While the success of embryo implantation involves many factors, the immune response of the endometrium likely plays an important role; recurrent implantation failure (RIF) of embryos may be linked to the mother’s immune system.

A recent study looked at the use of a drug called Enbrel (etanercept), which works by stopping the immune system from becoming overly-activated; while Enbrel is commonly used in women with rheumatoid arthritis (RA), there is very little information on using this drug in women undergoing in vitro fertilization (IVF). Important safety information about Enbrel can be found here.

Study Background

WHAT

• Using TNFα blocker etanercept (brand name Enbrel)

WHY

• Limited evidence suggests that TNFα blockers helped women with rheumatoid arthritis or endometriomas, but there is no known evidence using a TNFα blocker in women with recurrent implantation failure (RIF).

WHEN/WHERE

• January 2015 - August 2019, Ingenes Institute in Mexico City, Mexico

WHO

• 83 women who consented to participate after learning about Enbrel’s potential safety risks

• Female Inclusion Criteria:

  • no history of clinical pregnancy

  • three or more failed IVF cycles, transferring at least five good quality embryos = the study’s definition of RIF

  • completion of at least two cycles on clinic’s standard treatment protocol for embryo implantation failure (protocol = aspirin, low molecular weight heparin, and/or prednisone 20 mg)

• Female Exclusion Criteria

  • involvement of male factor infertility

  • immunocompromised at baseline with lupus, active RA, or anti-phospholipid syndrome

  • confirmed diabetes

  • endometrial alterations or Mullerian malformations

  • undergoing treatment that could otherwise impact TNFα

HOW

• Controlled ovarian stimulation, oocyte retrieval

• Oocyte insemination via intracytoplasmic sperm injection (ICSI)

• Pre-implantation Genetic Testing (PGT) was permitted

• Physician, with patient consent, decided fresh vs. frozen cycle and # of embryos to transfer

  • Fresh embryos = Day 5 blastocyst transfer

  • Frozen embryos = Day 3 cleavage-stage or Day 5 blastocyst transfer after controlled endometrial development minus gonadotropins; took progesterone for luteal phase support

• Enbrel dosing: 25 mg injection every 72 hours for four doses

  • Fresh transfer - started on day of oocyte retrieval

  • Frozen transfer - started on day coordinated with first day of embryo development, example below

    • Day 1 = first Enbrel dose

    • Day 3 = transfer of embryos that were previously frozen on day 3 of development

    • Day 4 = second Enbrel dose

• Implantation confirmed on Day 14 via β-hCG levels

• Fetal heartbeat confirmed 6-8 weeks

Study Results

• 83/360 (23%) qualified patients agreed to participate in the study

  • Most patients declined due to doubts about using Enbrel or due to costs (financial or emotional) of trying another IVF cycle

  • Two women excluded due to concomitant immunosuppression

  • Two patients stopped following up with the clinic

• Patient characteristics

  • Median age = 37.9 +/- 5.1 years

  • Median # previous IVF cycle failures: 4

  • 21.7% embryos genetically tested

  • Advanced Age 54.3%; Recurrent Pregnancy Loss 10.8%, Endometriosis 13.3%, Low Ovarian Reserve 7.2%, Polycystic Ovarian Syndrome 1.2%

• Safety - no side effects reported

• Efficacy

  • 75.9% successful implantation (+ β-hCG levels)

    • higher implantation using donor ova (78.9%) vs. own ova (69.2%) (p=0.337)

  • 74.7% detectable fetal heartbeats

  • 62.3% live birth (or still actively pregnant)

    • average gestation = 34.9 weeks

    • 60.5% babies had low birth weight, none were considered large

    • no birth defects

  • no outcome differences based on fresh (n = 45) vs. frozen transfer (n= 34)

Study Authors’ Thoughts

(+) Use of and dosing of Enbrel established in limited previous studies in RIF, will explore dose adjustments in future studies, giving Enbrel cautiously in context of COVID-19

(-) small sample size, lack of control group, no data on potential confounders (age, BMI, insulin resistance)

This Pharmacist’s Thoughts

(+) Enbrel risk assessments explained, reasonable inclusion/exclusion criteria

(-) ICSI outcomes only, frozen embryos either Day 3 or Day 5, missing post-transfer outcomes on four women, inconsistent PGT testing of embryos

Conclusions

With promising results and no safety issues noted, the use of Enbrel in RIF should be further characterized to optimize discretionary use in women who are most likely to benefit.

Resources

Bashiri A, Halper KI, Orvieto R. Recurrent Implantation Failure-update overview on etiology, diagnosis, treatment and future directions. Reprod Biol Endocrinol. 2018;16(1):121. Published 2018 Dec 5. doi:10.1186/s12958-018-0414-2

Cunningham MW, Jayaram A, Deer E, et al. Tumor necrosis factor alpha (TNF-α) blockade improves natural killer cell (NK) activation, hypertension, and mitochondrial oxidative stress in a preclinical rat model of preeclampsia. Hypertens Pregnancy. 2020;39(4):399-404. doi:10.1080/10641955.2020.1793999

Enbrel (etanercept) [package insert]. Thousand Oaks, CA: Amgen; 2020.

Jerzak M, Niemiec T, Nowakowska A, Klochowicz M, Górski A, Baranowski W. First successful pregnancy after addition of enoxaparin to sildenafil and etanercept immunotherapy in woman with fifteen failed IVF cycles - case report. Am J Reprod Immunol. 2010;64(2):93-96. doi:10.1111/j.1600-0897.2010.00826.x

Jerzak M, Ohams M, Górski A, Baranowski W. Etanercept immunotherapy in women with a history of recurrent reproductive failure. Ginekol Pol. 2012;83(4):260-264.

Malano DJ, Strusberg I. Embarazos a término por fertilización asistida en dos pacientes con artritis reumatoidea severa en tratamiento con etanercept [Assisted fertilization with at term pregnancies in two patients with severe rheumatoid arthritis while in treatment with etanercept.]. Rev Fac Cien Med Univ Nac Cordoba. 2019;76(1):59-62. Published 2019 Mar 6. doi:10.31053/1853.0605.v76.n1.21959

Nardo L, Chouliaras S. Adjuvants in IVF-evidence for what works and what does not work. Ups J Med Sci. 2020;125(2):144-151. doi:10.1080/03009734.2020.1751751

Önalan G, Tohma YA, Zeyneloğlu HB. Effect of Etanercept on the Success of Assisted Reproductive Technology in Patients with Endometrioma. Gynecol Obstet Invest. 2018;83(4):358-364. doi:10.1159/000484895

Santiago KY, Porchia LM, López-Bayghen E. Endometrial preparation with etanercept increased embryo implantation and live birth rates in women suffering from recurrent implantation failure during IVF [published online ahead of print, 2021 Jan 18]. Reprod Biol. 2021;21(1):100480. doi:10.1016/j.repbio.2021.100480

Wilcox AJ, Weinberg CR, O'Connor JF, et al. Incidence of early loss of pregnancy. N Engl J Med. 1988;319(4):189-194. doi:10.1056/NEJM198807283190401