Abstract
Intrauterine insemination (IUI) during ovarian stimulation cycles is typically performed 36 hours after human chorionic gonadotropin (hCG) injection. We hypothesized that adjusting the time interval to IUI to better coincide with ovulation may increase pregnancy rates. Patients undergoing induction of ovulation utilizing gonadotropins and gonadotropin releasing hormone (GnRH) antagonists and IUI were divided to three groups based on the time from hCG injection to IUI: 36, 42, and 48 hours. Primary outcome was defined as the clinical pregnancy rate. Secondary outcomes comprised additional parameters including multifetal pregnancy rate. A total of 92 patients completed the study. Baseline parameters were similar between the groups. The clinical pregnancy rate in the three groups was 20%, 38%, and 24%, respectively. While the 42 hour time interval had a higher numerical pregnancy rate, the pregnancy rates did not differ statistically among the study groups. The multifetal pregnancy rate did not differ among the three groups as well. A larger study is necessary to ascertain if a 42 hour time interval can indeed improve pregnancy rates.
Introduction
Controlled ovarian hyperstimulation combined with intrauterine insemination (IUI) is indicated for the treatment of male factor infertility, unexplained infertility, endometriosis, and ovulatory disorders [Merviel et al. Citation2010]. Success rates range between 10-20% per treatment [Dong et al. Citation2011; Duran et al. Citation2002; Erdem et al. 2007; Ferrareti et al. Citation2012; la Cour Freiesleben et al. Citation2009; Ragni et al. Citation2006], though higher rates have been reported [Zikopoulos et al. Citation2005]. Ovarian stimulation with gonadotropins achieve higher pregnancy rates than natural cycle IUI [Chaffkin et al. Citation1991; Guzick et al. Citation1999; Nulsen et al. Citation1993], but entail a high risk of multiple pregnancies including high order multiple pregnancies [Dickey et al. Citation2005, van Rumste et al. Citation2008]. The timing of IUI after human chorionic gonadotropin (hCG) administration has been studied and while a consensus regarding optimal timing has not been reached [Aydin et al. Citation2013; Claman et al. Citation2004; Ghanem et al. Citation2011; Ragni et al. Citation2004] 36 hours between HCG and IUI is considered good clinical practice [Guzick Citation2004].
Gonadotropin releasing hormone (GnRH) antagonists have been added to stimulation protocols with conflicting results [Bakas et al. Citation2011; Cantineau et al. Citation2011; Kosmas et al. Citation2008]. Utilizing antagonists offers additional advantages enabling weekend free planning of the insemination [Checa et al. Citation2006; Matorras et al. Citation2006] and conversion to in-vitro fertilization (IVF) should there be overstimulation for IUI [Quaas et al. Citation2010]; though they do entail a higher cost per pregnancy [Ertunc et al. Citation2010].
It is estimated that up to 42% of gonadotropin induced cycles have a premature luteinizing hormone (LH) surge by the time hCG is administered [Cantineau et al. Citation2007]. Clearly, these patients will ovulate sooner, on average, than women given GnRH antagonists; therefore the ideal timing of IUI may differ when GnRH antagonists are given to prevent endogenous increases in LH. The added control that the GnRH antagonist provides may allow for a more accurate assessment of an ideal time interval where IUI is most effective.
With fertile couples, pregnancy is most likely to be achieved if coitus takes place up to six days before ovulation, is increased on the day of ovulation, but drops precipitously after ovulation [Wilcox et al. Citation1995]. In a study on women undergoing IUI with donor sperm, pregnancy rates dropped if the insemination was conducted two days rather than one day after the LH surge [Blockeel et al. Citation2014]. For these reasons it is generally believed that insemination should take place before ovulation rather than after. But we hypothesize that with infertile couples, pregnancy rates may be increased if the insemination is timed to coincide as closely as possible to ovulation, even if insemination takes place a few hours after ovulation. This is because we know from IVF, that an increased concentration of motile spermatozoa in the oocyte's microenvironment improves the chances of fertilization [Toutnaye et al. Citation2002]. During the time that passes from insemination to ovulation sperm may disperse or become non-vital in infertile couples particularly those with a male factor. We conducted this pilot study to examine the feasibility of a two arm study, to assist in determining the time points and to ascertain that pregnancy did not drop precipitously if insemination was conducted shortly after ovulation.
We attempted to ascertain if extending the time interval between HCG injection and IUI in stimulated cycles utilizing GnRH antagonists could increase pregnancy rates. From IVF we know that when LH is suppressed using GnRH antagonists, women rarely ovulate before 36 hours from hCG administration. It is estimated that ovulation occurs within 48 hours of hCG administration [Testart and Frydman Citation1982], so in addition to the 36 hour lag time, two more time points were added, 42, and 48 hours. Three hypothetical situations were covered: insemination before ovulation (36 hours), insemination soon after ovulation (48 hours), and an intermediate state (42 hours) whereby the insemination is most likely to coincide with ovulation. We hypothesized that an insemination timed to coincide with ovulation (42 hours) would give the highest pregnancy rates.
Results
A total of 152 patients were offered to participate. Forty-five patients declined and 107 accepted. Fifteen patients were withdrawn from the study before hCG was administered () and involved seven for hyperstimulation of more than 4 follicles of 15 mm or more, three for advanced follicle growth before the GnRH antagonist began, one had an LH surge, one showed signs of ovulation (progesterone increased from 1.26 ng/mL to 2.43 ng/mL while the estradiol was reduced and the follicle size decreased), two were erroneously recruited though they did not satisfy the inclusion criteria, and one patient was withdrawn for not responding to gonadotropin stimulation. We did an intention to treat analysis on the data from all 107 patients () and a per protocol analysis on the data from the 92 patients who completed the protocol.
Figure 1. Patient flow diagram. Flow diagram presenting eligibility, recruitment, and randomization of patients. The reason for withdrawal of patients before the completion of the study is specified. ITT: intention to treat analysis; PP: per protocol analysis; LH: Luteinizing hormone.
Table 1. Baseline characteristics: intention to treat analysis.
Table 2. Stimulation cycle parameters: intention to treat analysis.
Table 3. Treatment outcomes: intention to treat analysis.
The three randomly assigned groups from the recruited patients did not differ significantly for age, body mass index (BMI), infertility etiology, the use of donor sperm, percentage of women with primary infertility, duration of infertility, or whether this was the first gonadotropin treatment. Follicle stimulating hormone (FSH) levels differed slightly between the three groups, though post hoc pairwise comparisons did not differ significantly between any of the two groups ().
There was no significant difference between the groups regarding the number of days of stimulation, the dose of gonadotropins received, the level of estradiol or progesterone, the number of follicles attained, endometrial thickness, the number of total motile sperm (TMS) inseminated, or the proportion of cycles with fewer than 10 million TMS at insemination. Group 1 received slightly more ampoules of antagonist than Group 2 (). There were no cases of ovarian hyperstimulation syndrome (OHSS).
Pregnancy rates did not differ statistically between the treatment groups. Treatment outcomes are summarized in . Clinical pregnancy rates for groups 1, 2, and 3 were 20%, 38%, and 24% when analyzed on a per protocol basis and did not differ significantly between the three groups.
Specifically, there were seven clinical pregnancies in Group 1 (36 hours) out of 35 participants (20%) who completed the protocol. Of those seven clinical pregnancies, two were twin pregnancies and one ended in miscarriage. One singleton pregnancy was terminated with feticide and delivery at 23 weeks for fetal cytomegalovirus (CMV) infection. All of the remaining five pregnancies including the two twin pregnancies delivered at term.
In Group 2 (42 hours) there were nine clinical pregnancies out of 24 participants (38%) who completed the protocol. None of these pregnancies ended in miscarriage. There were three twin pregnancies, a triplet pregnancy which spontaneously reduced to twins, and a quadruplet pregnancy. The quadruplet pregnancy was electively reduced to twins at seven weeks and delivered spontaneously at 34 weeks. All nine clinical pregnancies resulted in liveborn. There were six preterm deliveries, all between weeks 34 and 37.
In Group 3 (48 hours), there were eight clinical pregnancies out of 33 participants (24%) who completed the protocol. In addition, there was an ectopic pregnancy. Of the clinical pregnancies, one ended in miscarriage, two were twin pregnancies, one of which spontaneously reduced to a singleton, and a triplet pregnancy which spontaneously reduced to twins which eventually delivered preterm at 31 weeks. Overall seven pregnancies continued to delivery (21%), five of which delivered at term.
Thirty-four of the couples were determined to have male factor infertility or a combined male and female factor. Of the 16 couples in Group 1, three became pregnant (19%). Five of the 10 couples in Group 2 (50%) and one of the eight couples in Group 3 (13%) became pregnant.
We used stepwise logistic regression to determine which of the parameters: age, number of follicles over 12 mm diameter, number of follicles over 14 mm diameter, number of follicles over 18 mm diameter, estradiol level, and/or TMS, could predict clinical pregnancy for each group. The model was determined to be significant for Group 1 [F (1,24) = 8.616, p < 0.007], Group 2 [F (1,18) = 5.659, p < .029], and Group 3 [F (1,22) = 13.410, p < .001]. Only the number of follicles over 12 mm was predictive of clinical pregnancy in Groups 1 and 2, while the number of follicles over 14 mm was predictive in Group 3. Treatments that resulted in multiple gestations had more follicles over 12 mm than those that resulted in singletons (8.6 ± 5 vs. 5.0 ± 3, p < 0.046) while there was no difference in the number of follicles over 14 mm or over 18 mm.
Discussion
We hypothesize that in cycles utilizing GnRH antagonists, higher pregnancy rates could be achieved by delaying the time between recombinant HCG (rHCG) administration and intrauterine insemination to more closely coincide with the time of ovulation. In this pilot study pregnancy rates did not differ statistically between the three groups. Pregnancy rates did not drop when the insemination took place 48 hours after hCG administration.
As stated above, in our study only the number of follicles over 12 mm in Group 1 and 2, and the number of follicles over 14 mm in Group 3 were predictive of a clinical pregnancy. The number of mature follicles did not predict pregnancy. This is probably a statistical artifact since the total number of mature follicles per patient was narrow due to cancellation or transfer to IVF whenever an excessive number of mature follicles developed. In comparison, treatment was not restricted based on the number of smaller follicles, so that patients reached IUI with a range of small and medium follicles which nevertheless contributed to the clinical pregnancy rate. The discrepancy between Groups 1 and 2 where pregnancy was correlated with 12 mm and larger follicles and Group 3 where pregnancy was correlated with 14 mm follicles, is most likely a statistical artifact as well. The significance of this result is to reconfirm the finding that small and medium sized follicles can contribute to pregnancies and multiple gestations in stimulated IUI cycles.
The multiple pregnancy rate was 38% for those patients who completed the protocol. We aimed for up to four mature follicles and cancelled the cycle or transferred to IVF patients who had more. We did not, however, cancel cycles if there were a large number of small follicles. This is in accordance with the Israeli guidelines for controlled ovarian stimulation and intrauterine stimulation. The ESHRE position paper “Good clinical treatment in assisted reproduction” recommends cancelling the treatment attempt should more than three ‘mature’ follicles develop [Eshre Citation2008]. These guidelines do not account for smaller follicles, yet these smaller follicles can clearly contribute to pregnancies and multiple gestations. Gleicher et al. [Citation2000] observed that the risk of high order multiple pregnancies was not correlated with the number of follicles 16 mm or larger though they were correlated with the total number of follicles. Likewise, Dickey et al. [Citation2005] observed that high order multiple pregnancies could be reduced by counting all follicles over 10 mm and withholding therapy in the presence of seven or more follicles. Therefore, stricter guidelines should limit the number of small and medium follicles as well as mature follicles before continuing to IUI.
Multiple pregnancy rates can be reduced with less aggressive stimulation protocols and cancellation or transfer to IVF when accounting for follicles of all sizes. From the time of the completion of the study to May 2013, the twin delivery rate at our institution from stimulated cycles was 8% with no high order multiple pregnancies, though the clinical pregnancy rate was 15% which is lower than in the present study [Weiss et al. Citation2014]. Finally, we analyzed separately the chance of pregnancy for couples with a male factor infertility (male factor and combined) and no known male factor (female factor and unexplained) for the three different time groups among those patients that completed the protocol. The pregnancy rate for IUI at 36, 42, and 48 hours was 19%, 50%, and 13%, respectively for couples with a male factor infertility, though the small sample size precludes reaching a definitive conclusion.
The mechanism through which ovarian stimulation and IUI increase pregnancy rates is by increasing the likelihood of a sufficient number of motile spermatozoa being present in the fallopian tube in the proximity of an oocyte. While the sample size is too small to reach a definitive conclusion, numerically the 42 hour time group had more clinical pregnancies, particularly in couples with a male factor infertility. This suggests that at 42 hours there may be improved synchrony between insemination and ovulation. A larger study would be necessary to explore these results. We are presently planning a two arm prospective trial comparing a 36 hour interval to a 42 hour interval. A total of 138 participants in each arm would be needed to demonstrate an improvement from a 20% to 35% clinical pregnancy rate with 80% power.
Materials and Methods
This study was a three arm prospective, open randomized pilot trial which compared different time intervals between hCG administration and IUI in gonadotropin stimulated cycles utilizing GnRH antagonists in single women and infertile couples attending the Fertility Unit at the Obstetrics and Gynecology Department at Emek Medical Center in Afula, Israel; the Medical Center is a university hospital affiliated with the Rappaport faculty of Medicine at the Technion, Israel Institute of Technology. Each patient gave written informed consent to participate in the study which was approved by the local institutional review board (IRB) and registered with the NIH registry (NCT00675142). Patients were recruited from May 2008 to January 2011 and delivered by August 2011.
Patients were eligible if they were over 18 years of age with infertility and one or more of the following etiologies: ovulatory disorder, male factor, unilateral tubal disease, endometriosis, or unexplained infertility. Each patient was enrolled in the study only once.
Exclusion criteria
The exclusion criteria included known allergies to the utilized drugs, bilateral tubal occlusion, less than 1 million TMS, candidates for mono-ovulation, or women with baseline hormone producing functional cysts, or women who were not able to consent to the study because of language difficulties. Women wishing to conceive with donor sperm were included if they had undergone at least three prior natural cycle inseminations.
Withdrawal criteria
Patients could withdraw at any time from the study. Women were withdrawn from the study if they failed to achieve at least one follicle, if more than 4 follicles of 15 mm developed, if there was a spontaneous LH elevation or elevated progesterone before GnRH antagonist administration, or if patients reached the criteria for HCG administration before beginning GnRH antagonist injections.
A computer generated randomization table was used to divide women into one of three groups. Group allocation was concealed in closed consecutive envelopes. At the time of recruitment the envelope was opened and allocation was revealed to the patient and physician. Technician sonographers and laboratory personnel were blinded to group allocation. Patients were divided to three groups. Group 1 was to have insemination 36 h after HCG administration, Group 2, 42 h after, and Group 3, 48 h after HCG administration.
Stimulation protocol
A baseline pelvic ultrasound study was performed during the menstrual period to exclude ovarian cysts. If a cyst was demonstrated and estradiol or progesterone was elevated, the patient was not included in the study. Gonadotropins, either recombinant or urinary, were started on d 3 to 5 of the menstrual cycle. Dosing was individualized and based on the ovarian response from previous gonadotropin cycles, the patient's age, weight, FSH, and whether there were polycystic ovaries. Serial ultrasound examinations for follicle development were done as well as measurements of estradiol, progesterone, and LH hormones. The gonadotropin dose was adjusted as necessary. When the leading follicle reached 14 mm diameter, GnRH antagonist was started while the gonadotropin dose was maintained. When the leading follicle was 18 mm, instructions were given for the administration of rHCG. Women in Group one were instructed to inject rHCG at 10 PM two d before insemination. Women in Group two were instructed to inject rHCG at 4 PM, and women in Group three were instructed to inject HCG at 10 AM two d before insemination. Inseminations were performed between 10 a.m. and 12 noon. Progesterone support was given until eight weeks of pregnancy.
Outcome measures
The primary outcome measure was the clinical pregnancy rate. An intrauterine pregnancy with a fetal heart beat demonstrated on ultrasound 4-5 w after insemination was defined as a clinical pregnancy. Other endpoints included the miscarriage rate, multifetal pregnancy rate, live born children, gestational age at delivery, and neonatal weight.
Statistical analysis
Statistical analysis was performed utilizing SAS 9.2 software. Differences between the three groups regarding continuous data were analyzed with the Kruskall Wallis test and pairwise comparisons were performed using the Wilcoxon two sample test with the bonferroni correction. For categorical data we used the chi square or Fisher's exact test. Stepwise logistic regression was used when appropriate. p-Value of less than 0.05 was considered statistically significant.
| Abbreviations | ||
| BMI | = | body mass index |
| CMV | = | cytomegalovirus |
| FSH | = | follicle stimulating hormone |
| GnRH | = | gonadotropin releasing hormone |
| hCG | = | human chorionic gonadotropin |
| IVF | = | in-vitro fertilization |
| IUI | = | intrauterine insemination |
| LH | = | luteinizing hormone |
| OHSS | = | ovarian hyperstimulation syndrome |
| rHCG | = | recombinant HCG |
| TMS | = | total motile sperm |
Declaration of interest
The authors report no declarations of interest.
Author contributions
Conceived and designed the experiment, recruited patients, and wrote the manuscript: AW; Contributed to the study design, recruited patients, and reviewed the manuscript: RBF, ML, YG; Contributed to the execution of the study and reviewed the manuscript: JG, AE; Contributed to the study design, the writing of the manuscript, and supervision: ES.
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