ORIGINAL ARTICLE: INFERTILITY

1 60
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Evidence-based approach to 61
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unexplained infertility: 63
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a systematic review 66
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10 69
Q7 Deidre D. Gunn, M.D. and G. Wright Bates, M.D.
11 70
12 Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Alabama- 71
Birmingham, Birmingham, Alabama
13 72
14 73
15 74
16 75
17 Objective: To summarize the available evidence for the efficacy of various treatments for unexplained infertility. 76
18 Design: Systematic review. 77
19 Setting: Randomized, controlled trials in the English language literature from 1989 to present. 78
Patient(s): Patients aged 18–40 years with unexplained infertility.
20 79
Intervention(s): Clomiphene citrate, letrozole, timed intercourse, IUI, gonadotropins, IVF, and IVF–intracytoplasmic sperm injection.
21 Main Outcome Measure(s): Clinical pregnancy rate, ongoing pregnancy rate, and live birth rate. 80
22 Result(s): Thirteen studies with a total of 3,081 patients were identified by systematic search and met inclusion criteria. The available 81
23 literature demonstrates that expectant management may be comparable to treatment with clomiphene and timed intercourse or IUI. 82
24 Clomiphene may be more effective than letrozole, and treatment with gonadotropins seems more effective, albeit with significantly 83
25 higher risk of multiple gestations than either oral agent. On the basis of current data, IVF, with or without intracytoplasmic sperm in- 84
26
jection, is no more effective than gonadotropins with IUI for unexplained infertility. 85
Conclusion(s): Adequately powered, randomized controlled trials that compare all of the available treatments for unexplained infer-
27 86
tility are needed. Until such data are available, clinicians should individualize the management of unexplained infertility with appro-
28 priate counseling regarding the empiric nature of current treatment options including IVF. 87
29 (Fertil SterilÒ 2016;-:-–-. Ó2016 by American Society for Reproductive Medicine.) Use your smartphone 88
30 Key Words: Intrauterine insemination, in vitro fertilization, superovulation, unexplained to scan this QR code 89
infertility and connect to the
31 discussion forum for
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32 this article now.* 91
Discuss: You can discuss this article with its authors and with other ASRM members at http://
33 fertstertforum.com/gunnd-unexplained-infertility-systematic-review/ 92
* Download a free QR code scanner by searching for “QR
34 scanner” in your smartphone’s app store or app marketplace. 93
35 94
36 95
37 96
38

T
he diagnosis of unexplained However, there are limited data to was observed in the expectant manage- 97
39 infertility encompasses an support the efficacy of many of these ment group (4). Others observed a 13% 98
40 important subset of couples treatments in the management of spontaneous pregnancy rate in a group 99
41 seeking treatment for infertility. After unexplained infertility, and no of patients awaiting IVF, although this 100
42 evaluation of ovulatory function, tubal uniform protocol exists in clinical cohort consisted of patients with unex- 101
43 patency, and semen analysis, no etiol- practice. plained subfertility of 2 years' duration 102
44 ogy is identified in 10%–30% of cou- One must take into account that or more and may represent a poorer 103
45 ples seeking treatment for infertility unexplained infertility is perhaps best prognostic subgroup (5). Another 104
46 (1, 2). Any treatment for unknown characterized as subfertility (3). This cohort experienced only a 5.9% cumu- 105
47 infertility is empiric by default, and nomenclature is significant in that lative pregnancy rate over 12 months in 106
48 the broad range of treatment, some couples will conceive without an untreated group of patients awaiting 107
49 including expectant management, intervention. In one randomized trial IVF (6). Despite this variability, it is 108
50 superovulation, and IVF, reflects the of 253 patients with unexplained infer- evident that a proportion of couples 109
51 uncertainty with this diagnosis. tility, a 27% ongoing pregnancy rate will achieve pregnancy with no 110
52 intervention. 111
53 Received September 23, 2015; revised and accepted February 1, 2016.
Superovulation, which induces the 112
54 D.D.G. has nothing to disclose. G.W.B. has nothing to disclose. development of more than one follicle 113
Reprint requests: Deidre D. Gunn, M.D., University of Alabama-Birmingham, Department of Obstet-
55 per cycle, combined with either timed 114
rics and Gynecology, Division of Reproductive Endocrinology and Infertility, 1700 6th Avenue
56 South, Birmingham, Alabama 35249 (E-mail: ddowns@uabmc.edu). intercourse or IUI, is commonly used 115
57 to treat unexplained infertility. The 116
Fertility and Sterility® Vol. -, No. -, - 2016 0015-0282/$36.00
58 Copyright ©2016 American Society for Reproductive Medicine, Published by Elsevier Inc.
use of oral or injectable agents may in- 117
59 http://dx.doi.org/10.1016/j.fertnstert.2016.02.001 crease the number of dominant follicles 118

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119 available for fertilization (7) and correct subclinical ovulatory clomiphene citrate (CC) with or without IUI, letrozole with 178
120 dysfunction (8). Many argue that the addition of IUI ensures or without IUI, natural-cycle IUI, gonadotropins with or 179
121 that sufficient numbers of sperm overcome any cervical bar- without IUI, IVF, and IVF with intracytoplasmic sperm injec- 180
122 rier (8). Disadvantages of treatment with gonadotropins and tion (IVF-ICSI). Primary outcome measures were per-couple 181
123 IUI include significant cost, ovarian hyperstimulation syn- live birth rate (LBR), ongoing pregnancy rate (OPR), and clin- 182
124 drome, and higher rates of multiple pregnancy (9). In vitro ical pregnancy rate (CPR). Studies with a primary outcome 183
125 fertilization has also been used to treat unexplained infer- other than LBR, OPR, or CPR were included if these data 184
126 tility. According to 2013 Society for Assisted Reproductive were reported as secondary outcomes. Only randomized 185
127 Technology data, live birth rates per cycle of IVF ranged controlled trials were included in this analysis. Trials that 186
128 from 25% to 43% in patients with unexplained infertility did not report data separately for patients with unexplained 187
129 aged %40 years (10). infertility or subfertility were excluded. 188
130 Ideally a randomized controlled trial would be performed 189
131 to compare expectant management with oral superovulation, 190
132 superovulation with gonadotropins, and IVF, with a second- RESULTS 191
133 ary analysis of whether IUI is of benefit. No such trial has The systematic search produced 776 results (Fig. 1). After 192
134 yet been performed. The purpose of this review, therefore, is exclusion of duplicates, 690 records remained. Abstracts of 193
135 to summarize the available evidence from clinical trials these records were screened, resulting in the exclusion of an 194
136 regarding the relative efficacy of various treatments for unex- additional 581 records that clearly did not meet criteria for 195
137 plained infertility. this review. Additional articles were identified through review 196
138 of reference lists of screened articles. Full text of 117 articles 197
139 was then reviewed. Of these, only 13 studies met the inclusion 198
MATERIALS AND METHODS
140 criteria. The 13 studies included in this review comprised a to- 199
141
The systematic literature search and qualitative review were tal of 3,081 patients. These studies, including interventions, 200
142
performed according to PRISMA guidelines (11). All of the methodology, and outcome measures, are summarized in 201
143
data were obtained from previously published studies, and Tables 1–3. Demographic data of study participants are 202
144
therefore institutional review board approval was not summarized in Supplemental Table 1 (available online). 203
145
obtained. Interventions examined in this review include the 204
146 following: expectant management (four studies: Fisch, 205
147 Search Strategy Bhattacharya, Deaton, Steures); CC with or without IUI 206
148 A systematic literature search was conducted, with studies (eight studies: Fisch, Bhattacharya, Deaton, Fouda, 207
149 identified by searching MEDLINE (1966–September 2015). Diamond, Dankert, Berker, Reindollar); letrozole with or 208
150 Results were limited to peer-reviewed, English-language, without IUI (four studies: Fouda, Diamond, Baysoy, 209
151 and human studies only. The search strategy included the Gregoriou); natural-cycle IUI (two studies: Bhattacharya, 210
152 terms ‘‘unexplained infertility,’’ ‘‘subfertility,’’ ‘‘natural cy- Goverde); gonadotropins with or without IUI (eight studies: 211
153 cle,’’ ‘‘expectant management,’’ ‘‘conservative management,’’ Steures, Diamond, Dankert, Berker, Baysoy, Gregoriou, Gov- 212
154 ‘‘clomiphene citrate,’’ ‘‘letrozole,’’ ‘‘gonadotropins,’’ ‘‘inter- erde, Reindollar); IVF (three studies: Goverde, Foong, Rein- 213
155 course,’’ ‘‘insemination,’’ and ‘‘in vitro fertilization.’’ dollar); and IVF-ICSI (one study: Foong). 214
156 Retrieved records were screened by title and abstract for 215
157 relevance by one reviewer (D.D.G.). Full-text review of the re- 216
158 CC with Timed Intercourse vs. Expectant 217
maining articles was performed by the same reviewer. A sec-
159 Management 218
ond reviewer (G.W.B.) confirmed the validity of the review
160 and verified the accuracy of the data extraction. Assessment Two trials addressed CC with timed intercourse vs. expectant 219
161 of eligibility for inclusion in the systematic review was deter- management. In the Fisch study (3), 148 patients in a multi- 220
162 mined by consensus between the two authors. center trial were randomized to one of four treatment groups 221
163 A data extraction form was developed before data collec- for four consecutive cycles. Study arms included the 222
164 tion. Data extracted from each study included [1] characteris- following: placebo on cycle days 5–9 followed by saline injec- 223
165 tics of trial participants (including diagnostic subtype of tions on cycle days 19, 22, 25, and 28; placebo on cycle days 224
166 infertility), [2] type of intervention and comparison groups, 5–9 followed by hCG (5,000 IU) on cycle days 19, 22, 25, and 225
167 [3] type of outcome measures, and [4] type of study and level 28 for luteal support; CC (100 mg) on cycle days 5–9 followed 226
168 of evidence. by saline injections in the luteal phase as above; and CC 227
169 (100 mg) on cycle days 5–9 followed by hCG injections as 228
170 above. For the purposes of this review, the placebo/placebo 229
171 Eligibility and Outcome Measures group constituted ‘‘expectant management’’ compared with 230
172 Patients with unexplained infertility/subfertility aged 18– the CC/placebo intervention. The mean age of the patients 231
173 40 years were considered in this analysis. Unexplained infer- was 30 years, with a mean duration of infertility of 4.3 years. 232
174 tility/subfertility was defined as normal ovulatory status, The placebo/placebo group had no clinical pregnancies dur- 233
175 tubal patency, normal semen analysis, and attempt at concep- ing the study period, whereas the CC/placebo group had a 234
176 tion for duration of at least 1 year. Types of interventions CPR of 19%, a statistically significant difference. Of note, 235
177 studied included the following: expectant management, there were 25 treatment-independent pregnancies in the trial, 236

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FIGURE 1 297
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274 333
275 334
276 Flowchart of included studies. 335
277 Gunn. Systematic review of unexplained infertility. Fertil Steril 2016. 336
278 337
279 338
280 339
281 7 before the study and 18 after completion, representing 16% the study had a mean duration of infertility of 30 months 340
282 of all pregnancies in the study population. and a mean age of 32 years. The median number of treatment 341
283 Conversely, Bhattacharya et al. (8) in a larger trial of 580 cycles was five in the CC/timed intercourse group and four in 342
284 patients (507 with unexplained infertility) at four centers the natural-cycle IUI group. Spontaneous pregnancies 343
285 found no benefit of therapy, with a 16% LBR with expectant occurred in 2% of women in the CC group and 7% of women 344
286 management vs. 13% after CC therapy. This trial randomized in the IUI group, but it was unclear whether these were unex- 345
287 patients to one of three arms for a treatment period of plained infertility patients. The authors planned a comparison 346
288 6 months: [1] expectant management, consisting of no visits of expectant management with CC/timed intercourse and 347
289 or interventions; [2] CC at a starting dose of 50 mg on cycle with unstimulated IUI, and therefore no direct comparison 348
290 days 2–6 with timed intercourse on cycle days 12–18 (initial was made between the CC/timed intercourse and unstimu- 349
291 cycle monitored with ultrasound and mid-luteal serum P, lated IUI groups. 350
292 with subsequent cycles monitored only with mid-luteal pro- 351
293 gesterone); and [3] IUI in the spontaneous cycle, with moni- CC with IUI vs. Expectant Management 352
294 toring by urine LH kit starting on cycle day 12, with a Only one study, by Deaton et al. (12), examined CC with IUI in 353
295 single IUI performed at 20–30 hours after surge. Patients in comparison with expectant management, and it found no 354

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ORIGINAL ARTICLE: INFERTILITY

TABLE 1

Studies comparing oral superovulation methods. Q6

No. of patients with
unexplained infertility Maximum no. of treatment Outcome
Study (reference) randomized cycles per couple Interventions measures Conclusion
Fisch 1989 (3) 148 4 CC with TI vs. expectant CPR CC with TI more effective
Deaton 1990 24 8 CC þ IUI vs. expectant OPR No significant difference
Bhattacharya 2008 507 6 mo CC with TI vs. expectant; LBR CC with TI or natural-cycle
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natural-cycle IUI vs. expectant IUI were not superior

to expectant management
Fouda 2011 214 3 CC þ IUI vs. letrozole þ IUI OPR Letrozole þ IUI more effective
Diamond 2015 900 (599 in oral treatment arms) 4 CC þ IUI vs. letrozole þ IUIa CPR, OPR, LBR No significant difference
between CC þ IUI and
letrozole þ IUIa
a
See Table 2; this trial includes a gonadotropin treatment arm, which was superior to both oral interventions.
Gunn. Systematic review of unexplained infertility. Fertil Steril 2016.

TABLE 2

Studies comparing gonadotropin treatment with oral superovulation or IVF.

No. of patients with
unexplained infertility Maximum no. of treatment
Study (reference) randomized cycles per couple Interventions Outcome measures Conclusion
Goverde 2000 181 6 GND þ IUI vs. natural-cycle IUI LBR No significant difference
vs. IVF
Steures 2006 253 6 mo GND þ IUI vs. expectant OPR No significant difference
Baysoy 2006 80 1 GND þ IUI vs. letrozole þ IUI CPR No significant difference
Dankert 2007 68 4 GND þ IUI vs. CC þ IUI OPR, LBR No significant difference
Gregoriou 2008 50 3 GND þ IUI vs. letrozole þ IUI CPR, LBR No significant difference
Berker 2011 93 1 GND þ IUI vs. CC þ IUI OPR No significant difference
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Diamond 2015 900 4 GND þ IUI vs. CC þ IUI vs. CPR, OPR, LBR GND þ IUI more effective than
letrozole þ IUIa CC þ IUI or letrozole þ IUI
Note: GND ¼ gonadotropin.
a
See Table 1 for comparison of oral agents in this study.
Gunn. Systematic review of unexplained infertility. Fertil Steril 2016.
444
449
448

446
445

443
442

440
468

466

464
469

465

463
462

460
459
458

456
455
454
453
452

450

439
438

436

434

432

430
429
428

426
425

423
422

420
467

435

433

424
447

427
461

457

441

437

431

421
470
472

451
471

419

416
415
414
418
417
 Fertility and Sterility®

473 significant difference. Of the 51 patients included in the data 532

No difference in per-cycle PR of CC þ IUI vs.

474 533

GND þ IUI; significantly higher PR with

analysis of this trial, 24 patients had unexplained infertility,
475 and 27 patients had endometriosis. This study had a cross- 534
476 535

IVF and shorter time to live birth

over design whereby patients were randomized to either
477 four treatment cycles or four control cycles and would then 536
478 cross over to the other arm if pregnancy did not occur in 537

Conclusion
479 the first four cycles. Mean age was 33 years, with a mean 538

No significant difference
No significant difference
480 duration of infertility of 3.5 years. In the treatment cycles, pa- 539
481 tients received CC (50 mg) on cycle days 5–9 (or days 4–8 if 540
482 the patient's average cycle length was <27 days), with hCG 541
483 (10,000 IU) given when the lead follicle was 18 mm on ultra- 542
484 sound. Intrauterine insemination was performed 36 hours af- 543
485 ter hCG administration. In the control cycles, patients were 544
486 instructed to have intercourse during the periovulatory 545
487 period. The ongoing pregnancy rate in the treatment cycles 546
488 (defined in this study as >20 weeks' gestation) was 10 of 46 547
Time to pregnancy with a
Outcome measures

489 548
live birth; per-cycle

(21%), and OPR in the control cycles was 5 of 40 (12%).

490 549
pregnancy rate

Because of the cross-over design of the study, some patients

491 were counted twice in this analysis. 550
LBR
LBR

492 551
493 552
494 IUI (in Natural Cycle) vs. Expectant Management 553
495 One study compared IUI in the natural, unstimulated cycle 554
496 with expectant management. Bhattacharya et al. (8) noted a 555
497 556
and IVF) vs. accelerated arm (CC þ IUI, IVF)

23% LBR with natural-cycle IUI vs. 16% with expectant man-
498 agement, a difference that was not statistically significant. 557
Conventional arm (CC þ IUI, GND þ IUI,

499 558
GND þ IUI vs. natural-cycle IUI vs. IVF

500 559
501 Gonadotropins with IUI vs. Expectant 560
502 Management 561
Interventions

503 Only one trial, by Steures et al. (4), involving 253 patients 562
504 compared gonadotropins and IUI with expectant manage- 563
505 ment, and it found no significant difference in ongoing preg- 564
506 nancy rate over the 6-month study period. In the treatment 565
IVF vs. IVF-ICSI

507 arm, patients received FSH or hMG (average 75 IU, range 566
508 37–150 IU) starting on cycle day 3 until the lead follicle 567
509 measured 16 mm, when hCG was administered at a dose of 568
510 either 5,000 or 10,000 IU, with IUI performed 36–40 hours 569
511 later. If there were three or more follicles >16 mm or five fol- 570
512 licles >12 mm, hCG was withheld. Patients' mean age was 571
treatment cycles
Maximum no. of

513 33 years, with a mean duration of 2 years of infertility and 572

per couple

514 baseline mean FSH of 7.0 and 6.7 IU/L in the gonadotropin 573
6
1
–

515 and expectant management groups, respectively. Of note, 574

516 11% of the treatment cycles involved stimulation with CC 575
Gunn. Systematic review of unexplained infertility. Fertil Steril 2016.

517 instead of gonadotropins as specified by study protocol. Mul- 576

518 tiple gestations in the treatment arm consisted of one set of 577
infertility randomized

519 twins and one set of triplets selectively reduced to twins. Of 578
with unexplained
No. of patients

520 the 127 patients assigned to the treatment arm, there were 579
Studies with IVF comparison group.

521 29 ongoing pregnancies (23%) and 26 live births. In the 580

60
181

503

522 expectant management arm, there were 34 ongoing pregnan- 581

523 cies (27%) among 126 patients, and 30 live births. There was 582
524 no significant difference in OPR in the treatment arm 583
525 584
Note: GND ¼ gonadotropin.

compared with expectant management. However, a total of

526 13 of 42 pregnancies occurred spontaneously in the treatment Q1 585
Reindollar 2010

527 arm, and in the expectant management arm 20% of the pa- 586
Goverde 2000
Foong 2006

528 587
TABLE 3

(reference)

tients underwent treatment with gonadotropins/IUI before

529 the end of the study period. Fourteen percent of cycles were 588
Study

530 canceled in the intervention group (i.e., for over-response), 589

531 and a further limitation was the monofollicular response 590

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591 seen in 58% of the treatment cycles (4). The deviations from (11.6%) in the clomiphene arm vs. 9 of 50 (18%) in the gonad- 650
592 study protocol (use of CC instead of gonadotropins; use of go- otropin arm, which was not a statistically significant differ- 651
593 nadotropins in the expectant group), high number of sponta- ence. Data on ovarian hyperstimulation syndrome (OHSS) 652
594 neous pregnancies in the treatment group, low rate of and multiple gestations was provided for the overall study 653
595 multiple follicular recruitment on gonadotropins, and high population but not separately reported for the unexplained 654
596 cancellation rate all limit interpretation of this study's infertility subgroup. 655
597 findings. In the Dankert et al. trial (18), a total of 138 patients (68 656
598 with unexplained infertility) were randomized to CC/IUI or 657
599 FSH/IUI for up to four cycles. Clomiphene citrate was given 658
600 CC with IUI vs. Letrozole with IUI at a starting dose of 100 mg on cycle days 3–7, and FSH 659
601 Two trials examined CC with IUI vs. letrozole with IUI. In a trial was given at a starting dose of 75 IU. Ultrasound monitoring 660
602 of 214 patients, Fouda et al. (13) demonstrated an improved was performed, and a 5,000-IU hCG dose was administered 661
603 ongoing pregnancy rate with letrozole plus IUI (33%) when the lead follicle reached 18 mm, followed by IUI 38– 662
604 compared with CC plus IUI (19%), which was statistically sig- 40 hours later. Administration of hCG was withheld if there 663
605 nificant. Mean age of patients was 26 years, with a mean dura- were more than three follicles >14 mm. Mean age of the study 664
606 tion of infertility of 3.7 years in the letrozole group and 3.4 in population was 31 years, with a mean duration of infertility of 665
607 the CC group (no statistical difference); mean baseline FSH 33 months. This trial, like the Berker et al. study, showed no 666
608 was 5.7 and 5.5 IU/L, respectively. Patients underwent up to difference in these treatments, with a LBR of 31.4% in the 667
609 three cycles of treatment. The letrozole arm consisted of an CC group and 30.3% in the FSH group. Of note, neither of 668
610 extended letrozole regimen of 2.5 mg daily on cycle days 1– these studies achieved statistical power. 669
611 9, and in the CC group, patients received CC (100 mg) on cycle The Diamond et al. trial (16) also directly compared these 670
612 days 3–7. Ultrasound monitoring was performed, and IUI was two interventions but showed a statistically significant differ- 671
613 done 36–40 hours after administration of hCG (10,000 IU). The ence in LBR, with 32.2% in the gonadotropin group compared 672
614 number of multiple gestations (all twins) was four and three in with 23.3% in the clomiphene group. The rate of multiple ges- 673
615 the letrozole and CC groups, respectively. tations was also higher in the gonadotropin group, with 10 674
616 In the Diamond trial (14), 900 patients were randomized triplets and 24 twins, vs. 0 and 8, respectively, in the CC 675
617 to one of three treatment arms for a total of four cycles: [1] group. One patient in the gonadotropin group developed 676
618 letrozole (5 mg) on cycle days 3–7; [2] CC (100 mg) on cycle OHSS, compared with none in the CC group. 677
619 days 3–7; and [3] FSH (150 IU) starting on cycle day 3 through 678
620 the day of hCG administration. Mean age of patients in this 679
621 trial was 32 years, and mean duration of infertility was Gonadotropins with IUI vs. Letrozole with IUI 680
622 35 months. The mean antim€ ullerian hormone level was the Three trials assessed the efficacy of gonadotropins with IUI vs. 681
623 same (2.6 ng/mL) and baseline FSH was similar at 7.0, 7.2, letrozole with IUI. In the Baysoy et al. (19) and Gregoriou et al. 682
624 and 6.9 mIU/mL, respectively (15). The oral intervention (20) studies, the efficacy of letrozole with IUI was comparable 683
625 arms included a combined 599 patients and demonstrated a to that of gonadotropins with IUI. Of note, the Baysoy trial 684
626 higher live birth rate in the clomiphene group (23.3%) was characterized as a pilot study and did not calculate a sam- 685
627 compared with the letrozole group (18.7%), although the ple size needed to detect a significant difference in pregnancy 686
628 result was not statistically significant. Rates for ongoing clin- rates. This trial (19) randomized 80 patients to one cycle of 687
629 ical pregnancy and multiple gestation were also not signifi- either letrozole (5 mg) on cycle days 3–7 or hMG (75 or 150 688
630 cantly different between these two interventions, although IU; dose based on age). Mean age was 28 years, and mean 689
631 this study was powered for a comparison of the letrozole baseline FSH was 6.4 and 6.1 IU/L, with a mean duration of 690
632 group with the combined gonadotropin and clomiphene infertility of 5.3 years in the letrozole group and 5.9 years 691
633 groups, not for individual comparisons (15, 16). in the gonadotropin group. The primary outcome was clinical 692
634 pregnancy rate, which was 18.4% for letrozole and 15.7% for 693
635 gonadotropins. One triplet gestation occurred in the letrozole 694
636 Gonadotropins with IUI vs. CC with IUI group, and a twin gestation in the gonadotropin group. One 695
637 Three trials compared gonadotropins with clomiphene. The case of moderate OHSS occurred in the gonadotropin group. 696
638 Berker et al. trial (17) randomized 93 patients with unex- Gregoriou et al. (20) studied 50 patients and similarly 697
639 plained infertility to one treatment cycle. Patients had a found no significant difference in the efficacy of letrozole 698
640 mean age of 28 years and baseline FSH of 6.7 mIU/mL in vs. gonadotropins, with respect either to clinical pregnancy 699
641 both groups, with a mean duration of infertility of 44 months rate per cycle (the primary outcome) or live birth rate per 700
642 and 48 months in the CC and FSH groups, respectively (no sta- couple. In this study, 50 patients were randomized to receive 701
643 tistical difference). Interventions included CC (100 mg) begin- either FSH at a starting dose of 150 IU on cycle day 3, or le- 702
644 ning on cycle days 2–4, or FSH at a starting dose of 75 or 100 trozole (5 mg) on cycle days 3–7, for a maximum of three cy- 703
645 IU according to body mass index; both groups were moni- cles. Mean age was 32 years, and all patients had failed three 704
646 tored with ultrasound and serum E2 measurements, and prior cycles of CC/IUI. Mean duration of infertility and base- 705
647 hCG (10,000 IU) was administered at a follicle size of line FSH in the two groups was similar: 3.9 years and 7.4 IU/L 706
648 18 mm, with IUI 36–40 hours later. No luteal support was in the FSH group, and 3.6 years and 6.9 IU/L in the letrozole 707
649 given. Ongoing pregnancy occurred in 5 of 43 patients group. All patients underwent ultrasound monitoring, with 708

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709 serial E2 measurements in the gonadotropin group only, and Gonadotropins with IUI vs. IUI (in Natural Cycle) 768
710 hCG was administered at a dose of 10,000 IU in both groups. 769
The Goverde trial (21), as described above, was the only study
711 Intrauterine insemination was done 36 hours after hCG 770
included in this review that examined gonadotropins with IUI
712 trigger. Live birth rate in the gonadotropin group was 28%, 771
vs. natural-cycle IUI. The LBR for natural-cycle IUI was 24%,
713 compared with 20% in the letrozole group, which did 772
compared with 36% in the gonadotropin/IUI group, a differ-
714 not reach statistical significance, and there were no multiple 773
ence that did not achieve statistical significance.
715 gestations in either group. 774
716 In contrast to the Baysoy and Gregoriou studies, the Dia- 775
717 mond trial (16) showed a significantly higher live birth rate in IVF vs. IUI (in Natural Cycle) 776
718 the gonadotropin group (32.2%) compared with the letrozole The Goverde trial (21) also included IVF and natural-cycle IUI 777
719 group (18.7%). The letrozole group had 9 twin pregnancies treatment arms, and there was no significant difference in live 778
720 and no higher-order multiples, compared with 24 and 10, birth rates (39% vs. 24%). As described above, the per-cycle 779
721 respectively, in the gonadotropin group. pregnancy rate was higher for IVF compared with IUI. 780
722 781
723 782
724 Gonadotropins with IUI vs. IVF IVF vs. IVF with ICSI 783
725 One study, by Goverde et al. (21), that met inclusion criteria One study, by Foong et al. (22), was identified that compared 784
726 for this review examined the efficacy of gonadotropins IVF with IVF-ICSI in 60 patients with unexplained infertility 785
727 with IUI compared with IVF and did not show a statistically undergoing one treatment cycle. The mean age of study par- 786
728 significant difference in LBR. The authors also included a ticipants was 33 years; in the conventional IVF group, mean 787
729 cost-effectiveness analysis in their study, concluding that baseline FSH was 6.2 IU/L, and duration of infertility was 788
730 IUI cycles were more cost-effective than IVF. This trial ran- 57 months, vs. mean FSH of 6.5 IU/L and duration of infer- 789
731 domized 181 patients with unexplained infertility to one of tility of 64 months in the IVF-ICSI group (no statistical differ- 790
732 three interventions for up to six treatment cycles: IUI in ence). Patients underwent GnRH agonist suppression 791
733 spontaneous/natural cycles, IUI in FSH-stimulated cycles followed by stimulation with Gonal-F at variable dosing, Q2 792
734 (at a starting dose of 75 IU beginning on cycle day 3), with hCG (unspecified dose) given for trigger followed by 793
735 and IVF (variable treatment protocol based on age). Mean retrieval 35 hours later. A maximum of four embryos were 794
736 age of patients was 32 years, and the mean duration of transferred on day 3 after retrieval. The primary outcome 795
737 infertility was 3.9, 4.2, and 4.4 years in the three groups, was fertilization rate, although other outcomes were reported, 796
738 respectively. In the stimulated IUI group, patients were including clinical pregnancy rate and live birth rate. Live birth 797
739 monitored by ultrasound and urine LH testing, and hCG rate in the IVF group was 46.7%, compared with 50% in the 798
740 was given at a dose of 10,000 IU when the lead follicle IVF-ICSI group, a difference which was not statistically sig- 799
741 reached 18 mm if no endogenous surge had been detected. nificant. There was also no significant difference in any of 800
742 Intrauterine insemination was done 40–42 hours after hCG the other outcomes studied. 801
743 administration. In the IVF group the same dose of hCG was 802
744 used for trigger, followed by oocyte retrieval 35 hours later, 803
745 and then ET 48–72 hours after retrieval. A maximum of The FASTT Trial 804
746 two embryos were transferred in patients aged <35 years, The fast track and standard treatment (FASTT) trial demon- 805
747 and up to three embryos were transferred in patients strated a shorter time to pregnancy and higher per-cycle preg- 806
748 aged >35 years. nancy rates for IVF compared with treatment with oral agents 807
749 Of note, this trial included some male-factor patients but or gonadotropins in patients with unexplained infertility (23). 808
750 did report pregnancy data by subgroup, so live birth rates for Although the FASTT trial does not directly compare CC/IUI, 809
751 the unexplained infertility patients could be calculated from GND/IUI, and IVF in a parallel fashion with respect to live Q3 810
752 the reported data. The authors noted that the results for the birth rate, the study does report per-cycle pregnancy rates 811
753 overall study population did not differ by diagnostic sub- and also demonstrates a shorter time to pregnancy in the 812
754 group. In the unexplained infertility subgroup assigned to accelerated arm, with the interesting finding of no benefit 813
755 natural-cycle IUI, the LBR was 24%, compared with 36% in to gonadotropin treatment in the case of failed oral 814
756 the stimulated-cycle IUI group and 39% in the IVF group. superovulation. 815
757 There was also no difference between the pregnancy rates In this trial, Reindollar et al. (23) randomized patients to 816
758 of either of the IUI groups compared with IVF. The per-cycle one of two arms: [1] a conventional arm with three cycles 817
759 pregnancy rate was higher in the IVF group compared with of CC (at a starting dose of 100 mg on cycle days 3–7, with 818
760 the IUI groups. There were 18 spontaneous conceptions be- LH kit monitoring or ultrasound monitoring if no surge by cy- 819
761 tween treatment cycles in this study, all of which led to live cle day 15) followed by three cycles of gonadotropins (at a 820
762 births. The rate of multiple gestation was 4% in the natural- starting dose of FSH 150 IU) and then up to six cycles of 821
763 cycle IUI group (one twin pregnancy), 29% in the stimulated IVF; or [2] an accelerated arm with three cycles of CC followed 822
764 IUI group (nine twin pregnancies), and 21% in the IVF group by up to six cycles of IVF. The dose of hCG was 10,000 IU in 823
765 (one triplet and six twin pregnancies). Mild OHSS occurred in each group (used in CC group if ultrasound monitoring was 824
766 two of the stimulated IUI cycles, and three patients in the IVF required). Intrauterine insemination was done 36 hours later. 825
767 group had severe OHSS. In the IVF group, GnRH agonist suppression was followed by 826

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 ORIGINAL ARTICLE: INFERTILITY

827 administration of FSH (225 IU) as a starting dose. Oocyte rate and live birth rate with CC, although the difference was 886
828 retrieval occurred 36 hours after hCG trigger, with ICSI not statistically significant. Two studies that examined letro- 887
829 done in cases of failed fertilization or <10  106 sperm avail- zole with IUI vs. gonadotropins with IUI showed these inter- 888
830 able. Embryo transfer occurred on day 3 after retrieval, with ventions to be equally effective (19, 20), as did two other 889
831 the number transferred based on American Society for Repro- studies that examined clomiphene with IUI vs. 890
832 ductive Medicine guidelines. Mean age of patients was gonadotropins (17, 18). However, Diamond demonstrated 891
833 33 years, with a mean baseline FSH of 6.6 and 6.7 mIU/mL that gonadotropins were significantly more effective than 892
834 in the conventional and accelerated groups, respectively. either letrozole or clomiphene, despite a higher cycle 893
835 Duration of infertility was not reported. The primary endpoint cancellation rate of 6.9% vs. 3.7% and 3.3%, respectively. 894
836 was length of time from date of randomization to the date a Nonetheless, it may be argued that the increase in 895
837 pregnancy was established that led to a live birth. Per-cycle cumulative pregnancy rate may not be justified with the 896
838 pregnancy rates for CC/IUI, FSH/IUI, and IVF were 7.6%, high rate of multiple pregnancies (32%), including triplet 897
839 9.8%, and 30.7%, respectively. Median time to pregnancy pregnancies (6.2%) (16). Natural-cycle IUI was comparable 898
840 was 8 months in the accelerated arm, compared with to expectant management in one study (8), and with gonad- 899
841 11 months in the conventional arm. Of the clinical pregnan- otropins/IUI and IVF in another study, although the Goverde 900
842 cies, 52 were treatment-independent (14%). trial (21) did show a higher per-cycle pregnancy rate for IVF 901
843 vs. IUI. 902
844 Direct comparisons between oral agents, gonadotropins, 903
845 DISCUSSION and IVF are limited. Goverde et al. (21) showed no difference 904
846 In this systematic review, we examined the available evidence in efficacy when IVF was compared with gonadotropins with 905
847 from clinical trials for the relative efficacy of various treat- IUI for unexplained infertility (although the per-cycle preg- 906
848 ments for unexplained infertility with respect to the outcomes nancy rate was higher). The Reindollar study (23) also demon- 907
849 of clinical or ongoing pregnancy rate or live birth rate per strated an increased per-cycle pregnancy rate with IVF 908
850 couple. Among the 13 studies that met criteria for inclusion compared with gonadotropin treatment. There was also no 909
851 in this review, the following interventions were studied: [1] significant difference in treatment outcome when IVF-ICSI 910
852 CC with timed intercourse vs. expectant management (3, 8); was compared with IVF in one study (22). Additionally, an 911
853 [2] CC with IUI vs. expectant management (12); [3] natural- accelerated approach involving CC plus IUI followed by IVF 912
854 cycle IUI vs. expectant management (8); [4] gonadotropins seems to shorten the median time to pregnancy when 913
855 with IUI vs. expectant management (4); [5] CC with IUI vs. le- compared with a conventional stepwise method of CC plus 914
856 trozole with IUI (13, 16); [6] gonadotropins with IUI vs. CC IUI, gonadotropins plus IUI, then IVF (23). 915
857 with IUI (16–18); [7] gonadotropins with IUI vs. letrozole The strength of this review is the systematic search strat- 916
858 with IUI (16, 19, 20); [8] gonadotropins with IUI vs. IVF egy used and the large number of patients (more than 3,000) 917
859 (21); [9] gonadotropins with IUI vs. natural-cycle IUI (21); included in the 13 studies. In addition, this review included 918
860 [10] IVF vs. natural-cycle IUI (21); and [11] IVF vs. IVF/ICSI only studies with clear diagnosis of unexplained infertility 919
861 (22). Another study was included, which compared a stepwise, and separate data reporting for this subgroup of infertility. 920
862 conventional approach including CC þ IUI, gonadotropins þ With these strict criteria, however, some of the individual 921
863 IUI, and IVF vs. an accelerated approach of CC þ IUI followed comparison groups did not include more than one or two 922
864 by IVF (23). studies examining that particular intervention. Although 923
865 Although there is considerable clinical heterogeneity this approach limits the quantity of data available for review, 924
866 among the included studies that precluded performance of a it more precisely reflects the characteristics of unexplained 925
867 meta-analysis, this review demonstrates the following find- infertility, including the benefit of expectant management 926
868 ings. Clomiphene citrate with timed intercourse was more in this patient population. Any discussion of unexplained 927
869 effective than expectant management in an older study (3), infertility must bear in mind that many of the reports contain 928
870 although a larger, more recent trial found no benefit (8). treatment-independent pregnancies, highlighting the fact 929
871 When expectant management was compared either with CC that ‘‘subfertility’’ is a better descriptor for this patient popu- 930
872 with IUI (12) or with gonadotropins with IUI (4), it was as lation. This review was limited by the clinical heterogeneity of 931
873 effective as either intervention. Applicability of the Steures the included studies. There were variable numbers of treat- 932
874 gonadotropin IUI trial (4) to clinical practice is limited, given ment cycles per intervention across studies, different moni- 933
875 its clear potential for underestimation of pregnancy due to a toring methods, and different starting dosages of 934
876 high cycle cancellation rate (14.9%), in addition to underesti- medications. There were also some studies that did not 935
877 mation of multiple gestation rates due to the incidence of adequately describe randomization and allocation. Although 936
878 monofollicular recruitment (58%). Conversely, in a multi- all of the studies included mean age of participants, and all 937
879 center Reproductive Medicine Network trial in 1999 (excluded but one included duration of infertility, only 8 of the 13 re- 938
880 in this review because it included male-factor patients ported baseline serum measurements of ovarian reserve 939
881 without separate data reporting), a clear benefit was found (FSH or antim€ ullerian hormone). Many of the individual 940
882 for gonadotropins compared with natural-cycle IUI (7). studies had small sample sizes and lacked the statistical power 941
883 When CC and letrozole (both with IUI) were compared, letro- to detect significant differences between interventions. 942
884 zole with IUI was superior in one study (13); the larger, more In conclusion, on the basis of the currently available liter- 943
885 recent Diamond trial (16) showed a higher ongoing pregnancy ature, expectant management may be comparable to 944

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945 treatment with CC and timed intercourse or IUI in patients 9. Zeyneloglu HB, Arici A, Olive DL, Duleba AJ. Comparison of intrauterine 1004
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10. Society for Assisted Reproductive Technology. Society for Assisted Repro-
948 than letrozole. Treatment with gonadotropins seems to be 1007
ductive Technology National Summary, 2013. Available at: https://
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950 risk of multiple gestations is an obvious disadvantage that 11. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for sys- 1009
951 should limit utilization. Despite its cost and widespread utili- tematic reviews and meta-analyses: the PRISMA statement, 2009. Q5 1010
952 zation, IVF was no more effective than gonadotropins with 12. Deaton JL, Gibson M, Blackmer KM, Nakajima ST, Badger GJ, Brumsted JR. A 1011
953 IUI but may accelerate the time to clinical pregnancy. randomized, controlled trial of clomiphene citrate and intrauterine insemi- 1012
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954 Well-designed prospective trials with adequate sample 1013
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958 Until such data are available, clinicians should individualize crinol 2011;9:84. 1017
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1063 1122
1064
SUPPLEMENTAL TABLE 1 1123
1065 1124
Demographics of included studies.
1066 1125
Mean age in each Mean FSH in each group Duration of infertility
1067 1126
Study (reference) Interventions group (y) (IU/L or mIU/mL) in each group
1068 1127
1069 Fisch 1989 CC with TI vs. expectant 30 Not available 4.3 y 1128
Bhattacharya 2008 CC with TI vs. expectant; natural-cycle IUI vs. 32 Not available 30 mo
1070 expectant 1129
1071 Deaton 1990 CC þ IUI vs. expectant 33 Not available 3.5 y 1130
1072 Steures 2006 GND þ IUI vs. expectant 33 7.0, 6.7 2.0, 1.9 y 1131
Fouda 2011 CC þ IUI vs. letrozole þ IUI 26.1, 26.7 5.5, 5.7 3.4, 3.7 y
1073 1132
Diamond 2015 CC þ IUI vs. letrozole þ IUI vs. GND þ IUI 32.0, 32.2, 32.3 7.2, 7.0, 6.9 34.2, 35.2, 34.8 mo
1074 Dankert 2007 CC þ IUI vs. GND þ IUI 31.0, 31.6 Not available 33.4, 34.0 mo 1133
1075 Berker 2011 CC þ IUI vs. GND þ IUI 28.0, 28.2 6.7, 6.7 44.4, 47.9 mo 1134
1076 Baysoy 2006 Letrozole þ IUI vs. GND þ IUI 27.2, 28.1 6.4, 6.1 5.3, 5.9 y 1135
Gregoriou 2008 Letrozole þ IUI vs. GND þ IUI 32.1, 31.5 6.9, 7.4 3.6, 3.9 y
1077 Goverde 2000 GND þ IUI vs. natural-cycle IUI vs. IVF 31.7, 31.6, 32.0 Not available 4.2, 3.9, 4.4 y 1136
1078 Foong 2006 IVF vs. IVF-ICSI 33.0, 33.7 6.2, 6.5 57.2, 64.5 mo 1137
1079 Reindollar 2010 Conventional arm (CC þ IUI, GND þ IUI, 33 6.6, 6.7 Not available 1138
and IVF) vs. accelerated arm (CC þ IUI, IVF)
1080 1139
Note: GND ¼ gonadotropin.
1081 1140
Gunn. Systematic review of unexplained infertility. Fertil Steril 2016.
1082 1141
1083 1142
1084 1143
1085 1144
1086 1145
1087 1146
1088 1147
1089 1148
1090 1149
1091 1150
1092 1151
1093 1152
1094 1153
1095 1154
1096 1155
1097 1156
1098 1157
1099 1158
1100 1159
1101 1160
1102 1161
1103 1162
1104 1163
1105 1164
1106 1165
1107 1166
1108 1167
1109 1168
1110 1169
1111 1170
1112 1171
1113 1172
1114 1173
1115 1174
1116 1175
1117 1176
1118 1177
1119 1178
1120 1179
1121 1180

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