1 RBMO VOLUME 00 ISSUE 00 2023 103770

1 REVIEW 59
2 60
3 61
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5
Nutritional supplements and IVF: 62
63
6
7
an evidence-based approach 64
65
8 66
9 BIOGRAPHY 67
10 68
Q1 Roger J .X X Hart is a subspecialist in reproductive endocrinology and infertility, National Medical
11 69
Director of City Fertility, Professor of Reproductive Medicine at the University of Western Australia,
12 70
13
Australia and lead clinician for the Western Australia public fertility service. He has research interests 71
14 in the early-life origins of reproductive disorder and longer term health outcomes of IVF. 72
15 73
16 Q2 D1X X
Roger J. HartD*2X X 74
17 75
18 76
19 77
20 KEY MESSAGE 78
21 Q3 XX
Many women undertaking IVF treatment are either prescribed, or self-medicate with, one or more nutritional 79
22 supplements. Limited evidence exists for the majority, although a straightforward intervention that may have merit is the 80
23 Mediterranean diet. Beyond this, some benefit may be derived, in certain situations, for the use of 81
24 dehydroepiandrosterone, co-enzyme Q10, melatonin and possibly omega-3 fatty acids supplements. 82
25 83
26 ABSTRACT 84
27 Many women undergoing IVF take supplements during treatment. The purpose of this review was to systematically review these 85
28 86
nutritional supplements. The therapies studied are dehydroepiandrosterone (DHEA), melatonin, co-enzyme Q10 (CoQ1O),
29 87
carnitine, selenium, vitamin D, myo-inositol, omega-3, Chinese herbs and dietary interventions. A literature search up to May
30 88
2023 was undertaken. The data suggest that a simple nutritional approach would be to adopt a Mediterranean diet. With regards
31 89
to supplements to treat a potential poor ovarian response to ovarian stimulation, starting DHEA and COQ-10 before cycle
32 90
33
commencement is better than control therapies. Furthermore, medication with CoQ10 may have some merit, although it is 91
34
unclear whether its place is for older women, for those with a poor response to ovarian stimulation or for poor embryonic 92
35 development. There appears a benefit for some IVF outcomes for the use of melatonin, although it is unclear what group of 93
36 patients would derive the benefit and the appropriate dosing regimen. For women with polycystic ovary syndrome, there may be 94
37 a benefit to the use of myo-inositol, although again the dosing regimen is unclear. Furthermore, the place of vitamin D 95
38 supplementation has yet to be clarified, and supplementation with omega-3 free fatty acids may lead to improvements in clinical 96
39 and embryological IVF outcomes. 97
40 98
41 99
INTRODUCTION a poor ovarian response or poor ovarian stimulation profiles and
42 100
embryonic development, or for whom no implantation rates. However, the literature
43 101

F
ertility professionals are all healthy ongoing pregnancy has occurred, with respect to the use of adjuvant
44 102
engaged, perhaps even trapped, in we, as compassionate healthcare therapies to improve IVF outcomes is
45 103
a perennial search for the nuance professionals, seek the ‘silver bullet’ that either lacking or appears to frequently
46 104
of or a tweak to the stimulation will help the woman conceive. change with respect to the benefit, or lack
47 105
Q4 profile of a patient undergoing an IVF X Xcycle thereof, of a therapy. While benefit
48 106
to help a patient to conceive. For a patient The best-attended sessions at a fertility appears to be derived from the use non-
49 107
for whom all previous treatment cycles meeting often involve presentations on the pharmacological supplements for
50 108
have resulted in either cancellation due to use of adjuvant therapies to improve psychological distress when taken as part
51 109
52 110
Division of Obstetrics and Gynaecology, University of Western Australia, Perth, Western Australia, Australia. KEY WORDS
53 Fertility Specialists of Western Australia and City Fertility Clinic, Claremont, Western Australia, Australia. 111
Adjuvant
54 112
Co-enzyme Q1O
55 © 2023 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved. 113
*Corresponding author. E-mail address: roger.hart@uwa.edu.au (R.J. Hart). https://doi.org/10.1016/j.rbmo.2023.103770 1472-
Dehydroepiandrosterone
56 6483/© 2023 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved. IVF 114
57 Declaration: R.J.H. is the Medical Director of Fertility Specialists of Western Australia and National Medical Director of City Melatonin 115
58 Fertility Clinic, is a shareholder in CHA SMG, and has received educational sponsorship from MSD, Merck-Serono, Origio, Supplement 116
Igenomix, Gideon-Richter, Organon and Ferring Pharmaceuticals.
 2 RBMO VOLUME 00 ISSUE 00 2023

117 of an IVF cycle (Chu et al., 2017), a SEARCH STRATEGY generation of the energy substrate 180
118 previous review of nutritional supplements adenosine triphosphate; it also acts as an 181
119 for women undertaking IVF concluded that On 22 May 2023 an English-language antioxidant within the oocyte (Xu et al., 182
120 the only nutritional supplements that may literature search was performed of 2018). Observational studies and an 183
121 have a positive influence on reproductive PubMed, EMBASE, Science Direct, RCT suggest that the follicular fluid 184
122 outcomes in IVF were folic acid Cochrane Google Scholar and the concentration of CoQ10 diminishes with 185
123 supplementation and a Mediterranean diet Cochrane Controlled Trials Register, age (Ben-Meir et al., 2015b), and low 186
124 (Kermack and Macklon, 2015). published from 1 January 2015 to 22 May CoQ10 antioxidant status may indeed 187
125 2023 relating to dietary supplements, correlate with oocyte aneuploidy (Bentov 188
126 The purpose of this review is to vitamins used, adjuvants or ‘add-ons’ in IVF et al., 2014). Therefore, there is a rationale 189
127 undertake a systematic review of the treatment, intracytoplasmic sperm for the use of CoQ10 during fertility 190
128 nutritional supplementations that women injection (ICSI) or assisted reproductive treatment for women with perceived ‘poor 191
129 may be prescribed, or may take of their technology, with respect to oocyte oocyte quality’. The rationale for CoQ10 192
130 own volition, while undertaking IVF number, embryo or blastocyst supplementation is that the age-related 193
131 treatment. For the purposes of this development and clinical pregnancy or live decline in oocyte quality is believed to be 194
132 review the term ‘nutritional’ is birth rates. The search criteria were: associated with declining oocyte 195
133 interpreted as an oral therapy that a ’Reproductive Techniques, Assisted OR mitochondrial function and increased 196
134 patient can commence themselves, Fertilization in Vitro OR Sperm Injections, oxidative stress within the oocyte 197
135 although perhaps not in all jurisdictions, Intracytoplasmic OR IVF (keyword) or ICSI (Rodriguez-Varela and Labarta, 2021). 198
136 but is not considered a standard (keyword) (include all subheadings) AND Adequate mitochondrial function is 199
137 medication influencing reproduction. Supplement (keyword) OR add-on imperative for correct assembly of the 200
138 The reason for this broad interpretation (keyword) adjuvant (keyword) OR vitamin meiotic spindle, correct chromosomal 201
139 of ‘nutritional’ is that this review excludes (include all subheadings) AND Oocyte segregation, oocyte maturation and its 202
140 therapies that are usually only available number (keyword) OR embryo fertilization, leading on to appropriate 203
141 when prescribed by the treating clinician, development (keyword) OR blastocyst normal embryonic development 204
142 such as different stimulation protocols or (keyword) OR pregnancy (keyword) OR (Rodriguez-Varela and Labarta, 2021). This 205
143 the administration of growth hormone clinical pregnancy (keyword) OR livebirth hypothesis is supported by an animal study 206
144 or testosterone. Hence, the focus is on (keyword) OR side-effect. Other Medical that demonstrates a beneficial effect of its 207
145 supplements with which a patient may Subject Headings (MeSH) terms and key use on embryonic development (Ben-Meir 208
146 self-medicate, as these supplements words were used to find articles on specific et al., 2015a). 209
147 are generally readily available ‘over the aspects of the topic: melatonin, CoQ10 210
148 counter’, and may be taken without and vitamin D. The full search strategy is A non-blinded randomized study of 211
149 the clinician’s knowledge or indeed be listed in TABLE 1. CoQ10 (200 mg three times per day for 2 212
150 advised or prescribed by the treating months), was undertaken in China on 169 213
151 clinician. The author (R.J.H.) conducted a review of women less than 35 years of age with an 214
152 abstracts generated by the search, which expected poor prognosis for their 215
153 This review does not address the multiple was undertaken by King Edward Memorial forthcoming IVF cycle. Their poor 216
154 antioxidant agents that many women take Hospital library staff. It was planned that if prognosis was inferred from their low 217
155 while attending a fertility clinic, which have any uncertainty, or conflict of interest, in serum anti-M€ ullerian hormone (AMH) 218
156 been analysed in a Cochrane review the data extraction arose, this would be concentration (less than 1.2 ng/ml), and 219
157 (Showell et al., 2020), but instead focuses resolved by a colleague. The data were antral follicle count (less than 5). The 220
158 on the therapies frequently suggested or interpreted according to the Preferred hypothesis was that high oxidative stress 221
159 prescribed by clinicians with the purpose Reporting Items for Systematic Reviews was responsible for a premature decline in 222
160 of improving ovarian response, embryonic and Meta-analyses (PRISMA) 2020 ovarian function, which might improve in 223
161 development and live birth rates in an IVF guidelines (Page et al., 2021) and a PRISMA response to treatment with a course of 224
162 cycle. Poor ovarian response is not defined flowchart was constructed (FIGURE 1). Of the CoQ10. The primary outcome measure 225
163 according to a particular definition due to 106 reports assessed for eligibility 39 were was the number of embryos that reached 226
164 the heterogenous inclusion criteria within excluded due the wrong intervention or 6
8 cells on the 3rd day of culture. Most 227
165 reported studies. wrong end-point, and a further 40 were women were treatment naive and had 228
166 excluded as they were superseded by a primary infertility. 229
167 The therapies addressed are systematic review. A summary table of the 230
168 dehydroepiandrosterone (DHEA), 27 main included studies is provided in After treatment, favourable outcomes 231
169 melatonin, co-enzyme Q10 (CoQ1O), TABLE 2. were recorded with respect to the 232
170 carnitine, selenium, vitamin D, myo- duration of stimulation required, dose of 233
171 inositol, omega-3 and Chinese herbs. To gonadotrophin required, number of 234
172 ensure a concise summary of the current NUTRITIONAL THERAPIES oocytes collected, fertilization rate and 235
173 evidence base for each supplement improvement in embryo quality, and a lack 236
174 studied, the data are presented in order of CoQ10 of benefit of use on clinical pregnancy rate 237
175 priority, with the most recent meta-analysis CoQ10 is an essential component of the or live birth was demonstrated (Xu et al., 238
176 or systematic review, most recent inner mitochondrial membrane and is 2018). The power calculation for the study 239
177 randomized controlled trial (RCT) or, if responsible for electron transport in the was based on an improvement of embryo 240
178 these are not available, the most recent mitochondrial respiratory chain for development, which was demonstrated. 241
179 observational data. oxidative phosphorylation leading to the Perhaps a more appropriate group for 242
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243 306
244
TABLE 1 SUMMARY OF THE SEARCH STRATEGY USED IN THIS SYSTEMATIC REVIEW OF NUTRITIONAL SUPPLEMENTS IN IVF 307
245 308
Q5 Parameter X X Definitions
246 309
247 Search date 22 May 2023 310
248 Sources searched PubMed, EMBASE, BioMed Central, PsycInfo, Science Direct, Cochrane Google Scholar and the Cochrane Controlled Tri- 311
249 als Register 312
250 Limited to publications dated from 1 January 2015 to 2023 313
251 314
Search criteria used for the title and abstract were: Reproductive Techniques, Assisted OR Fertilization in Vitro OR Sperm
252 Injections, Intracytoplasmic OR IVF (keyword) or ICSI (keyword) (include all subheadings) 315
253 AND 316
254 Supplement (keyword) OR add-on (keyword) adjuvant (keyword) OR vitamin (include all subheadings) 317
255 AND 318
256 Oocyte number (keyword) OR embryo development (keyword) OR blastocyst (keyword) OR pregnancy (keyword) OR clini- 319
257 cal pregnancy (keyword) OR livebirth (keyword) OR side-effect 320
258 Other MeSH terms and keywords used to find articles on specific aspects of the topic were: Melatonin, CoQ10, Vitamin D 321
259 Other information sources Reference lists of included studies were searched to identify additional relevant papers 322
260 checked 323
261 324
Inclusion criteria Published in an English-language peer-reviewed journal
262 Q6 Studies limited to the following treatments: IVF, frozen embryo transfer ,X X minimal stimulation IVF 325
263 Studies that involved giving the female partner nutritional supplements before and/or during her IVF stimulation and 326
264 recorded the IVF outcomes: oocyte number, embryo and blastocyst development, and pregnancy and live birth rates 327
265 Studies involving data collection and/or comparison with a contemporary cohort of individuals from the general population 328
266 or who underwent a randomized controlled trial, or a systematic review of such papers 329
267 Exclusion criteria Articles not published in English 330
268 Articles where it was not possible to identify the fertility treatment employed 331
269 Studies analysing an intervention with conventional gonadotrophin or hormone or adjuvant therapies that are not consid- 332
270 ered nutritional supplements, such as FHS, LH, human chorionic gonadotrophin, testosterone, oestrogens, progesterone, 333
271 metformin or clomiphene 334
272 Studies that involved treatment of the male partner or sperm donor 335
273 Studies that involved treatment of the laboratory culture media 336
274 Studies without an identifiable comparison cohort and case studies 337
275
Studies where it was not possible to identify the fertility treatment employed to enable analysis of the IVF outcomes 338
276 Categories of studies Case-control studies, cohort studies, randomized control trials, systematic reviews AND 339
277 Method for assessing Abstracts were provisionally classified and full-text articles obtained for critical appraisal. Each publication was evaluated by 340
278 and interpreting the evidence one reviewer (R.J.H.) 341
279 342
MeSH, Medical Subject Headings.
280 343
281 344
282 analysis would have been women with stimulation for 330 women with an maturation rates and post-meiotic 345
283 ‘poor oocyte’ or ‘poor embryo’ quality. expected poor response to stimulation, euploidy in women over 37 years of age, 346
284 with both CoQ10 interventions leading to a with no difference recorded for women 347
285 A retrospective study of the use of CoQ10 higher antral follicle count at the start of under 30 years (Ma et al., 2020). 348
286 (and DHEA) for an average of 11 months treatment and improvements in clinical 349
287 involved 330 women who had a previous pregnancy rates (Qi et al., 2022). When both of these RCT of oral 350
288 poor response to ovarian stimulation and supplementation were analysed within the 351
289 were undergoing either insemination A further RCT of the use of CoQ10 among Cochrane review of subfertile women 352
290 treatment or IVF. The study group was 39 women undergoing IVF, which analysed attending a fertility clinic including, but not 353
291 compared with a control group (467 its effect on the rate of oocyte aneuploidy exclusively, women undergoing IVF, the 354
292 patients) derived from a previous cohort of detected by polar body biopsy, was chance of a live birth was not significantly 355
293 poor responders who were taking DHEA prematurely terminated due to the safety increased (odds ratio [OR] 1.50, 95% 356
294 prior to their treatment cycle. The dual concerns of the biopsy technique (Bentov confidence interval [CI] 0.78
2.88; 357
295 intervention group recorded an increase in et al., 2014). Although the rate of P = 0.23; 2 RCT, 225 women), although 358
296 ovarian antral follicles, and more dominant aneuploidy appeared to be lower in the with the inclusion of two further studies 359
297 follicles at the time of trigger prior to CoQ10 group (46.5%) compared with the the clinical pregnancy rate was increased 360
298 intrauterine insemination and IVF. No control group (62.8%), the difference was (OR 2.49, 95% CI 1.50
4.13; P < 0.001, 361
299 difference was recorded in pregnancy not statistically significant. Another RCT I2 = 47%; 4 RCT, 397 women), suggesting 362
300 rates or oocytes retrieved in the IVF group using polar body biopsy exposed discarded that the use of CoQ10 may have some 363
301 (Gat et al., 2016). This is similar to an germinal vesicle oocytes to either merit (Showell et al., 2020). However, from 364
302 observational study where CoQ10 for 2 50 mmol/l of CoQ10 or a control in in-vitro the included studies, and reviews, it is 365
303 months’ pre-treatment was compared culture, and noted that CoQ10 unclear whether its place is for older 366
304 alone, and in combination with supplementation was associated with a women, those with a poor response to 367
305 acupuncture, with standard IVF substantial improvement in oocyte ovarian stimulation or those with poor 368
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369 432
370 433
371 434
372 435
373 436
374 437
375 438
376 439
377 440
378 441
379 442
380 443
381 444
382 445
383 446
384 447
385 448
386 449
387 450
388 451
389 452
390 453
391 454
392 455
393 456
394 457
395 458
396 459
397 460
398 461
399 462
400 463
401 464
402 465
403 466
404 467
405 468
406 FIGURE 1 PRISMA 2020 flow diagram for the identification of studies on nutritional supplements in IVF. 469
407 470
408 471
409 embryonic development, with fewer less patients, they propose that it may be too chiro-inositol under the influence of 472
410 competent, mature oocytes (Rodriguez- late to recover from age-related oocyte insulin, and this stimulates glycogen 473
411 Varela and Labarta, 2021; Showell et al., deterioration, leading to higher aneuploidy production and facilitates glucose uptake 474
412 2020). rates (Rodriguez-Varela and Labarta, (Teede et al., 2023). 475
413 2021). 476
414 In summarizing the use of oral CoQ10 for There are conflicting reports in the 477
415 women undergoing IVF treatment, Myo-inositol literature with respect to the potential 478
416 Rodriguez-Varela and Labarta highlighted Myo-inositol, a naturally occurring sugar, benefit of myo-inositol. A meta-analysis by 479
417 the fact that if investigators seek to has been used for women with polycystic Mendoza and co-workers (Mendoza et al., 480
418 determine any positive influence on oocyte ovary syndrome (PCOS) as it believed to 2017), performed on women undergoing 481
419 quality, parameters such as fertilization, improve insulin sensitivity as a result of its ICSI treatment, showed no benefit for its 482
420 blastocyst formation and embryo quality role as an intracellular mediator of insulin use for any parameter studied. However, 483
421 are better indicators of any benefit derived signal transduction (Merviel et al., 2021; another meta-analysis suggested that there 484
422 from CoQ10 than are implantation rates Motuhifonua SK et al., 2023). It has been could be some favourable benefits for a 485
423 (Rodriguez-Varela and Labarta, 2021). The suggested to have a positive influence on subgroup of women with PCOS, although 486
424 authors’ conclusion was that oral CoQ10 oocyte quality (Merviel et al., 2021) at a the generalizability of this study should be 487
425 supplementation prior to ovarian dose of 4 g per day in a divided dose, and questioned as all the included studies were 488
426 stimulation for IVF treatment may improve possibly on intracellular calcium performed in one country (Zheng et al., 489
427 the ovarian response and the follicular oscillations in women with a poor ovarian 2017). 490
428 environment, leading to the improved response to stimulation (Nazari et al., 491
429 oocyte and embryonic outcomes 2020). Nine isomers of inositol exist in With respect to women with PCOS, 492
430 highlighted by Xu and colleagues (Xu et al., humans, with myo-inositol being the most XX
Merviel and collaborators (Merveil et al .,) Q7 493
431 2018); however, unfortunately for older abundant. Myo-inositol is converted to D- undertook the most recent review of the 494
 RBMO VOLUME 00 ISSUE 00 2023 5

495 558
496
TABLE 2 SUMMARY OF THE INCLUDED STUDIES ON NUTRITIONAL SUPPLEMENTS FOR WOMEN UNDERGOING IVF 559
TREATMENT
497 560
498 Authors (year) Type of study Dosage Inclusion criteria Outcomes Benefit? 561
499 562
CoQ10
500 563
501 Xu et al. Non-blind RCT 200 mg three times per Age <35 years, AMH <1.2 ng/ml Improvement in: duration of stimu- § 564
502
(2018) day for 2 months and AFC <5 lation (#) dose of gonadotrophin 565
(n = 169) required (#), number of oocytes
503 566
collected ("), fertilization rate (")
504 and embryo quality ("). No differ- 567
505 ence in CPR ($) or LBR ($) 568
506 Gat et al. Retrospective study CoQ10 600 mg/ Age; combined treatment The dual intervention recorded an + 569
507 (2016) day + DHEA 75 mg/day, 39 § 2.7 years versus DHEA alone increase in ovarian antral follicles (") 570
508 or DHEA 75 mg/day 39.2 § 3.6years, AFC <6, and pre- and more dominant follicles at the 571
509 alone for on average 11 vious poor response <4 eggs time of trigger before IVF ("). No 572
months retrieved during IVF differences in pregnancy rates ($)
510 573
(n = 330 compared with 467 histori- or oocytes retrieved ($)
511 cal controls taking DHEA) 574
512 575
Qi et al. Retrospective study CoQ10 30 mg/day for 2 Age 35 years old, with DOR: AFC Both the CoQ10 interventions led +
513 (2022) months before IVF <5, AMH <1.2 ng/ml; BMI <30 kg/ to a higher AFC at the start of 576
514 treatment alone or in m2; or FSH <18 IU/l; with tubal or treatment ("), number of mature 577
515 combination with male factor infertility oocytes collected (") and improve- 578
516 acupuncture, with (n = 330) ment in embryo quality ("), with 579
standard IVF improvements in CPR and LBR only
517 580
for dual therapy (")
518 581
Bentov et al. RCT (terminated early) 600 mg/day CoQ10 or Age 35
43 years, BMI <37 kg/m2, Prematurely terminated; at close:

519 582
(2014) placebo for 2 months baseline FSH <20 IU/l no significant difference in rate of
520 583
(n = 39) aneuploidy ($) (46.5% in the
521 CoQ10 group versus control 584
522 62.8%) or CPR ($) (33% for the 585
523 CoQ10 group versus control 586
26.7%)
524 587
525 Showell et al. Systematic review and Included dosage from Indication previous POR, age CoQ10 associated with increased + 588
526
(2020) meta-analysis, 63 RCT, 60 to 300 mg/day 36
43 years with expected poor CPR (") versus placebo or no treat- 589
with a subset of 4 RCT ovarian response or anovulatory ment (OR 2.49, 95% CI 1.50
4.13;
527 590
on CoQ10 use in sub- PCOS P < 0.001, I2 = 47%). LBR (OR 1.50,
528 fertile women attending (n = 397 women) 95% CI 0.78
2.88; P = 0.23; 2 591
529 a fertility clinic, not RCT, 225 women) ($) 592
530 exclusively undergoing 593
531 IVF 594
532 Myo-inositol 595
533 Mendoza et Systematic review and Myo-inositol dose PCOS patients undergoing ICSI Myo-inositol supplementation did
596
534 al. (2017) meta-analysis 1.2
4 g/day treatment not improve oocyte quality ($) (OR 597
535 8 RCT (n = 1,019) 2.21, 95% CI 0.83
5.89), embryo 598
quality ($) (OR 1.62, 95% CI
536 599
0.39
6.71) or pregnancy rate ($)
537 (OR 1.28, 95% CI 0.87
1.89) and 600
538 more oocytes were retrieved (#) in 601
539 the control patients than the myo- 602
540 inositol-treated patients (mean dif- 603
ference 1.518, 95% CI 3.63
0.59)
541 604
542 Zheng et al. Systematic review and Myo-inositol 4 g/day Patients <42 years (4 studies Myo-inositol supplement group + 605
(2017) meta-analysis included women with PCOS, 3 showed improved CPR (") (OR 1.45,
543 606
7 RCT studies excluded women with 95% CI 1.08
1.95) and reduced
544 607
PCOS) miscarriage (#) (OR 0.26, 95% CI
545 (n = 935) 0.12
0.59). Grade 1 embryo pro- 608
546 portion increased (") (OR 1.73, 95% 609
547 CI 1.10
2.74), germinal vesicles and 610
degenerated oocytes retrieved
548 611
decreased (#) (OR 0.31, 95% CI
549 612
0.11
0.86), and less stimulation
550 required (#) (mean difference 613
551
327.40, (95% CI
567.38 to 614
552
87.42) 615
553
No differences in total oocytes 616
retrieved ($) or mature oocytes
554 617
retrieved ($)
555 618
556 (continued on next page) 619
557 620
 6 RBMO VOLUME 00 ISSUE 00 2023

621 TABLE 2 (Continued) 684

622 685
623 Authors (year) Type of study Dosage Inclusion criteria Outcomes Benefit? 686
624 Merviel et al. Systematic review Myo-inositol 1.2
4 g/ Patients with PCOS Conclusion: ’Myo-inositol 4 g day
1 + 687
625 (2021) 11 RCT day (majority dose 4 g/ (n = 1,055) (2 g twice day
1), three months 688
626 day) prior to ovarian stimulation, is effec- 689
627 tive in normalizing ovarian function, 690
improving oocyte and embryo
628 691
quality’
629 692
Nazari et al. RCT Myo-inositol 4 g/day Patients undergoing ICSI with POR No difference regarding dose of +
630 693
(2020) started 1 month pre-IVF defined as: AFC < 5 or AMH < gonadotropin used ($) or total
631 694
in conjunction with 1.2 ng/ml, aged 20
45 years with number of oocytes ($) and mature
632 400 mg folic acid ovulatory cycles, basal FSH oocytes ($) retrieved. Higher num- 695
633 <15 mIU/ml and BMI 18
30 kg/m2 ber of grade A embryos (") (67.2% 696
634 (n = 112) versus 36.5%, P < 0.001) and 697
higher fertilization rate with the
635 698
intervention (") (88.3% versus
636 699
72.3%, (P = 0.001). Pregnancy rates
637 were not different ($) 700
638 701
Wdowiak RCT Combination therapy All ovulatory patients undergoing Myo-inositol was associated with +
639 and Filip (2020) of myo-inositol (initially first cycle of IVF with ICSI despite improvements in oocyte quality ("), 702
640 2 g/day then reduced to partners with normal semen param- blastocyst development (") and 703
641 0.6 g/day), melatonin, eters), aged 20
35 years CPR (") (42% versus 24% in the 704
642 vitamin D, a-lactalbu- (n = 100) control group) 705
min and folic acid
643 706
(commenced 3 months
644 before the ICSI cycle) 707
645 708
Mohammadi RCT Myo-Inositol 4 g/day for 20
43 years, POR defined as: AFC Higher fertilization rate (") (68.6% §
646 et al. (2021) 12 weeks prior to IVF <7 or AMH <1.2 ng/ml with BMI versus 40.8%) and lower require- 709
647 treatment 19
25 kg/m2; excluded PCOS ment for gonadotropin stimulation 710
648 patients undergoing ICSI (#) in the intervention group. No 711
649 (n = 60) difference in the number of oocytes 712
retrieved ($), number of MII
650 713
oocytes ($) or CPR ($)
651 714
Melatonin
652 715
653 Hu et al. Systematic review and Melatonin 2
8 mg/day Various inclusion criteria; first IVF Higher CPR with melatonin (") (OR + 716
(2020) meta-analysis cycle, unexplained infertility, unex- 1.43, 95% CI 1.11
1.86), but no
654 717
10 RCT (3 studies plained infertility with sleep distur- effect on LBR ($) (OR 1.38, 95% CI
655 718
included combination bance, mixed aetiology, PCOS, 0.78
2.46). Melatonin was associ-
656 therapies and 1 studied POR, ‘low oocyte quality’ ated with an increased number of 719
657 melatonin added to the (n = 1023) oocytes collected (") (mean differ- 720
658 culture medium) ence 0.34, 95% CI 0.01
0.67), 721
number of mature oocytes (")
659 722
(mean difference 0.56, 95% CI
660 723
0.27
0.85) and number of good-
661 quality embryos (") (mean differ- 724
662 ence 0.36, 95% CI 0.18
0.55), 3 725
663 RCT, X n
X o effect on miscarriage rate Q8 726
664
($) (OR 1.28, 95% CI 0.65
2.51) 727
665 Mejlhede et Systematic review and Melatonin 3
8 mg/day Various inclusion criteria; unex- Higher mature oocyte count with + 728
666 al. (2021) meta-analysis during the IVF plained infertility, unexplained infer- melatonin (") (mean difference 1.82, 729
7 RCT (2 studies treatment tility with sleep disturbance, mixed 95% CI 0.37
3.27). CPR ($) (OR
667 730
included combination aetiology, PCOS, POR, ‘low oocyte 1.35, 95% CI 0.97
1.87). No differ-
668 therapies) quality’ ence in number of oocytes col- 731
669 (n = 889) lected ($), embryo quality ($) or 732
670 miscarriage rate ($) 733
671 Fernando et Pilot dose-finding RCT Placebo or melatonin First cycle of IVF No differences between the groups § 734
672 al. (2018) 2 mg/day or melatonin (n = 160) for CPR ($), LBR ($), total oocyte 735
673 4 mg/day or melatonin number ($), number of mature 736
8 mg twice per day dur- oocytes ($), number of fertilized
674 737
ing IVF stimulation oocytes ($) or number or quality of
675 embryos ($). Combining all mela- 738
676 tonin groups in comparison with 739
677 placebo, CPR was 21.7% for melato- 740
678 nin versus 15.0% for placebo ($) 741
(OR 1.57, 95% CI 0.59
4.14)
679 742
680 (continued on next page) 743
681 744
682 745
683 746
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747 TABLE 2 (Continued) 810

748 811
749 Authors (year) Type of study Dosage Inclusion criteria Outcomes Benefit? 812
750 DHEA 813
751 814
Nagels et al. Systematic review and DHEA 75 mg/day for Patients undergoing IVF for POR DHEA was associated with an +
752 (2015) meta-analysis 6
12 weeks prior to IVF with various definitions. Mean ages increase in ongoing pregnancy or 815
753 8 RCT cycle (most studies 12 of patients across studies 30
40 live birth: live birth or ongoing preg- 816
754 weeks) years nancy rate X (X ") (OR 1.81, 95% CI Q9 817
755 (n = 878) 1.25
2.62) and CPR (") (OR 1.34, 818
756
OR X 1X .01
1.76) Q10 819
757 Qin et al. Systematic review and DHEA 75 mg/day for Patients undergoing IVF for POR Treatment with DHEA was associ- + 820
(2017) meta-analysis 6
12 weeks prior to the with various definitions with wide ated with an increase in CPR (")
758 821
4 RCT, 4 retrospective IVF cycle (most studies age range inclusion criteria (OR 1.47, 95% CI 1.09
1.99) in
759 822
studies, 1 observational 12 weeks) (n = 540 active treatment versus comparison to control, with no dif-
760 study 668 controls) ferences in the number of oocytes 823
761 retrieved ($) or miscarriage rate 824
762 ($) 825
763 Neves et al. Systematic review and DHEA 75 mg/day for Patients undergoing IVF for POR Treatment with DHEA was not asso- § 826
764 (2022) meta-analysis 6
12 weeks prior to the with various definitions, with wide ciated with an increase in oocyte 827
765 8 RCT IVF cycle (most studies age range inclusion criteria yield ($), mature oocytes collected 828
12 weeks) (n = 1782) ($), embryo development ($),
766 829
miscarriage rate ($), CPR ($) or
767 LBR ($) 830
768 831
Wang et al. Systematic review and DHEA 60
90 mg for Patients with POR by various defini- DHEA administration was associ- +
769 (2023) meta-analysis 8
12 weeks (most stud- tions, one study’s inclusion was age ated with more oocytes collected 832
770 8 RCT, 5 observational ies 75 mg/day) >37 years (") (mean difference 1.09, 95% CI 833
771 studies, 3 retrospective (n = 1998) 0.38
1.80), mature oocytes (") 834
772 studies (mean difference 0.78, 95% CI 835
0.16
1.40), fertilized oocytes (")
773 836
(mean difference 0.84, 95% CI
774 0.42
1.26) and top
quality 837
775 embryos developed (") (mean dif- 838
776 ference 0.60, 95% CI 0.34
0.86). 839
777 Higher CPR (") (RR 1.35, 95% CI 840
1.13
1.61) and ongoing pregnancy
778 841
rate (") (RR 1.82, 95% CI
779 1.34
2.46), live birth rate ($) (RR 842
780 1.35, 95% CI 0.94
1.94) 843
781 844
Vitamin D
782 845
Zhou et al. Systematic review and Dose regimen for indi- Infertile patients undergoing IVF Vitamin D supplementation was §
783 846
(2022) meta-analysis vidual studies: vitamin D treatment with vitamin D deficiency associated with an increased bio-
784 5 RCT (3 from Iran, 2 32,000 IU/day for 12 (serum vitamin D <30 ng/ml) (mean chemical pregnancy rate (") (RR 847
785 from Italy) weeks, calcitriol pills BMI 20.8
26.9 kg/m2 and mean 1.53, 95% CI 1.06
2.20) but not 848
786 0.25 mg/day for 4 age 28.5
35.9 years across the CPR ($), fertilization rate ($), 849
787
weeks, a single dose of studies) embryo quality ($) or miscarriage 850
600,000 IU of vitamin (n = 938) rate ($)
788 851
D or 50,000 IU vitamin
789 D weekly for 6
8 weeks 852
790 (2 studies) 853
791 Meng et al. Systematic review Various vitamin D doses Inclusion criteria of the studies var- Vitamin D use was associated with + 854
792 (2023) 9 RCT, 3 observational and regimens for 6
9 ied and included all patients, an increased CPR (") in vitamin D- 855
793 studies weeks (1 study was a sin- patients with PCOS, vitamin D-defi- deficient patients (OR 1.70, 95% CI 856
794 gle depot dose), some cient patients and patients with 1.24
2.34), with no difference in 857
studies were combina- implantation failure the rate of miscarriage ($). When
795 858
tion therapies, most (n = 2548) the vitamin D concentration in
796 studies measured vita- serum before treatment was 859
797 min D concentrations <75 nmol/ml, CPR doubled (") 860
798 pre-treatment, and vita- (post-treatment over control OR 861
799 min D status pre-treat- 2.06, 95% CI 1.32
3.22). Suggested 862
ment varied favourable dose is
800 863
1000
10,000 IU/day for 30
60
801 days 864
802 865
Bezerra Espi- Pilot RCT A combination inter- Unselected patients undergoing Implantation rate in the group with +
803 nola et al. vention of myo-inositol, IVF, age <42 years, BMI 18.5
25 kg/ addition of vitamin D increased (") 866
804 (2021) melatonin, a-lactalbu- m2, basal FSH <15 IU/l (37.1%) in comparison to the non- 867
805 min and folic acid ver- (n = 100) vitamin D-supplemented group 868
806 sus control, the same (19.2%) (P = 0.015). No differences 869
807 870
(continued on next page)
808 871
809 872
 8 RBMO VOLUME 00 ISSUE 00 2023

873 TABLE 2 (Continued) 936

874 937
875 Authors (year) Type of study Dosage Inclusion criteria Outcomes Benefit? 938
876 supplements plus the in ongoing pregnancy ($) or 939
877 addition of 2000 IU/ miscarriage ($) rate 940
878 day. Vitamin D 941
879 supplementation in the 942
luteal phase
880 943
881 L-Carnitine 944
882 Sheida et al. RCT L-Carnitine3 g/day Patients with PCOS aged L-Carnitine was associated with § 945
883 (2023) from stimulation until 18
40 years undergoing IVF higher serum oestradiol concentra- 946
trigger (n = 83) tions (") on the day of oocyte trig-
884 947
gering (2974.67 versus 1954.62 pg/
885 948
ml, P = 0.01). No difference in the
886 number of retrieved oocytes, ($), 949
887 mature oocytes ($), fertilization 950
888 rate ($) or embryo development 951
889
($) 952
890 Chinese herbs 953
891 Guo et al. Non-blind RCT Intervention of combi- 433 women undertaking IVF for Taking the Chinese herb supple- + 954
892 (2014) nation of Chinese herbs either tubal or male factor infertility, ment was associated with an 955
893 versus placebo ovulatory, age 22
42 years, basal increase in fertilization rate (") 956
FSH <15 IU/l, AFC 5 (58.5% versus 54.7%, P = 0.003),
894 957
(n = 433) high-quality embryo rate (") (52.1%
895 versus 48.7%, P = 0.036) and CPR 958
896 (") (44.2% versus 34.8%, 959
897 P = 0.043). No difference in the 960
898 number of oocytes collected ($) or 961
LBR ($)
899 962
900 Song et al. Multicentre RCT Ding-Kun pill (>30 Patients starting IVF 35 years, BMI Ding-Kun led to the development of § 963
(2021) components) twice <35 kg/m2, basal AFC <5 or AMH more top-quality blastocysts
901 964
Q11 XX
daily 5
6 weeks <1.2 ng/ml, or previous POR (median 2 versus 1, P = 0.003) and
902 before IVF trigger (<4 oocytes after standard ovarian increased high-quality embryo rate 965
903 stimulation) (") (P = 0.014); no differences in 966
904 (n = 462) CPR ($) or ongoing pregnancy rate 967
905 ($) between the Ding-Kun pill and 968
placebo
906 969
907 Omega-3 fatty 970
acids
908 971
909 Abodi et al. Systematic review Intake of foods as a Patients starting IVF; studies No synthesis of data undertaken + 972
910
(2022) 3 RCT, 2 observational source of omega- 3 fatty included patients with BMI due to the heterogeneity of the 973
studies acids as assessed by 18
35 kg/m2, age 19
42 years studies and risk of bias, although
911 974
food frequency ques- (n = 731) all studies demonstrated a benefit
912 tionnaires, or supple- of omega-3 (either dietary or 975
913 mentation with omega- supplemental) on embryonic 976
914 3 (1 study tablet of 180 g development (") 977
915 EPA + 120 g DHA/day; 1 978
study a 6-week dietary
916 979
supplementation of
917 olive oil for cooking, an 980
918 olive oil-based 981
919 spread, + a daily drink 982
920 with 10 mg vitamin D 983
and 2 g omega-3) com-
921 984
pared with women with-
922 out a high intake of 985
923 omega-3, or when given 986
924 over 4
6 weeks 987
925 Q12 Resveratrol X X 988
926 Ochiai et al. Retrospective study Resveratrol 200 mg/day All patients undergoing cleavage After matching patients by age at
989
927 (2019) throughout the IVF and stage embryo transfer (excluded the time of oocyte retrieval, embryo 990
928 Q13 embryo transfer cycle poor-prognosis patients; X aX ge grade and stage, the number of 991
929 >43 years or poor-quality embryos embryos transferred, and fresh or 992
transferred) versus no supplement frozen cycle, multivariate logistic
930 993
(n = 204 taking resveratrol versus regression analysis showed that
931 994
7073 without) resveratrol supplementation halved
932 the CPR (OR 0.54, 95% CI 995
933 0.34
0.85) and doubled the risk of 996
934 miscarriage (OR 2.60, 95% CI 997
1.07
6.33)
935 998
(continued on next page)
 RBMO VOLUME 00 ISSUE 00 2023 9

999 TABLE 2 (Continued) 1062

1000 1063
1001 Authors (year) Type of study Dosage Inclusion criteria Outcomes Benefit? 1064
1002 Antioxidants 1065
1003 1066
Showell et al. Systematic review and Studies of subfertile Subgroup of patients undergoing Subgroup analysis focusing on
1004 (2020) meta-analysis women attending a fer- IVF taking a antioxidant supplement patients undergoing IVF treatment 1067
1005 63 RCT including a sub- tility clinic, interven- versus placebo or standard treat- demonstrated no increase in CPR 1068
1006 group of 18 RCT for tions included ment ($) for use of antioxidants when 1069
1007 outcome CPR, 9 RCT treatments with combi- (n = 2341 for outcome CPR, compared with placebo or standard 1070
for outcome LBR in nations of antioxidants, n = 806 for outcome LBR) treatment (OR 1.15, 95% CI
1008 1071
patients undergoing IVF N- acetylcysteine, mela- 0.95
1.40; I2 = 0%) or LBR ($)
1009 1072
tonin, L-arginine, myo- compared with placebo or no inter-
1010 inositol, carnitine, sele- vention (OR 1.36, 95% CI 1073
1011 nium, vitamin E, vitamin 0.96
1.93; P = 0.08, I2 = 0%) 1074
1012 B complex, vitamin C, 1075
vitamin D and calcium,
1013 1076
CoQ10 and omega-3
1014 1077
versus placebo, no
1015 treatment/standard 1078
1016 treatment or another 1079
1017 antioxidant 1080
1018 (#), negative significant difference; ("), positive significant difference; ($), no significant difference; (+), general positive benefit from use; (
), generally no benefit from use. 1081
1019 AFC, antral follicle count; AMH, anti-M€
ullerian hormone; BMI, body mass index; CI, confidence interval; CoQ10, co-enzyme Q10; CPR, clinical pregnancy rate; DHA, 1082
1020 docosahexaenoic acid; DHEA, dehydroepiandrostenedione; DOR, diminished ovarian reserve; EPA, eicosapentaenoic acid; ICSI, intracytoplasmic sperm injection; LBR, live birth 1083
1021 rate; MII, metaphase II; OR, odds ratio; PCOS, polycystic ovary syndrome; POR, poor ovarian response; RCT, randomized controlled trial; RR, risk ratio. 1084
1022 1085
1023 1086
1024 literature and concluded that myo-inositol Fertilization and the number of A grade be derived by using metformin instead; 1087
1025 normalizes ovarian function, leading to embryos were significantly improved in the hence head-to-head studies are required 1088
1026 improved oocyte and embryo quality for group administered myo-inositol. No other (Teede et al., 2023). 1089
1027 women with PCOS who were undergoing differences in the stimulation or outcome 1090
1028 IVF, although they encouraged more RCT variables were evident (Nazari et al., Melatonin 1091
1029 to assess influences on clinical pregnancy 2020). A further, smaller, blinded RCT was Melatonin is a free radical scavenger, as 1092
1030 and live birth rates. A further recent study performed in Iran at a similar time; this well as having a role in the sleep/wake cycle 1093
1031 of the use of 4 g of myo-inositol for women involved patients requiring ICSI, and also (Mejlhede et al., 2021). A systematic review 1094
1032 with PCOS also studied the gene confirmed a positive influence of 4 g myo- of seven RCT, including studies published 1095
1033 expression within the cumulus cells of inositol on the oocyte fertilization rate, in to end of 2020, of the use of melatonin for 1096
1034 women with PCOS undergoing IVF an addition to a positive impact on the women undergoing IVF treatment 1097
1035 (Tabatabaie et al., 2022). Myo-inositol use ovarian sensitivity index of predicted poor reported some potential promise for its 1098
1036 led to a decrease in the expression of responding patients (Mohammadi et al., use, although no distinct patient group was 1099
1037 follicular and LH receptors within the 2021). studied. This review included 354 1100
1038 cumulus cells, and a normalization of gene participants who had taken the placebo 1101
1039 expression within key steps of the steroid An RCT of a combination of myo-inositol, and 535 who had taken melatonin at a dose 1102
1040 pathway, reporting a gene expression melatonin, vitamin D, a-lactalbumin and of 3
8 mg per day concurrently with 1103
1041 similar to that found in normo-ovulatory folic acid in comparison to the use of folic ovarian stimulation. The meta-analysis of 1104
1042 women undergoing IVF, with a acid alone, with supplementation the primary outcome of the clinical 1105
1043 commensurate improvement in oocyte commenced 3 months prior to oocyte pregnancy rate, with low heterogeneity 1106
1044 maturation, fertilization and embryonic retrieval and continued into pregnancy, between the studies, resulted in an odds 1107
1045 development (Tabatabaie et al., 2022). was associated with improvements in ratio of 1.35 in favour of melatonin 1108
1046 oocyte quality and blastocyst development supplementation; however, this was not 1109
1047 With respect to women with an expected and a significant improvement in clinical statistically significant (95% CI 0.97
1.87; 1110
1048 poor response to ovarian stimulation, pregnancy rates of 42% versus 24% P = 0.07). A similar number of oocytes 1111
1049 preliminary work has suggested that 4 g of (Wdowiak and Filip, 2020). This suggested were collected, although they more were 1112
1050 myo-inositol may have a favourable benefit that a combination of therapies may be mature when melatonin was used (mean 1113
1051 on ovarian stimulation (Caprio et al., 2015). beneficial, although determining the difference of 1.82, 95% CI 0.37
3.27; 1114
1052 More recently, an RCT in Iran by Nazari beneficial supplement or combination of P = 0.01). No difference in embryo quality 1115
1053 and colleagues reported on 112 predicted supplements and the appropriate dosing was reported, although disparate measures 1116
1054 poor responder patients, of whom 56 were regimen will be a challenge for the future. of embryonic assessment were reported in 1117
1055 assigned in a non-blinded manner to 4 g of Furthermore, with the recent publication the various studies (Mejlhede et al., 2021). 1118
1056 myo-inositol and folic acid daily for 1 month of the international PCOS guidelines it is 1119
1057 before starting the ICSI cycle until important to state that, for women with Further evidence reinforcing a potential 1120
1058 triggering of ovulation (Nazari et al., 2020). PCOS, while there are possible benefits to benefit for the use of melatonin was 1121
1059 The control group were provided with only be derived from inositol, the dosing reported in an earlier systematic review of 1122
1060 folic acid, with the primary end-point being regimen is unclear, and it is also unclear 10 RCT for varying clinical indications, with 1123
1061 the number of oocytes retrieved. whether more favourable outcomes may search censoring at the end of 2019, and 1124
 10 RBMO VOLUME 00 ISSUE 00 2023

1125 including one study that added melatonin 1.01
1.76; 12 RCT) (Nagels et al., 2015). receptors are present in most tissues of 1188
1126 to the embryo culture media. This This was superseded by several further the body, and hence it is implicated in a 1189
1127 systematic review demonstrated a meta-analyses. With the inclusion of some diverse number of physiological functions; 1190
1128 significant improvement in the clinical observational data in 2017, the clinical it has also been implicated in the regulation 1191
1129 pregnancy rate (OR 1.43, CI 1.11
1.86; pregnancy rates were increased of up to 200 genes (Nagpal et al., 2005). 1192
1130 P < 0.01) with the use of melatonin, significantly for women with decreased 1193
1131 although no positive influence on the live ovarian reserve who were pre-treated with A low serum vitamin D concentration has 1194
1132 birth rate was reported (Hu et al., 2020). DHEA (OR 1.47, 95% CI 1.09
1.99) (Qin et been implicated in infertility in normal- 1195
1133 al., 2017). However, the most recent meta- weight women (Paffoni et al., 2014), 1196
1134 An interesting report was published by a analysis including just RCT investigating the prompting interest in this form of 1197
1135 Melbourne group (Fernando et al., 2018). use of DHEA for women with a poor supplementation to potentially improve 1198
1136 This studied several different dosing response to ovarian stimulation, with the situation. However, it is unclear if any 1199
1137 regimens of melatonin prescribed to inclusion of studies to September 2021, benefit is to be derived or where it would 1200
1138 women undertaking their first IVF cycle was notably less encouraging of the use of occur (Abedi et al., 2019; Paffoni et al., 1201
1139 and was a pilot study to inform future RCT DHEA, reporting no differences in oocyte 2019). Animal studies suggest that vitamin 1202
1140 planning. Although the use of melatonin yield, metaphase II oocytes collected, D is involved at the endometrial, follicular 1203
1141 compared with placebo did not embryo development (few studies) and and embryonic development level 1204
1142 significantly improve the clinical pregnancy miscarriage, clinical or live birth rates (summarized by Luk et al., 2012 ).XX Q15 1205
1143 rate (OR 1.57, 95% CI 0.59
4.14) the between the DHEA use and control groups Furthermore, vitamin D deficiency has 1206
1144 authors suggested that the power (Neves et al., 2022). been linked to miscarriage (Tamblyn et al., 1207
1145 calculation would require the inclusion of 2022) and women who are vitamin D 1208
1146 approximately 1500 patients to confirm or In addition, to generate further confusion, replete have been reported to have a 1209
1147 refute any potential benefit. This the most recent published meta-analysis, higher likelihood of developing euploid 1210
1148 emphasizes the challenge involved when which includes both prospective and blastocysts (Arnanz et al., 2021), although it 1211
1149 establishing RCT in IVF, particularly if only retrospective studies, demonstrated is unclear whether supplementation will 1212
1150 a clinical benefit is expected. A further significant improvements in all parameters improve IVF outcomes for women who are 1213
1151 conclusion from this study, which including pregnancy rates, apart from the vitamin D deficient or replete (Shen et al., 1214
1152 measured serum and follicular live birth rate (OR 1.35, 95% CI 2019, Somigliana et al., 2021). 1215
1153 concentrations of melatonin, is that the 0.94
1.94), for women prescribed DHEA 1216
1154 dosing regimens employed in some studies (Wang et al., 2023). More oocytes were As serum and follicular concentrations of 1217
1155 may be inadequate, as this study employed collected (weighted mean difference vitamin D have been reported to be 1218
1156 doses of up to 8 mg twice daily. [WMD] 1.09, 95% CI 0.38
1.80), and correlated with each other and with IVF 1219
1157 there were more metaphase II oocytes outcomes (Esencan et al., 2022; Wu et al., 1220
1158 Furthermore, many studies included in the (WMD 0.78, 95% CI 0.16
1.40), fertilized 2018), many studies have focused on 1221
1159 two systematic reviews (Hu et al., 2020; oocytes (WMD 0.84, 95% CI 0.42
1.26) supplementation with vitamin D. A 1222
1160 Mejlhede et al., 2021) only prescribed and top-quality embryos (WMD 0.60, 95% systematic review, published in 2023 with 1223
1161 melatonin concurrent with stimulation, CI 0.34
0.86). Improvements in the inclusion of literature to February 2022, 1224
1162 Q14 and it could be postulated that a benefit clinical pregnancy rate (risk ratio X X[RR] 1.35, reported that being vitamin D deficient, or 1225
1163 may be derived from pre-cycle 95% CI 1.13
1.61) and ongoing pregnancy replete, did not appear to influence IVF 1226
1164 commencement due to the duration of rate (RR 1.82, 95% CI 1.34
2.46) with pregnancy outcomes, nor did 1227
1165 folliculogenesis; large studies on this are DHEA supplementation were shown, while supplementation improve outcomes; 1228
1166 awaited. the live birth rate (RR 1.35, 95% CI however, the possibility exists that the 1229
1167 0.94
1.94) was not significantly different effect of vitamin D supplementation may 1230
1168 DHEA (Wang et al., 2023). vary due to the patient’s ethnicity (Eller et 1231
1169 DHEA is an endogenous androgen al., 2023). Likewise, another systematic 1232
1170 produced by the adrenal gland and the It is important to state that the dosage of review, published at a similar time, 1233
1171 ovary and is a steroid pre-cursor of DHEA and the timing of starting therapy included RCT until August 2021 and 1234
1172 androstenedione, testosterone and are unclear and vary substantially in the focused on women who were vitamin D 1235
1173 ultimately oestradiol (or literature, but DHEA generally deficient; supplementation with vitamin D 1236
1174 dihydrotesterone); it has been used for administered at a dose of 50
90 mg per did not lead to improvements in clinical 1237
1175 many years as a potential treatment for day from 1 to 12 months before pregnancy or any embryological outcome 1238
1176 women with perceived reduced ovarian commencing treatment (Neves et al., (Zhou et al., 2022). Another, earlier, 1239
1177 reserve and poor embryonic development 2022). systematic review, inclusive of data until 1240
1178 (Neves et al., 2022). July 2019, reported that women replete 1241
1179 Vitamin D with vitamin D had higher live birth rates 1242
1180 Historically, the Cochrane review of eight Vitamin D can be made in the skin from than women deficient in vitamin D, 1243
1181 RCT in 2015 studying pre-treatment with exposure to sunlight as well as being although a sensitivity analysis 1244
1182 DHEA in IVF cycles for the main indication ingested; it consists of two forms, D2 and demonstrated non-significant findings on 1245
1183 of poor ovarian response demonstrated D3. Whether derived from the skin or diet closer scrutiny (Cozzolino et al., 2020). 1246
1184 that DHEA use was associated with higher it requires hydroxylation in the liver and 1247
1185 rates of live birth or ongoing pregnancy kidneys to form the biologically active form In interpreting these studies, it is important 1248
1186 (OR 1.81, 95% CI 1.25
2.62; 8 RCT) and of vitamin D, 1,25-dihydroxyvitamin D, for to note that they have been performed in a 1249
1187 clinical pregnancy (OR 1.34, 95% CI its activity (Holick et al., 2011). Vitamin D limited number of countries, with varying 1250
 RBMO VOLUME 00 ISSUE 00 2023 11

1251 dosing regimens of vitamin D and with cell production and B
cell proportions, as to a reduction of the body’s carnitine pool, 1314
1252 varying durations of supplementation, well as an adverse influence on T-helper/T- speculating that patients undergoing 1315
1253 impacting the generalizability of the cytotoxic cellular ratios in women who IVF may benefit from carnitine 1316
1254 conclusions (Zhou et al., 2022). It is were vitamin D deficient, suggestive of a supplementation (V arnagy et al., 2013). An 1317
1255 important to note not only that vitamin D systemic non-ovarian influence (Wu et al., RCT of the use of L-carnitine as an adjunct 1318
1256 concentrations were negatively impacted 2018). to the IVF cycle of women with PCOS led 1319
1257 by adiposity, but that this was exacerbated to higher oestradiol concentrations, but 1320
1258 by bariatric surgery leading to A further registered systematic review of there were no differences in any other 1321
1259 malabsorption, anticonvulsant therapy and the relevance of vitamin D reproductive indices studied (Sheida et al., 1322
1260 poor sunlight exposure (Holick et al., 2011). supplementation for women undergoing 2023).There is evidence from animal 1323
1261 The Endocrine Society defines vitamin D IVF is underway (Morshed-Behbahani et studies for the therapeutic use of carnitine 1324
1262 concentrations as follows (Holick et al., al., 2023), and interested readers are supplementation to improve embryo 1325
1263 2011): deficient, below 50 nmol/l, referred to a detailed description of the development in several species (Dunning 1326
1264 insufficient, 50
75 nmol/l, and sufficient, potential place of vitamin D in et al., 2014), although in humans studies 1327
1265 above 75 nmol/l; it also recommends using reproduction (Esencan et al., 2022). have been mainly focused on the 1328
1266 a reliable serum 25-hydroxyvitamin D management of PCOS and hypothalamic 1329
1267 assay. To demonstrate the difficulty of amenorrhoea (summarized by Agarwal et 1330
1268 ‘unpacking’ the data on nutritional al., 2018). 1331
1269 A systematic review of the literature supplements used in IVF, an interesting 1332
1270 reporting the use of vitamin D Italian pilot RCT of 100 consecutive Chinese herbs 1333
1271 supplementation for women undergoing unselected patients undergoing IVF Many patients will have sought alternative 1334
1272 IVF was performed on the assumption that treatment with a combination of therapies from Chinese herbal medicine 1335
1273 vitamin D insufficiency was associated with supplements has been reported (Bezerra (CHM) to assist them to conceive, and 1336
1274 a poor reproductive outcome (Meng et al., Espinola et al., 2021). Women were many may persist in taking such herbs into 1337
1275 2023). The study included 12 studies (nine randomized to a combination of myo- their IVF cycle; however, few of these 1338
1276 RCT), with data analysed to March 2021. inositol, melatonin, a-lactalbumin and folic interventions have been scrutinized by an 1339
1277 Although live birth rates were not acid, or the same supplements with the RCT, and it is recognized that most studies 1340
1278 reported, an improvement was shown in addition of vitamin D supplementation in in this field have been performed in China 1341
1279 the clinical pregnancy rate of vitamin-D- the luteal phase of the cycle (Bezerra and may require replication in other 1342
1280 insufficient women who received Espinola et al., 2021). Despite the small populations. The principal of CHM 1343
1281 supplementation (OR 1.70, 95% CI numbers of participants in this pilot study employed for fertility treatment is to ‘tonify 1344
1282 1.24
2.34; P = 0.001), with no difference the implantation rate for the group with the kidney’, which has traditionally been 1345
1283 in the rate of miscarriage. When the serum additional vitamin D supplementation was the focus of reproductive medicine theory 1346
1284 concentration of vitamin D before 37.1%, in comparison to 19.2% in the non- in traditional Chinese medicine (Liu et al., 1347
1285 treatment was lower than 75 nmol/ml, the vitamin D supplemented group, again 2021). 1348
1286 clinical pregnancy rate doubled after suggestive of a non-ovarian influence 1349
1287 supplementation in the supplemented (Bezerra Espinola et al., 2021). In one study of 433 women undertaking 1350
1288 group compared with the control group standard IVF treatment for either tubal or 1351
1289 (OR 2.06, 95% CI 1.32
3.22, P = 0.001) L-Carnitine male factor infertility women were 1352
1290 (Meng et al., 2023). The conclusion of this L-Carnitine is an endogenous compound randomly allocated (non-blinded) to 1353
1291 systematic review was that vitamin D consisting of lysine and methionine and is supplementation with Chinese herbs or a 1354
1292 supplementation was encouraged for integral to the process of oxidation of fatty placebo (Guo et al., 2014). While there was 1355
1293 infertile patients with serum vitamin D acids by assisting their transport across the a reported statistically significant 1356
1294 concentrations lower than 75 nmol/l mitochondrial membrane (Mohd Shukri et difference in several parameters the 1357
1295 (30 ng/ml). When the total vitamin D al., 2022). Low serum concentrations are clinical significance of the differences 1358
1296 dosage was too low (lower than 10,000 IU) reported in some women with PCOS, with reported must be considered as the study 1359
1297 or too high (higher than 500,000 IU), no metabolic benefits reportedly derived was not blinded and the regimen of 1360
1298 significant increase in clinical pregnancy from its supplementation (Mohd Shukri et Chinese herbs was very complex (Guo et 1361
1299 rate was found. An improvement in al., 2022); it also possesses antioxidant and al., 2014). The difference in endometrial 1362
1300 reproductive indices was apparent only anti-apoptotic properties (Agarwal et al., thickness was 0.3 mm, the fertilization rate 1363
1301 with daily administration, and it is essential 2018). A build-up of acylcarnitines is was 58.5% versus 54.7%, and the clinical 1364
1302 to monitor for an adequate response, as believed to be a marker of disordered pregnancy rate was 44.2% versus 34.8%, 1365
1303 patients with different genotypes may mitochondrial fatty acid oxidation (Hoppel, all favouring the Chinese herb 1366
1304 respond differently to dosing. 2003). intervention, with no differences in oocytes 1367
1305 collected or live birth rate (Guo et al., 1368
1306 Interestingly, a recent observational study A small study that involved the 2014). 1369
1307 reiterated the previously reported data measurement of serum and follicular fluid 1370
1308 that vitamin D deficiency is associated with carnitine and their metabolites noted that A further study of CHM was performed in 1371
1309 a decreased number of mature oocytes patients who produced more oocytes and women with an expected poor response to 1372
1310 available in an IVF cycle, and a reduced embryos had a relative depletion of serum ovarian stimulation (Song et al., 2021). The 1373
1311 blastocyst formation rate. It also reported and follicular fluid carnitine and acetyl Ding-Kun pill (DKP) is a traditional CHM 1374
1312 peripheral blood cellular immune carnitine, which led the authors to develop with approximately 40 components. A 1375
1313 activation, including increased natural killer the hypothesis that IVF treatment may lead multicentre RCT of DKP use involved 462 1376
 12 RBMO VOLUME 00 ISSUE 00 2023

1377 patients embarking on IVF who were over recommendations being drawn (Abodi et While the previous sections singled out 1440
1378 35 years of age and had a low serum AMH al., 2022). some of the more common individual 1441
1379 or antral follicle count, or an expected supplements used by patients, a Cochrane 1442
1380 poor response to ovarian stimulation; DKP The EARTH prospective cohort study, review of 63 RCT published to the end of 1443
1381 use led to the development of more top- published subsequent to the systematic 2019 (Showell et al., 2020) analysed the 1444
1382 quality blastocysts, but ultimately there review, analysed dietary questionnaire data use of oral antioxidant supplementation as 1445
1383 were no differences in the clinical or from 229 couples prior to IVF treatment a whole in comparison with placebo, no 1446
1384 ongoing pregnancy rates between DKP (Salas-Huetos et al., 2022). It treatment or treatment with another 1447
1385 and placebo (Song et al., 2021) demonstrated a positive association of the antioxidant for women with infertility. 1448
1386 consumption of long-chain omega-3 fatty Studies included treatments with 1449
1387 Furthermore, for women with PCOS a acids, as assessed by a food frequency combinations of antioxidants, N- 1450
1388 meta-analysis of studies using CHM questionnaire and intake of nuts and fish, acetylcysteine, melatonin, L-arginine, myo- 1451
1389 including 10 RCT demonstrated some with live birth, controlling for the inositol, carnitine, selenium, vitamin E, 1452
1390 benefit of the use of CHM with respect to confounding of any influence on semen vitamin B complex, vitamin C, vitamin D 1453
1391 the clinical pregnancy rates of women with parameters. The multivariable-adjusted and calcium, CoQ10 and omega-3- 1454
1392 PCOS undergoing IVF treatment, with a probability of live birth for women in the polyunsaturated fatty acids versus placebo, 1455
1393 reduction in the rate of ovarian lowest quartile of DHA and EPA intake was no treatment/standard treatment or 1456
1394 hyperstimulation syndrome. However, the 0.36 (95% CI 0.26
0.48), in contrast to another antioxidant. The review concluded 1457
1395 CHM used was inconsistent, with a limited the highest quartile (0.54, 95% CI that due to the very low quality of the 1458
1396 overlap between the different constituents 0.42
0.66), and they were negatively evidence it was uncertain whether or not 1459
1397 of the CHM, leading to substantial associated with miscarriage. With respect antioxidants improved the primary 1460
1398 heterogeneity in the analysis, and hence to the type of fish within a diet, intake of outcome of live birth rate compared with 1461
1399 limiting the generalizability of the findings shellfish had the most positive association placebo (OR 1.81, 95% CI 1.36
2.43; 1462
1400 (Liu et al., 2021). with live birth (Salas-Huetos et al., 2022). P < 0.001; 13 RCT, 1227 women). The 1463
1401 secondary outcome of low-quality 1464
1402 evidence also suggested that antioxidants 1465
1403 Omega-3 polyunsaturated fatty acids Antioxidants may improve clinical pregnancy rate 1466
1404 Omega-3 fatty acids are derived from the While not the focus of this review, it is compared with placebo or no treatment/ 1467
1405 dietary intake from foods such as nuts and difficult to separate antioxidant therapies standard treatment (OR 1.65, 95% CI 1468
1406 fish, and are the most studied dietary fatty for IVF from the data presented on 1.43
1.89; P < 0.001; 35 RCT, 5165 1469
1407 acids in the IVF literature, due to their nutritional supplements. Antioxidants are women). In addition, the evidence suggests 1470
1408 perceived potential positive influences on chemicals that reduce oxidative damage to that the use of antioxidants makes no 1471
1409 general health and reproductive outcomes the tissues. Oxidative stress is the difference for the outcome of miscarriage 1472
1410 (Abodi et al., 2022; Stanhiser et al., 2022), imbalance between the creation of and has a low rate of gastrointestinal 1473
1411 with omega-3 supplementation being reactive oxygen species and the body’s disturbances. 1474
1412 associated with a reduction in the time to ability to neutralize the effects of reactive 1475
1413 natural conception if taken on at least 20% oxygen species. When subgroup analyses were performed 1476
1414 of days while trying to conceive (Stanhiser to determine whether there was a specific 1477
1415 et al., 2022). a-Linolenic acid is a short Reactive oxygen species and reactive group of patients who might potentially 1478
1416 chain omega-3 fatty acid, and nitrogen species can damage the oocyte, derive a benefit from the use of an 1479
1417 docosahexaenoic acid (DHA) and disrupt the final stages of oocyte antioxidant, the only specific group who 1480
1418 eicosapentaenoic acid (EPA) are long chain maturation and impair cumulus cell appeared to derive a benefit was women 1481
1419 omega-3 fatty acids. function, an integral part of oocyte with PCOS with respect to the chance of a 1482
1420 metabolism within the cumulus
oocyte live birth, although only one of the three 1483
1421 In a systematic review of the literature of complex (Camp et al., 2023; Mauchart et studies included women undergoing IVF 1484
1422 omega-3 fatty acid intake with the inclusion al., 2023). Furthermore, reactive oxygen treatment. However, when the nine trials 1485
1423 of five studies (3 RCT, with 1 considered of species may wreak more harm during that focused on the use of antioxidants for 1486
1424 moderate quality and 2 observational fertilization and during embryonic women undergoing IVF treatment were 1487
1425 studies) to the end of 2021 (Abodi et al., development, whether derived from the analysed in this review, antioxidants were 1488
1426 2022), all five studies demonstrated that spermatozoa, leukocytes present within not associated with an increase in the 1489
1427 omega-3 FAs may be beneficial in seminal plasma, the method of sperm chance of a live birth compared with taking 1490
1428 improving IVF clinical outcomes, and preparation or the environment within the a placebo supplement or no treatment in 1491
1429 embryo quality evaluated according to laboratory, such as the culture media, the women undergoing IVF/ICSI (OR 1.36, 1492
1430 morphology and morphokinetic oxygen concentration at incubation and 95% CI 0.96
1.93; P = 0.08) (Showell et 1493
1431 parameters; however, no meta-analysis light exposure (Mauchart et al., 2023). For al., 2020). 1494
1432 could be undertaken due to the a detailed review of the impact of oxidative 1495
1433 heterogeneity of the studies (Abodi et al., stress within the IVF laboratory readers are Since the Cochrane review an 1496
1434 2022). Furthermore, the individual studies referred to Agrawal and colleagues observational study of the intervention of B 1497
1435 in the review did not focus on specific (Agarwal et al., 2022). Consequently, it is complex (methyltetrahydrofolate, vitamins 1498
1436 subpopulations of IVF patients, included all believed that as an excess of reactive B12 and B6) for women undergoing IVF, in 1499
1437 ages of patients and were inconsistent in oxygen species is harmful for oocyte comparison to standard folate 1500
1438 terms of dosages of supplements and quality, supplementation may potentially administration, demonstrated significant 1501
1439 dietary assessment, preventing any firm be beneficial. associations with improvements in 1502
 RBMO VOLUME 00 ISSUE 00 2023 13

1503 embryological outcomes and clinical and et al., 2022). Consequently, there is a need demonstrated some significant beneficial 1566
1504 live birth rates (Cirillo et al., 2021). for further studies in this area to clarify associations with embryonic development. 1567
1505 Furthermore, a small pilot randomized both the influence of resveratrol on follicle While these preliminary findings are 1568
1506 study investigating supplementation with development and the endometrium. interesting, and should be further 1569
1507 1200 mg N-acetyl cysteine per day or explored, this study had a relatively short 1570
1508 placebo (38 patients in each arm) was Dietary interventions duration of intervention and both the male 1571
1509 performed in young women undergoing While dietary restriction is not a nutritional and female partners were treated, making 1572
1510 the long protocol IVF treatment; perhaps supplement, it is potentially a nutritionally it difficult to determine where, if any, a 1573
1511 due to the patients included and the deficient state and ketotic state, so calorie potential benefit might originate (Kermack 1574
1512 limited sample size no significant reduction is briefly discussed here. Being et al., 2020). A previous observational 1575
1513 differences were detected in any clinical or overweight or obese significantly reduces study had suggested that adherence to a 1576
1514 embryological outcomes or markers of the success rate of IVF treatment, with Mediterranean diet had favourable 1577
1515 apoptosis in the granulosa cells (Devi et al., respect to the clinical pregnancy and live outcomes with respect to clinical 1578
1516 2020). birth rates, with an increased risk of pregnancy and live birth rates, particularly 1579
1517 miscarriage (Rittenberg et al., 2011). in women under 35 years of age 1580
1518 Resveratrol Consequently, there is a perception that (Karayiannis et al., 2018). 1581
1519 Some interesting data are emerging that weight loss interventions for women trying 1582
1520 resveratrol (a naturally occurring sirtuin to conceive improve natural fecundability, In contrast, considering a ‘Western diet’, 1583
1521 activator), present in grapes, nuts, although the evidence is not strong, and evidence derived from animal research 1584
1522 cranberries and red wine, is believed to systematic reviews report conflicting (Gonnella et al., 2022) suggests that a high- 1585
1523 stimulate mitochondrial numbers in results (RCT to mid-2020) (Boyle et al., fat diet is associated with negative 1586
1524 granulosa cells, and increase energy 2022; Hunter et al., 2021). influences on oocyte maturation and 1587
1525 production, and may lead to follicular development, increasing 1588
1526 improvements in the early stages of The outcome of a systematic review inflammation and oxidative stress markers 1589
1527 embryonic development (Gerli et al., assessing whether a benefit is derived from within the follicle and oocyte, and 1590
1528 2022). weight loss interventions prior to IVF influencing the expression of genes related 1591
1529 treatment is awaited (Evans-Hoeker et al., to follicular maturation and oocyte growth. 1592
1530 A retrospective review of 102 women 2022), as evidence to date from two large It is also associated with aberrant 1593
1531 taking a 200 mg per day resveratrol RCT suggests that there is no increased methylation levels, leading to 1594
1532 supplement matched these participants chance of live birth after lifestyle developmental defects in embryos (for a 1595
1533 with those who were not taking the intervention for obesity (Einarsson et al., review, see Gonnella et al., 2022). 1596
1534 supplement and excluded poor-prognosis 2017; Mutsaerts et al., 2016). The results of 1597
1535 patients. After matching patients by their a recent narrative review of weight loss A systematic review of the literature to 1598
1536 age at the time of oocyte retrieval, embryo prior to IVF treatment, inclusive of data to mid-2021 of the dietary patterns of 1599
1537 grade and stage, the number of embryos 2022 (Hoek et al., 2022), conclude that individuals undergoing IVF treatment, 1600
1538 transferred and whether it was a fresh or while lifestyle intervention leads to an assessed by food frequency questionnaires 1601
1539 frozen cycle, multivariate logistic increase in natural conception compared or dietary recall (Kellow et al., 2022), 1602
1540 regression analysis showed that resveratrol with no intervention, there appears to be reported on 13 studies with a moderate or 1603
1541 supplementation halved the clinical no beneficial effect of lifestyle intervention high risk of bias (12 cohort studies) and in 1604
1542 pregnancy rate and led to a doubling in the for obesity prior to IVF treatment. which 7% of the participants were men. 1605
1543 risk of miscarriage. This preliminary study Furthermore, it states that there is a The authors concluded that while they 1606
1544 would certainly suggest a potential negative paucity of data with respect to the effect of could not determine the diet that was 1607
1545 influence on the endometrium and lifestyle intervention on pregnancy associated with the highest live birth rate in 1608
1546 embryo implantation and is a call for complications for the mother and baby, as conjunction with IVF treatment, they 1609
1547 further investigation (Ochiai et al., 2019). there is the potential that calorie identified four dietary patterns that were 1610
1548 restriction may lead to an increased risk of associated with the best IVF outcomes; a 1611
1549 While it would appear that there may be miscarriage (Legro et al., 2022). ‘pro-fertility diet’, the national Dutch 1612
1550 potential endometrial harm from the use recommended diet, the Mediterranean 1613
1551 of resveratrol, the influence of its use on With respect to the type of diet that a diet and an Iranian traditional medicine 1614
1552 folliculogenesis appears promising. One patient may consume prior to embarking diet. Common features of these diets were 1615
1553 group studied the influence of 150 mg of on IVF treatment, the Mediterranean diet high intakes of fruits and vegetables, with 1616
1554 resveratrol on the expression the micro- (rich in nuts, vegetable oils, vegetables, high intakes of whole grains, legumes, nuts, 1617
1555 RNA profile within follicular fluid in fruits, fish and legumes, with a low dairy fish and monounsaturated or 1618
1556 comparison to a control group (Battaglia intake) appears to be the most beneficial polyunsaturated oils, with a limited intake 1619
1557 et al., 2022). Although the intervention with respect to the chance of pregnancy of highly processed foods. These diets are 1620
1558 study only included six women in each after IVF treatment, and is associated with high in B vitamins, antioxidants, omega-3 1621
1559 arm, micro-RNA functional enrichment higher follicular concentrations of vitamin polyunsaturated fatty acids and fibre, and 1622
1560 pathway analysis demonstrated significant B6 and folate (Vujkovic et al., 2010). A are low in saturated fat, sugar and sodium. 1623
1561 improvements in gene pathways double blind RCT consisting of a 6-week Due to some contradictory data the 1624
1562 associated with follicle development and Mediterranean dietary intervention (a daily authors encouraged an exploration of the 1625
1563 fertility, with an increase in the percentage supplement drink enriched with omega-3 potential impact of high-pesticide fruit and 1626
1564 of mature oocytes collected for those fatty acids and vitamin D plus additional vegetable intake on clinical fertility 1627
1565 women taking the supplement (Battaglia olive oil and olive oil-based spread) outcomes, which will detract from any 1628
 14 RBMO VOLUME 00 ISSUE 00 2023

1629 benefits derived. Consequently, one fatty acids may lead to improvements in REFERENCES 1692
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Effect of Vitamin D Supplementation on
1632 although avoiding a high-fat diet rich in studies are required to clarify any potential Intracytoplasmic Sperm Injection Outcomes: A
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1634 common positive theme to be early data on the use of resveratrol in Trial. Int J Fertil Steril 13, 18–23. 1697
1635 encouraged. folliculogenesis and in the setting of poor Abodi, M., De Cosmi, V., PARAZZINI, F., 1698
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1638 CONCLUSIONS resveratrol appears to have a detrimental systematic review. European journal of obstetrics 1701
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1640 In trying to draw conclusions from the 105. 1703
1641 literature to facilitate moving forward with Agarwal, A., Maldonado Rosas, I., 1704
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1642 possible therapeutic strategies to assist DATA AVAILABILITY Munoz, L.V., Finelli, R., Durairajanayagam, D.,
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1643 women undertaking IVF treatment, one Henkel, R., Saleh, R., 2022. Oxidative Stress and 1706
1644 relatively straightforward approach would Data will be made available on request. Assisted Reproduction: A Comprehensive 1707
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1649 elucidation of the underlying cause of the R.J.H. is very grateful to Helen Adams of Reproductive biology and endocrinology 16, 1712
1650 difficulty in conceiving. For instance, if a the King Edward Memorial Hospital Library 5-5. 1713
1651 poor ovarian response to treatment is the for undertaking the literature search. Arnanz, A., De Munck, N., El Khatib, I., Bayram, A., 1714
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1664 (Zhang et al., 2020). Furthermore, the use Chong, J, Wong, E, Yavorska, T, Naranian, T, 1727
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1674 benefit to the use of myo-inositol; Bentov, Y., Hannam, T., Jurisicova, A., Esfandiari, N., 1737
1675 however, the appropriate dose is not clear, Casper, R.F., 2014. Coenzyme Q10 1738
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