infertility, FSH, number of transferred embryos and 14-day HCG, a unicornuate uterus was associated with an increased risk of early pregnancy loss (aOR 1.88, 95% CI 1.25–2.83; P = 0.002), premature delivery (aOR 2.11, 95% CI 1.45–3.07; P < 0.001), perinatal mortality (aOR 3.35, 95% CI 1.89–5.94; P < 0.001), LBW (aOR 1.43, 95% CI 1.04–1.79; P = 0.005) and VLBW (aOR 2.58, 95% CI 1.53–4.34; P < 0.001) compared with those of pregnancies in women with a normal uterus. Additionally, significantly lower rates of term delivery (aOR 0.43, 95% CI 0.31–0.58; P < 0.001) and live birth (aOR 0.53, 95% CI 0.37–0.76; P ≤ 0.001) were observed in the unicornuate group (Table 2). Pregnancy and obstetric outcomes in singleton pregnancies

In the unicornuate group with singleton pregnancies, the presence of a unicornuate uterus was associated with an increased risk of early pregnancy loss (aOR 1.75, 95% CI, 1.08–2.83; P = 0.023), premature delivery (aOR 3.89, 95% CI, 1.99–7.62; P < 0.001), Caesarean section (aOR 2.67, 95% CI, 1.50–4.77; P = 0.001) and LBW (aOR 5.57, 95% CI 2.44–12.68; P < 0.001) compared with those of pregnancies in women with a normal uterus after adjusting for MA, FSH, infertility duration, number of transferred embryos, cause of infertility and insemination methods. Additionally, a unicornuate uterus was associated with a significantly lower live birth rate (aOR 0.60, 95% CI 0.39–0.94; P = 0.024) (Table 3).

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Pregnancy and obstetric outcomes in twin pregnancies

Regarding twin pregnancies, after adjustment for the insemination methods, the unicornuate uterine anomaly conferred an increased risk of early pregnancy loss (aOR 4.89, 95% CI 1.47–16.21; P = 0.010), premature delivery (aOR 1.88, 95% CI 1.03–3.44; P = 0.040), perinatal mortality (aOR 5.12, 95% CI 2.68–9.79; P < 0.001), VPB (aOR 2.75, 95% CI 1.15–6.54; P = 0.022), LBW (aOR 1.63, 95% CI 1.01–2.61; P = 0.044) and VLBW (aOR 3.96, 95% CI 2.15–7.28; P < 0.001) compared with those of pregnancies in women with a normal uterus. A significantly lower live birth rate (aOR 0.27, 95% CI 0.13–0.57; P = 0.001) was found in the unicornuate group (Table 4).

Discussion In this study, we compared the pregnancy and obstetric outcomes between the unicornuate and the control groups after IVF–ET and found that the presence of a unicornuate uterus was associated with an increased risk of early pregnancy loss, premature delivery, perinatal mortality, LBW and VLBW. We also found an increased risk for low live birth rate and gestational age at delivery in women with a unicornuate uterus after IVF–ET. The incidence of congenital uterine malformations in infertile women was 13.0%, and the unicornuate uterus accounted for 8% of all congenital uterine malformations in this study. A rudimentary horn was found in 79.1% of the patients with a unicornuate uterus. These results were consistent with previous studies (Jayaprakasan et al., 2011; Lin et al., 2002; Woelfer et al., 2001). The prevalence of a unicornuate uterus in the infertile patients was much higher than the estimated rate in the general population [1% (560/53,428) versus 0.02% (1/4020)] (Reichman et al., 2009), which suggested that correlations between the unicornuate uterine anomaly and infertility may exist as previously described (Raga et al., 1997; Reichman et al., 2009). Differences were observed in several characteristics between these two groups; thus, we conducted multiple logistic regression analyses by adjusting for these potentially confounding effects. Previous studies (Fox et al., 2014; Shim et al., 2016) reported that congenital uterine malformations did not impair the pregnancy rate in infertile patients undergoing IVF–ET. In the present study, the unicornuate group had a pregnancy rate that was similar to the control group rate [65.5% (290/443) versus 64.8% (929/1434)], which was consistent with previous results, suggesting that the morphology of the uterus did not affect embryo implantation.

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Patients with a unicornuate uterus have been reported to have higher frequencies of premature delivery and spontaneous abortion in the first and second trimesters (Jaslow and Kutteh, 2013; Raga et al., 1997; Reichman et al., 2009). In our study, the rates of early pregnancy loss and premature delivery in the unicornuate group were significantly higher than the rates in the control group, which was consistent with previous studies. As described previously (Heinonen and Pystynen, 1983; Rackow and Arici, 2007), the diminished muscle mass with the addition of an abnormal nervous distribution, uneven pressure of the uterine cavity, uncoordinated contraction of the uterus, abnormal uterine blood flow and cervical incompetence may play important roles in early pregnancy loss, premature delivery and other complications. Unexpectedly, the late miscarriage rate was similar between the two groups in our study. Further studies with larger sample sizes are needed to explain this discrepancy. EP was found in 2.9% (7/238) of the unicornuate patients after IVF in the present study, which was similar to the estimated incidence in the general population (1.2-4%) (Akar et al., 2005; Reichman et al., 2009), and no rudimentary horn pregnancy was found. Our data showed that the unicornuate uterus did not increase the risk of EP during IVF treatment. Additionally, for heterotopic pregnancies (intrauterine pregnancy combined with EP), laparoscopy was implemented to resect the bilateral Fallopian tubes. The intrauterine pregnancy was preserved, and a live baby was delivered at term. For singleton pregnancies, the perinatal mortality was similar between the two groups, and only one case of stillbirth occurred in the unicornuate group in this study. However, for twin pregnancies, we found that the unicornuate uterus was associated with a 5-fold increased risk of perinatal mortality compared with that of the control group, and a significantly lower live birth rate (70.9% versus 91.2%; P = 0.001) was also found. Among the 55 cases of twin pregnancies, there were seven cases of miscarriage, five stillbirths of both babies, four cases of early neonatal death of both babies, two pregnancies with one fetal death and one heterotopic pregnancy. Only 75 out of 95 babies were born alive, and the other 20 babies resulted in perinatal deaths in this study. The gestational age at delivery of all these 20 infants was less than 32 weeks, and their weights were all lower than 1500 g. Because the gestational capacity is jeopardized by the presence of only half of the full complement of uterine musculature (Moutos et al., 1992), the anatomic and functional defects of a unicornuate uterus may lead to a poor tolerance for twin pregnancies and result in more serious negative outcomes. The Caesarean section rate was similar between two groups, which may be because the indications for Caesarean section were loosened for patients

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with both unicornuate and normal uteri to ensure maternal and infant safety through IVF treatment, consistent with the results of Fox et al. (2014). While the unicornuate group with singleton pregnancies had a much higher risk of Caesarean delivery, with respect to twin pregnancies, the Caesarean delivery rate was higher in the control group. We postulated that in addition to the anatomy of a unicornuate uterus, the high spontaneous preterm delivery rate of twin pregnancies from patients with a unicornuate uterus may also play a role in reducing the Caesarean delivery rate. Our study offered several strengths. The large sample size allowed us to study a relatively rare diagnosis and its association with important adverse pregnancy outcomes. Adjusting for known confounders made our results more convincing. However, one potential weakness was that our centre was only a reproductive centre; thus, all pregnancy outcomes were obtained via telephone calls or faxes. Therefore, some detailed obstetric complications, such as an abnormal fetal position or placenta previa, were not studied here. The other potential weakness was that this was a retrospective study, and the control group was not screened randomly, which may cause selection and confounding biases. Additionally, three embryos were transferred in some patients, which could have caused twin or multiple pregnancies in this high-risk population. However, the practice of three-embryo transfer was ceased in our hospital beginning in 2015, and our future work will focus on how to avoid multiple pregnancies in the unicornuate population. A previous study (McLernon et al., 2010) showed that single ET could reduce the probability of multiple pregnancies and that pregnancy outcomes were better for single ET than for two ET. In conclusion, our study found a significant increase in some adverse pregnancy outcomes complicated by the unicornuate uterine anomaly compared with pregnancies with normal uterine morphology. The unicornuate uterus had a much poorer tolerance for twin pregnancies. These findings can be used to counsel women whose pregnancies are complicated by a unicornuate anomaly and help guide appropriate antenatal treatment and surveillance.

Acknowledgements This work was funded by the National Basic Research Program of China (No. 2012CB944901), the National Nature Science Foundation of China (No. 81501328) and the Citic-Xiangya Research Fund. We thank Qingqing Wu, Kailan Xiong and Lizhi Huang for assistance with collecting and sorting the raw data.

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References Akar, M.E., Bayar, D., Yildiz, S., Ozel, M., Yilmaz, Z., 2005. Reproductive outcome of women with unicornuate uterus. Aust. New Zeal. J. Obstet. Gynaecol. doi:10.1111/j.1479-828X.2005.00346.x Andrews, M.C., Jones, H.W.J., 1982. Impaired reproductive performance of the unicornuate uterus: intrauterine growth retardation, infertility, and recurrent abortion in five cases. Am. J. Obstet. Gynecol. 144, 173–176. Chan, Y.Y., Jayaprakasan, K., Zamora, J., Thornton, J.G., Raine-Fenning, N., Coomarasamy, A., 2011. The prevalence of congenital uterine anomalies in unselected and high-risk populations: A systematic review. Hum. Reprod. Update 17, 761–771. doi:10.1093/humupd/dmr028 Fox, N.S., Roman, A.S., Saltzman, D.H., Klauser, C.K., Rebarber, A., 2014. Twin pregnancy in patients with a uterine anomaly. J. Matern. Fetal. Neonatal Med. 27, 360–4. doi:10.3109/14767058.2013.819331 Ghi, T., Casadio, P., Kuleva, M., Perrone, A.M., Savelli, L., Giunchi, S., Meriggiola, M.C., Gubbini, G., Pilu, G., Pelusi, C., Pelusi, G., 2009. Accuracy of three-dimensional ultrasound in diagnosis and classification of congenital uterine anomalies. Fertil. Steril. 92, 808–813. doi:10.1016/j.fertnstert.2008.05.086 Grimbizis, G.F., Camus, M., Tarlatzis, B.C., Bontis, J.N., Devroey, P., 2001. Clinical implications of uterine malformations and hysteroscopic treatment results. Hum. Reprod. Update. doi:10.1093/humupd/7.2.161 Grimbizis, G.F., Di Spiezio Sardo, A., Saravelos, S.H., Gordts, S., Exacoustos, C., Van Schoubroeck, D., Bermejo, C., Amso, N.N., Nargund, G., Timmermann, D., Athanasiadis, A., Brucker, S., De Angelis, C., Gergolet, M., Li, T.C., Tanos, V., Tarlatzis, B., Farquharson, R., Gianaroli, L., Campo, R., 2016. The Thessaloniki ESHRE/ESGE consensus on diagnosis of female genital anomalies. Gynecol. Surg. 13, 1–16. doi:10.1007/s10397-015-0909-1 Grimbizis, G.F., Gordts, S., Di Spiezio Sardo, A., Brucker, S., De Angelis, C., Gergolet, M., Li, T.C., Tanos, V., Brölmann, H., Gianaroli, L., Campo, R., 2013. The ESHRE-ESGE consensus on the classification of female genital tract congenital anomalies. Gynecol. Surg. 10, 199–212. doi:10.1007/s10397-013-0800-x Hardarson, T., Hanson, C., Sjögren, a, Lundin, K., 2001. Human embryos with unevenly sized blastomeres have lower pregnancy and implantation rates: indications for aneuploidy and multinucleation. Hum. Reprod. 16, 313–318. doi:10.1093/humrep/16.2.313 Heinonen, P.K., Pystynen, P.P., 1983. Primary infertility and uterine anomalies. Fertil. Steril. Jaslow, C.R., Kutteh, W.H., 2013. Effect of prior birth and miscarriage frequency on the prevalence of acquired and congenital uterine anomalies in women with recurrent miscarriage: A cross-sectional study. Fertil. Steril. 99. doi:10.1016/j.fertnstert.2013.01.152 Jayaprakasan, K., Chan, Y.Y., Sur, S., Deb, S., Clewes, J.S., Raine-Fenning, N.J., 2011. Prevalence of uterine anomalies and their impact on early pregnancy in women conceiving after assisted reproduction treatment. Ultrasound Obstet. Gynecol. 37, 727–732. doi:10.1002/uog.8968

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Lin, P.C., Bhatnagar, K.P., Nettleton, G.S., Nakajima, S.T., 2002. Female genital anomalies affecting reproduction. Fertil. Steril. 78, 899–915. doi:10.1016/S0015-0282(02)03368-X McLernon, D.J., Harrild, K., Bergh, C., Davies, M.J., de Neubourg, D., Dumoulin, J.C.M., Gerris, J., Kremer, J.A.M., Martikainen, H., Mol, B.W., Norman, R.J., Thurin-Kjellberg, A., Tiitinen, A., van Montfoort, A.P.A., van Peperstraten, A.M., Van Royen, E., Bhattacharya, S., 2010. Clinical effectiveness of elective single versus double embryo transfer: meta-analysis of individual patient data from randomized trials. BMJ 341, c6945. doi:10.1136/bmj.c6945 Moutos, D.M., Damewood, M.D., Schlaff, W.D., Rock, J.A., 1992. A comparison of the reproductive outcome between women with a unicornuate uterus and women with a didelphic uterus. Fertil. Steril. 58, 88–93. Ozgur, K., Berkkanoglu, M., Bulut, H., Humaidan, P., Coetzee, K., 2015. Perinatal outcomes after fresh versus vitrified-warmed blastocyst transfer: Retrospective analysis. Fertil. Steril. 104, 899–907e3. doi:10.1016/j.fertnstert.2015.06.031 Rackow, B.W., Arici, A., 2007. Reproductive performance of women with müllerian anomalies. Curr. Opin. Obstet. Gynecol. 19, 229–237. doi:10.1097/GCO.0b013e32814b0649 Raga, F., Bauset, C., Remohi, J., Bonilla-Musoles, F., Simón, C., Pellicer, A., 1997. Reproductive impact of congenital Mullerian anomalies. Hum. Reprod. 12, 2277–2281. doi:10.1093/humrep/12.10.2277 Reichman, D., Laufer, M.R., Robinson, B.K., 2009. Pregnancy outcomes in unicornuate uteri: a review. Fertil. Steril. 91, 1886–1894. doi:10.1016/j.fertnstert.2008.02.163 Salim, R., Woelfer, B., Backos, M., Regan, L., Jurkovic, D., 2003. Reproducibility of three-dimensional ultrasound diagnosis of congenital uterine anomalies. Ultrasound Obstet. Gynecol. 21, 578–582. doi:10.1002/uog.127 Saravelos, S.H., Cocksedge, K.A., Li, T.C., 2008. Prevalence and diagnosis of congenital uterine anomalies in women with reproductive failure: A critical appraisal. Hum. Reprod. Update. doi:10.1093/humupd/dmn018 Shim, S., Hur, Y.-M., Kim, D.H., Seong, S.J., Kim, M.-L., Shin, J.S., S., S., Y.-M., H., D.H., K., S.J., S., M.-L., K., 2016. Evidence for No Significant Impact of Mullerian Anomalies on Reproductive Outcomes of Twin Pregnancy in Korean Women. Twin Res. Hum. Genet. 19, 146–153. doi:10.1017/thg.2016.4 Sugaya, S., 2010. Twin pregnancy after in vitro fertilization in a woman with a unicornuate uterus. Clin. Exp. Obstet. Gynecol. 37, 317–318. Veleva, Z., Karinen, P., Tomás, C., Tapanainen, J.S., Martikainen, H., 2009. Elective single embryo transfer with cryopreservation improves the outcome and diminishes the costs of IVF/ICSI. Hum. Reprod. 24, 1632–1639. doi:10.1093/humrep/dep042 Venetis, C.A., Papadopoulos, S.P., Campo, R., Gordts, S., Tarlatzis, B.C., Grimbizis, G.F., 2014. Clinical implications of congenital uterine anomalies: A meta-analysis of comparative studies. Reprod. Biomed. Online. doi:10.1016/j.rbmo.2014.09.006 Woelfer, B., Salim, R., Banerjee, S., Elson, J., Regan, L., Jurkovic, D., 2001. Reproductive outcomes in women with congenital uterine anomalies detected by

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three-dimensional ultrasound screening. Obstet. Gynecol. 98, 1099–1103. doi:10.1016/S0029-7844(01)01599-X Zegers-Hochschild, F., Adamson, G.D., de Mouzon, J., Ishihara, O., Mansour, R., Nygren, K., Sullivan, E., Vanderpoel, S., 2009. International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO) revised glossary of ART terminology, 2009*. Fertil. Steril. 92, 1520–1524. doi:10.1016/j.fertnstert.2009.09.009

Declaration: The authors report no financial or commercial conflicts of interest. Figure 1. Flow diagram showing the cases included in both the study and control groups. MA = maternal age; BMI = body mass index; IVF-ET = IVF–embryo transfer; PGD = preimplantation genetic diagnosis; PGS = preimplantation genetic screening. *Including three cases with dichorionic triamniotic triplets. Including five cases with dichorionic triamniotic triplets.

&

Page 13 of 24

Table 1. Comparison of patient characteristics between the unicornuate group and the control group. Characteristics

Maternal age (years)

Unicornua Control te Singleton and twin (n = 238) (n = 818)

30–34, n (%)

29.6 ± 4. 2 21 (8.8) 107 (45.0) 80 (33.6)

35–40, n (%)

30 (12.6)

≤24, n (%) 25–29, n (%)

BMI (kg/m2) 18–19, n (%) 19.1–24, n (%) 24.1–28, n (%) Infertility duration (years) ≤3, n (%)

21.7 ± 3. 5 32 (13.6) 160 (67.8) 44 (18.6) 4.7 ± 3.1

3.1–6.9, n (%)

100 (42.0) 78 (32.8)

7, n (%)

60 (25.2)

30.3 ± 4. 3 62 (7.6) 305 (37.3) 314 (38.4) 137 (16.7) 21.6 ± 2. 8 98 (12.0) 569 (69.8) 148 (18.2) 5.8 ± 3.6 262 (32.0) 289 (35.3) 267 (32.6)

P-valu e

NSa

Unicornua te Singleton (n = 183) 29.6 ± 4. 4 15 (8.2) 85 (46.4) 58 (31.7) 25 (13.7)

NSa

21.7 ± 3. 5 26 (14.4) 121 (66.9) 34 (18.8) 4.6 ± 3.1

0.011a

80 (43.7) 59 (32.2) 44 (24.0)

Control

(n = 567 ) 30.6 ± 4. 5 44 (7.8) 198 (34.9) 212 (37.4) 113 (19.9) 21.8 ± 2. 9 61 (10.8) 389 (69.0) 114 (20.2) 5.9 ± 3.8 188 (33.2) 184 (32.5) 195 (34.4)

P-valu e

0.028a

Unicornua te Twin (n = 55)

Control

29.4 ± 3. 8 6 (10.9) 22 (40.0)

29.6 ± 3. 8 18 (7.2) 107 (42.6) 102 (40.6) 24 (9.6)

22 (40.0) 5 (9.1)

NSa

0.011a

21.8 ± 3. 2 6 (10.9) 39 (70.9)

(n = 251)

10 (18.2)

21.2 ± 2. 6 37 (14.7) 180 (71.7) 34 (13.5)

5.0 ± 3.1

5.5 ± 3.2

20 (36.4)

74 (29.5)

19 (34.5)

105 (41.8) 72 (28.7)

16 (29.1)

P-valu e

NSa

NSa

NSa

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Previous miscarriage No, n (%) Yes, n (%) Infertility type Primary, n (%) Secondary, n (%) Cause of infertility Male factor, n (%) Female factor, n (%) Combined female and male factors, n (%) Unexplained, n (%) FSH (mIU/ml) ≤1.36, n (%) 1.37–9.9, n (%) 10.0, n (%)

202 (84.9) 36 (15.1)

726 (88.8) 92 (11.2)

NSa

122 (51.3) 116 (48.7)

413 (50.5) 405 (49.5)

NSa

10 (4.2) 142 (59.7) 82 (34.5)

59 (7.2) 386 (47.2) 366 (44.7) 7 (0.9) 6.2 ± 2.6 1 (0.1) 788 (96.3) 29 (3.5)

0.002a

450 (55.0) 166 (20.3) 202 (24.7) 1.2 ± 0.5

NSa

4 (1.7) 6.0 ± 2.8 9 (3.8) 223 (93.7) 6 (2.5)

158 (86.3) 25 (13.7)

503 (88.7) 64 (11.3)

NSa

99 (54.1)

277 (48.9) 290 (51.1)

NSa

44 (7.8) 265 (46.7) 253 (44.6) 5 (0.9) 6.3 ± 2.9 1 (0.2) 540 (95.2) 26 (4.6)

0.005a

<0.00 1a

57 (31.1)

351 (61.9) 126 (22.2) 90 (15.9)

1.1 ± 0.4

1.2 ± 0.6

84 (45.9)

<0.00 1b

9 (4.9) 111 (60.7) 60 (32.8) 3 (1.6) 6.1 ± 3.1 8 (4.4) 170 (92.9) 5 (2.7)

44 (80.0)

223 (88.8) 28 (11.2)

NSa

136 (54.2) 115 (45.8)

NSa

NSb

1 (1.8)

15 (6.0) 121 (48.2) 113 (45.0) 2 (0.8) 5.8 ± 1.7 0 248 (98.8) 3 (1.2)

40 (72.7)

99 (39.4)

<0.00 1a

7 (12.7)

40 (15.9)

8 (14.5)

112 (44.6) 1.2 ± 0.4

11 (20.0) 23 (41.8) 32 (58.2)

1 (1.8%) 31 (56.4) 22 (40.0)

<0.00 1a

1 (1.8) 5.8 ± 1.5 1 (1.8) 53 (96.4)

NSb

Insemination methods IVF, n (%)

133 (55.9) 40 (16.8)

ICSI, n (%) IVF/ICSI, n (%) Transfer cycle

65 (27.3) 1.1 ± 0.4

93 (50.8) 33 (18.0)

1.2 ± 0.5

Page 15 of 24

1, n (%)

208 (87.4)

680 (83.1)

2, n (%)

30 (12.6)

99 (41.6) 12.4 ± 2. 1 1 (0.4) 208 (87.4) 29 (12.2) 1.9 ± 0.4

138 (16.9) 12.4 ± 4. 4 488 (59.7) 330 (40.3) 12.3 ± 2. 1 3 (0.4) 721 (88.1) 94 (11.5) 2.0 ± 0.3

25 (10.5) 202 (84.9) 11 (4.6) 512.2 ± 3 85.4 110 (46.2) 128 (53.8)

24 (2.9) 735 (89.9) 59 (7.2) 583.5 ± 4 63.2 318 (38.9) 500 (61.1)

Number of retrieved oocytes <12, n (%)

12.4 ± 4. 3 139 (58.4)

12, n (%) EM thickness on transfer day (mm) ≤7.9, n (%) 8–14.9, n (%) 15, n (%) Number of embryos transferred 1, n (%) 2, n (%) 3, n (%) 14-day HCG (mIU/ml) <420, n (%) 420, n (%)

NSa

160 (87.4)

464 (81.8)

23 (12.6)

103 (18.2) 12.0 ± 4. 6 362 (63.8) 205 (36.2) 12.1 ± 2. 1 2 (0.4) 508 (89.6) 57 (10.1) 2.0 ± 0.4

12.0 ± 4. 2 111 (60.7) NSa

NSb

<0.00 1a

0.042a

72 (39.3) 12.5 ± 2. 2 1 (0.5) 159 (86.9) 23 (12.6) 1.9 ± 0.4 25 (13.7) 150 (82.0) 8 (4.4) 421.7 ± 3 08.9 101 (55.2) 82 (44.8)

24 (4.2) 496 (87.5) 47 (8.3) 459.4 ± 350.7 267 (47.1) 300 (52.9)

NSa

48 (87.3)

216 (86.1)

7 (12.7)

35 (13.9)

13.9 ± 4. 6

13.1 ± 4. 0 126 (50.2) 125 (49.8) 12.7 ± 2. 2 1 (0.4) 213 (84.9) 37 (14.7) 2.1 ± 0.2

28 (50.9) NSa

NSa

27 (49.1) 12.2 ± 2. 0 0 49 (89.1) 6 (10.9) 2.1 ± 0.2

<0.00 1a

0 52 (94.5)

NSa

3 (5.5) 813.2 ± 4 58.7 9 (16.4) 46 (83.6)

0 239 (95.2) 12 (4.8) 863.9 ± 5 55.6 51 (20.3)

NSa

NSa

NSb

NSb

NSa

200 (79.7)

BMI = body mass index; EM = endometrium; HCG = human chorionic gonadotrophin ICSI = intracytoplasmic sperm injection. a

Comparisons were made using the chi-squared test.

Page 16 of 24

b

Comparisons were made using Fisher’s exact test.

Page 17 of 24

Table 2. Pregnancy and obstetric outcomes in the unicornuate group and the control group Pregnancy outcomes Pregnancy Early pregnancy loss rate, % (n) Late miscarriage rate, % (n) Ectopic pregnancy rate, % (n) Premature delivery rate, % (n) Term delivery rate, % (n)

Unicornuate 238 18.1 (43/238)

818 10.5 (86/818)

0.8 (2/238)

0.4 (3/818)

2.9 (7/238)

2.4 (20/818)

23.9 (57/238)

9.0 (21/234)

15.0 (123/818) 71.6 (586/818) 78.6 (557/709) 950 919 84.4 (690/818) 3.3 (31/950)

5.6 (13/234)

2.6 (25/950)

3.4 (8/234)

0.6 (6/950)

37.1 ± 3.5 69.5 (130/187)

38.0 ± 3.0 82.4 (584/709)

54.2 (129/238)

Caesarean section rate, % (n) 82.9 (155/187*) Babies born 234 Live births 213 Live birth rate, % (n) 74.4 (177/238) Perinatal mortality, % (n) Stillbirth Early neonatal mortality Gestational age at delivery 37 weeks, % (n)

Control

Unadjusted

Adjusted

OR (95% CI)

P-value

OR (95% CI)

P-value

1.88 (1.26–2.80) 2.30 (0.38–13.86) 1.21 (0.51–2.90) 1.78 (1.25–2.54) 0.47 (0.35–0.63) 1.32 (0.87–2.01)

0.002a

1.88 (1.25–2.83)

0.002

NSa

NS

NSa

2.27 (0.36–14.37) 1.23 (0.51–2.98)

0.001a

2.11 (1.45–3.07)

<0.001

<0.001a

0.43 (0.31–0.58)

<0.001

NSa

1.37 (0.89–2.11)

NS

0.54 (0.38–0.76) 3.23 (1.85–5.66) 2.53 (1.31–4.89) 5.57 (1.91–16.21)

<0.001a

0.53 (0.37–0.76)

<0.001

<0.001a

3.35 (1.89–5.94)

<0.001

0.006a

2.73 (1.39–5.34)

0.003

0.002a

5.42 (1.80–16.35)

0.003

0.43 (0.29–0.64)

<0.001

0.49 (0.34–0.70)

0.002b <0.001a

NS

Page 18 of 24

<37 weeks, % (n)

30.5 (57/187)

VPB 20–31+6 weeks, % (n) 6.4 (12/187) Live birthweight (g) ≥2500 g, % (n) LBW <2500 g, % (n) VLBW <1500 g, % (n)

2683 ± 810 67.5 (158/234) 32.5 (76/234) 10.3 (24/234)

17.6 (125/709) 3.8 (27/709) 2918 ± 732 77.1 (732/950) 22.9 (218/950) 4.4 (42/950)

2.05 (1.42–2.96) 1.73 (0.86–3.49) 0.62 (0.45–0.85) 1.62 (1.18–2.21) 2.46 (1.48–4.07)

<0.001a

2.32 (1.57–3.42)

<0.001

NSa

1.80 (0.87–3.72)

NS

<0.001b 0.003a

0.71 (0.56–0.94)

0.005

0.003a

1.43 (1.04–1.79)c

0.005

<0.001a

2.58 (1.53–4.34)

<0.001

Adjusted for FSH, infertility duration, number of transferred embryos, cause of infertility, and 14-day HCG. CI = confidence interval; LBW = low birthweight; OR = odds ratio; VLBW = very low birthweight; VPB = very preterm birth. a

Comparisons were made using the chi-squared test.

b c

Comparisons were made using a two-sample t-test. One case of heterotopic pregnancy was included, the intrauterine pregnancy of which was maintained and received Caesarean section.

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Table 3. Pregnancy outcomes among singleton pregnancies in the unicornuate group and the control group. Pregnancy outcomes

Unicornuate

Pregnancy Early pregnancy loss rate, % (n) Late miscarriage rate, % (n) Ectopic pregnancy rate, % (n) Premature delivery rate, % (n) Term delivery rate, % (n) Caesarean section rate, % (n) Babies born Live births Live birth rate, % (n) Perinatal mortality, % (n) Stillbirth Early neonatal mortality Gestational age at delivery 37 weeks, % (n)

183 20.2 (37/183)

Control

Unadjusted

Adjusted

OR (95% CI)

P-value

OR (95% CI)

P-value

567 14.1 (80/567)

1.54 (1.00–2.38)

0.048a

1.75 (1.08–2.83) 0.023

0.5 (1/183)

0.2 (1/567)

3.11 (0.19–49.97) NSa

3.3 (6/183)

3.2 (18/567)

1.03 (0.40–2.65)

NSa

3.14 NS (0.18–54.96) 1.39 (0.52–3.74) NS

13.7 (25/183)

3.9 (22/567)

3.92 (2.15–7.14)

<0.001a

3.89 (1.99–7.62) <0.001

62.3 (114/183)

78.7 (446/567)

0.45 (0.31–0.64)

<0.001a

0.40 (0.27–0.60) <0.001

86.3 (120/139)

73.9 (346/468)

2.23 (1.32–3.77)

0.002a

2.67 (1.50–4.77) 0.001

139 138 75.4 (138/183)

468 461 81.3 (461/567)

0.71 (0.47–1.05)

NSa

0.60 (0.39–0.94) 0.024

0.7 (1/139)

1.5 (7/468)

0.48 (0.06–3.91)

NSa

0.60 (0.07–5.48) NS

0.7 (1/139) 0

1.5 (7/468) 0

0.48 (0.06–3.91)

NSa

38.2 ± 2.0

38.9 ± 2.3

82.0 (114/139)

95.1 (445/468)

0.001b 0.24 (0.13–0.43)

<0.001a

0.24 (0.12–0.47) <0.001

Page 20 of 24

<37 weeks, % (n) VPB 20–31+6 weeks, % (n) Live birthweight (g) ≥2500 g, % (n) LBW <2500 g, % (n) VLBW <1500 g, % (n)

18.0 (25/139)

4.9 (23/468)

4.24 (2.32–7.75)

<0.001a

4.17 (2.13–8.16) <0.001

1.4 (2/139)

1.7 (8/468)

0.84 (0.18–4.00)

NSa

0.84 (0.15–4.62) NS

3095.0 ± 530.0 87.8 (122/139) 12.2 (17/139)

3390.0 ± 450.0 97.4 (456/468) 2.6 (12/468)

<0.001b 0.19 (0.09–0.41) <0.001a 5.30 (2.46–11.39) <0.001a

1.4 (2/139)

1.7 (8/468)

0.84 (0.18–4.00)

NSa

0.18 (0.08–0.41) <0.001 5.57 <0.001 (2.44–12.68) 0.84 (0.15–4.62) NS

Adjusted for maternal age, FSH, infertility duration, number of transferred embryos, cause of infertility, and insemination methods. CI = confidence interval; LBW = low birthweight; OR = odds ratio; VLBW = very low birthweight; VPB = very preterm birth. a

Comparisons were made using the chi-squared test.

b

Comparisons were made using a two-sample t-test.

Page 21 of 24

Table 4. Pregnancy and obstetric outcomes among twin pregnancies in the unicornuate group and the control group Pregnancy outcomes

Unicornuate

Control

Pregnancy Early pregnancy loss rate, % (n) Late miscarriage rate, % (n) Ectopic pregnancy rate, % (n) Premature delivery rate, % (n) Term delivery rate, % (n)

55 10.9 (6/55)

251 2.4 (6/251)

1.8 (1/55)

0.8 (2/251)

1.8 (1/55)

0.8 (2/251)

58.2 (32/55)

Caesarean section rate, % (n) Babies born Live births Live birth rate, % (n)

72.9 (35/48c)

21.0 (20/95)

40.2 (101/251) 55.8 (140/251) 87.6 (211/241) 482 458 91.2 (229/251) 5.0 (24/482)

12.6 (12/95)

3.7 (18/482)

8.4 (8/95)

1.2 (6/482)

33.9 ± 4.7 33.3 (16/48)

36.2 ± 3.4 57.7 (139/241)

Perinatal mortality, % (n) Stillbirth Early neonatal mortality Gestational age at delivery ≥37 weeks, % (n)

27.3 (15/55)

95 75 70.9 (39/55)

Unadjusted

Adjusted

OR (95% CI)

P-value

OR (95% CI)

5.00 (1.55–16.15) 2.31 (0.21–25.89) 2.31 (0.21–25.89) 2.07 (1.14–3.74) 0.30 (0.16–0.57) 0.38 (0.18–0.80)

0.010a

4.89 (1.47–16.21) 0.010

NSa

1.36 (0.08–22.26) NS

NSa

2.17 (0.18–26.43) NS

0.015a

1.88 (1.03–3.44)

0.040

<0.001a

0.33 (0.17–0.63)

0.001

<0.001a

0.45 (0.21–0.99)

0.046

0.23 (0.11–0.49) 5.09 (2.68–9.67) 3.73 (1.73–8.02) 7.30 (2.47–21.54)

<0.001a

0.27 (0.13–0.57)

0.001

<0.001a

5.12 (2.68–9.79)

<0.001

<0.001a

4.34 (2.04–9.19)

<0.001

<0.001a

5.26 (1.64–16.86) 0.005

0.002b 0.002a

0.40 (0.21–0.78)

0.37 (0.19–0.70)

P-value

0.007

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<37 weeks, % (n) VPB 20–31+6 weeks, % (n) Live birthweight (g)

66.7 (32/48) 20.8 (10/48) 2205 ± 620

≥2500 g, % (n)

37.9 (36/95)

LBW <2500 g, % (n)

62.1 (59/95)

VLBW <1500 g, % (n)

23.2 (22/95)

42.3 (102/241) 7.9 (19/241) 2510 ± 510 57.3 (276/482) 42.7 (206/482) 7.1 (34/482)

2.73 (1.42–5.23) 3.08 (1.33–7.12) 0.46 (0.29–0.72) 2.20 (1.40–3.45) 3.97 (2.20–7.17)

0.002a

2.50 (1.29–4.85)

0.007

0.006a

2.75 (1.15–6.54)

0.022

<0.001b 0.001a

0.61 (0.38–0.98)

0.044

0.001a

1.63 (1.01–2.61)

0.044

<0.001a

3.96 (2.15–7.28)

<0.001

Adjusted for insemination methods. CI = confidence interval; LBW = low birthweight; OR = odds ratio; VLBW = very low birthweight; VPB = very preterm birth. a

Comparisons were made using the chi-squared test.

b c

Comparisons were made using a two-sample t-test. One case of heterotopic pregnancy was included, the intrauterine pregnancy of which was maintained and received Caesarean section.

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