Your Fertility Pharmacist

Resources Deeks J. When can odds ratios mislead? Odds ratios should be used only in case-control studies and logistic regression analyses. BMJ. 1998;317(7166):1155-1157. doi:10.1136/bmj.317.7166.1155a Miranda ML, Edwards SE, Myers ER. Adverse birth outcomes among nulliparous vs. multiparous women. Public Health Rep. 2011;126(6):797-805. doi:10.1177/003335491112600605 Riwa S, Alison M, Ann K, et al. Pregnancy outcomes with increasing maternal age, greater than 40 years, in donor oocyte cycles. Hum Reprod. Published online March 20, 2025. doi:10.1093/humrep/deaf044

Resources Alemu BK, Wang CC, Li L, Zhu Z, Li Q, Wang Y. Effect of preconception antibiotics exposure on female reproductive health and pregnancy outcomes: a systematic review and meta-analysis. EClinicalMedicine. 2024;78:102935. Published 2024 Nov 22. doi:10.1016/j.eclinm.2024.102935 Shao S, Pan W, Wang B, et al. Association between antibiotic exposure and the risk of infertility in women of childbearing age: A case-control study. Ecotoxicol Environ Saf. 2023;249:114414. doi:10.1016/j.ecoenv.2022.114414 Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, Moher D, Becker BJ, Sipe TA,Thacker SB. Meta-analysis of observational studies in epidemiology: a proposal for reporting. JAMA 2000;283:2008-12.

Resources Racicot K, Sakkas D, Barrett B, Chiang K, Jenkins C, Validation of a mailin delayed semen analysis protocol developed for home collection, F&S Reports (2024), doi: https:// doi.org/10.1016/j.xfre.2024.10.005. ReproSource

This study compared efficacy of two r-FSH medications: follitropin alpha (Gonal-F) vs. follitropin beta (Puregon) on the number of live births cumulatively (CLBR). This was looking at patients 21-45yrs doing fresh embryo transfer after their first IVF or ICSI cycle. Resources Cao JX, Song JY. Follitropin Alpha versus Follitropin Beta in IVF/ICSI Cycle: A Retrospective Cohort Study. Drug Des Devel Ther. 2024;18:4359-4369. Published 2024 Sep 26. doi:10.2147/DDDT.S479700 Van den Haute L, Drakopoulos P, Verheyen G, De Vos M, Tournaye H, Blockeel C. Follitropin alpha versus beta in a first GnRH antagonist ICSI cycle: a retrospective cohort study. Reprod Biomed Online. 2021;43(4):655-662. doi:10.1016/j.rbmo.2021.06.014

New format with shorter episodes! A quick discussion on a survey sent to parents who conceived via IVF after preimplantation genetic testing (PGT).

The most rigorously designed trial of intraovarian PRP (to date) demonstrated no improvements in # of mature oocytes obtained or # of live births versus placebo. Study BackgroundWHAT Comparison of intraovarian platelet-rich plasma (PRP) to placebo for improving the number of mature oocytes (MII) obtained after controlled ovarian stimulation in women with a history of poor ovarian response (POR) with in-vitro fertilization (IVF) WHY Low and modest quality research has shown promising results with PRP for POR High-quality study is needed to investigate PRP’s impact for POR with IVF WHERE/WHEN Two academically affiliated reproductive centers (one in the USA and one in Turkey) January 2020 - November 2022 WHO Inclusion Criteria: females ages 18-37 with POR defined as at least two IVF cycles cancelled due to poor follicle growth or just 0-2 follicles developing despite max FSH daily injections or 0-3 mature oocytes retrieved male partner must have 100k or greater total motile sperm count Female Exclusion Criteria: BMI >35 kg/m2, surgically obtained sperm, or continued use of adjuncts that could result in improved ovarian response to treatment (specified CoQ10, DHEA, but presumably others per clinician’s discretion) for additional exclusion criteria, see p 2 within article HOW Randomized at each site in 1:1 ratio via computer-generated block schema to PRP or no injection (control) Unblinded: patients + physicians performing PRP administration Blinded: physicians performing oocyte retrievals + physicians performing ultrasounds for antral follicle count (AFC) + all involved embryologists Statistics (Briefly)Used intention-to-treat analysis (ITT); tests varied by normality of distibution of variables Primary outcome = 0 for randomized patients who withdrew from study, who lacked mature oocytes, or had cycles cancelled ResultsCharacteristics: 224 screened —> 112 eligible —> 87 enrolled —> 83 randomized into the two groups —> 76 proceeded with oocyte retrieval (PRP = 39, control = 37) Efficacy: no improvements found in markers of ovarian reserve (AMH, AFC), # mature oocytes retrieved, # blastocysts formed, or implantation rates with PRP vs. control Safety: no women experienced infections or hematomas with the PRP injection, though most of them were in mild discomfort for three days after getting PRP Authors’ Thoughts & ConclusionsIncreased rigor of this study design (inclusion of control group + randomization) may explain results that differ from previous PRP studies Additional strengths were validated PGT-A platform, strong patient adherence/retention, and stringent inclusion criteria Study limitations were PRP prep is not necessarily universally generalizable (though used commercially available product), PRP composition was not analyzed, randomization method might have been predictable, and results not generalizable beyond POR PRP will not improve IVF results in POR Conclusions This is the highest-quality PRP trial conducted thus far, which randomized, blinded, and compared PRP injections to no injections in infertile women with poor ovarian response. Results showed that PRP does not improve fertility markers nor outcomes compared to not giving the PRP. Future studies should be conducted with similar methodology (but recruiting additional participants at more study sites) to confirm results, especially since the results from this study conflict with previous, albeit lower-quality studies. Resources Cakiroglu Y, Yuceturk A, Karaosmanoglu O, et al. Ovarian reserve parameters and IVF outcomes in 510 women with poor ovarian response (POR) treated with intraovarian injection of autologous platelet rich plasma (PRP). Aging (Albany NY). 2022;14(6):2513-2523. doi:10.18632/aging.203972 Herlihy NS, Cakiroglu Y, Whitehead C, et al. Effect of intraovarian platelet-rich plasma injection on IVF outcomes in women with poor ovarian response: the PROVA randomized controlled trial. Hum Reprod. Published online May 9, 2024. doi:10.1093/humrep/deae093 Food and Drug Administration. BK210591 - Platelet-Rich Plasma (PRP) Procedure Pack. Accessed September 7, 2024. BK210591 - Platelet-Rich Plasma (PRP) Procedure Pack | FDA

Resources Bronson R. and Kruljac I, Butorac D, Vrkljan M. and Legro RS, Zhang H; Eunice Kennedy Shriver NICHD Reproductive Medicine Network. Letrozole or clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med. 2014;371(15):1463-1464. doi:10.1056/NEJMc1409550 Centers for Disease Control and Prevention. PCOS (Polycystic Ovary Syndrome) and Diabetes. https://www.cdc.gov/diabetes/basics/pcos.html. Accessed April 21, 2024. Franik S, Kremer JA, Nelen WL, Farquhar C. Aromatase inhibitors for subfertile women with polycystic ovary syndrome. Cochrane Database Syst Rev. 2014;(2):CD010287. Published 2014 Feb 24. doi:10.1002/14651858.CD010287.pub2 Franik S, Le QK, Kremer JA, Kiesel L, Farquhar C. Aromatase inhibitors (letrozole) for ovulation induction in infertile women with polycystic ovary syndrome. Cochrane Database Syst Rev. 2022;9(9):CD010287. Published 2022 Sep 27. doi:10.1002/14651858.CD010287.pub4 Legro RS, Brzyski RG, Diamond MP, et al. Letrozole versus clomiphene for infertility in the polycystic ovary syndrome [published correction appears in N Engl J Med. 2014 Oct 9;317(15):1465]. N Engl J Med. 2014;371(2):119-129. doi:10.1056/NEJMoa1313517 Legro RS, Diamond MP, Coutifaris C, et al. Pregnancy registry: three-year follow-up of children conceived from letrozole, clomiphene, or gonadotropins. Fertil Steril. 2020;113(5):1005-1013. doi:10.1016/j.fertnstert.2019.12.023 Palomba S, Santagni S, Falbo A, La Sala GB. Complications and challenges associated with polycystic ovary syndrome: current perspectives. Int J Womens Health. 2015;7:745-763 https://doi.org/10.2147/IJWH.S70314 World Health Organization. Polycystic Ovary Syndrome. World Health Organization; 2023. Accessed April 21, 2024. https://www.who.int/news-room/fact-sheets/detail/polycystic-ovary-syndrome Zhang H. Pregnancy in Polycystic Ovary Syndrome II (PPCOSII). ClinicalTrials.gov identifier: NCT00719186 . Updated June 14, 2018. Accessed April 20, 2020. https://classic.clinicaltrials.gov/ct2/show/NCT00719186

A new study examined associations between pregnancy and miscarriage rates and infection with COVID-19, looking at the first ten weeks after fresh embryo transfer.

Resources Giagulli VA, Carbone MD, Ramunni MI, et al. Adding liraglutide to lifestyle changes, metformin and testosterone therapy boosts erectile function in diabetic obese men with overt hypogonadism. Andrology. 2015;3(6):1094-1103. doi:10.1111/andr.12099 Jensterle M, Podbregar A, Goricar K, Gregoric N, Janez A. Effects of liraglutide on obesity-associated functional hypogonadism in men. Endocr Connect. 2019;8(3):195-202. doi:10.1530/EC-18-0514 Latif W, Lambrinos KJ, Rodriguez R. Compare and Contrast the Glucagon-Like Peptide-1 Receptor Agonists (GLP1RAs). In: StatPearls. Treasure Island (FL): StatPearls Publishing; March 27, 2023. La Vignera S, Condorelli RA, Calogero AE, Cannarella R, Aversa A. Sexual and Reproductive Outcomes in Obese Fertile Men with Functional Hypogonadism after Treatment with Liraglutide: Preliminary Results. J Clin Med. 2023;12(2):672. Published 2023 Jan 14. doi:10.3390/jcm12020672 Papadakis G. Sex Steroids Balance for Metabolic and Reproductive Health in Klinefelter Syndrome (KLIN-HEALTH). ClinicalTrials.gov identifier: NCT05586802. Updated April 4, 2023. Accessed September 27, 2023. https://www.clinicaltrials.gov/ct2/show/NCT05586802

Resources Boniface C, Schnorr JN, Gray J, et al. The role of elagolix in the suppression of ovulation in donor oocyte cycles. F S Rep. 2023;4(2):179-182. Published 2023 Mar 25. doi:10.1016/j.xfre.2023.03.006 Check JH, Brasile D, Choe JK, Amui J, Wilson C. The effect of cetrorelix vs. ganirelix on pregnancy outcome using minimal gonadotropin stimulation in women with elevated day 3 serum follicle stimulating hormone levels. Clin Exp Obstet Gynecol. 2009;36(3):148-149. Fyremadel [package insert]. Parsippany, NJ: Ferring Pharmaceuticals, Inc.; 2022. manufactured by Sun Pharma (India) Kay, C. Contaminated Drugs, Shredded Papers: US FDA Uncovers Failures in India Pharma Factories. May 31, 2013. Accessed July 11, 2023. https://www.bloomberg.com/news/articles/2023-05-31/us-finds-contaminated-drugs-further-lapses-in-india-pharma-factories-post-covid#xj4y7vzkg Keenan, J. Sun Pharma pauses US drug exports from India plant after FDA scolding. April 27, 2023. Accessed July 10, 2023. https://www.fiercepharma.com/manufacturing/sun-pharma-hits-pause-mohali-plant-response-fda-letter/ Orilissa [package insert]. North Chicago, IL: Abbvie; 2021. Zhang J, Zhou X, Chen Y, et al. Nan Fang Yi Ke Da Xue Xue Bao. 2019;39(10):1207-1212. doi:10.12122/j.issn.1673-4254.2019.10.12

Resources Borgert BJ, Bacchus MW, Hernandez AD, Potts SN, Campbell KJ. The availability of gonadotropin therapy from FDA-approved pharmacies for men with hypogonadism and infertility. Sex Med. 2023;11(2):qfad004. Published 2023 Apr 10. doi:10.1093/sexmed/qfad004 Kumar TR. Rerouting of follicle-stimulating hormone secretion and gonadal function. Fertil Steril. 2023;119(2):180-183. doi:10.1016/j.fertnstert.2022.12.005 Luu TH, Kuhn K, Bradford AP, Wempe MF, Wittenburg L, Johnson RL, Carlson NE, Kumar TR, Polotsky AJ, Effects of Pulsatile IV FSH Treatment on Ovarian Function in Women with Obesity, Fertility and Sterility (2023), doi: https://doi.org/10.1016/j.fertnstert.2023.05.170 University of Colorado, Denver. Dysregulation of FSH in Obesity: Functional and Statistical Analysis. ClinicalTrials.gov identifier: NCT02478775. Updated April 7, 2022. Accessed June 12, 2023. https://clinicaltrials.gov/ct2/show/NCT02478775

New study on combining low-dose dexamethasone with letrozole in women with PCOS who failed to ovulate with letrozole alone. This study looked at ovulation, pregnancy, and live birth rates and took place at the Mayo Clinic from 2019 to 2022. Resources Barbieri RL and Ehrmann DA. Diagnosis of polycystic ovary syndrome in adults. In: Post T, ed. UpToDate. Waltham, Mass.: UpToDate; 2034. www.uptodate.com. Accessed May 20, 2023. Legro RS, Brzyski RG, Diamond MP, et al. Letrozole versus clomiphene for infertility in the polycystic ovary syndrome [published correction appears in N Engl J Med. 2014 Oct 9;317(15):1465]. N Engl J Med. 2014;371(2):119-129. doi:10.1056/NEJMoa1313517 Neblett MF 2nd, Baumgarten SC, Babayev SN, Shenoy CC. Ovulation induction with letrozole and dexamethasone in infertile patients with letrozole-resistant polycystic ovary syndrome [published online ahead of print, 2023 May 2]. J Assist Reprod Genet. 2023;10.1007/s10815-023-02817-9. doi:10.1007/s10815-023-02817-9

Women report their use of herbs and supplements to a fertility clinic that assesses their herb-drug interactions. Resources Friedman J, Sheeder J, Lazorwitz A, Polotsky AJ. Herbal supplement use among reproductive-aged women in an academic infertility practice. F S Rep. 2022;4(1):104-111. Published 2022 Dec 17. doi:10.1016/j.xfre.2022.12.001 Natural Medicines Database Checker. Therapeutic Research Center. Updated 2023. Accessed April 26, 2023. https://naturalmedicines.therapeuticresearch.com

Bordewijk EM, Li W, Gurrin LC, Thornton JG, van Wely M, Mol BW. An investigation of seven other publications by the first author of a retracted paper due to doubts about data integrity. Eur J Obstet Gynecol Reprod Biol. 2021;261:236-241. doi:10.1016/j.ejogrb.2021.04.018 Carmichael SL, Shaw GM, Laurent C, Croughan MS, Olney RS, Lammer EJ. Maternal progestin intake and risk of hypospadias. Arch Pediatr Adolesc Med. 2005 Oct;159(10):957-62. doi: 10.1001/archpedi.159.10.957. PMID: 16203941. Casarramona G, Lalmahomed T, Lemmen C, et al. The efficacy and safety of luteal phase support with progesterone following ovarian stimulation and intrauterine insemination: A systematic review and meta-analysis. Front Endocrinol (Lausanne). 2022;13:960393. Published 2022 Sep 2. doi:10.3389/fendo.2022.960393 Coomarasamy A, Devall AJ, Cheed V, et al. A Randomized Trial of Progesterone in Women with Bleeding in Early Pregnancy. N Engl J Med. 2019;380(19):1815-1824. doi:10.1056/NEJMoa1813730. Devall AJ, Papadopoulou A, Podesek M, et al. Progestogens for preventing miscarriage: a network meta-analysis. Cochrane Database Syst Rev. 2021;4(4):CD013792. Published 2021 Apr 19. doi:10.1002/14651858.CD013792.pub2 McLindon LA, James G, Beckmann MM, et al. Progesterone for women with threatened miscarriage (STOP trial): a placebo-controlled randomized clinical trial [published online ahead of print, 2023 Feb 20]. Hum Reprod. 2023;dead029. doi:10.1093/humrep/dead029 Meurer WJ, Tolles J. Interim Analyses During Group Sequential Clinical Trials. JAMA. 2021;326(15):1524-1525. doi:10.1001/jama.2021.10174 Oripro (progesterone pessary used in clinical trial) accessible at https://www.healthdirect.gov.au/medicines/brand/amt,124041000036109/oripro Şükür YE, Göç G, Köse O, et al. The effects of subchorionic hematoma on pregnancy outcome in patients with threatened abortion. J Turk Ger Gynecol Assoc. 2014;15(4):239-242. Published 2014 Dec 1. doi:10.5152/jtgga.2014.14170 Yan X, Xu H, Li J, Xu Z, Niu Y, Wang Y. Subchorionic hematoma and risk of preterm delivery: a systematic review and meta-analysis. Am J Obstet Gynecol MFM. 2023;5(1):100791. doi:10.1016/j.ajogmf.2022.100791

This is the first meta-analysis published in seven years to examine dose-response associations between caffeine or coffee consumption and pregnancy loss. Study BackgroundWHAT Is there a dose-response relationship between caffeine (including coffee) and pregnancy loss? WHY To update and expand upon existing research that examines the associations between caffeine, coffee, and miscarriage risks HOW “new one-stage random effect dose-response analytic approach” Utilized PRISMA and MOOSE guidelines for overall approach - see Supplementary Index Searched Medline/Pubmed, Scopus, and ISI Web of Knowledge Included observational studies published through May 2022 Search terms noted in Supplementary Index Evaluated evidence quality using GRADE approach Did NOT limit studies based on publication language Study selection, data extraction, and risk of bias discussed further in study here Studies included: cohort or case-control studies of pregnant women with dietary caffeine or coffee intake, with outcomes of pregnancy loss (PL), miscarriage, or stillbirth Statistics Measured Odds Ratio (OR) in case-control studies and Relative Risk (RR) in cohort studies* *OR and RR were considered practically equal in cohort studies due to low incidence of PL Subgroup analyses controlled for BMI, smoking, alcohol, race, employment, education, and vitamin supplements Additional details found on pages 3-4 of meta-analysis Results 2253 records originally identified —> excluded all but 46 publications due to irrelevance, duplications, and not meeting inclusion criteria —> excluded all but 34 studies (18 cohort, 16 case-control) after a full review 7 included coffee consumption effect sizes; 25 included caffeine intake effect sizes; 2 included coffee AND caffeine intake effect sizes; 6 included prenatal coffee consumption; 10 included prenatal caffeine consumption; 12 included perinatal coffee consumption; 24 reported perinatal caffeine consumption 12 US studies (31, 544 participants) and 22 non-US studies (261,251 participants) 26 studies used dietary records or recall, 8 used food frequency questionnaire Variable control of risk factors based on study 27/34 studies had a serious risk of bias; 7/34 showed moderate risk of bias GRADE assessments: low for prenatal coffee and caffeine intake; moderate for perinatal coffee intake; very low for perinatal caffeine intake Resources Blehar MC, Spong C, Grady C, Goldkind SF, Sahin L, Clayton JA. Enrolling pregnant women: issues in clinical research. Womens Health Issues. 2013;23(1):e39-e45. doi:10.1016/j.whi.2012.10.003 Jafari A, Naghshi S, Shahinfar H, et al. Relationship between maternal caffeine and coffee intake and pregnancy loss: A grading of recommendations assessment, development, and evaluation-assessed, dose-response meta-analysis of observational studies. Front Nutr. 2022;9:886224. Published 2022 Aug 9. doi:10.3389/fnut.2022.886224 New World Encyclopedia contributors, "Caffeine," New World Encyclopedia, , https://www.newworldencyclopedia.org/p/index.php?title=Caffeine&oldid=794371 (accessed November 27, 2022). Sasaki S, Limpar M, Sata F, Kobayashi S, Kishi R. Interaction between maternal caffeine intake during pregnancy and CYP1A2 C164A polymorphism affects infant birth size in the Hokkaido study. Pediatr Res. 2017;82(1):19-28. doi:10.1038/pr.2017.70 White JR Jr, Padowski JM, Zhong Y, et al. Pharmacokinetic analysis and comparison of caffeine administered rapidly or slowly in coffee chilled or hot versus chilled energy drink in healthy young adults. Clin Toxicol (Phila). 2016;54(4):308-312. doi:10.3109/15563650.2016.1146740 Yang A, Palmer AA, de Wit H. Genetics of caffeine consumption and responses to caffeine. Psychopharmacology (Berl). 2010;211(3):245-257. doi:10.1007/s00213-010-1900-1

This is the first study to test the use of vaginal tadalafil on endometrial thickness and pregnancies in women using IVF to conceive.

A recent randomized controlled trial compares ovarian stimulation protocols for freezing oocytes or embryos used in women diagnosed with breast cancer.

Links and study details can be found at www.yourfertilitypharmacist.com

This episode covers several studies, with summary tables and relevant resources provided below. Table Summary on Studies of Patients Doing IVF, ICSI and/or Frozen Embryo Transfer While Actively Testing Positive for COVID-19 Table Summary on Studies of Patients doing IVF and/or Embryo Transfer After Recently Testing Positive for COVID-19 Resources Actively Testing COVID+ Boudry L, Essahib W, Mateizel I, et al. Undetectable viral RNA in follicular fluid, cumulus cells, and endometrial tissue samples in SARS-CoV-2-positive women. Fertil Steril. 2022;117(4):771-780. doi:10.1016/j.fertnstert.2021.12.032 Clain E, Johnson J, Roeca C. Triggered with COVID: What are my chances, Doc?. Fertil Steril. 2022;117(4):781-782. doi.org/10.1016/j.fertnstert.2022.01.039 Demirel C, Tulek F, Celik HG, Donmez E, Tuysuz G, Gökcan B. Failure to Detect Viral RNA in Follicular Fluid Aspirates from a SARS-CoV-2-Positive Woman. Reprod Sci. 2021;28(8):2144-2146. doi:10.1007/s43032-021-00502-9 Kteily K, Pening D, Diaz Vidal P, et al. Risk of contamination of semen, vaginal secretions, follicular fluid and ovarian medulla with SARS-CoV-2 in patients undergoing ART. Hum Reprod. 2022;37(2):235-241. doi:10.1093/humrep/deab255 Recently Tested COVID+ Aizer A, Noach-Hirsh M, Dratviman-Storobinsky O, et al. The effect of coronavirus disease 2019 immunity on frozen-thawed embryo transfer cycles outcome. Fertil Steril. 2022;117(5):974-979. doi:10.1016/j.fertnstert.2022.01.009 Herrero Y, Pascuali N, Velázquez C, et al. SARS-CoV-2 infection negatively affects ovarian function in ART patients. Biochim Biophys Acta Mol Basis Dis. 2022;1868(1):166295. doi:10.1016/j.bbadis.2021.166295 Orvieto R, Segev-Zahav A, Aizer A. Does COVID-19 infection influence patients' performance during IVF-ET cycle?: an observational study. Gynecol Endocrinol. 2021;37(10):895-897. doi:10.1080/09513590.2021.1918080 Wang M, Yang Q, Ren X, et al. Investigating the impact of asymptomatic or mild SARS-CoV-2 infection on female fertility and in vitro fertilization outcomes: A retrospective cohort study. EClinicalMedicine. 2021;38:101013. doi:10.1016/j.eclinm.2021.101013 Yossef KB, Bentov Y, Gil M, et al. IVF and Early Pregnancy Outcome in Recent COVID 19 Recoverees., 30 November 2021, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-1055952/v1] preprint, not peer-reviewed Youngster M, Avraham S, Yaakov O, et al. The impact of past COVID-19 infection on pregnancy rates in frozen embryo transfer cycles [published online ahead of print, 2022 May 7]. J Assist Reprod Genet. 2022;1-6. doi:10.1007/s10815-022-02517-w