TWO DAYS MINIMAL STIMULATION PROTOCOL WITH INTRAUTERINE INSEMINATION IN THE TREATMENT OF UNEXPLAINED INFERTILITY

Mostafa Abdulla Elsayed Mahmoud. Prof Doctor, Assistant professor of obstetrics and gynecology, Benha university hospital, Qalubia district – Egypt. ...................................................................................................................... Manuscript Info Abstract ......................... ........................................................................ Manuscript History


ISSN: 2320-5407
Int. J. Adv. Res. 6(7), 888-893 889 A combination of CC and hMG have been devised to decrease costs by reducing the amount of hMG necessary in an ovarian stimulation cycle, without sacrificing effectiveness. [3][4][5] Corfman et al. developed a novel ovarian stimulation protocol of CC and hMG termed 'minimal stimulation' which is less expensive, requires minimal monitoring, minimizes patient discomfort and is easy to administer. 6 It was used in cases undergoing in vitro fertilization procedures. This protocol produced pregnancy rates comparable to conventional hMG stimulation at a much lower expense.
This prospective study planned to compare the two ovarian stimulation protocols of CC and hMG combination in couples with unexplained infertility and CC failures in whom IUI is planned. But with 2 alternate day regimen instead of one shot

Materials and Methods:-
The present study was conducted in the infertility clinic Elshorok infertility Hospital Benha city Qalubia district Egypt, from January 2017 to January 2018.
Two hundred women with unexplained infertility or ovulatory dysfunction cases who ovulated with clomiphene but failed to conceive were booked in to the study (Table 1) and were offered COS with clomiphene and hMG along with IUI.
After recruitment in the study the cases were divided into two groups according to random table before starting the first cycle of ovarian stimulation. A total of 200 ovarian stimulation cycles, minimal stimulation (100) and full conventional stimulation (100), were included in the analysis.

Inclusion criteria of patients:-
Infertility of at least 2 years Normal history and physical examination Adequate coital frequency Normal semen analysis Regular ovulatory menstrual cycles Adequate cervical mucus and a normal postcoital test Normal FSH, LH, PRL and TSH levels Normal hysterosalpingography and/or laparoscopy Criteria for clomiphene (CC) failures A-Anovulatory women who ovulate with CC but fail to conceive in 3 cycles Women with unexplained infertility who have been given CC empirically Conventional stimulation protocol:-Patients assigned for CC/hMG standard protocol received 100 mg of CC daily on days 3-7, and 75-150 IU of hMG was given intramuscularly, daily on days 5-9. Further hMG dosage was adjusted according to follicular monitoring by transvaginal sonography (TVS) and serum estradiol (E2) results done for the first time on day 10, and then afterwards TVS was done on alternate days or daily.
When the leading follicle was of diameter > 18 mm, 5000 IU of hCG was given to trigger ovulation. An E2 sample was taken prior to administration of hCG. Intrauterine insemination of husband's semen was performed 36 hours after hCG injection.

Minimal stimulation protocol:-
One hundred milligrams of CC was administered during cycle days 3-7; on day 5, 7, a single injection of 75 IU of hMG (total of 2ampoules) was given. On day10, TVS was performed to assess follicle development and growth. 5000 IU of Hcg (choriomon: IBSA) was given accordingly and IUI was done 36 after hCG injection.

Semen preparation and insemination technique:-
Couples were advised abstinence for 3-4 days. Semen collected in sterile containers after masturbation was allowed to liquefy at 37°C and then prepared by wash and swim-up technique using Ham's F-10 culture medium. 21-22 890 0.3 mL sample was injected into the uterine cavity with an IUI cannula, the rest of the sample was injected at the external os of the cervix. The patient asked to remain supine with buttocks elevated for 10 to 15 min.

Monitoring of outcome:-
Pregnancy was tested by pregnancy urine test (babycheck) 4-5 days after the missed periods followed by ultrasound (USG) examination 2 weeks later for detection of gestational sac and cardiac activity.
Multiple pregnancies and ovarian hyperstimulation syndrome (OHSS) was assessed. It was considered mild to moderate when there was ovarian enlargement with abdominal discomfort and weight gain.
Severe OHSS was diagnosed when there was massive ovarian enlargement, ascites, hemoconcentration, hypovolemia, oliguria, hypercoagulability and electrolyte imbalance. Cost of CC, hMG and hCG were assessed according to the current market rate of drugs. Monitoring cost was assessed according to number of USG examinations and serum hormones.

Statistical analysis:-
The data statistically analyzed and compared by applying 'test of proportion' and correlation coefficient (Pearson's r) where applicable by smith statistical package. Life table analysis was applied to calculate cumulative PRs by treatment. P < 0.05 defined the level of significance.

Results:-
A total of 200 couples completed 200 ovarian stimulation cycles along with IUI. There was no difference between the two stimulation protocols regarding mean age, years of infertility, type of infertility or the indication for treatment ( Table 2).
Among the 100 subjects who received minimal stimulation for 100 cycles, mean number of dominant follicles (DF) per cycle was 1.8 ± 0.51 and the mean number of DF in the 100 treatment cycles of full hMG stimulation given to the other 100 women was 3.2 ± 1.50. The difference was not statistically significant.
There was a significant correlation between E2 level and maximum number of follicles developed.
Maximum number of DF and pregnancies were observed when the E2 levels were between 500 and 1500 pg/mL. The number of ampoules of hMG used in the two treatment groups was significantly different, two for minimal stimulation (1 amp of 75 IU of hMG on day 5 and 7) and 12 ± 5.4 for full hMG stimulation.
Follicle monitoring in minimal stimulation required a one visit for trans-vaginal ultrasound while three to four visits were required in subjects receiving conventional stimulation protocol.
The pregnancy rate per couple as well as per cycle did not differ significantly in the two stimulation protocols. Though the luteal phase support was the same in both the protocols, miscarriage rate was higher in women who conceived on full stimulation. One patient in minimal stimulation had multiple gestation and no cases of ovarian hyperstimulation.

Discussion:-
Anovulation in women desiring fertility is the most common indication for use of ovulation induction therapy. Ovarian stimulation is also quite often recommended for women who apparently have spontaneous ovulation.9 Clomiphene citrate is the most commonly used drug because of its relative economy and ease of administration. 7 Women who remain anovulatory on CC or who have not conceived after five or six ovulatory cycles with CC are considered appropriate candidates for controlled ovarian hyperstimulation with hMG.( 9-12) Controlled ovarian hyperstimulation (COH) with hMG has been used along with IUI in couples with unexplained infertility. However, the cost of superovulation regimens is high.
Sequential regimens using a combination of CC and hMG have been devised to decrease costs by reducing the total amount of hMG necessary in an ovarian stimulation cycle, without sacrificing effectiveness.3-5 Corfman et al.6 described ovarian stimulation protocol termed 'minimal stimulation' which is less expensive, requires minimal monitoring, minimizes patient discomfort and is easy to administer. This protocol produced a clinical pregnancy rate comparable to conventional hMG stimulation at a lower expense.6 In the present study, minimal stimulation protocol was compared with the standard conventional protocol for ovarian stimulation, along with IUI in couples with unexplained infertility and CC failures. The pregnancy rate achieved per couple was 37% and the with minimal stimulation regimen while in conventional stimulation protocol cases these rates were 40%.
Pregnancy rates with COH with CC plus hMG as well as IUI in couples with unexplained infertility have been reported to range from 12.4% to 34%, and the per cycle pregnancy rate from 8.6% to 26.4%.10-13 The pregnancy rates achieved in the present study were 23.07% and 29.41% with minimal and conventional regimens; in cases of unexplained infertility, they were 14.63% and 18.75% per cycle, respectively. 7, 8 A single USG visit sufficed for minimal stimulation group while patients in conventional group required an average of 3.16 ± 1.50 visits per cycle. The total number of ampoules of hMG required in a cycle differed significantly (2.0 for minimal stimulation vs 12 ± 5.4 for conventional stimulation). Cost of minimal protocol was even less than onefourth of that of the conventional protocol.
In the present prospective study all pregnancies in minimal stimulation and 95% in the conventional stimulation protocol were singleton. Pregnancy wastage in minimal stimulation group was 5% only and it was 15% in the conventional stimulation group in this study. With the conventional stimulation with multiple hMG injections, premature leutinizing hormone surge plays a significant adverse role. 9 Patients who undergo full stimulation will have post-hCG E2 levels in excess compared to minimal stimulation; hence the altered E2 and progesterone balance may affect embryonic implantation.

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None of the patients in our study had ectopic pregnancy. The incidence of OHSS was 2% in conventional stimulation cycles while none of the cases had OHSS among minimal stimulation group.
The minimal stimulation protocol for COH in our study showed comparable pregnancy rates. It was easy to administer, required less intensive monitoring, fewer medications, lower pregnancy wastage and virtually eliminated the risk of OHSS. (15-20) The savings in cost and no morbidity suggests minimal stimulation as a viable alternative to conventional stimulation. Minimal stimulation should be offered to unexplained and CC failure cases and it is a good alternative before doing ICSI.10