|Year : 2018 | Volume
| Issue : 4 | Page : 201-207
Effect of uterine anomalies on pregnancy rates and reproductive outcomes in women undergoing artificial insemination by husband
Zi-Yin Chang, Hao Shi, Zhi-Qin Bu, Jun Zhai
Center for Reproductive Medicine in the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China
|Date of Submission||28-Sep-2018|
|Date of Web Publication||11-Jan-2019|
Center for Reproductive Medicine in the First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou 450000
Source of Support: None, Conflict of Interest: None
Objective: Congenital uterine anomalies are common; however, their effects on artificial insemination by husband (AIH) and the period during which AIH is converted to in vitro fertilization (IVF) are unclear. We examined the influence of uterine malformations on reproductive outcomes following AIH and the optimum number of AIH cycles before resorting to IVF-embryo transfer (IVF-ET).
Methods: We retrospectively recruited 168 patients with uterine malformations (anomalous group) undergoing AIH between January 2011 and December 2016. Meanwhile, 168 patients with infertility but with normal uteri (normal group) were matched as controls according to age.
Results: The clinical pregnancy rate was similar in both groups (12.4% vs. 12.3%, P = 0.950); the cancellation (21.6% vs. 4.4%, P < 0.001), early pregnancy loss (35.7% vs. 11.4%, P = 0.032), and preterm birth rates (21.4% vs. 2.9%, P = 0.038) were higher in the anomalous group, resulting in lower term birth (32.1% vs. 74.3%, P = 0.001) and live birth rates (50.0% vs. 77.1%, P = 0.034). After two AIH cycles, the clinical pregnancy rate was lower (3.6% vs. 23.1%, P = 0.037) among women with uterine anomalies than among those with normal uteri. There was no difference in the pregnancy rates (52.5% vs. 53.7%, P = 0.908) between the two groups of patients with unsuccessful AIH who then underwent IVF-ET.
Conclusions: IVF-ET can be performed immediately after two unsuccessful AIH cycles in patients with uterine malformations. In patients undergoing AIH or IVF, uterine malformations increase the risk of adverse obstetric outcomes.
Keywords: Artificial Insemination by Husband; In vitro Fertilization-Embryo Transfer; Reproductive Outcomes; Uterine Malformations
|How to cite this article:|
Chang ZY, Shi H, Bu ZQ, Zhai J. Effect of uterine anomalies on pregnancy rates and reproductive outcomes in women undergoing artificial insemination by husband. Reprod Dev Med 2018;2:201-7
|How to cite this URL:|
Chang ZY, Shi H, Bu ZQ, Zhai J. Effect of uterine anomalies on pregnancy rates and reproductive outcomes in women undergoing artificial insemination by husband. Reprod Dev Med [serial online] 2018 [cited 2019 Mar 24];2:201-7. Available from: http://www.repdevmed.org/text.asp?2018/2/4/201/249889
| Introduction|| |
Congenital uterine malformations are defined as deviations from the normal anatomy, resulting in elongation, fusion, and absorption disorders of the Müllerian ducts at approximately 6–18 weeks of embryogenesis. Various classification systems have been developed, which mainly include the American Fertility Society (AFS) classification system and the European Society of Human Reproduction and Embryology (ESHRE) system. Uterine malformations are grouped into seven types in the AFS classification system: hypoplasia/agenesis (I), unicornuate (II), didelphys (III), bicornuate (IV), septate (V), arcuate (VI), and diethylstilbestrol-associated uterine malformation (VII). It is the most widely used classification system; however, to address the lack of morphological classification for AFS classification standards, a new ESHRE system has been proposed in recent years. Female genital tract congenital anomalies in the ESHRE/European Society for Gynaecological Endoscopy (ESGE) system are also classified into seven main types. However, the category of arcuate uteri has been removed in this system. Indeed, some have argued that the ESHRE/ESGE system is illogical. These morphological defects are asymptomatic and difficult to detect. The prevalence of congenital uterine anomalies was estimated to be approximately 6.7% in the general population and 7.3% and 16.7% in women with infertility and recurrent miscarriage, respectively.,
Many recent studies and reviews have reported the obstetric outcomes of in vitro fertilization (IVF) and natural pregnancy with congenital uterine anomalies. Congenital uterine anomalies yield a greater risk of infertility, recurrent pregnancy loss, prematurity, intrauterine growth retardation, and other obstetric complications.,,,,,,, It is generally accepted that different types of Müllerian anomalies are individually related to these outcomes in various manners and to different degrees, with greater complications being evident in women with more profound defects.
To the best of our knowledge, there are no reports on the reproductive outcomes of patients with subfertility and congenital uterine anomalies, including those undergoing artificial insemination by husband-intrauterine insemination (AIH-IUI); further, data regarding the optimum number of AIH-IUI treatment cycles in women with unicornuate uterus are limited. The clinical pregnancy rate in AIH-IUI is approximately 12% and is impacted by maternal age, ovulation stimulation, time of insemination, frequency of insemination, semen quality, degree of tubal patency, and other unknown causes. The primary aim of this study was to evaluate the effect of uterine anomalies (by type) on the pregnancy rates and reproductive outcomes in women undergoing AIH. The secondary aim included estimation of the optimum number of AIH-IUI treatment cycles to provide a reasonable and feasible treatment protocol for patients with uterine malformations.
| Methods|| |
In this retrospective study, patients diagnosed with congenital uterine anomalies had their first infertility AIH treatment at our assisted reproduction technique center between January 2011 and December 2016. All enrolled patients had indications for AIH, and only women aged between 20 and 40 years with basal follicle-stimulating hormone (FSH) levels <12 U/L and antral follicle counts (AFCs) ≥5 were recruited. Patients with chromosomal abnormalities, endometriosis, hydrosalpinx, uterine fibroids or polyps, and a history of corrective surgery for deformities were excluded from this analysis. One hundred and sixty-eight patients with an abnormal uterus were selected for this study. Matched control patients (1:1) were selected from 818 patients meeting the inclusion criteria during the study according to age and number of inseminations per AIH cycle.
At the first consultation, all patients in this study underwent standard infertility workup procedures and tests (medical and fertility history evaluation, physical examination, transvaginal ultrasound [TVS], sex hormone level assessment, and semen analysis). All TVS examinations were three-dimensional and performed by experienced physicians using two ultrasound systems (Voluson S8 Pro and Voluson E8 Pro, GE Healthcare Ultrasound, Milwaukee, WI, USA) during the study. Three-dimensional TVS was used to screen patients for features that suggested the presence of uterine or intrauterine anomalies. If uterine malformation was suspected in a patient during ultrasound examination, hysterosalpingography, hysteroscopy, and/or laparoscopy were then performed to confirm the diagnosis. Uterine malformations were classified using the AFS classification system; therefore, Class I and Class VII uteri were ruled out. The criteria in the modified AFS classification system for uterine anomalies were followed for the three-dimensional ultrasound diagnosis of congenital uterine anomalies. If the external contour of the uterus was uniformly convex or had an indentation of <10 mm, but there was a cavity indentation with a central point of indentation at an obtuse angle (>90°), it was defined as arcuate. The subseptate uterus was defined as the presence of a septum, which does not extend to the cervix, with a central point of the septum at an acute angle (<90°). If the septum extended to the internal cervical os, the uterus was defined as septate.
Artificial insemination by husband-intrauterine insemination
Ovarian stimulation and ovulation detection
The natural cycle was used for patients with regular periods. Induced ovulation was used for ovulation failure, abnormalities of menstruation (cycle irregularity or prolongation of ≥35 days), and follicular dysplasia. The ovarian stimulation protocol consisted of administration of clomifene citrate (Cyprusgote Pharmaceutics, Limassol, Cyprus), human menopause gonadotropin (Lizhu Pharmaceutics, Zhuhai, China), FSH (Lizhu Pharmaceutics, Zhuhai, China), and letrozole (Jiangsu Hengrui Pharmaceutics, Lianyungang, China). From the 5th or 7th day of the menstrual cycle, follicular development was monitored via TVS. When the leading follicle had a diameter ≥14 mm, the urine luteinizing hormone (LH) level was measured twice a day. The cycles were canceled when the number of large follicles (mean diameter, ≥16 mm) was more than three (to avoid multiple pregnancies), the ovarian ovulation in this period was not on the same side with the only Fallopian tube More Details remaining, there was no dominant follicle growth, and/or there was a cavity or an occupying lesion in the endometrium.
Collection of semen
The AIH-IUI semen samples were collected following the WHO procedures (1999). The participants' husbands were instructed to abstain from sexual intercourse for 3–7 days before insemination. Semen was obtained via masturbation in a sterile plastic container. After the semen was treated and washed through Percoll or Pureception density gradient centrifugation, 0.5 mL of semen was used for artificial insemination. Routine and PTMS analyses were performed for the semen. The following formula was employed: PTMS = Posttreated density × activity ratio of posttreated a + b grade sperm × volume of semen injected to the uterine cavity.
Timing of artificial insemination by husband
Routine double IUI was used in our reproductive medical center. The ovulatory human chorionic gonadotropin (hCG) dose (10,000 IU) was administered when the mean diameter of the leading follicle reached ≥18 mm and an LH surge was detected during or after ovulation. The first AIH was performed 24 h after injection. If there was evidence of follicular rupture on TVS on the 2nd day, insemination was performed once. If not, intramuscular injection of 5,000 IU chorionic gonadotropin was performed in the afternoon. Thereafter, TVS was performed on the 3rd day. If ovulation was observed, second artificial insemination was performed immediately, and luteal support was provided. If ovulation did not occur at the end of the 3rd day, luteal support was not provided; these individuals were not included in the study.
Artificial insemination by husband procedures
The participants were instructed to perform perineal cleaning before surgery. They were placed in the lithotomy position. The cervical area was exposed using a vaginal speculum. A syringe was used to connect the artificial insemination tube, and the washed semen was extracted (0.5 mL). After the vaginal and cervical secretions were cleaned, the semen was slowly injected to the uterine cavity at approximately 1.5 cm from the bottom of the uterus; thereafter, the patients were placed in the dorsal decubitus position for 20 min.
In vitro fertilization-embryo transfer
Ninety-four patients (40 and 54 with abnormal and normal uteri, respectively) underwent fresh cycles of IVF-embryo transfer (IVF-ET) after an unsuccessful AIH. Controlled ovarian hyperstimulation was performed as a routine procedure in our center, as described previously.
Patients' characteristics recorded included age, AFC, infertility duration, body mass index (BMI), basal FSH level, and the percentage of cycles that ovarian stimulation was used. Pregnancy and obstetric outcome measures were recorded using the following regime. Serum β-hCG levels were measured 16 days after AIH and 14 and 18 days after the transfer of day 3 embryos and blastocysts, respectively. Thereafter, transabdominal ultrasound was performed in patients with positive findings for β-hCG 35 days after AIH or ET. Clinical pregnancy was diagnosed when gestational sacs were observed on ultrasound. All patients were monitored until the end of delivery.
The pregnancy and obstetric outcomes were defined as follows. According to the definition of abortion diagnosis of criterion in China, early pregnancy loss referred to miscarriages before 12 gestational weeks. Late miscarriages were defined as those occurring after at least 12 but before 28 gestational weeks. Preterm delivery referred to childbirth occurring at least 28 but before 37 gestational weeks. Term delivery was defined as childbirth occurring at ≥37 but before 42 gestational weeks. Gestational age was converted to unit weeks. Live birth was defined as delivery after at least 28 weeks of gestation with a live infant discharged from the hospital.
For patients with unsuccessful AIH cycles who then decided to undergo IVF, only the outcomes from the first IVF treatment cycle were compared to those of the normal group.
SPSS version 16.0 (SPSS Inc., Chicago, IL, USA) software was used to perform statistical analyses. Statistics were presented as means ± standard deviations for normally distributed data or medians with interquartile ranges (M [P25, P75]) for nonnormally distributed data. Differences in the means between groups were analyzed using the independent samples t-test. The Chi-square test or Fisher's exact test was used to determine statistical significance between percentages. P < 0.05 was considered statistically significant.
| Results|| |
From January 2011 to December 2016, 336 patients with a total of 587 cycles were recruited. Among these patients, there were 168 with abnormal uteri, including 69 with unicornuate uteri, 49 with arcuate uteri, 20 with septate uteri (10 complete septate and 10 subseptate uteri; no history of recurrent miscarriage and surgical resection), 9 with bicornuate uteri, and 21 with didelphys uteri.
Comparison of clinical data between the two groups
At the time of enrolment, the age of patients with malformed uteri ranged from 20 to 39 years with a median age of 27 years. A total of 114 and 54 patients were determined to have primary and secondary infertilities, respectively. The age of patients in the normal group ranged from 20 to 39 years with a median age of 28 years. One hundred and twenty-six patients were diagnosed with primary infertility and 42 with secondary infertility. The average baseline characteristics, including age, AFC, FSH level, BMI, LH level, infertility period, and the percentage of cycles of ovarian stimulation protocol, were similar between the two groups (P > 0.05)[Table 1].
|Table 1: Comparison of patient characteristics between the anomalous group and the normal group|
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Pregnancy and obstetric outcomes between the two groups
The average AIH clinical pregnancy rates per cycle were not significantly different between the two groups. Patients with uterine malformations had significantly higher rates of cancellation (21.58% vs. 4.41%, P < 0.001), early pregnancy loss (35.71% vs. 11.42%, P < 0.001), and premature delivery (21.43% vs. 2.86%, P = 0.038) than patients in the normal group. The term delivery rate (32.14% vs. 74.29%, P = 0.001), live birth rate (50.00% vs. 77.14%, P = 0.034), and gestational weeks (P < 0.001) were significantly lower in patients with uterine malformations than in the controls. The clinical pregnancy rates were similar between the subtypes of uterine malformations, although a trend toward an increased rate of early miscarriage, premature delivery, and cesarean section, as well as a lower rate of term delivery and live birth, was observed in patients with a septate or didelphys uterus. The septate uterus included four cases of complete septate uterus, and no clinical pregnancy occurred in patients with complete septate uterus. Only the cancellation rate was higher (P < 0.05) in patients with unicornuate uterus. Exception of patients with arcuate uterus, others with uterine malformations had no late abortion in this study [Table 2].
|Table 2: Pregnancy and obstetric outcomes in the anomalous group and the normal group|
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Pregnancy in the different artificial insemination by husband cycles
The clinical pregnancy outcomes in the different AIH treatment cycles were as follows. In the anomalous group, 168 were first AIH treatments with 43 canceled cycles and 18 cycles with clinical pregnancies; 90 were second AIH treatments with 14 canceled cycles and nine cycles with clinical pregnancies; and 34 were AIH treatments after the second treatments with six canceled cycles and one cycle with a clinical pregnancy. In the normal group, 168 were first AIH treatments with 12 canceled cycles and 17 cycles with clinical pregnancies; 87 were second AIH treatments with no canceled cycles and nine cycles with clinical pregnancies; and 40 were AIH treatments after the second treatments with one canceled cycle and nine cycles with clinical pregnancies. The clinical pregnancy rate for more than two cycles of AIH was significantly higher in the normal group than in the anomalous group (23.08% vs. 3.57%, P = 0.037) [Table 3].
|Table 3: Pregnancy outcomes among different cycles of AIH in the anomalous group and the normal group|
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Comparison of ovarian stimulation and clinical pregnancy outcomes between the two groups of patients with unsuccessful artificial insemination by husband who then underwent in vitro fertilization-embryo transfer
Patients with unsuccessful AIH treatment for all cycles eventually underwent IVF-ET. On average, the anomalous group and normal group, respectively, experienced about 2.00 and 1.89 AIH cycles before IVF transfer. All patients with abnormal uteri who underwent IVF treatments were followed up; however, only the first IVF treatment cycle outcomes of the anomalous group (n = 40) were compared with those of the matched control group (normal group, n = 54). Then, we compared the first IVF cycle pregnancy outcomes of patients with uterine abnormalities and the matched control patients. These patient characteristics were similar between the two groups, and the clinical pregnancy rate was not significantly different between them (52.50% vs. 53.70%, P > 0.05). The anomalous group had significantly higher rates of early pregnancy loss (33.33% vs. 3.45%, P = 0.007) and premature delivery (47.62% vs. 13.79%, P = 0.012) than the normal group; conversely, their gestational weeks significantly decreased (P < 0.05) [Table 4].
|Table 4: Comparison of ovarian stimulation outcomes and clinical pregnancy outcomes among the two groups with fresh ET for the patients who failed in AIH and next to receive IVF-ET treatment|
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| Discussion|| |
This is the first study to evaluate the reproductive outcomes after AIH treatment for patients with congenital uterine anomalies and the optimum number of AIH cycles attempted before IVF. In this study, patients with AIH treatment, two groups had a similar rate of conception (12.4 vs. 12.3%, P > 0.05). We observed that the presence of uterine defects was associated with increased risks of cycle cancellation, early pregnancy loss, and premature delivery after AIH, and there was an increased risk of low live birth rate and gestational age at delivery in the women with an abnormal uterus. One meta-analysis examined the effect of uterine malformations on reproductive outcomes and reported that septate uteri were associated with reduced clinical pregnancy rates; patients with other types of anomalies and those with normal uteri showed no difference in terms of the clinical pregnancy rates. However, in our study, patients with septate uteri have a relatively higher clinical pregnancy rate, possibly because the selected patients had no previous history of recurrent abortion. Further, the rates of cycle cancellation, early pregnancy loss, and premature delivery in the anomalous group were significantly higher than those in the normal group; conversely, the rate of late miscarriage was similar between them. These results are consistent with those of previous studies on natural or IVF conception outcomes.,,,,,,, The high rates of early pregnancy loss in patients with uterine anomalies may be caused by the abnormal uterine blood flow and poor endometrial receptivity. Compared with normal patients, the prevalence of HOXA gene mutations and polymorphisms is higher in patients with uterine malformations.,,,, HOXA10 gene mutation resulted in endometrial agenesis, poor endometrial receptivity, and reduced uterine blood flow, causing pregnancy loss, premature delivery, and abnormal fetal position in patients with uterine malformations.,,,, In our study, the rate of late miscarriage was similar between the two groups, although the anomalous group had significantly higher rates of early pregnancy loss. We suspect that patients with uterine malformations who were able to sustain pregnancy up to 12 weeks had sufficient endometrial blood flow and endometrial receptivity to maintain pregnancy; thus, the risk of late abortion was greatly reduced. However, with fetal growth and development, the anatomy of uterine malformations, reduction of uterine cavity volume, and fetal growth restriction were key factors for adverse outcomes. Considering these findings, together with decreased muscle mass and cervical incompetence in the abnormal uterus, the rate of preterm birth was much higher in the anomalous group than in the normal group (21.4 vs. 2.9%, P = 0.038).
Most recent studies have reported different effects of the subtypes of uterine anomalies on reproductive outcomes. A meta-analysis of pregnancy outcomes in different types of uterine malformations found that women with septate uteri had reduced clinical pregnancy rate and increased first-trimester miscarriage and preterm delivery rates; further, women with unicornuate, bicornuate, and didelphys uteri had similar clinical pregnancy rates, but a greater risk of preterm delivery, malposition, and abortion. The women with arcuate uteri had an increased risk of late miscarriage compared with women with normal uteri., In this study, sample size was relatively small. Thus, this study was underpowered to show a statistical significance for the clinical differences in the reproductive outcomes. There were nonsignificant differences among the various types of uterine malformations, although the rate of first-trimester miscarriage and preterm delivery was higher in patients with septate and didelphys uteri. The causes of abortion in patients with septate uteri remain unresolved. Homer et al. suggested that septate uteri disrupted the normal uterine cavity and exhibited ultrastructural abnormalities and defective development of the endometrium, which were insufficient to maintain pregnancy. Dabirashrafi et al. proposed that the septum had fewer muscle fibers and more connective tissues and abnormalities in the ratio of constituent blood vessels, resulting in uncoordinated uterine contraction. For didelphys uteri, we predicted that intrauterine pregnancy had a risk of fetal growth restriction, while the endometrium of nonpregnant uteri displayed decidual degeneration and bleeding, which may also cause contraction and abortion in pregnant uteri.
The optimum number of cycles of AIH-IUI before IVF-ET for women with uterine anomalies is a pragmatic concern when counseling an infertile couple; however, there is no consensus regarding this in the literature yet. Previous studies on the treatment of unexplained infertility have reported that the optimum number of IUI cycles before resorting to IVF or ICSI was three. The pregnancy rate in the third IUI cycle group was significantly lower than in the first IUI cycle group (P < 0.05), and IUI was not recommended for women aged more than 35 years. It was not reported that the optimum number of cycles of AIH-IUI that should be performed in patients with uterine malformations. In our study, there were no significant differences in the pregnancy rate in the first and second cycles between the two groups. Unexpectedly, the pregnancy rate decreased significantly after three cycles (3.6% vs. 23.1%, P = 0.037). Although the reason for this outcome is unclear, we postulated that women with uterine malformations have a higher cancellation rate, making the duration of assisted reproduction therapy longer. In particular, patients with unicornuate uteri have only one fallopian tube, and if the fallopian tube is not on the same side as that at which ovulation occurs, the AIH cycle will be canceled, extending the time for pregnancy success via this method. In addition, the psychology of fear of failure must not be ignored, as it can affect the pregnancy rate after failed attempts during some cycles. We further analyzed the women who were transferred to IVF after AIH failure. We found that both groups experienced about two AIH cycles before IVF transfer. Importantly, the rate of pregnancy has no significant difference between two groups. Hence, we recommend that patients with uterine malformations should be offered IVF if they fail to conceive after two trials of AIH.
In conclusion, the morphology of the uterus does not affect clinical pregnancy for patients underwent either AIH or IVF-ET. To treat infertility as soon as possible, we should limit the number of AIH cycles to two for women with uterine malformations in clinics, especially those with unicornuate uteri. For older women with a long duration of infertility, IVF treatment should be recommended if they have indications for IVF to avoid adverse pregnancy outcomes. Considering the increased risk for pregnancy-associated complications in patients with uterine malformations after IVF-ET or natural conception, these patients, if pregnant, must be informed that they might have a 30% risk of preterm delivery or threatened preterm delivery and a 45% risk of pregnancy loss. In addition, obstetrical management and surveillance should be strengthened to reduce the incidence of maternal and neonatal complications. Future studies on uterine malformations should include a higher number of pregnant patients and use a multicenter prospective design to verify the findings of this study.
The authors wish to thank Aaron J. W. Hsueh of Stanford University for critically reading the manuscript and providing helpful comments.
Financial support and sponsorship
This work was supported by the emergency management project of the National Natural Science Foundation of China (No. 31741094).
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]