Case Scenario 

Melissa, 38, recently had some progesterone pessaries dispensed at your pharmacy. She tells you she won’t need a repeat as her in-vitro fertilisation (IVF) cycle was unsuccessful. Melissa becomes teary as she explains that she will need to start a frozen egg (oocyte) cycle, as the first fresh transfer did not result in a pregnancy. She says she wasn’t really listening when they informed her about what would happen if the first transfer wasn’t successful, as she was so hopeful it would work the first time. She asks what medicines she can expect this time.

Learning Objectives

After reading this article, pharmacists should be able to: 

  • Discuss the medicines used for in-vitro fertilisation 
  • Describe the adverse effects of the medicines used for in-vitro fertilisation 
  • Describe the role of pharmacists in assisting patients undergoing in-vitro fertilisation. 

Competency (2016) standards addressed: 1.1, 1.4, 1.5, 2.2, 3.1, 3.5 

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Introduction 

Infertility is defined by the World Health Organization as ‘a disease of the reproductive system defined by the failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse’.1 An alternative definition, which encompasses all forms of infertility, is ‘a condition of an individual with intent of parenthood but unable to produce conception due to social or physiological limitations within a period of 12 months’.2

In-vitro fertilisation (IVF) is a form of assisted reproductive technology (ART) where an egg (oocyte) is fertilised in a laboratory and the resulting embryo is then placed in the woman’s uterus. IVF can be used to treat several causes of infertility and can also be used in some situations when a disease is not apparent, including following tubal ligation and to prevent genetic problems.3,4 IVF is a long and complex process that involves several steps to facilitate embryo development and requires multiple appointments with a specialist. 

Pharmacists are able to support patients who are undergoing fertility treatment by providing advice on the medicines used in IVF, including the role of each medicine in the treatment cycle, how to use associated injectable devices, and the possible adverse effects and signs and symptoms that require urgent evaluation. Pharmacists are also able to provide advice and support with lifestyle modifications to optimise fertility. 

This article provides a general overview of the IVF process and medicines that can be used in the process. There are currently no Australian IVF guidelines, and the specific process and medicines used vary based on patient factors and individual specialist protocols and experience.

Epidemiology 

There is no clear data on the prevalence of infertility; however, it is thought to affect around 15% of couples trying to conceive.3,4 Of these, about 30% of cases relate to female infertility, 30% to male infertility, and 30% to infertility in both partners.5 Unexplained or idiopathic infertility occurs in about 10% of couples.

IVF indications 

IVF is commonly used for medical reasons, including ovulation problems (e.g. due to polycystic ovary syndrome), fallopian tube damage or blockage, endometriosis, uterine fibroids, impaired sperm production or function, and failed delivery of sperm.4 It can also be used following tubal ligation or removal, for unexplained fertility, to allow for preimplantation testing for genetic conditions to ensure affected embryos are not used (in people with a genetic disorder), and for fertility preservation for people with cancer or other health conditions that may affect their fertility.3

Lifestyle modifications 

Promoting lifestyle modifications to optimise fertility should occur prior to and throughout the IVF process. Pharmacists are able to suggest and reinforce evidence-based lifestyle modifications including3: 

  • Optimising nutrition – folate and iron supplements should be recommended for all females to promote normal fetal development of the brain and spinal cord. Supplementing vitamin D in males and females who are deficient and increasing dietary zinc and selenium in males may have fertility benefits. 
  • Appropriate body weight and exercise – BMI should be within normal range. For overweight or obese females, losing 5% of body weight can improve fertility and reduce the risk of gestational diabetes. 
  • Avoiding tobacco, recreational drugs and alcohol. 

IVF process 

Once the decision to proceed with IVF is confirmed, further investigations are undertaken. This includes ovarian reserve testing, semen analysis, infectious disease screening, practice embryo transfer if needed, and ultrasound.4 Pre-treatment counselling is also undertaken. Counselling allows questions, including what the patient would like to do with any extra embryos, to be discussed.4

The IVF process begins with baseline blood tests, followed by harvesting oocytes from a female and sperm from a male. These are then incubated in special conditions that allow fertilisation to occur. The resulting embryos are selected according to morphology, at which point genetic testing can be required, before being transferred into the uterus.3 Typically, only one embryo is transferred to reduce the risk of multiple pregnancy (e.g. twins, triplets).3

Each IVF cycle takes approximately 6 weeks, but the exact length varies from person to person. The usual process is6: 

  1. Ovarian stimulation 
  • Gonadotrophins are administered to stimulate the ovaries to produce more than one follicle. There are several different stimulation protocols used in IVF (see below). 
  • A vaginal ultrasound and blood tests are conducted to monitor follicle growth and determine the best time to stimulate ovulation. 
  • A ‘trigger’ injection, usually human chorionic gonadotropin (hCG), is administered to stimulate ovulation and final oocyte maturation. 
  1. Oocyte and sperm collection 
  • Ultrasound-guided oocyte collection occurs 34–36 hours after the trigger injection under general anaesthetic; a long, thin needle retrieves the mature oocytes from the follicles, through the vagina. 
  • A sperm sample is collected, washed and checked for morphology and motility. 
  1. Fertilisation and embryo development 
  • Oocytes and sperm are placed into a culture fluid for fertilisation to occur. If male infertility is suspected, a single sperm may be injected directly into each oocyte in a process known as intracytoplasmic sperm injection (ICSI). ICSI (pronounced ‘ick-see’) is used in 60–80% of IVF treatments in Australia and carries a slightly increased risk of congenital abnormalities compared to IVF alone.3
  • The combined oocyte and sperm are monitored to determine fertilisation and progress. A photo is taken within the incubator every 5–7 minutes, for up to 5 days, to allow embryologists to grade development, based on expected cell-division and differentiation milestones.
  1. Embryo transfer 
  • Most commonly, one embryo is transferred into the top third of the uterus 2–5 days after fertilisation. A woman must be well, without a high temperature, for an embryo to be placed. 
  • Additional embryos are frozen in liquid nitrogen to be transferred later if required. 
  1. Luteal phase 
  • For the next 2 weeks or more, progesterone is given to support uterine growth lining and increase the potential for successful implantation of the embryo. 
  • A blood test or sensitive home pregnancy test confirms the pregnancy outcome. 

A frozen embryo transfer (FET) will occur if a fresh cycle has been unsuccessful or is not possible. FET follows a slightly different process, as it doesn’t include oocyte collection or fertilisation. FET can take place during a natural menstrual cycle or by using hormone replacement or ovulation induction.7 The usual process using hormone replacement is as follows7:

  1. A GnRH agonist is administered during the midluteal phase (day 21) or overlapping with an oral contraceptive. 
  2. An ultrasound and blood test are undertaken to confi rm down-regulation of the cycle. 
  3. Estrogen is started following the menstrual period to build the uterine lining thickness. 
  4. Progesterone supplementation commences once the endometrium has developed adequately. 
  5. The embryo transfer occurs 3–6 days later. 
  6. Estrogen and progesterone are continued during the luteal phase. 
  7. A blood test confirms the pregnancy outcome.

Different IVF treatment protocols can be used to stimulate ovulation. The protocol used is selected based on the patient’s individual needs and cause of infertility. The following are commonly used protocols8,9: 

  • Antagonist protocol: the patient starts taking gonadotrophins at the start of their cycle to stimulate follicles to grow (day 3 of menstruation). Approximately 4–6 days later, a GnRH antagonist is commenced to prevent early ovulation. Once the follicles have reached their target size (typically 8–12 days), either a GnRH agonist or hCG is used to trigger final oocyte maturation and ovulation.
  • Long agonist protocol: the patient starts taking a GnRH agonist 1 week before expected menstruation to stop the body producing reproductive hormones, which helps to prevent early ovulation. On day 3 of menstruation, the patient starts gonadotrophin injections, and both the gonadotrophins and GnRH agonist are continued until the trigger is given. 

IVF medicines 

Patient’s undergoing IVF are provided with an individualised treatment protocol that needs to be follow closely. Missed doses or mixing up medicines in the cycle can mean the cycle needs to be abandoned, which is costly and time-consuming. Pharmacists can support patients to understand their individual protocol and the importance of following it precisely. 

Many IVF medicines are high cost. Some are covered by the Pharmaceutical Benefits Scheme (PBS) for certain indications as section 100 IVF medicines. 

IVF specialist prescribers should be employed or affiliated with an IVF clinic that is accredited by the Fertility Society of Australia’s Reproductive Technology Advisory Committee (RTAC). Inclusion of the RTAC accreditation number for the practice the specialist prescriber is affiliated in the PBS online claim is mandatory for section 100 IVF medicines.10

Additionally, IVF medicines require time-sensitive administration. Close interaction with clinic nurses and specialists is essential to enable timely supply and optimise IVF cycles. 

Some of the key medicines used for IVF are summarised in Table 1. 

Table 1 – Medicines commonly used for IVF

Class  Active Ingredient Brands Indication Administration
Gonadotrophin Follitropin alfa (recombinant FSH) Bemfola pen, Gonal-f pen, Ovaleap cartridge (for use with Ovaleap pen) Anovulatory infertility; controlled ovarian stimulation in ART; stimulation of spermatogenesis in hypogonadotrophic hypogonadism Subcutaneous (SC) injection 
Follitropin beta (recombinant FSH) Puregon cartridge (for use with Puregon pen) Anovulatory infertility; controlled ovarian stimulation in ART; stimulation of spermatogenesis in hypogonadotrophic hypogonadism SC injection
Choriogonadotropin alfa (recombinant hCG) Ovidrel pen  Ovulation induction in infertility and ART SC injection
hCG Choriomon, Brevactid powder for injection (available through Section 19A) Ovulation induction; stimulation of spermatogenesis Intramuscular injection. Choriomon can also be injected SC
Corifollitropin alfa (recombinant FSH) Elonva solution for injection  Controlled ovarian stimulation in ART SC injection
Follitropin delta (recombinant FSH) Rekovelle pen Controlled ovarian stimulation in ART SC injection
Human menopausal gonadotrophin (hMG) Menopur powder for injection Ovulation induction in infertility and ART  SC injection
Lutropin alfa (recombinant LH) Luveris powder for injection Stimulation of follicular development, with a recombinant FSH, in severe LH and FSH deficiency SC injection
Lutropin alfa with follitropin alfa (fixed-dose combination) Pergoveris pen  Stimulation of follicular development in severe LH and FSH deficiency  SC injection
GnRH agonists Goserelin^ Zoladex SC implant Pituitary down regulation to prepare for controlled ovarian stimulation Administered by doctor or nurse
Nafarelin Synarel nasal spray Nasal spray
Triptorelin Decapeptyl pre-filled syringe  SC injection
GnRH antagonists Cetrorelix Cetrotide powder for injection Prevention of premature ovulation during controlled ovarian stimulation SC injection
Ganirelix Orgalutran pre-filled syringe SC injection

 

Progesterone supplementation or replacement is used to provide luteal phase support. It should be started around the time of the embryo transfer and be continued at least until a positive pregnancy test, and is often continued for up to 10 weeks.14,15 It comes as a pessary (Endometrin, Oripro), vaginal capsule (Utrogestan), injection (Prolutex) or vaginal gel (Crinone 8%). 

In the days or weeks leading up to the start of an IVF cycle, the oral contraceptive pill is sometimes prescribed by specialists.8 This is referred to as priming, and is used primarily to schedule the timing of cycles.

Adverse effects of IVF medicines 

Mild bruising, redness and soreness at the injection site is common for all injectable fertility medicines.12

The main adverse effect of gonadotrophins used as part of IVF is abdominal discomfort (including pelvic pain, stomach pain and bloating) due to enlargement of the ovaries.16 Other adverse effects include breast tenderness, mood swings, fatigue, headache and dizziness.12 Some of these mimic early pregnancy symptoms. 

GnRH analogues adverse effects are related to decreased estrogen levels and include hot flushes, headache, fatigue, weight gain, fluid retention, cyst development, insomnia, vaginal dryness, and decreased libido.17,18

Adverse effects of vaginal progesterone include headaches, nausea, local itching, vaginal discomfort, burning, discharge, dryness, bleeding, uterine cramping and abdominal pain or bloating.12 Patients with moderate to severe pain, uterine cramping or vaginal bleeding should be referred to their fertility clinic for evaluation.14 Additionally, progesterone can cause a hypersensitivity reaction; patients should report swelling of face, lips, mouth or throat.12,19

Complications of the IVF process 

Mild cramping, bloating and vaginal spotting is common during oocyte collection and embryo transfer.14 Paracetamol can be used for pain relief following oocyte retrieval. Recovery generally occurs within a day or so. 

Constipation is also possible, due to increased levels of progesterone, use of opioids in the process and decreased movement following recovery. Ensuring adequate hydration, along with stool softeners or fibre supplements, can assist with management. 

More serious complications of IVF include bleeding, infection, injuries to surrounding structures, ovarian torsion, ovarian hyperstimulation syndrome (OHSS), ectopic pregnancy and heterotopic pregnancy.14

Pelvic infections can occur following oocyte retrieval and embryo transfer; however, the Therapeutic Guidelines does not recommend antibiotic prophylaxis for oocyte retrieval,20 and saline flushes are used instead. Previous pelvic infections or endometriosis increase the risk of this complication.21 Injuries to surrounding organs are very rare.22

OHSS is a serious complication of controlled ovarian stimulation. It is generally mild to moderate; however, when it is severe, it is life-threatening, so prompt identification and management is essential.3,23 In OHSS, there is an abnormal release of cytokines from the ovaries, which increases blood vessel permeability causing leakage of fluid, from the intravascular to extravascular space.3,23 It usually occurs in the 7–10 days following the hCG trigger injection and presents as a broad range of symptoms, including abdominal discomfort or pain, bloating, nausea, vomiting, diarrhoea, shortness of breath, confusion and dehydration.3,23,24 It can lead to serious complications, including ascites, pleural or pericardial effusions, respiratory failure, renal failure, thromboembolism, cerebral oedema, ovarian torsion, ileus and death.3,23,24 Patients presenting with any signs of OHSS should be referred to their specialist for evaluation. Patients with abdominal pain, nausea, vomiting, shortness of breath, confusion or reduced urine output should be immediately referred to an emergency department (ED). 

Information on the management of OHSS can be found in the South Australian Perinatal Practice Guideline: Ovarian hyperstimulation syndrome24 and the Royal College of Obstetricians and Gynaecologists’ Green-top Guideline Number 5.25

Knowledge to practice

Historically, most medicines have been supplied by the patient’s IVF clinic. However, due to the introduction of eScripts and an increased number of IVF medicines included on the PBS, pharmacists are likely to see more prescriptions for IVF medicines and can provide support and reassurance during the dispensing process. 

IVF protocols are often complex and require several different medicines, many of which require subcutaneous administration, have strict storage requirements, and require time-sensitive administration. Patients undergoing IVF are given an individual medicine protocol outlining the dose and frequency of each prescribed medicine. 

Pharmacists can support patients to adhere to individual protocols by providing advice on the role of each medicine and the importance of medicine dose timing. IVF medicines for subcutaneous injection are usually recommended to be injected into the lower abdomen.6,12 The injection site should be rotated daily to prevent lipoatrophy. Many IVF medicines require refrigeration but can be stored out of the refrigerator for a specified period (see the individual product information for specific storage requirements). 

Pharmacists can advise on storage and administration of IVF medicines as well as the safe disposal of needles. Patients should be referred to their fertility specialist if a medicine is out of stock, a dose has been missed, or if OHSS is suspected. Referral to an ED should occur when a patient presents with abdominal pain, nausea, vomiting, shortness of breath, confusion or reduced urine output following commencement of an IVF cycle, as severe OHSS is possible and life-threatening.3 Pharmacists can assist patients, both male and female, by recommending a healthy diet, assisting with quitting smoking, reducing or cutting out alcohol, and suggesting regular exercise to boost fertility.3 

Language around IVF and infertility is important to ensure patients do not feel excluded from care.26 

Blame and judgement about the cause of infertility may be damaging to patient-pharmacist relationships and must be avoided.

Conclusion 

IVF treatment is a complex journey for patients and can be challenging. It can cause anxiety and stress in patients undergoing treatment. Providing accurate and succinct information about using IVF medicines will assist in reassuring people as they undergo treatment.

Case Scenario Continued 

You advise Melissa that the protocol and medicines used vary based on patient factors and the experience of individual specialists. You explain that one of the common protocols used for FET includes starting a GnRH agonist injection daily, about a week before an expected period. Following this, another ultrasound and blood test will be carried out to check the injections are working, before starting on estrogen and progesterone, following which the FET will occur. You also explain that possible adverse effects of the GnRH agonist include bruising and redness at the injection site, hot flushes, headache, fatigue, insomnia and vaginal dryness. You advise her to contact her fertility clinic for advice on the protocol that would be most suitable for her.

 

Key Points 

  • IVF is a form of assisted reproductive technology where an oocyte (egg) is collected and fertilised in a laboratory dish by a sperm to create an embryo which is then transferred into the woman’s uterus. 
  • Combinations of gonadotrophins, gonadotrophin-releasing hormone agonists and antagonists and other hormones are used to enable oocyte retrieval and encourage a successful embryo transfer. 
  • Ovarian hyperstimulation syndrome (OHSS) is a possible complication of the IVF process, and when it is severe, it is life threatening. Pharmacists and patients should be aware of the signs and know how to best manage it, including when emergency referral is required. 
  • The use of inclusive language is an essential part of supporting patients undergoing IVF. 

 

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Further resources

Patient information booklets and videos for patients demonstrating the use of a large range of common IVF medicines can be found on the IVF Australia website at www.fertilityportal.com.au/IVF-Australia or at Your Fertility www.yourfertility.org.au/ 

FertilityIQ (www.fertilityiq.com/ivf-in-vitro-fertilization) is an American resource which provides information on the principles of IVF. 

References

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  2. Expanding the clinical definition of infertility to include socially infertile individuals and couples. In: Lo W, Campo-Engelstein L, editors. Reproductive ethics II. Springer International Publishing; 2018. At: https://link.springer.com/book/10.1007/978-3-319-89429-4#about-authors
  3. Infertility. In: Therapeutic Guidelines. Melbourne: Therapeutic Guidelines Limited; 2021.
  4. Mayo Clinic. In vitro fertilization (IVF). 2021. At: www.mayoclinic.org/tests-procedures/in-vitro-fertilization/about/pac-20384716
  5. Better Health Channel. Infertility in women. 2021. At: www.betterhealth.vic.gov.au/health/conditionsandtreatments/infertility-in-women
  6. IVF Australia. IVF treatment and process. IVF Australia; 2022. At: www.ivf.com.au/treatments/fertility-treatments/ivf-treatment
  7. Ghobara T, Gelbaya TA, Ayeleke RO. Cycle regimens for frozen-thawed embryo transfer. Cochrane Database of Systematic Reviews 2017;7(7).
  8. Zwingerman R. Different types of IVF protocols explained. All about fertility. At: https://all-about-fertility.com/ivf-protocols-explained/
  9. Shrestha D, La X, Feng HL. Comparison of different stimulation protocols used in in vitro fertilization: a review. Ann Transl Med. 2015;3(10):137.
  10. Australian Government Department of Health. Pharmaceutical Benefits Scheme (PBS) IVF medicines: frequently asked questions new arrangements from 1 July 2015. Australian Government department of Health; 2016. At: www.pbs.gov.au/files/ivf-medicines-files/revised-faqs-ivf-medicines-25-june-2015.pdf
  11. Infertility. In: Rossi S, ed. Australian Medicines Handbook. Adelaide: Australian Medicines Handbook; 2022.
  12. eMIMs cloud. Sydney: MIMS Australia; 2022.
  13. Chorionic gonadotropin. In: Society of Hospital Pharmacists of Australia. Australian Injectable Drugs Handbook 8th Edition. SHPA; 2022. At: https://shpa.org.au/publicassets/d58ecc42-e2df-ec11-9104-00505696223b/Chorionic%20gondaotropin%20Update%20June%202022.pdf
  14. Ho J. In vitro fertilization: procedure. UpToDate; 2022. At: www.uptodate.com/contents/in-vitro-fertilization-procedure?search=progestrone%20for%20IVF&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1
  15. European Society of Human Reproduction and Embryology. Guideline on ovarian stimulation for IVF/ICSI. Belgium: ESHRE; 2019. At: www.eshre.eu/Guidelines-and-Legal/Guidelines/Ovarian-Stimulation-in-IVF-ICSI
  16. Fauser B. Patient education: Infertility treatment with gonadotropins (Beyond the Basics). UpToDate; 2022. At: www.uptodate.com/contents/infertility-treatment-with-gonadotropins-beyond-the-basics?search=patient%20education:%20infertility%20treatment%20with%20gonadotropins&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1
  17. Depalo R, Jayakrishan K, Garruti G, et al. GnRH agonist versus GnRH antagonist in in vitro fertilization and embryo transfer (IVF/ET). Reprod Biol Endocrinol 2012;10(1):26.
  18. Gonadotropin Releasing Hormone (GnRH) Analogues. In: National Institute of Diabetes and Digestive and Kidney Diseases. LiverTox: Clinical and research information on drug-induced liver injury. Bethesda (MD); 2012. At: www.ncbi.nlm.nih.gov/books/NBK547863/
  19. Foer D, Buchheit KM. Presentation and natural history of progestogen hypersensitivity. Ann Allergy Asthma Immunol 2019;122(2):156–9.
  20. Surgical antibiotic prophylaxis for specific procedures. In: Therapeutic Guidelines. Melbourne: Therapeutic Guidelines Limited; 2021.    
  21. Aslam MF. Pelvic infection after IVF. In: Sharif K, Coomarasamy A, ed. Assisted reproduction techniques: challenges and management options. Wiley Online; 2012. p. 271–3.
  22. Ee TX, Toh WL, Chan JKY. Rare surgical complication of in vitro fertilisation treatment: bladder injury during oocyte retrieval. J Med Cases 2021;12(3):102–6.
  23. Busso C, Soares SR, Pellicer A. Pathogenesis, clinical manifestations, and diagnosis of ovarian hyperstimulation syndrome. UpToDate; 2022. At: www.uptodate.com/contents/pathogenesis-clinical-manifestations-and-diagnosis-of-ovarian-hyperstimulation-syndrome?sectionName=Onset&search=ovarian%20hyperstimulation%20syndrome&topicRef=101383&anchor=H412720819&source=see_link#H412720819
  24. Government of South Australia. South Australian perinatal practice guidelines ovarian hyperstimulation syndrome. SA: Government of South Australia; 2018. At: www.sahealth.sa.gov.au/wps/wcm/connect/9b61ed004ee5348da663afd150ce4f37/Ovarian+Hyperstimulation+Syndrome_PPG_v3_0.pdf?MOD=AJPERES&CACHEID=ROOTWORKSPACE-9b61ed004ee5348da663afd150ce4f37-ocQ-19L
  25. Royal College of Obstetricians and Gynaecologists. The management of ovarian hyperstimulation syndrome green-top guideline no. 5. RCOG; 2016. At: www.rcog.org.uk/media/or1jqxbf/gtg_5_ohss.pdf
  26. Mosconi L, Crescioli G, Vannacci A, et al. Communication of diagnosis of infertility: A systematic review. Front Psychol 2021;12(6):615699.

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