Pregnancy outcomes following oral and injectable ovulation induction in infertile women with low anti-müllerian hormone level compared to normal anti-müllerian hormone level

Abstract

Objective:

Determine ongoing pregnancy rate among infertile patients with a low AMH compared to a normal AMH following oral and injectable ovulation induction(OI)/intrauterine insemination(IUI)

Design:

Retrospective cohort

Setting:

Academic center

Patients:

Patients completing ≥1 medicated OI/IUI cycle at our center between 2015-2019 were included. AMH levels were measured within 12 months of treatment initiation. The cohort was stratified into low AMH (AMH level <1.0ng/mL) and normal AMH (AMH ≥1.0ng/mL) groups. All subsequent medicated OI/IUI cycles occurring within one year of initial cycle start date were included up to the third completed cycle or until an ongoing pregnancy was recorded. Patients were stratified by age (<35, 35-40, and >40 years) and the relationship between low versus normal AMH group and each binary endpoint were quantified as risk ratios using age-adjusted Poisson models.

Intervention:

None

Main Outcome Measure:

Ongoing Pregnancy

Results:

3,122 patients completed 5,539 oral antiestrogen cycles and 1,060 patients completed 1,630 injectable gonadotropin cycles. For oral antiestrogen treatment, pregnancy outcomes including ongoing pregnancy rate per cycle for patients with a low AMH were comparable to those with a normal AMH (<35 years: 15.4% versus 14.9%; 35-40 years: 10.0% versus 11.0%; >40 years: 2.8% versus 3.3%). For injectable gonadotropin treatment, the ongoing pregnancy rate was lower in the low AMH compared to the normal AMH group for ages <35 years (12.1% versus 23.5%;RR 0.52 (95%CI=0.28-0.97)) and 35-40 years (12.5% versus 18.5%;RR 0.70 (95%CI=0.49-0.99) but comparable for patients >40 years (3.0% versus 4.0%; RR 0.86 (95%CI=0.31-2.35)). The proportion of multi-fetal gestations was similar between low and normal AMH groups treated with oral antiestrogens (13.1% versus 10.8%), however for injectable gonadotropin treatment, patients with normal AMH had a higher proportion of multi-fetal gestations (18.6% versus 31.1%).

Conclusion:

Compared to normal ovarian reserve, treatment with oral antiestrogens for OI/IUI for patients with low ovarian reserve results in comparable follicular development and comparable ongoing pregnancy rates for all age groups. When patients with low ovarian reserve are treated with gonadotropins for OI/IUI, multi-follicular recruitment is less likely resulting in a significantly decreased ongoing pregnancy rate for patients <35 and 35-40 years old, but also a decrease in multi-fetal gestations. Overall, the ongoing pregnancy rates of 8.7% per oral antiestrogen cycle and 8.1% per injectable gonadotropin cycle in patients with low ovarian reserve are comparable to the expected rates in the general infertility population.

Capsule:

Ongoing pregnancy was comparable between low and normal AMH with oral antiestrogen OI treatment. Decreased ongoing pregnancy but decreased multi-fetal gestations was observed with gonadotropin treatment for low AMH patients.

Introduction

Anti-müllerian hormone (AMH) is routinely measured as a component of the infertility evaluation to measure ovarian reserve and estimate a patient’s reproductive potential in terms of the number of oocytes (1-3). In the context of ovarian stimulation for in vitro fertilization (IVF), low AMH levels have been associated with a lower number of oocytes retrieved, a longer course of stimulation, and a higher rate of cycle cancellation due to a poor response to gonadotropin stimulation (4,5). However, before proceeding to ovarian stimulation for IVF, ovulation induction (OI) with or without intrauterine insemination (IUI) should be considered when appropriate due to a decreased risk of procedural complications and a lower cost per individual cycle when compared to IVF. For an infertile patient with low ovarian reserve, a clinician must determine whether OI is an appropriate first-line treatment option or if the pregnancy rates are poor enough that these patients should proceed straight to ovarian stimulation for IVF to not waste valuable time.

Multiple previous studies have evaluated ovarian reserve markers as predictors of pregnancy following IUI cycles with conflicting results (6-9). One difficulty in assessing ovarian reserve markers on pregnancy outcomes is that they are intimately tied to female age (2). Without a well-designed study and analysis to properly control for female age, markers of low ovarian reserve will always result in lower live birth because of the association with older female age. Further, the combination of OI cycle types (oral antiestrogens and injectable gonadotropins) confounds study outcomes due to the significant differences in infertility indication and number of follicles recruited for each OI cycle type (10).

Thus, it remains poorly understood whether young patients with a low AMH will produce an oocyte and corpus luteum that has similar competency compared to an age-matched patient with a normal AMH level. This information has great importance in our field as it would guide the recommendation made to these women for when to undergo OI treatment and when to proceed straight to IVF based on AMH levels. The primary objective of this study was to evaluate whether a low AMH level (<1.0 ng/mL) is associated with ongoing pregnancy outcomes compared to a normal AMH level (≥1.0 ng/mL) after stratification by female age and OI cycle type.

Methods

Study Population and Design

This study was approved by the institutional review board at our institution. This was a retrospective cohort study performed at a large academic reproductive medicine center. Patients who completed at least one medicated OI cycle with IUI at our center between 2015 and 2019 were included. The recommendation to use oral antiestrogens or injectable gonadotropins was made by the treating physician with the patient based on their infertility history, diagnosis, and treatment goals. All included patients had an AMH level measured within 12 months of the IUI cycle start date. The cohort was stratified into a low AMH group (defined as AMH level <1.0 ng/mL) and a normal AMH group (AMH ≥1.0 ng/mL) based on the baseline AMH level prior to the first OI cycle. The AMH threshold of 1.0 ng/mL was used to define low AMH given that this is a commonly accepted threshold to classify patients with diminished ovarian reserve in clinical research, as defined by the American College of Obstetrics & Gynecology (11).

All subsequent medicated OI/IUI cycles that occurred within one year of the initial cycle start date were included for each patient up to the third completed cycle or until an ongoing pregnancy was recorded. Patients who underwent timed intercourse instead of IUI or those who did not undergo OI but instead were monitored in the natural cycle without medications were excluded.

Study Outcomes and Definitions

The primary outcome of this study was ongoing pregnancy, defined as a viable intrauterine pregnancy at ≥8 weeks of gestation. Secondary outcomes included pregnancy, clinical pregnancy, and pregnancy loss. Pregnancy was defined as a serum beta hCG level >5 mIU/mL 14 days following IUI. Clinical pregnancy was defined as the observation of at least an intrauterine gestational sac on transvaginal ultrasound. Pregnancy loss was defined as all pregnancies which failed prior to 8 weeks of gestation.

Clinical Protocols

Oral Antiestrogen Protocol (Clomiphene or Letrozole)

Patients treated with oral antiestrogens (either clomiphene or letrozole) were evaluated on cycle day 2 with a pelvic ultrasound and serum hormone levels (FSH, LH, estradiol, beta hCG). Once patients were confirmed to be in the early follicular phase, oral medication was initiated on cycle day 2. Clomiphene was typically initiated at 50-100mg daily for five days. Letrozole was typically initiated at 2.5-5mg daily for five days. Patients returned on cycle day 8-10 for pelvic ultrasound and serum hormone levels (FSH, LH, estradiol) to assess follicular response to treatment. For patients that failed to respond to medication, the clomiphene dose was increased in 50mg increments to a maximum of 150mg for five days and the letrozole was increased in 2.5mg increments to a maximum of 7.5mg for five days. After evaluation on cycle day 8-10, serial ultrasound and hormone levels were performed until a leading follicle measured >20mm at which point an ovulatory trigger with hCG was administered. The IUI was then performed 24-36 hours later. If an LH surge was detected prior to hCG administration, the IUI was performed the following day.

Injectable Gonadotropin Protocol

Patients treated with injectable gonadotropins were evaluated on cycle day 2 with a pelvic ultrasound and serum hormone levels (FSH, LH, estradiol, beta hCG). Once patients were confirmed to be in the early follicular phase, nightly injections were initiated on cycle day 2 with recombinant FSH and/or human menopausal gonadotropin. Patients returned serially every 2-3 days for pelvic ultrasound and serum hormone levels (FSH, LH, estradiol) to assess follicular response to treatment. Dose adjustments were made throughout the cycle by the treating physician based on the follicular response. Once a leading follicle measured >17mm, an ovulatory trigger with hCG was administered. The IUI was then performed 24-36 hours later. If an LH surge was detected prior to hCG administration, the IUI was performed the following day. Luteal support was provided with a vaginal progesterone suppository beginning two days after the IUI.

Sperm Wash and Intrauterine Insemination

After an average abstinence of 2-5 days, sperm was collected either fresh via masturbation or from a thawed cryopreserved sample on the day of IUI. The sperm preparation was performed with centrifugation using density gradient selection as previously described (12). After preparation, 5μL was assessed in the Makler chamber to record post-wash concentration and motility according to the World Health Organization criteria (13).

For the IUI, a sterile speculum exam was performed and cervical mucus was removed with a cotton swab. The prepared sperm with media was aspirated into an IUI catheter and deposited beyond the internal cervical os into the uterine cavity. The patient remained supine for ten minutes prior to ambulation.

Pregnancy Monitoring

Patients returned 14 days following the IUI for serum hCG, progesterone, and estradiol measurements. If the hCG measured >5 mIU/mL, the hCG level was measured again 48 hours later. Patients with a normally rising hCG underwent a viability ultrasound in the 5th–6^th weeks of gestation. Follow-up ultrasounds were performed to monitor fetal growth and development as indicated. Patients with an ongoing pregnancy initiated care with an obstetrician between 8 and 10 weeks of gestation.

Statistical Analysis

Patient baseline characteristics and OI treatment cycle variables are reported in Table 1. The specific infertility diagnoses were not available in the ovulation induction dataset that was utilized for this study and therefore this variable was not reported. However, patients treated at our center with oral antiestrogens for OI/IUI are generally patients diagnosed with anovulatory infertility, unexplained infertility, and/or male factor infertility. Gonadotropin treatment is generally reserved for patients with anovulatory infertility with or without male factor infertility.

Table 1:

Demographic and clinical variables of the study cohort from the first treatment cycle

	Oral ovulation induction (clomid or letrozole)			Gonadotropin ovulation induction
	Low ovarian reserve (AMH <1.0) N=605	Normal ovarian reserve (AMH ≥1.0) N=2,517		Low ovarian reserve (AMH <1.0) N=484	Normal ovarian reserve (AMH ≥1.0) N=576
Patient age	38.9 (36.1-41.5) (27.4-49.0)*	35.2 (32.6-37.9) (21.7-46.8)*		40.5 (37.5-42.7) (25.8-48.8)*	36.6 (33.4-39.6) (20.4-47.9)*
BMI (kg/m2)	22.9 (20.7-26.7)	22.7 (20.6-25.8)		23.2 (21.3-26.9)	22.8 (20.9-27.1)
Race
White	380 (62.8%)	1462 (58.1%)		287 (59.3%)	312 (54.2%)
Black	27 (4.5%)	86 (3.4%)		28 (5.8%)	21 (3.7%)
Asian	79 (13.1%)	471 (18.7%)		71 (14.7%)	130 (22.6%)
Other/Unknown	119 (19.7%)	498 (19.8%)		98 (20.3%)	113 (19.6%)
AMH (ng/mL)	0.6 (0.3-0.8)	3.1 (1.9-5.5)		0.4 (0.2-0.7)	2.5 (1.5-4.7)
Cycle type:
Clomiphene citrate	543 (89.8%)	2155 (85.6%)		N/A	N/A
Letrozole	62 (10.3%)	362 (14.4%)		N/A	N/A
Gonadotropin	N/A	N/A		484 (100.0%)	576 (100.0%)
Number of follicles ≥14mm the day of trigger:
1	188 (31.1%)	783 (31.1%)		228 (47.1%)	108 (18.8%)
2	233 (38.5%)	940 ( 37.4%)		123 (25.4%)	122 (21.2%)
3	141 (23.3%)	558 (22.2%)		68 (14.1%)	145 (25.2%)
≥4	43 (7.1%)	236 (9.4%)		65 (13.4%)	201 (34.9%)
Endometrial thickness (mm)	8.0 (6.7-9.4)	8.2 (6.9-9.8)		9.0 (7.8-10.4)	9.6 (8.5-11.1)
Post-wash total motile sperm count (million):
<10 x106	76 (12.6%)	294 (11.7%)		63 (13.0%)	57 (9.9%)
10-20 x106	150 (24.8%)	485 (19.3%)		99 (20.5%)	105 (18.2%)
>20 x106	379 (62.6%)	1738 (69.1%)		322 (66.5%)	414 (71.9%)

Data are median (interquartile range) or n(%)

^*Range

The primary analysis was stratified by OI cycle type (oral antiestrogen or injectable gonadotropin) to assess the primary outcome of ongoing pregnancy and the secondary pregnancy outcomes among patients with a low AMH level compared to patients with a normal AMH level using mixed-effects modified Poisson models with robust error variance. This model can account for the occurrence of multiple OI/IUI cycles for patients (correlation between cycles from the same patient through the use of patient-level random effects) and the missingness pattern (missing at random) (14). To assess the relationship more closely between ovarian reserve and ongoing pregnancy within pre-specified age groups previously found to be related to success of the procedure, patients were stratified into female age groups <35 years, 35-40 years, and >40 years (15,16).

All models were adjusted a priori for female patient age to estimate the relative risks with 95% confidence intervals (CI) of the study outcomes. Further covariates were added to the model individually and were retained in the multivariate model if their addition changed the relative risk from the crude model by 10% or more (17,18). Covariates that were tested as confounders of the relationship between low AMH and ongoing pregnancy included cycle number (1-6), body mass index, race, endometrial thickness, and total motile sperm count <10 million. None of these covariates met criteria for inclusion in the final model. The number of follicles measuring ≥14mm the day of hCG trigger/LH surge was considered to be on the causal pathway between ovarian reserve and ongoing pregnancy and was therefore not considered for inclusion in the model (19).

To further assess the association between ovarian reserve and ongoing pregnancy outcomes, a sensitivity analysis was performed by stratifying the low AMH group into tertiles. The ongoing pregnancy rate in each low AMH tertile and in the normal AMH group was described for each age group. Descriptive statistics were reported to observe patterns and a nonparametric test for trend was performed across AMH subgroups to evaluate for a linear trend with decreasing AMH level. Statistical significance was denoted by a p-value of <0.05. Statistical analyses were performed using Stata/MP 17 (StataCorp LLC, College Station, TX, USA).

Results

A total of 3,122 patients completed 5,539 oral antiestrogen cycles (Low AMH group: 970 cycles; Normal AMH group: 4,569 cycles) and a total of 1,060 patients completed 1,630 injectable gonadotropin cycles (Low AMH group: 728 cycles; Normal AMH group: 902 cycles) during the study period. The patient demographics and clinical variables from the first OI/IUI cycle are reported in Table 1. Compared to the normal AMH group, the median age with interquartile range (IQR) was older in the low AMH group for both patients treated with oral antiestrogens (35.2 (32.6-37.9) versus 38.9 (36.1-41.5) years) and with gonadotropins (36.6 (33.4-39.6) versus 40.5 (37.5-42.7) years). The number of follicles ≥14mm at hCG trigger/LH surge was comparable between the normal AMH and low AMH group for patients treated with oral antiestrogens. However, for patients treated with gonadotropins, a higher number of follicles ≥14mm were measured for patients with normal AMH compared to patients with low AMH. The remaining demographic and clinical variables were comparable between the AMH groups.

The pregnancy outcomes per cycle for patients treated with oral antiestrogens are shown in Table 2. Within each age group, the ongoing pregnancy rate was comparable between patients with low AMH and normal AMH levels. For patients <35 years, the ongoing pregnancy rate was 15.4% (n=23) in the low AMH group and 14.9% (n=331) in the normal AMH group (age-adjusted RR 1.01 (95% CI 0.68-1.48)). For patients 35-40 years, the ongoing pregnancy rate was 10.0% (n=53) in the low AMH group and 11.0% (n=224) in the normal AMH group (age-adjusted RR 0.96 (95% CI 0.72-1.28)). For patients >40 years, the ongoing pregnancy rate was 2.8% (n=8) in the low AMH group and 3.3% (n=10) in the normal AMH group (age-adjusted RR 1.01 (95% CI 0.41-2.52)). Additionally, pregnancy, clinical pregnancy, and ongoing pregnancy rates were comparable between the low and normal AMH levels within all three age groups.

Table 2:

Pregnancy outcomes per cycle for oral antiestrogen treatment

AMH, antimüllerian hormone; IQR, interquartile range

Data are n (%) unless otherwise noted

AMH units are ng/mL

The pregnancy outcomes per cycle for patients treated with injectable gonadotropins are shown in Table 3. The pregnancy, clinical pregnancy, and ongoing pregnancy rates were significantly decreased in the low AMH group for patients <35 years and patients 35-40 years. For patients <35 years, the ongoing pregnancy rate was 12.1% (n=10) in the low AMH group and 23.5% (n=76) in the normal AMH group (age-adjusted RR 0.52 (95% CI 0.28-0.97)). For patients 35-40 years, the ongoing pregnancy rate was 12.5% (n=39) in the low AMH group and 18.5% (n=79) in the normal AMH group (age-adjusted RR 0.70 (95% CI 0.49-0.99)). For patients >40 years, there were no significant differences in pregnancy, clinical pregnancy, or ongoing pregnancy rates with an ongoing pregnancy rate of 3.0% (n=10) in the low AMH group compared to 4.0% (n=6) in the normal AMH group. The pregnancy loss rate between the low and normal AMH groups was not significantly different in any age group.

Table 3:

Pregnancy outcomes per cycle for injectable gonadotropin treatment

AMH, antimüllerian hormone; IQR, interquartile range

Data are n (%) unless otherwise noted

AMH units are ng/mL

The ongoing pregnancy rates per treatment cycle with the low AMH group stratified into tertiles are shown in the Supplemental Tables. For patients treated with oral antiestrogens (Supplemental Table 1), there was no discernible difference in ongoing pregnancy rates in any age group as AMH level declined further away from 1.0 ng/mL (test for linear trend, all p-values >0.05). For patients treated with injectable gonadotropins (Supplemental Table 2), there was a significant trend for decreasing ongoing pregnancy rates as AMH levels declined further away from 1.0 ng/mL for patients <35 years (test for linear trend, p-value=0.02) and for patients 35-40 years (test for linear trend, p-value=0.009). For patients >40 years, there was no significant difference observed for ongoing pregnancy rates between the different AMH levels (test for linear trend, p-value=0.47)

The multi-fetal gestations among ongoing pregnancies are shown in Table 4 for patients treated with oral antiestrogens and for patients treated with injectable gonadotropins. For oral antiestrogen treatments, the twin gestation rate in the low AMH group was 13.1% (n=11) and in the normal AMH group was 10.4% (n=59). There were no higher order gestations in the low AMH group and there were 2 in the normal AMH group (0.4%). For injectable gonadotropin treatments, the twin gestation rate in the low AMH group was 13.6% (n=8) and in the normal AMH group was 23.0% (n=37). There were also 3 higher order gestations in the low AMH group (5.1%) and there were 13 in the normal AMH group (8.1%).

Table 4:

Multi-fetal gestations among ongoing pregnancies

	Oral ovulation induction (clomid or letrozole)			Gonadotropin ovulation induction
	Low ovarian reserve (AMH <1.0) N=84	Normal ovarian reserve (AMH ≥1.0) N=565		Low ovarian reserve (AMH <1.0) N=59	Normal ovarian reserve (AMH ≥1.0) N=161
Singleton Gestation	73 (86.9%)	504 (89.2%)		48 (81.4%)	111 (68.9%)
Twin Gestation	11 (13.1%)	59 (10.4%)		8 (13.6%)	37 (23.0%)
Higher Order Gestation	0 (0.0%)	2 (0.4%)		3 (5.1%)	13 (8.1%)

AMH, antimüllerian hormone

Data are n (%)

AMH units are ng/mL

Discussion

In this large retrospective cohort study, when treated with oral antiestrogens, a low AMH level resulted in an ongoing pregnancy rate that was comparable to patients with a normal AMH level. However, when treated with injectable gonadotropins, a low AMH level resulted in an ongoing pregnancy rate that was significantly decreased compared to a normal AMH level for patients <35 and 35-40 years, but was comparable for patients >40 years. Further, treatment with oral antiestrogens was observed to result in comparable ongoing pregnancy rates in a sensitivity analysis of low AMH subgroups. For injectable gonadotropin treatment, ongoing pregnancy rates declined as AMH levels declined further away from 1.0 ng/mL for patients <35 and 35-40 years, however this trend was not observed for patients >40 years.

The 7,169 OI/IUI cycles included in our study is a strength of our study design. With this large cohort, we were able to adequately stratify patients based on known clinically important outcomes, including treatment type (oral antiestrogens or injectable gonadotropins) which clarifies the relationship between ovarian reserve and OI/IUI. For patients with low ovarian reserve, the number of follicles recruited with oral antiestrogen treatment is similar to patients with normal ovarian reserve and thus patients with a low ovarian reserve do not have a decreased likelihood of achieving an ongoing pregnancy in these cycles. On the other hand, patients with normal ovarian reserve are more likely to have multi-follicular recruitment and multiple competent oocytes ovulated with injectable gonadotropins resulting in a significantly increased ongoing pregnancy rate compared to patients with low ovarian reserve. It should be noted that the significant difference in ongoing pregnancy between the AMH groups treated with gonadotropins is not due to a low ongoing pregnancy rate among the low AMH group, but rather due to an unexpectedly high ongoing pregnancy rate in the normal AMH group. Indeed, the ongoing pregnancy rates among patients with a low AMH treated with gonadotropins are high enough in each age strata to conclude that this type of treatment is reasonable to consider for these patients.

The critical trade-off for the increased ongoing pregnancy rates per cycle that was observed for patients <35 years and 35-40 years with normal ovarian reserve treated with gonadotropins was the increased risk of multi-fetal gestations (31.1%). Despite the known risk of multi-fetal pregnancy associated with ovulation induction treatment, the incidence of this outcome was higher than what is targeted for this population (20). The goal of any infertility treatment is the live birth of a healthy singleton. This desired outcome must be weighed against the known risks of each type of infertility treatment and efforts should be made to mitigate the risk of multi-fetal pregnancies. Strategies that can be employed with ovulation induction cycles to reduce this risk, as recommended by the American Society for Reproductive Medicine, include consideration of cycle cancellation if >2 follicles ≥16mm or >3 follicles ≥14mm develop in patients <40 years (21). Additionally, with gonadotropin treatment, the lowest possible starting dose to achieve ovulation (37.5-75 IU) is recommended with careful slight adjustments as needed. We encourage the use of these recommendations in addition to the appropriate patient counseling prior to ovulation induction treatment regarding the risk of a multi-fetal gestation.

The differences observed between AMH groups for oral antiestrogen treatment versus injectable gonadotropins highlights the importance of separating these treatments in the study design. To our knowledge, only one prior study evaluated low AMH level (<1.0 ng/mL) as a predictor of OI/IUI outcome with positive serum hCG as the primary outcome . This well-powered study included only patients <35 years, but similar to our oral antiestrogen analysis, observed similar pregnancy rates between low and normal AMH groups. However, this study combined oral antiestrogen treatments with gonadotropin treatments which limits the interpretation of the results due to the different indications between the types of treatment and the different follicular response that results. The inclusion of patients ≥35 years is another novel component of our study and provides missing clinical data to counsel patients in this age range, which during the study period at our center accounted for 61.3% of OI/IUI cycles performed.

In our study design, the decision to dichotomize AMH at 1.0 ng/mL was made to narrow the focus and aid in the presentation of the ongoing pregnancy outcomes among patients with low ovarian reserve. In medicine, there are countless continuous measurements that are often dichotomized into “normal” and “abnormal” with the intent to simplify the data and guide when specific treatments are needed. AMH, FSH, and antral follicle count are all examples that have been dichotomized to define low ovarian reserve, but broader examples in medicine include blood pressure, hemoglobin A1C, and body mass index (11). While clinically useful, the operationalization of ovarian reserve into dichotomous groups is not without its drawbacks. First, dichotomization of a continuous variable does result in a loss of statistical power by grouping the AMH values instead of utilizing their exact measured value in the model (22). Second, it is important to recognize that these measurements occur on a gradual continuum and that a patient with an AMH of 1.1 ng/mL is predicted to respond more similarly to a patient with an AMH of 0.9 ng/mL rather than a patient with an AMH of 3.5 ng/mL, even though an AMH of 1.1 ng/mL is still categorized as normal ovarian reserve according to our approach. Therefore, clinical reasoning must still be applied when interpreting these results and applying them to practice.

It should be noted that ovarian reserve is not the only parameter that is considered when making treatment recommendations and the results of this study do not indicate that OI/IUI is a necessary first-line treatment for all patients with low ovarian reserve. Instead, these results should be used when considering the likelihood of achieving a successful ongoing pregnancy in the immediate future. Patients with low ovarian reserve that desire multiple additional children may consider IVF treatment prior to or rather than OI/IUI in order to bank embryos with an intention to improve the chance of achieving their desired family size given their ovarian reserve would be further diminished should they present again for subsequent treatment after a achieving a successful live birth.

This study has several limitations to acknowledge. First, because this was a retrospective study design, we could not control for the number of ovarian stimulation cycles a patient attempted before treatment discontinuation. However, our study design maintains external validity for the effectiveness of OI/IUI in this population given that in clinical practice, there are many variables that influence a patient’s decision to initiate one or more cycles, including infertility and pregnancy history, ability to tolerate treatment, and physician recommendations. In addition, we could not directly analyze pregnancy outcomes between the oral antiestrogen and the injectable gonadotropin groups because treatment medication decisions are made based on infertility history and treatment goals and therefore could have multiple known and unknown confounders in a retrospective design. Lastly, in an ideal study, AMH level would be measured at the beginning of each treatment cycle. However, in clinical practice there is rarely an indication to measure ovarian reserve at such short intervals given the gradual and predictable decline in ovarian reserve that occurs over decades (2). We therefore only included cycles that occurred within one year of the initial cycle start date so that the AMH level remained a reasonable estimate of the ovarian reserve for each treatment cycle.

Conclusion

Compared to patients with normal ovarian reserve, treatment with oral antiestrogens for OI/IUI in patients with low ovarian reserve results in comparable follicular development and comparable ongoing pregnancy rates in all age groups. When patients with low ovarian reserve are treated with injectable gonadotropins for OI/IUI, multi-follicular recruitment is less likely resulting in a significantly decreased ongoing pregnancy rate for patients <35 and 35-40 years but also a decrease in multi-fetal gestations. Overall, the ongoing pregnancy rates of 8.7% per oral antiestrogen cycle and 8.1% per injectable gonadotropin cycle in patients with low ovarian reserve are comparable to the expected rates in the general infertility population (10,24,25). We conclude that patients with low ovarian reserve are good candidates for OI/IUI treatment and low ovarian reserve alone should not be an absolute indication for immediate IVF treatment.