Your Fertility Pharmacist

This is a large-scale international collaboration that examined evidence associating infertility, miscarriage, and stillbirth with stroke risks.

Study Background

WHAT

• What are the associations of infertility, recurrent miscarriage, and stillbirth with risks of stroke?

WHY

• Previous research into this topic yielded scant and/or inconclusive evidence

• Common cause of morbidity and mortality in women worldwide

WHERE

• Australia, China, Japan, Netherlands, Sweden, the United Kingdom, and the United States (pooled databases through InterLACE consortium)

WHEN

• Studies started 1989-2010

WHO

• Included women with data on infertility, miscarriage, OR stillbirth AND data on race/ethnicity, body mass index (BMI), smoking history, educational history, and hypertension status

• Excluded women who had non-fatal stroke before age 40

HOW

• Procured reproductive history through baseline and/or follow-up questionnaires

• Reproductive questions were based on standardized definitions

  • infertility: twelve months or more of unsuccessfully trying to conceive, doctor diagnosis, or received infertility treatment

  • recurrent miscarriages: three more more miscarriages

  • recurrent stillbirths: two or more stillbirths (subsequent or interspersed with live birth)

• Stroke data derived from hospital data and/or self-reported questionnaires

  • Linked hospital data came from Australia, Netherlands, UK BioBank, and Sweden

  • Fatal stroke data came through death registries in Australia, China, Netherlands, Japan, and UK Biobank

  • Sub-typed strokes as hemorrhagic or ischemic; all non-fatal strokes that were unclassified were called “unspecified stroke”

• Collected baseline covariates

  • Asian women had different BMI scale: underweight (<18.5), normal (18.5-22.9), overweight (23-27.4), and obese (≥27.5)

  • race/ethnicity defined as white, Asian or “others”

  Statistics

• Included Kaplan-Meier survival curves, Cox proportional hazards tested with Schoenfeld residuals, Fine-Gray sub-distribution hazards using SAS

• Survival time models adjusted for history of use of oral contraceptive pill (OCP) or hormone replacement therapy (HRT)

  • this data not available from China or Japan

  • led to significant exclusions in both fatal and non-fatal assessments of association

• See page 3 of study for additional details

  Results

• 618, 851 women included

  • data on non-fatal + fatal stroke = 275,863

  • data on non-fatal stroke only = 54,716

  • data on fatal stroke only = 288,272

• Compared to women without infertility, miscarriages, or stillbirth,

  • Women with infertility had higher risks of non-fatal stroke

  • Women with miscarriages had:

    • higher risks of fatal and non-fatal stroke

    • risks increased with increasing # of miscarriages

  • Women with stillbirths had:

    • higher risks of fatal and non-fatal stroke

    • risks increased with increasing # stillbirths

• Insufficient outcomes

  • association of infertility with fatal stroke

  • unspecified fatal stroke with miscarriage or with stillbirth

Authors’ Conclusions

Recurrent miscarriages or stillbirths are a risk factor for strokes in women.

Resources

Hure AJ, Chojenta CL, Powers JR, Byles JE, Loxton D. Validity and reliability of stillbirth data using linked self-reported and administrative datasets. J Epidemiol. 2015;25(1):30-37. doi:10.2188/jea.JE20140032

International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events. https://public-health.uq.edu.au/interlace InterLACE website

Liang C, Chung HF, Dobson AJ, et al. Infertility, recurrent pregnancy loss, and risk of stroke: pooled analysis of individual patient data of 618 851 women. BMJ. 2022;377:e070603. Published 2022 Jun 22. doi:10.1136/bmj-2022-070603

Mishra GD, Anderson D, Schoenaker DA, et al. InterLACE: A New International Collaboration for a Life Course Approach to Women's Reproductive Health and Chronic Disease Events. Maturitas. 2013;74(3):235-240. doi:10.1016/j.maturitas.2012.12.011

OHSU Brain Institute. Understanding Stroke. Accessed June 28th, 2022. https://www.ohsu.edu/brain-institute/understanding-stroke

Resources

CDC-State-Specific Assisted Reproductive Technology Surveillance. https://www.cdc.gov/art/state-specific-surveillance/index.html Accessed May 20, 2022.

Herbenick D, van Anders SM, Brotto LA, Chivers ML, Jawed-Wessel S, Galarza J. Sexual Harassment in the Field of Sexuality Research. Arch Sex Behav. 2019;48(4):997-1006. doi:10.1007/s10508-019-1405-x brilliant paper!

Horvath K. Does Bragdon v. Abbott Provide the Missing Link for Infertile Couples Seeking Protection under the ADA?, 2 DePaul J Health Care L. 1999; 819 https://via.library.depaul.edu/jhcl/vol2/iss4/4 Accessed May 20, 2022. Legal background for asserting workplace protection during infertility treatments.

Ikemoto Y, Kuroda K, Endo M, et al. Analysis of severe psychological stressors in women during fertility treatment: Japan-Female Employment and Mental health in Assisted reproductive technology (J-FEMA) study. Arch Gynecol Obstet. 2021;304(1):253-261. doi:10.1007/s00404-020-05923-6

Imai Y, Endo M, Kuroda K, et al. Risk factors for resignation from work after starting infertility treatment among Japanese women: Japan-Female Employment and Mental health in Assisted reproductive technology (J-FEMA) study [published online ahead of print, 2020 Dec 3]. Occup Environ Med. 2020;78(6):426-432. doi:10.1136/oemed-2020-106745

Spiggle T. Workplace Rights for Those Suffering From Infertility. Law blog published May 2015. https://spigglelaw.com/workplace-rights-for-those-suffering-from-infertility/#:~:text=According%20to%20the%20United%20States,the%20employer%20violated%20the%20ADA. Accessed May 20, 2022. Law blog summarizing legal protections for infertility care.

Volk H, Hadler M. Work Orientations and Perceived Working Conditions across Countries: Results from the 2015 ISSP Survey. International Journal of Sociology. 2018; 48:2, 103-123, DOI: 10.1080/00207659.2018.1446116

Ueda Y, Endo M, Kuroda K, et al. Risk factors for infertility treatment-associated harassment among working women: a Japan-Female Employment and Mental health in assisted reproductive technology (J-FEMA) study [published online ahead of print, 2022 May 13]. Int Arch Occup Environ Health. 2022;10.1007/s00420-022-01872-6. doi:10.1007/s00420-022-01872-6

This study adds letrozole to hormonal therapy before frozen embryo transfer (FET).

Study Background

WHAT

• Does adding letrozole for five days onto estrogen-progesterone protocols for FET improve rates of pregnancy?

WHY

• Increasing studies show that letrozole can benefit embryo implantation

• Lack of research adding letrozole to hormone treatment shortly before embryo implantation = interest in impact on ongoing rate of pregnancy

WHERE

• Obstetrics and Gynecology Department, Zagazig University, Cairo, Egypt

WHEN

• August 2020- February 2021

WHO

• Women ages 18-37

• One good-quality blastocyst (day 5) available for transfer

• Endometrial lining at least 9 mm after supplemental estrogen

HOW

• Oral estradiol valerate (2 mg three times daily) started on Day 2 or 3 targeting endometrial thickness of 9 mm or greater

• Once desired thickness reached, randomization by sealed envelope method* in 1:1 ratio into two groups

  • Letrozole Group = added on five days of oral letrozole (2.5 mg twice daily) to oral estrogen before starting intramuscular progesterone in oil (100 mg daily)

  • Control Group = oral estrogen, no letrozole, then addition of intramuscular progesterone

    *Uninvolved assistant determined randomization, patient selected envelope

• Frozen embryos warmed and transferred on progesterone day 6

• Post-embryo transfer, added daily progesterone (100 mg intramuscular once daily + oral 100 mg three times daily) and continued estradiol

• If clinically pregnant, started vaginal progesterone at 100 mg three times daily, continued oral estrogen and progesterone, and decreased intramuscular progesterone to every third day.

• Stopped supplemental estrogen and progesterone at 10 and 12 weeks gestation, respectively

• Ongoing pregnancy: fetal cardiac pulsation at 12+ weeks gestation

Statistics (for the Uber Curious)

Sample size N= 56 women per group calculated from:

• Needed 54 women per group for Chi-square test for independent samples; alpha error 0.05, power of 80%

• Pilot study of 25 women showing ongoing pregnancy of 80% (letrozole) vs. 55% (control)

• expected cancellation of embryo transfer of 4%

Results

• 55 women analyzed in Letrozole Group; 54 women analyzed in Control Group

• Ongoing pregnancy rates higher in Letrozole Group vs. Control Group (RR 1.39, 95% CI 1.04-1.86, p =0.023)

• Clinical pregnancy rates higher in Letrozole Group vs. Control Group (RR 1.31, 95% CI 1.02-1.68, p =0.03)

• No statistical significance between groups for endometrial compaction (p =. 0.776)

• Estradiol levels in N = 40 of Letrozole Group:

  • 26.6% decline from reaching target endometrial thickness on estrogen and finishing letrozole (p < 0.001)

  • 12.6% increase on day of FET (p =0.015)

  • 16% median decline from reaching target endometrial thickness to day of FET ( (p < 0.001)

Authors’ Thoughts

• Study limitations: no placebo, no data on live births, results limited to inclusion criteria

• Letrozole: used here to decrease estradiol and increase implantation

  • Drug may accrue within endometrium, lasting beyond half-life of ~48hr; mechanism of action is presently unknown

  • First known study of this drug used, not with gonadotropins, but after / during estrogen prep and before starting progesterone

• Supplementary estradiol and progesterone (HRT) based on prior research + unit protocol

• Endometrium

  • Necessary to have adequate estradiol priming to proliferate endometrium and induce progesterone receptors - selected target of 9 mm endometrial thickness to maximize outcomes

  • Ongoing and clinical pregnancy not affected by state of endometrial compaction (and compaction not impacted by estradiol)

This Pharmacist’s Thoughts

(+) carefully researched prior to manuscript publication, adequately powered, letrozole is cheap and convenient to take (feasible add-on for most women doing embryo transfer)

(-) unblinded, study did not disclose all methodology involving sealed envelope randomization - were additional security measures used?

Conclusions

This study offers an exciting first look at a new role for letrozole in helping women to conceive. Clearly, more studies are needed that are blinded, record live birth rates, and test alternate dosing regimens of estradiol and progesterone.

Resources

Bülow NS, Dreyer Holt M, Skouby SO, et al. Co-treatment with letrozole during ovarian stimulation for IVF/ICSI: a systematic review and meta-analysis [published online ahead of print, 2021 Dec 22]. Reprod Biomed Online. 2021;S1472-6483(21)00604-0. doi:10.1016/j.rbmo.2021.12.006

Comhaire F, Decleer W. Comparing the effectiveness of infertility treatments by numbers needed to treat (NNT). Andrologia. 2012;44(6):401-404. doi:10.1111/j.1439-0272.2012.01295.x

Elgindy EA, Abdelghany AA, Sibai AbdAlsalam H, Mostafa MI. The novel incorporation of aromatase inhibitor in hormonal replacement therapy cycles: a randomized controlled trial [published online ahead of print, 2021 Dec 20]. Reprod Biomed Online. 2021;S1472-6483(21)00611-8. doi:10.1016/j.rbmo.2021.10.025

Hart RJ. Stimulation for low responder patients: adjuvants during stimulation. Fertil Steril. 2022;117(4):669-674. doi:10.1016/j.fertnstert.2022.01.027

Moini A, Lavasani Z, Kashani L, Mojtahedi MF, Yamini N. Letrozole as co-treatment agent in ovarian stimulation antagonist protocol in poor responders: A double-blind randomized clinical trial. Int J Reprod Biomed. 2019;17(9):653-660. Published 2019 Sep 22. doi:10.18502/ijrm.v17i9.5101

Torgerson DJ, Roberts C. Understanding controlled trials. Randomisation methods: concealment. BMJ. 1999;319(7206):375-376. doi:10.1136/bmj.319.7206.375

Yang AM, Cui N, Sun YF, Hao GM. Letrozole for Female Infertility. Front Endocrinol (Lausanne). 2021;12:676133. Published 2021 Jun 16. doi:10.3389/fendo.2021.676133

This is the first study to examine the perspectives of mothers whose daughters used fertility treatments to have their first child. This study looked at how the mothers (struggled to) support their daughters.

This study sought to answer how five-year-olds, born from egg donation or biological IVF, perceive their family relationships.

This is the largest retrospective study to examine how obstructive sleep apnea (OSA) relates to infertility.

Resources

Jhuang YH, Chung CH, Wang ID, et al. Association of Obstructive Sleep Apnea With the Risk of Male Infertility in Taiwan. JAMA Netw Open. 2021;4(1):e2031846. Published 2021 Jan 4. doi:10.1001/jamanetworkopen.2020.31846

Kline LR. Clinical presentation and diagnosis of obstructive sleep apnea in adults. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on December 18, 2021.)

Lim ZW, Wang ID, Wang P, et al. Obstructive sleep apnea increases risk of female infertility: A 14-year nationwide population-based study. PLoS One. 2021;16(12):e0260842. Published 2021 Dec 15. doi:10.1371/journal.pone.0260842

Mayo Clinic Staff. Obstructive Sleep Apnea. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/obstructive-sleep-apnea/symptoms-causes/syc-20352090#:~:text=Obstructive%20sleep%20apnea%20occurs%20when,breathing%20is%20momentarily%20cut%20off. Published July 27, 2021. Accessed December 21, 2021.

Peppard PE, Young T, Barnet JH, Palta M, Hagen EW, Hla KM. Increased prevalence of sleep-disordered breathing in adults. Am J Epidemiol. 2013;177(9):1006-1014. doi:10.1093/aje/kws342

Wang ID, Liu YL, Peng CK, et al. Non-Apnea Sleep Disorder Increases the Risk of Subsequent Female Infertility-A Nationwide Population-Based Cohort Study. Sleep. 2018;41(1):10.1093/sleep/zsx186. doi:10.1093/sleep/zsx186

Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med. 1993;328(17):1230-1235. doi:10.1056/NEJM199304293281704

Disposal of Unused Medicines: What You Should Know. Food and Drug Administration Web site. https://www.fda.gov/drugs/safe-disposal-medicines/disposal-unused-medicines-what-you-should-know Accessed November 30, 2021.

Drug Disposal: Drug Take Back Locations. Food and Drug Administration Web site. https://www.fda.gov/drugs/disposal-unused-medicines-what-you-should-know/drug-disposal-drug-take-back-locations. Accessed November 30, 2021.

Foxon G, Mitchell P, Turner N, McConnell A, Kendrew H, Jenkins J. Bemfola® fixed dose pens potentially reduce drug wastage and associated costs of infertility treatment. Hum Fertil (Camb). 2018;21(4):275-280.

Somigliana E, Bertoli M, Caputo A, et al. Wastage of gonadotropins during IVF cycles: Real life data from two Italian infertility centers [published online ahead of print, 2021 Oct 20]. Eur J Obstet Gynecol Reprod Biol. 2021;267:56-60.

Resources

Anderson JW. Orlistat for the management of overweight individuals and obesity: a review of potential for the 60-mg, over-the-counter dosage. Expert Opin Pharmacother. 2007;8(11):1733-1742. doi:10.1517/14656566.8.11.1733

Best D, Avenell A, Bhattacharya S. How effective are weight-loss interventions for improving fertility in women and men who are overweight or obese? A systematic review and meta-analysis of the evidence. Hum Reprod Update. 2017;23(6):681-705. doi:10.1093/humupd/dmx027

Gorgojo-Martínez JJ, Basagoiti-Carreño B, Sanz-Velasco A, Serrano-Moreno C, Almodóvar-Ruiz F. Effectiveness and tolerability of orlistat and liraglutide in patients with obesity in a real-world setting: The XENSOR Study. Int J Clin Pract. 2019;73(11):e13399. doi:10.1111/ijcp.13399

Li J, Wang Z, Wei D, et al. Effect of preconceptional orlistat treatment on in-vitro fertilization outcome in overweight/obese women: study protocol for a randomized controlled trial. Trials. 2018;19(1):391. Published 2018 Jul 18. doi:10.1186/s13063-018-2780-7

Practice Committee of the American Society for Reproductive Medicine. Electronic address: [email protected]. Obesity and reproduction: a committee opinion [published online ahead of print, 2021 Sep 25]. Fertil Steril. 2021;S0015-0282(21)01941-5. doi:10.1016/j.fertnstert.2021.08.018

Roche Laboratories Inc.. Xenical (orlistat) [package insert]. U.S. Food and Drug Administration website. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020766s035lbl.pdfRevised January 2019. Accessed October 17, 2021.

Wang Z, Zhao J, Ma X, et al. Effect of Orlistat on Live Birth Rate in Overweight or Obese Women Undergoing IVF-ET: A Randomized Clinical Trial. J Clin Endocrinol Metab. 2021;106(9):e3533-e3545. doi:10.1210/clinem/dgab340

World Health Organization. Body mass index - BMI. Accessed October 18, 2021. https://www.euro.who.int/en/health-topics/disease-prevention/nutrition/a-healthy-lifestyle/body-mass-index-bmi

Resources

Barishansky SJ, Shapiro P, Meyman G, Pavone ME, Lawson AK. Reproductive endocrinologists' knowledge and attitudes in the identification of intimate partner violence [published online ahead of print, 2021 Sep 16]. Fertil Steril. 2021;S0015-0282(21)01934-8. doi:10.1016/j.fertnstert.2021.08.011

https://stacks.cdc.gov/view/cdc/60893

Cheng D, Horon IL. Intimate-partner homicide among pregnant and postpartum women. Obstet Gynecol. 2010;115(6):1181-1186. doi:10.1097/AOG.0b013e3181de0194

National Domestic Violence Hotline www.thehotline.org or 1-800-799-SAFE (7233)

Sharifi, F., J. Jamali, M. Larki, and R. L. Roudsari. “Domestic Violence Against Infertile Women : A Systematic Review and Meta-Analysis”. Sultan Qaboos University Medical Journal [SQUMJ], vol. 1, no. 1, June 2021, doi:10.18295/squmj.5.2021.075.

How relevant are a woman's feelings on getting pregnant to her sexual satisfaction? This study attempted to find out.

Resources

Byers ES, MacNeil S. Further validation of the interpersonal exchange model of sexual satisfaction. J Sex Marital Ther. 2006;32(1):53-69. doi:10.1080/00926230500232917

Daniels K, Daugherty J, Jones J. Current contraceptive status among women aged 15-44: United States, 2011-2013. NCHS Data Brief. 2014;(173):1-8.

Johnson, David R. The National Survey of Fertility Barriers, 2010 [United States]. Ann Arbor, MI: Inter-university Consortium for Political and Social Research [distributor], 2017-11-02. https://doi.org/10.3886/ICPSR36902.v1

Shreffler KM, Gibbs L, Tiemeyer S, McQuillan J, Greil AL. Is Reproductive Orientation Associated with Sexual Satisfaction Among Partnered U.S. Women? [published online ahead of print, 2021 Aug 3]. Arch Sex Behav. 2021;10.1007/s10508-021-01984-z. doi:10.1007/s10508-021-01984-z