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Performing IUI Simultaneously with hCG Administration Does Not Compromise Pregnancy Rate: A Retrospective Cohort Study.


Although success rate for intrauterine insemination (IUI) is relatively low (1) (around 10% per cycle), IUI is generally considered as the primary modality for infertility treatment. It involves mild ovarian stimulation or natural cycle and processed sperm insemination. The prognostic factors for success rate depend on women age (1), processed total motile sperm (1, 2), endometrium thickness (1), and number of dominant follicles (3).

Conventionally, human chorionic gonadotropin (hCG) is administered when dominant follicles are reached on ultrasonography. The IUI is then scheduled 36-40 hr afterward. However, the prob ability of conception occurs only during five days before and ends on the day of ovulation in natural cycle (4). Hence, the necessity of scheduled IUI after ovulation has been challenged. It is hypothesized that IUI can be scheduled on the same day as the dominant follicle achieves on ultrasonography without compromising the pregnancy outcome (5-10). The limitation of previous studies is the lack of powerful sample size to tell the difference among each treatment arm. The pooled data of the published studies might overcome this limitation (5-8, 10-13).

The aims of the present study were to compare the pregnancy outcomes between preovulatory and postovulatory IUI to study the pregnancy outcomes between such timing of hCG and IUI.


Study design and participants: The retrospective cohort study was carried out at the infertility clinic in a tertiary-care university hospital. The study was conducted in accordance to the ethical principles of the Declaration of Helsinki, and the Vajira Institutional Review Board approved the study protocol.

All data were collected from IUI cycles between October 2007 to October 2015, after excluding the couples that were diagnosed with severe male factor infertility and bilateral tubal obstruction. Totally, 29 preovulatory IUI, and 221 postovulatory IUI couples were recruited. The patients were diagnosed with endometriosis, or endometrial polyp by laparoscopic or hysteroscopic surgery with histopathologic confirmation.

Ovarian stimulation: In each IUI cycle, ovarian stimulation was performed either by clomiphene citrate (CC) alone (Ovinum, Biolab, Samutrprakarn, Thailand), gonadotrophin alone (Menopur, Ferring, Saint-Prex, Switzerland), or combination of CC and gonadotrophin, based on physician's discretion starting on the 3rd to 5 th day of menstrual cycle. The growth of follicles and endometrial response were monitored by transvaginal ultrasonography on cycle days 9 to 14.

Timing of hCG injection: The standard protocol in our unit had been to inject 5,000 IU of hCG (Pregnyl, MSD, New Jersey, USA) when at least one dominant follicle reached 17 mm in mean diameter. The IUI was performed 36 to 40 hr after hCG administration. During October 2007 to December 2014, all patients were treated according to the standard protocol (postovulatory group). From January 2015, hCG was administered and IUI was performed on the same day when at least one dominant follicle reached 17 mm in mean diameter (preovulatory group).

Sperm preparation and IUI procedure: The semen samples were collected by masturbation following an abstinence of 3-5 days and then left to be liquefied in the 37[degrees]C incubator for 30 min. A droplet of undiluted semen was analyzed according to 5th edition of WHO laboratory manual (14). After semen analysis, the samples were centrifuged at 300 g for 15 min in a 45% and 90% Sil-Select-STOCK sperm preparation medium (FertiPro, Beernem, Belgium). The supernatant was discarded and the pellet was washed twice in sperm washing medium (FertiCult Beernem, Belgium) at 250 g in 5 min in each washing. The prepared sperm was kept in the 37[degrees]C incubator until used.

The prepared sperm was inseminated into the uterus through the cervix using an in-house compile soft IUI catheter.

Patient follow: Two weeks after the IUI procedure, the urine pregnancy test (UPT) was done. In case of positive UPT, a serum level of [beta]-hCG is often determined for the confirmation of biochemical pregnancy. For the clinical pregnancy, the vaginal sonography was performed every 2 weeks after the positive pregnancy result to inspect the gestational sac and fetal heart beat activity until gestational age of 12 weeks.

Statistical analysis: All data were analyzed by SPSS software (version 22.0). Data were presented as mean[+ or -]standard deviation (SD), number (%), or percentage (95% confidence interval, CI), as appropriate. Data comparisons were analyzed using independent sample t test for continuous data and [chi square] or Fisher's exact test as appropriate for categorical data. The binary logistic regression analysis adjusted for duration of infertility, number of dominant follicles, endometrium thickness, and total motile sperm count were used to compare the pregnancy rates among preovulatory and postovulatory IUI group. A p-value of <0.05 was considered statistically significant.


Between October 2007 and December 2014, there were 466 IUI cycles from 221 couples who underwent IUI after 36-40 hr of hCG injection (postovulatory group) while between January 2015 and October 2015, there were 54 IUI cycles from 29 couples who underwent IUI on the same day of hCG injection (preovulatory group). The baseline characteristics of both groups were comparable (Table 1). The average women age was 35 years, and mean duration of infertility was 3.5[+ or -]2.5 years in preovulatory group and 3.8[+ or -]2.7 years in postovulatory group, respectively. The major etiologies of infertility were unexplained, endometriosis, and anovulation, respectively. No mild male factor infertility was observed. Most of the cycles were stimulated with clomiphene citrate alone. However, mean total motile sperm count after sperm preparation in postovulatory IUI group was significantly higher than preovulatory IUI group (56x[10.sup.6]/ml versus 23x[10.susp.6]/ml, respectively, p<0.001).

Pregnancy outcomes: The pregnancy outcomes were displayed in table 2. The biochemical pregnancy rates were comparable among both groups (10.3%, 95% CI 1.0-22.0, and 16.3%, 95% CI 11.0-21.0, p=0.587 in preovulatory IUI, and postovulatory IUI group, respectively). These biochemical pregnancies resulted in 3 live-births in pre-ovulatory IUI group (10.3%, 95% CI 1.0-22.0), and 25 live-births in postovulatory IUI group (11.3%, 95% CI 7.0-16.0). The live-birth rates among both group were not different (p=1.000). There was no miscarriage in preovulatory IUI group while there were 11 miscarriages in post-ovulatory IUI group (5.0%, 95% CI 2.0-8.0, p= 0.622). The binary logistic regression was applied to adjust for the effect of duration of infertility, number of dominant follicles, endometrium thickness, and total motile sperm count to the pregnancy outcomes among both IUI group as represented in table 3. There was no significant effect of timing of IUI to the pregnancy results.


The concept of performing IUI after expected ovulation (36-40 hr after hCG administration) has been challenged for decades. Performing IUI before expected time of ovulation (preovulatory IUI) should not decrease the pregnancy rate or even increase the chance of pregnancy according to many reasons. Firstly, the ovulation occurs 24-56 hr after LH surges (median 36 hr) in natural cycles (15). On the other hand, the ovulation prevails 36-48 hr after hCG administration (16, 17). However, the premature LH surges occur in stimulated IUI cycle (18), which contributes to spontaneous ovulation about 24 hr after the surges (19). The conventional postovulatory IUI might be too late if premature LH surges occurred while preovulatory IUI still makes fertilization possible. Secondly, the cycle fecundability in natural cycle is maximum when the intercourse takes place between two days before ovulation, and the day of ovulation (4).

In our data set, biochemical pregnancy rate and clinical pregnancy rate in preovulatory IUI were lower than those in postovulatory IUI but not significantly different (10.3% versus 16.3%, p=0.407, and 10.3% versus 12.2%, p=0.77, respectively). The live-birth rate was not different among both groups (10.3% versus 11.3%, p=0.877, in preovulatory, and postovulatory IUI, respectively) according to higher miscarriage rate in postovulatory IUI (0.0% versus 5.0%, p=0.219, in preovulatory, and postovulatory IUI, respectively).

The characteristics of relevant publications were summarized in table 4. Fuh et al.'s investigated the time-related manner between spontaneous endogenous luteinizing hormone surge, hCG administration, and pregnancy rates in IUI cycles (20). Propst et al. (2012) used the same data set as Propst et al. (2007) did which might consequently deviate from the data in the previous studies.

From our study, unexplained infertility was the major cause of infertility in postovulatory IUI group while it was only about one fourth in preovulatory IUI (56.6% versus 27.6%, respectively). From previous studies, they found that spontaneous pregnancy rates in these patients were high up to 15% in one year, and might be up to 35% in two years (22). These might explain the reason for better biochemical and clinical pregnancy rates in our postovulatory IUI group. However, the duration of infertility in our patients was higher than 3 years in both groups, which was a poor prognostic predictor for fecundability (23). Furthermore, invasive investigations such as diagnostic hysteroscopy and diagnostic laparoscopy were not performed in every patient. The combined diagnostic surgeries can reveal the concealed pelvic pathology in 50% of unexplained infertility patients (24).

The pregnancy rate in IUI treatment improves with an increased processed total motile sperm count (1, 2, 25). It can predict clinical pregnancy rate better than sperm chromatin dispersion test (26) with the threshold concentration of 10x[10.sup.6]/ml (27). Processed total motile sperm count in our study is higher than the threshold in both groups but significantly higher in postovulatory IUI (23.1 x[10.sup.6] versus 56.1x[10.sup.6]/ml, p<0.001 in preovulatory IUI, and postovulatory IUI, respectively). These also explain the higher biochemical, and clinical pregnancy rate in postovulatory IUI but not livebirth rate.

The higher miscarriage rate in postovulatory IUI than preovulatory IUI in our data can be explained by our hypothesis that premature LH surges occurred more frequently in postovulatory IUI group. These findings are also in line with previous studies that higher LH concentration at the time of maximum follicular growth was associated with lower conception, and may contribute to higher early pregnancy loss in PCOS patients (28). Unfortunately, the direct correlation of premature LH surges and adverse pregnancy outcomes has not been explored. It was postulated that premature LH surges may give rise to the sequence of events that leads to pregnancy loss. First, it stimulates premature cumulus expansion, premature initiation of oocyte meiosis, and postmature oocyte at the time of fertilization (21). The postmature oocytes are found to have lower rate of normal fertilization, lower cleavage rate, and more than 1 pro-nuclear or pronuclear asynchrony (29). Second, premature progesterone secretion that appears after premature ovulation results in advanced endometrial dating, endometrium-embryo asynchrony and change in implantation window (21). Thus, more abnormal embryos and poor endometrium receptivity affect the pregnancy loss.

Our study has some limitations. Firstly, the retrospective nature of the study limits the variables that could be analyzed such as hormone monitoring, and the unmatched sample size among both groups. Secondly, the heterogeneity among each included study existed such as the timing of IUI after hCG administration in preovulatory IUI group which varied from simultaneously with IUI, 12 hr, and 24 hr. The outcome measures also varied among each study. Thus, these discrepancies made it difficult to perform a meta-analysis.


It seems preovulatory IUI gives comparable pregnancy outcomes as postovulatory IUI. Performing IUI on the same day as hCG injection has numerous benefits. For patients, the lower number of clinic visits, and flexible time of hCG injection contribute to less stress, and more flexible treatment cycle. For the clinic, this protocol provides a flexible schedule for sperm preparation and IUI. However, a larger study with enough power to detect the live-birth rate difference with our protocol should be performed.

Conflict of Interest

Financial support: none; Conflict of interest/financial disclosure: none.


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(2.) Merviel P, Heraud MH, Grenier N, Lourdel E, Sanguinet P, Copin H. Predictive factors for pregnancy after intrauterine insemination (IUI): an analysis of 1038 cycles and a review of the literature. Fertil Steril. 2010;93(1):79-88.

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(5.) Aydin Y, Hassa H, Oge T, Tokgoz VY. A randomized study of simultaneous hCG administration with intrauterine insemination in stimulated cycles. Eur J Obstet Gynecol Reprod Biol. 2013;170(2):444-8.

(6.) Dehghani-Firouzabai R, Aflatoonian A, Davar R, Farid-Mojtahedi M. A comparison of pregnancy rate before and after the administration of HCG in intra-uterine insemination. Arch Gynecol Obstet. 2014; 289(2):429-32.

(7.) Jarvela IY, Tapanainen JS, Martikainen H. Improved pregnancy rate with administration of hCG after intrauterine insemination: a pilot study. Reprod Biol Endocrinol. 2010;8:18.

(8.) Mostafa MS, El Huseiny AM, Soliman BS, Mohammed MM. Effect of postponing hCG injection after intrauterine insemination on pregnancy rate. Middle East Fertil Soc J. 2014;19(3):183-6.

(9.) Propst AM, Thoppil JJ, Groll JM, Frattarelli JL, Robinson RD, Retzloff MG. A single pre-ovulatory IUI at 12 hours after hCG trigger is comparable to a traditional IUI at 36 hours. Fertil Steril. 2012;98(3): S85-S6.

(10.) Propst AM, Thoppil JJ, Groll JM, Frattarelli JL, Robinson RD, Retzloff MG. Pre-ovulatory vs. ovulatory intrauterine insemination in controlled ovarian hyperstimulation cycles. Fertil Steril. 2007;88 (Supplement 1):S172-S3.

(11.) Robb PA, Robins JC, Thomas MA. Timing of hCG administration does not affect pregnancy rates in couples undergoing intrauterine insemination using clomiphene citrate. J Natl Med Assoc. 2004;96 (11):1431-3.

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(17.) Testart J, Frydman R. Minimum time lapse between luteinizing hormone surge or human chorionic gonadotropin administration and follicular rupture. Fertil Steril. 1982;37(1):50-3.

(18.) Cantineau AE, Cohlen BJ; Dutch IUI Study Group. The prevalence and influence of luteinizing hormone surges in stimulated cycles combined with intrauterine insemination during a prospective cohort study. Fertil Steril. 2007;88(1):107-12.

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(26.) Vandekerckhove FW, De Croo I, Gerris J, Vanden Abbeel E, De Sutter P. Sperm Chromatin Dispersion Test before Sperm Preparation Is Predictive of Clinical Pregnancy in Cases of Unexplained Infertility Treated with Intrauterine Insemination and Induction with Clomiphene Citrate. Front Med (Lausanne). 2016;3:63.

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Patsama Vichinsartvichai (*), Khanitta Traipak, Chirawattana Manolertthewan

- Infertility Unit, Department of Obstetrics and Gynecology, Vajira Hospital, Faculty of Medicine, Navamindradhiraj University, Bangkok, Thailand

(*) Corresponding Author: Patsama Vichinsartvichai, Infertility Unit, Department of Obstetrics and Gynecology, Faculty of Medicine Vajira Hospital, Navamindradhiraj University, 681 Samsen rd., Dusit, Bangkok 10300, Thailand E-mail:

Received: May 20, 2017

Accepted: Aug. 15, 2017
Table 1. Baseline characteristics of preovulatory and postovulatory IUI
groups. Data are presented as mean[+ or -]standard deviation or number

                              Preovulatory IUI  Postovulatory IUI
                                   (n=29)            (n=221)

Age (years)                   34.7[+ or -]4.8    35.0[+ or -]4.4
Duration of infertility
(years)                        3.5[+ or -]2.5     3.8[+ or -]2.7
Causes of infertility
  Endometriosis                5 (17.2)          60 (27.1)
  Endometrial polyp            4 (13.8)           2 (0.9)
  Anovulation                  4 (13.8)          21 (9.5)
  Unexplained infertility      8 (27.6)         125 (56.6)
  Number of cycle              1.9[+ or -]0.8     2.2[+ or -]1.6
Stimulation cycle
Stimulation protocols
  CC alone                    27 (93.1)         194 (87.8)
  CC + FSH                     0 (0)             15 (6.8)
  FSH alone                    2 (6.9)           12 (5.4)
Number of dominant follicle    1.7[+ or -]0.8     1.4[+ or -]0.7
Size of largest dominant
follicle (mm)                 21.1[+ or -]3.4    20.4[+ or -]3.2
Endometrium thickness (mm)     8.4[+ or -]2.0     8.0[+ or -]2.4
Processed total motile
sperm count (x[10.sup.6]/ml)  23.1[+ or -]18.2   56.1[+ or -]48.6


Age (years)                    0.758 (*)
Duration of infertility
(years)                        0.542 (*)
Causes of infertility         <0.001 (**)
  Endometrial polyp
  Unexplained infertility
  Number of cycle              0.291 (*)
Stimulation cycle
Stimulation protocols          0.341 (**)
  CC alone
  CC + FSH
  FSH alone
Number of dominant follicle    0.03 (*)
Size of largest dominant
follicle (mm)                  0.256 (*)
Endometrium thickness (mm)     0.43 (*)
Processed total motile
sperm count (x[10.sup.6]/ml)  <0.001 (*)

(*) Data were analyzed using independent sample t-test; (**) Data were
analyzed using the [chi square] test; IUI: intrauterine insemination;
CC: Clomiphene citrate; FSH: Follicle stimulating hormone

Table 2. Comparison of pregnancy rate per couple with different timing
in hCG injection. Data are presented as number (%)

                            Preovulatory IUI  Postovulatory IUI  p (*)
                                 (n=29)            (n=221)

Biochemical pregnancy rate      3 (10.3)          36 (16.3)      0.587
Clinical pregnancy rate         3 (10.3)          27 (12.2)      1.000
Live birth rate                 3 (10.3)          25 (11.3)      1.000
Miscarriage rate                0 (0)             11 (5.0)       0.622

(*) Data were analyzed using the Fisher's exact test; IUI: intrauterine

Table 3. Binary logistic regression analysis of pregnancy rate per
couple among preovulatory and postovulatory IUI group (Postovulatory
IUI is the reference group)

                                Adjusted OR        p
                               (95% CI) (*)

Biochemical pregnancy rate  0.539 (0.144-2.024)  0.360
Clinical pregnancy rate     0.804 (0.208-3.107)  0.752
Live birth rate             0.796 (0.205-3.096)  0.742

(*) Adjusted for duration of infertility, number of dominant follicles,
endometrium thickness, and total motile sperm count

Table 4. Overview and characteristics of studies discussing IUI and
timing of hCG administration

Author, year          Location        Study type            Patients

Fuh et al., 1997      Australia  Retrospective cohort   N=463, 1990-1995

Robb et al., 2004        USA     Restrospective cohort   N=90 2000-2001

Wang et al., 2006      Taiwan             NA                 N=135

Propst et al., 2007      USA              RCT                N=206,

Jarvela et al., 2010   Finland   Retrospective cohort   N=233, 200/-2009

Rahman et al., 2011     India             RCT                N=204

Propst et al., 2012      USA              RCT                N=213

Aydin et al., 2013     Turkey             RCT           N=220 2011-2013

Dehghani- Firouzabai    Iran              RCT                N=100
et al., 2014
Mostafa et al., 2014    Egypt             RCT           N=100, 2010-2011

Author, year                          Intervention

                         Group A, endogenous LH surge; group B,
Fuh et al., 1997       hCG after LH surge; group C, hCG before LH
Robb et al., 2004      IUI performed 24 hr versus 36 hr after hCG
Wang et al., 2006     Group 1, IUI 24 hr after hCG; group 2, IUI 36
                                      hr after hCG
Propst et al., 2007    IUI performed 12 hr versus 36 hr after hCG
Jarvela et al., 2010   IUI performed 24 hr versus 36 hr after hCG
Rahman et al., 2011    IUI performed 24 hr versus 36 hr after hCG
Propst et al., 2012    IUI performed 12 hr versus 36 hr after hCG
Aydin et al., 2013    IUI simultaneously versus 34-36 hr after hCG
Dehghani- Firouzabai  IUI simultaneously versus 34-36 hr after hCG
et al., 2014                            injection
Mostafa et al., 2014  IUI simultaneously versus 24-32 hr after hCG

RCT: Randomized controlled trial; N: Number of couples; NA: Not
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Title Annotation:Original Article; human chorionic gonadotropin and intrauterine insemination
Author:Vichinsartvichai, Patsama; Traipak, Khanitta; Manolertthewan, Chirawattana
Publication:Journal of Reproduction and Infertility
Article Type:Report
Date:Jan 1, 2018
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