Predictive factors affecting pregnancy rate after intrauterine insemination: A retrospective study

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1 Research Chronicle in Health Sciences 2017,3(1),1-7 An official journal of Reschrone Medico Publisher Original Article Predictive factors affecting pregnancy rate after intrauterine insemination: A retrospective study Pratibha Baldawa a, Sampat Baldawa b, Rakhi Sarda c, Sandesh Kamdi d a. MBBS, MS. Consultant Obstetrician and Gynaecologist, Department of Obstetrics and Gynaecology, Baldawa Hospital, Solapur, Maharashtra, India b.mbbs, MD. Consultant Obstetrician and Gynaecologist, Department of Obstetrics and Gynaecology, Baldawa Hospital, Solapur, Maharashtra, India c. MBBS, DGO. Consultant Obstetrician and Gynaecologist, Department of Obstetrics and Gynaecology, Sadasukh Hospital, Latur, Maharashtra, India d. M. Pharm. Medical Advisor, Department of Medical affairs, Akumentis Healthcare Ltd, Thane, Maharashtra, India Abstract The aim of the present investigation to explore the predictive factors for pregnancy rate after controlled ovarian hyperstimulation (COH) and intrauterine insemination (IUI). We performed a retrospective, cross-sectional study to find the IUI success rate at a private setting in Solapur, Maharashtra, India. A total number of 465 infertile couples were retrospectively analyzed for their age, duration of infertility, number of preovulatory follicles, endometrial thickness and motile sperm count to explore their relationship with the IUI success. All infertile women underwent basic fertility tests and the controlled ovarian stimulation was done with clomiphene citrate & human menopausal gonadotropin (hmg) alone or in combination. Out of 465 patients, 94 patients (20.22%) became pregnant after IUI treatment. Women age, duration of infertility, number of preovulatory follicles and post wash motile sperm count significantly affects pregnancy rate during IUI treatment (P). Keywords: Intrauterine insemination, pregnancy rate, sperm count, controlled ovarian stimulation, predictive factors, IUI success.. Introduction Intrauterine insemination (IUI) is one of the treatment modalities for infertile couples when male factor is a major cause for infertility. IUI can be performed with or without controlled ovarian stimulation using oral or injectable ovulation inducing agents [1]. Maternal age [2-3], problems with the ovulation [4], number of preovulatory follicles [5], endometrial thickness [6] and motile sperm counts [7] are some of the factors affecting rate of pregnancy in IUI. Many studies suggest an inverse relationship between the maternal age and IUI success [2,3,8]. Moreover, it has been reported that, pregnancy rate does not have any independent relation to sperm count, type of infertility, number and size of follicle [9]. The more the maternal age, the less the chances of patient conceiving after IUI and vice versa [8]. Post wash motile sperm count has also been implicated as an important predictive factor for IUI success. Postwashed total motile sperm count independently predicts success with IUI wherein cycles with less than 10 million total motile sperm are significantly less likely to result in a pregnancy [7]. Problems with the ovulation due to obesity, polycystic ovarian changes, Article History: Article received: July 28, 2016; Article revised: Sept 10, 2016; Article published: Sept 30, 2016 Correspondence Author: Dr. Pratibha Baldawa, Consultant Obstetrician and Gynaecologist, Department of Obstetrics and Gynaecology, Baldawa Hospital, Solapur, Maharashtra, India

2 erratic levels of progesterone or endometriosis has also been suggested as a factor responsible for infertility [4]. Ovarian response with two or more preovulatory follicles showed better pregnancy rate indicating the positive association between rate of pregnancy and the number of preovulatory follicles [2]. Although endometrial thickness is independent of age of female it also has significant effect on predicting the IUI success, wherein the highest pregnancy rate was recorded with endometrial thickness (ET) 6< ET 10 mm [10]. Several prognostic factors with regards to IUI treatment outcome have been identified, which includes factors such as patient profile, duration of infertility, type of infertility, stimulation protocol, follicular response, endometrial thickness, post-wash sperm motility [5,7,8,10]. IUI is a less expensive and simpler form of treatment compared with IVF but, it still requires frequent monitoring and supervision under specialist care. The success rates of IUI are not very encouraging combined with the effort, time and financial implications of such treatment. Hence, for the couple attempting IUI cycle could be a challenging decision. Moreover, couples travelling long distance from the town seeking treatment in other cities/centers would opt for one attempt of IVF rather than undergo three to four cycles of IUI. Since our hospital is a tertiary care center attached with different cities/towns for couples coming from different cities/towns for treatment, we decided to analyze the variables that contribute to the success of stimulated IUI cycles. Materials and Methods Present retrospective, cross-sectional study was carried out at our IUI laboratory of Baldawa Hospital, Solapur district, Maharashtra, India The primary outcome measures were clinical pregnancy and live birth rates. Secondary outcome measures were predictive factors influencing IUI success rate. The common conditions for which we performed IUI are unexplained infertility, problems of ovulation, polycystic ovarian syndrome, male factor infertility, endometriosis, fibroids and inability to have coitus due to erectile dysfunction or vaginismus. However, it is not advised in severe male factor infertility, tubal blockade, ovarian failure (menopause) and in women with advanced endometriosis. Clinical assessment of female partner: Along with detailed medical history we recorded pulse rate, blood pressure, haemoglobin level and blood group. Further test for HIV, hepatitis (HBsAg, surface antigen of the hepatitis B virus), and hormonal profile (Day 2; serum FSH, serum LH, serum TSH, serum prolactin and serum AMH) were performed. The tubal patency of the female partner was confirmed by Video hysterolaparoscopy or by hysterosalpingography. Clinical assessment of male partner: Basic semen examination on day 2 of their female partners was performed. Interventions For female: Controlled ovarian stimulation was done TM using clomiphene citrate (CC) & Melatonin (BESTOVA, Akumentis Healthcare Ltd, Mumbai) in a dose of 50/100 mg from day 2 to day 6 and HMG (PROTOCOL TM HMG Injection, Samsan Pharmaceuticals Ltd.) units alone or in combination. The basic antral follicular count was assessed on day 2 of menstrual cycle. The number of preovulatory follicles was assessed by serial follicular transvaginal ultrasonography from day 8 onwards till a dominant follicle of mm size was seen. Then a trigger for follicular rupture was given with 10,000 IU HCG (FERTIGYN TM Injection 1000 IU, Emcure Pharmaceutical Ltd). IUI was done 36 hrs after HCG administration. For male: For semen preparation, couples were requested to avoid intercourse for 3 to 5 days before the day of semen collection. Male partners collected semen samples in sterile containers by masturbation. WHO guidelines were used to assess the sperm morphology, sperm count and sperm motility. IUI was declined if the sperm count was less than 10 million/ml. For swim up method, 0.5 ml Page2

3 Page3 volume of semen was over layered with equal volume of Fertiplus medium and centrifuged for 15 min at 1800 rpm. The supernatant was discarded and cell pellet was mixed and washed in the medium. Mixture was again centrifuged for 10 min at 1500 rpm. The supernatant was again discarded and cell pellet was resuspended in IVF fertilisation medium and incubated for min. This was kept at 45 degree inclination and incubated until the time of insemination. Suspension of the processed semen ( ml) was inseminated into the uterine cavity about 0.5 cm below the uterine fundus with a soft 18 mm catheter. After insemination, 200 mg progesterone (daily, intravaginal) was prescribed for luteal phase support. To confirm the occurrence of initial pregnancy, urine pregnancy test was performed. When pregnancy test was positive, the clinical pregnancy was defined as presence of embryonic or foetal heart by means of ultrasonography at 6 to 8 weeks of gestational age. Live birth rate was defined as those pregnancies proceeding to deliver a live neonate. Statistical analysis Results were presented using descriptive statistics as mean±sd. Statistical analysis was performed by SAS 9.2 statistical software using Chi square test. The variables selected were patient parameters like age of woman, duration of infertility, type of infertility and cause of infertility. Logistic regression analysis was used to investigate the existence of any correlation between the variables and the occurrence of pregnancy. P<0.05 was regarded as statistically significant. Results We evaluated 465 patients undergoing a total of 610 stimulated IUI cycles between June 2012 and December Of the total around 26% of women visited from the towns and around 67% women were housewives. The characteristics of infertile women and the parameters that influence the success of IUI is shown in table 1. The overall pregnancy rate was 20.21% (94 out of 465). Out of the 94 pregnancies that occurred during the study, there were 8 sets of twins, 2 sets of triplets which were reduced to twins. There were 101 live births & 9 abortions occurred. Table 1: The mean value of women characteristics and the parameters that influence the IUI success Variables Min- Max Mean ± SD Female Age ±3.64 BMI (kg/m2) ±3.19 Infertility Duration ±3.09 Post wash TMSC ±10.85 No of Preovulatory follicles (> 16 mm) ±1.44 Size of the dominant follicle ±2.05 Endometrial Thickness (mm) ±1.09 No. of Cycles ±0.99 BMI (Body Mass Index), TMSC (Total motile sperm count). The mean follicle number was found to be 3.56±1.44 and preovulatory endometrial thickness was found to be 7.01±1.09 by transvaginal ultrasonography. The average number of post wash TMSC was determined to be 30.86± Before the multivariate analysis, univariate analysis was performed and the results are shown in table 2. In the univariate analysis increase in maternal age and increase in duration of infertility leads to decrease in chances of pregnancy. The pregnancy rates were realized as 33.33% and 10.64% in women age 30 and >30 years respectively. In the group of women with BMI <25 kg/m 2 pregnancy rate (20.72%) was higher compared to the group of women with BMI 25 kg/m 2 (18.93%). However the difference was not statistically significant. Fertility anamnesis of the couple was investigated in order to find out any relation between pregnancy rates and couple characteristics. We investigated duration of infertility and type of infertility (primary or secondary). In univariate analysis significantly higher pregnancy rate was observed in the group of couples having 5 years compared to >5 years duration of infertility (68.53% vs. 8.77% respectively). Also a positive correlation was observed between potential IUI success and type of infertility. In

4 Page4 a group of patients with primary infertility pregnancy rates was observed as 23.61%. Table 2: Univariate analysis of the variables VARIABLES Clinical Pregnancies Total value p- Yes, n (%) No, n (%) Age of woman (33.33) 168 (66.66) 252 > (4.69) 203 (95.30) 213 BMI (kg/m 2 ) <25 69 (20.72) 264 (79.27) (18.93) 107 (81.06) Duration of infertility 5 years 61 (68.53) 28 (31.46) 89 > 5 years 33 (8.77) 343 (91.22) 376 Type of infertility Secondary 13 (10.65) 109 (89.34) 122 Primary 81 (23.61) 262 (76.38) Endometrial Thickness (mm) > 8 38 (45.78) 45 (54.21) (14.65) 326 (85.34) 382 Size of the dominant follicle <19 14 (9.86) 128 (90.14) (24.77) 243 (75.23) 323 No of Preovulatory follicles (>16 mm) 1 follicle 2 follicles 1 (5.56) 7 (5.79) 17 (94.44) 114 (94.21) follicles > 3 follicles 25 (24.75) 61 (27.11) 76 (75.25) 164 (72.89) No. of cycles < 3 72 (100) 0 (0.0) (100) 0 (0.0) 22 NA 0 (0.0) 371 (100) 371 Post wash TMSC 5 million 0 (0.0) 0 (0.0) (0.0) 0 (0.0) (9.01) 10 (90.91) >30 million 10 (3.64) 83 (46.37) 265 (96.36) 96 (53.63) BMI (Body Mass Index), TMSC (Total motile sperm count). Thirty-eight pregnancies (45.78%) occurred within the group of the patients with endometrial thickness >8mm whereas 56 pregnancies (14.65%) occurred within the group of the patients with endometrial thickness 8mm at the day of hcg administration and the difference was found statistically significant. In cycles with a preovulatory dominant follicle having 19mm size the pregnancy rate was significantly higher compared to <19mm size of the preovulatory dominant follicle (24.77% vs. 9.86%). Moreover, in cycles with a single preovulatory dominant follicle the pregnancy rate (5.56%) was significantly lower than in cycles with more follicles. Pregnancy rate was observed as 5.79%, 24.75% and 27.11% with two, three and >3 preovulatory dominant follicles respectively. This difference was also found statistically significant in univariate analysis. Clinical pregnancy rate per couple was 0% when post wash TMSC was <5 and between million, 9.01% with million and 3.64% with million. However in univariate analysis significantly higher clinical pregnancy rates (46.37%) were observed when post wash TMSC count exceeded >30 million in comparison to the other groups. When the variables were evaluated by multivariate logistic regression analysis, majority of the variables had no significant effect on pregnancy rates. Five predictive variables such as age, duration of infertility, type of infertility, endometrial thickness and post wash TMSC were revealed for IUI success by multivariate analysis (Table 3). Table 3: Analysis of predictive factors for IUI VARIABLES P Value OR 95% CI Lower Upper Age of woman 30 vs. > BMI of woman (kg/m 2 ) <25 vs. >= Infertility Duration 5 years vs. > 5 yrs Type of Infertility Primary vs. Secondary Endometrial Thickness (mm) > 8 vs Size of the dominant follicle <19 vs Post wash TMSC vs. > 30 million vs. > 30 million < Comparison of factors affecting success of conception between pregnant and non-pregnant women. Response variable Y= Pregnancy (Yes vs. No). BMI (Body Mass Index), TMSC (Total motile sperm count). OR: odds ratio; CI: Confidence interval.

5 Page5 Discussion In our study, we made an effort to determine the prognostic factors that would determine the success of IUI. The overall pregnancy rate in our study was 20.22%. All the 94 pregnant patients had postwash motile sperm count of more than 10 million/ml. We have been observed that the high post-wash motile sperm count is a significantly positive predictor of IUI success rate. In accordance with the previous studies, number of inseminated motile sperms significantly affects the outcome of IUI treatment [11]. Hence, high post-wash motile sperm count is important positive predictor for IUI success. Moreover, Luco and co-workers also reported that total motile sperm count was found to be a predictor of pregnancy suggesting low pregnancy rates should be considered when deciding whether to suggest IUI and when selecting a protocol for ovulation induction for couples with male factor infertility [12]. Interestingly, it has been stated that, despite better semen parameters in the previously treated male infertile patient, pregnancy rates were found to be much higher in the low motile sperm count counterparts on the day of IUI [13]. However, Hassan and his co-workers in their retrospective study in 981 couples undergoing 2231 IUI cycles stated that pregnancy rates is unaffected by sperm count in IUI [14]. Also, it has been observed that pregnancy rate does not differ when comparisons is based on the presence of abnormal parameters like motile sperm concentration [15]. The reported pregnancy rates in previous studies have been varied from 2.7% to 66% [9,12,16). This wide variability may be due to lack of standard criteria for semen analysis, like variations in the method of semen preparation for insemination or non uniform reporting of semen characteristics. Also, this wide variability in success rate may be due to the different methods of insemination or a protocol used for ovulation induction for couples with male factor infertility or various male or female associated factors. Our results showed that woman s age is a very important factor in determining the pregnancy rate in IUI. We found that the majority of pregnancies happened in young patients aged less than 30 yrs. Out of the 94 pregnant patients 84 (89.36%) patients were less than 30 years of age. Of all pregnant women conceived after IUI, only 10 (10.64%) women were more than 30 years of age. However, the success rate declined as female age increases, in congruity with other reports [3,17]. This age related decline in IUI success is probably due to a combination of factors like progressive follicular depletion [18], decline in granulosa function, poor oocyte quality [19], reduced endometrial receptivity [20], higher rate of chromosomal abnormalities [21], increase in anovulatory cycles after 40 years of age, aging of the reproductive tract and diseases of the reproductive tract [22]. Our observation was in support of earlier reports which suggest that for younger female chances of conception are better following IUI. The duration of infertility also had a highly significant impact on the pregnancy rates after IUI. In our study we observed that, when the IUI was done within 5 years of married life, the conception rate was 68.53%, whereas this conception rate decreased (8.77%) by more than 7 folds when the duration of infertility was more than 5 years. We also noticed that pregnancy rate decreased with increasing infertility duration, particularly if the duration was greater than 5 years in primary infertility cases. Similar to our observation, previous studies have also reported that the increased duration of infertility may function as a negative factor of assisted reproductive treatment [2,5,23,24]. Hence, we inferred that females with secondary infertility were mostly above 35 years of age which may be a responsible factor for their low IUI success rate (4.28%). Although, few studies did not find significant difference in pregnancies between the groups with primary and secondary infertility [17,25], we would suggested that lesser the duration of infertility, more is the success rate with IUI. Multiple studies focused on the correlation between number of preovulatory follicles and pregnancy rate in ovarian stimulation with IUI. However, reports are contradictory. We observed positive correlation between the number of preovulaory follicles and pregnancy rates. Majority of the studies reported a positive association between

6 Page6 the number of follicles and pregnancy rate [5,4,23]. However, few studies have reported negative correlation between preovulatory follicles and pregnancy rates [26,27]. The present study showed positive correlation between endometrial thickness and IUI success. The average endometrial thickness in the women who conceived was 8.25 ± 0.6 mm and in non-pregnant women it was 6.69 ± 0.6 mm. There is a possibility of higher chances of pregnancy when endometrial thickness is in the range of 6<ET 10 mm [10]. However, earlier studies showed no significant correlation in the endometrial thickness of woman who conceived and who did not followed IUI [28]. It is stated that endometrial thickness is having no correlation with age, number of gonadotropin ampule and number of follicles [10]. Previous researches suggest effect of age, etiology of infertility and factors such as dominant follicle number on endometrial thickness and some of studies suggest strong effect of endometrial thickness on the pregnancy rate [29,30]. Thus to conclude, younger the patient, the lesser the duration of infertility and higher the number preovulatory follicles and post wash motile sperms, better is the IUI success rate. Perhaps, a larger sample size may be needed in formulating a better predictive model for IUI success. The information could be used by clinicians during counselling to arrive at a decision with regards to their treatment options. Acknowledgement We would like to thank Dr. Kartik Nakhate for his assistance during the writing of the manuscript. Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. All authors do not have a direct financial relation with the commercial identities mentioned in the paper. References 1. Levene MI, Wild J, Steer P. Higher multiple births and the modern management of infertility in Britian. The British Association of Perinatal Medicine. Br J Obstet Gynecol. 1992,99, Iberico G, Vioque J, Ariza N, Lozano JM, Roca M, Llacer J, et al. Analysis of factors influencing pregnancy rates in homologous intrauterine insemination. Fertil Steril. 2004,81, Schorsch M, Gomez R, Hahn T, Hoelscher- Obermaier J, Seufert R, Skala C. Success Rate of Inseminations Dependent on Maternal Age? An Analysis of 4246 Insemination Cycles. Geburtshilfe Frauenheilkd. 2013,73, Dickey RP, Taylor SN, Lu PY, Sartor BM, Rye PH, Pyrzak R. Effect of diagnosis, age, sperm quality, and number of preovulatory follicles on the outcome of multiple cycles of clomiphene citrate intrauterine insemination. Fertil Steril. 2002,78, Nuojua-Huttunen S, Tomas C, Bloigu R, Tuomivaara L, Martikainen H. Intrauterine insemination treatment in subfertility: an analysis of factors affecting outcome. Hum Reprod. 1999,14, Esmailzadeh S, Faramarzi M. Endometrial thickness and pregnancy outcome after intrauterine insemination. Fertil Steril. 2007,88, Miller DC, Hollenbeck BK, Smith GD, Randolph JF, Christman GM, Smith YR, et al. Processed total motile sperm count correlates with pregnancy outcome after intrauterine insemination. Urology. 2002,60, Ghosh C, Buck G, Priore R, Wacktawski-Wende J, Severino M. Follicular response and pregnancy among infertile women undergoing ovulation induction and intrauterine insemination. Fertil Steril. 2003,80, Zadehmodarres S, Oladi B, Saeedi S, Jahed F, Ashraf H. Intrauterine insemination with husband semen: an evaluation of pregnancy rate and factors affecting outcome. J Assist Reprod Genet.2009,26, Habibzadeh V, Mahani SNN, Kamyab H. The correlation of factors affecting the endometrial thickness with pregnancy outcome in the IUI cycles. Iran J Reprod Med. 2011,9, Khalil MR, Rasmussen PE, Erb K, Laursen SB, Rex S, Westergaard LG. Homologous intrauterine insemination. An evaluation of prognostic factors based on a review of 2473 cycles. Acta Obstet Gynecol Scand. 2001,80,74-81.

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