Approximately 1.5% of babies born in the US are conceived with In Vitro Fertilization (IVF). As we strive for increased success, we also strive to make it as safe as possible for both the patient and subsequent pregnancies.
As reproductive endocrinologists, we plan treatment protocols to minimize patients’ risk with the goal of singleton healthy pregnancies.
There are 4 main types of risks associated with IVF:
- Stimulation/Medication Risks
- Procedure Risks
- Pregnancy/Maternal Risks
- Fetal Risks
I plan to review the risks associated with IVF and what we are doing to reduce them.
Risks from the stimulation/medication are limited. Most people feel well during stimulation due to the elevated estrogen level, but also have an increased risk of thromboembolic events, especially if they are genetically predisposed. The chances of an allergic reaction or injection site hematoma or infection are rare.
The most common stimulation risk is ovarian hyperstimulation syndrome (OHSS). OHSS is an exaggerated response to ovulation which occurs in 3-6% of IVF cycles. This is typically self-limited but can be prolonged in the setting of pregnancy. It is thought to be vascular endothelial growth factor (VEGF) mediated and caused by the human chorionic gonadotropin (HCG) either from the trigger injection or pregnancy itself. Symptoms typically peak in a bimodal fashion either 5 days after retrieval or at approximately 4 weeks gestation. Signs include ascites, weight gain, hyperkalemia, hyponatremia, hemoconcentration, leukocytosis, dyspnea, and pleural effusion. Life-threatening complications such as thromboembolic events, cardiac arrhythmias, renal failure, and respiratory compromise can be rarely encountered. Women at risk are typically those with the following risk factors: age under 30, Low BMI <25, high antral follicle count >20, high estradiol >2500 pg/mL, high AMH >5 ng/mL, history of OHSS in the past, polycystic ovary syndrome (PCOS). Treatments are to correct electrolyte abnormalities, give normal saline Intravenous fluids, and perform culdocentesis if needed.
OHSS prevention is better than treatment.
For patients who have risk factors for OHSS, we can plan treatment to decrease their risk. One option is to lower their dose of gonadotropins to keep their estrogen levels in a lower range. Another main strategy is to change the type of trigger we are using. Since HCG stimulates VEGF release, we can use a GNRH agonist trigger (Lupron) to cause a surge of LH from the patients’ pituitary that causes egg maturation. This technique has some pitfalls: 1. this can only be used in a GnRH antagonist protocol 2. It cannot be used for patients who have hypothalamic amenorrhea as it requires a pituitary that is responsive to the medication. 3. This causes a disruption in the receptivity of the uterine lining that can interfere with embryo implantation- because of this often we will freeze all embryos to prevent hyperstimulation and subsequently perform a frozen embryo transfer.
Because using a GNRH agonist trigger causes decreased pregnancy rates in a fresh cycle, often, we will give a combination of the GnRH agonist trigger along with a small amount of HCG to “rescue” the corpus luteum and endometrial lining from the detrimental effects of the Lupron. This has been shown to normalize pregnancy rates compared to the GnRH agonist alone.
Another method is to use a lower dose of our typical HCG trigger. Typically we use a 10,000 IU dose and we can decrease the level of HCG dose to reduce the risk in higher-risk patients. This lowers but does not completely eliminate the risk.
If patients are feeling worse instead of better after their egg retrieval, we will often freeze all of their embryos to reduce the risk of severe ovarian hyperstimulation. When this is done, symptoms peak at 7 days after the trigger and resolve typically on their own within a few weeks.
Many of us will use cabergoline, a dopamine 2 receptor agonist, that has been shown to decrease the incidence of severe hyperstimulation without decreasing pregnancy rates.
Procedure risks are rare. Overall chances of procedural complications are <1% of cases. These include bleeding, injury to internal organs, infection, ovarian torsion, and risks of anesthesia. Infections or infected ovarian hematomas are rare, and can more frequently occur in the setting of an endometrioma. Unlike other procedures, during egg retrieval, the vagina is not prepped with betadine but typically saline or media. Patients at high risk can receive preoperative antibiotics. Data about procedure risks is mainly retrospective. Two large studies with a total of approximately 5,500 patients demonstrated pelvic infection risk of 4 per 1000, intraperitoneal bleeding risk 2 per 1000. A prospective trial with approximately 1000 patients from 2006 found no cases of intra-abdominal bleeding, no case of pelvic infection, but one case of unexplained fever, 0.7% of patients required hospitalization for pain treatment. No cases of adnexal torsion.
Overall, egg retrievals are safe and well-tolerated.
Pregnancy and Maternal Risks include ectopic or heterotopic pregnancy, multiples, and higher-order multiple pregnancies, and long term risks mainly cancers.
One prospective study of 4,000 pregnancies demonstrated a reduction in ectopic/heterotopic risk with IVF (1.23%) compared to natural conception (2.01%). The heterotopic risk was higher with IVF 0.46% compared to 0.01% with natural conception. Interestingly, another retrospective study found that ectopic risk was lower with frozen embryo transfers (0.85%) compared to fresh IVF (1.77%) embryo transfers.
One of our main goals and objectives are to increase success without increasing multiple pregnancy rates. The American Society of Reproductive Medicine has guidelines on how many embryos to transfer based on a patient’s age and prognosis.
The guidelines recommend that all euploid embryos tested by pre-implantation genetic testing (PGT) should be single embryo transfers regardless of the maternal age.
Nationwide, there are huge disparities among different areas of the country. This is likely due to insurance coverage in those areas. The entire team of physicians, embryologists, and nurses at Fertility Centers of Illinois work very hard to educate our patients about the importance of singleton pregnancies. Single embryo transfers allow for a dramatic reduction in twins from 40% to 1% in this good prognosis population. Transferring two embryos does not double the pregnancy rates. They are approximately 63% with a single embryo and 68% with a double transfer.
One common misperception is that IVF increases cancer risk. There is no evidence that IVF increases the risks of ovarian, breast, or endometrial cancer. Two large cohort trials published in JAMA and Lancet Oncology reviewed these findings. A diagnosis of infertility has a known increased risk of ovarian and breast cancer in women who have not carried a pregnancy, but this is not related to the treatment. Endometrial cancer risk is increased in women who have PCOS. Helping these women conceive only decreases their chances of long term cancer risks.
Finally, fetal risks with IVF will be reviewed. The main focus is to reduce the risks of aneuploidy and single-gene diseases. We do this with preimplantation genetic testing comprised of preimplantation genetic testing (PGT) for aneuploidy (PGT-A) for aneuploidy or PGT for single genes (PGT-M) or PGT for translocations or structural rearrangements (PGT-SR).
Aneuploidy increases with increasing maternal age and is the most common cause of pregnancy loss. Traditional IVF without PGT-A gives us no genetic information on the embryos. Even normally appearing embryo can be genetically abnormal. PGT-A allows us to more successfully transfer single embryos in older patients who would be at higher risk for pregnancy complications. This has transformed our ability to help our patients have successful pregnancies by reduces the chance of twins because we are performing single embryo transfers, by reduces the chance of miscarriage and increases the chance of pregnancy. The benefit increases with increasing maternal age. For women in their 40’s, the chances of pregnancy are double by transferring a PGT-A tested euploid embryo.
The limitations of PGT for include that we cannot screen for genetic diseases (e.g. CF) unless gene mutations in the family already known, there is a chance for no/inconclusive results, there is a chance of no normal embryos for transfer, and it does not guarantee a pregnancy.
PGT-M can be used for couples who are carriers for a specific gene which can affect their offspring. We can then preferentially select embryos with results showing the absence of the particular familial mutation(s). This technology can transform our ability to help them have healthier babies.
Imprinting diseases occur from abnormal DNA-methylation leading to abnormal protein expression. While this is very rare, it may be associated with intracytoplasmic sperm injection. Beckwith-Wiedemann Syndrome (BWS) is a type of imprinting disorder that occurs in about 1 in 14,000 pregnancies. A 2013 meta-analysis found a significant positive association between IVF/ICSI treatment and BWS, with relative risks of 5.2 (95% CI 1.6–7.4). The study found that ICSI raises risks to 1:2,700 births for BWS. So why do we do ICSI for patients? Well, without ICSI in patients with unexplained infertility 16-19% of cases have no fertilization. As with all therapy, we need to weigh the risks and benefits of our therapy. Most providers think that the benefits of better fertilization that leads to more pregnancies outweigh the very rare risk of an imprinting disorder.
In summary, risks associated with IVF are rare but can be serious. There are various techniques and technologies we use to reduce these risks. Some risks are avoidable, but some are not. OHSS can usually be prevented by identifying patients at risk and modifying treatment protocols. Single embryo transfers reduce multiple pregnancies. PGT can help improve successful pregnancy rates in women especially with advanced reproductive age. As with all therapy, appropriate and complete informed consent is important for patients undergoing IVF.
van den Belt-Dusebout AW et al. Ovarian Stimulation for In Vitro Fertilization and Long-term Risk of Breast Cancer. JAMA. 2016 Jul 19;316(3):300-12.
Vermeiden, Are imprinting disorders more prevalent after human in vitro fertilization or intracytoplasmic sperm injection? Fertil Steril 2013;99:642–51.
Brinton. In vitro fertilization and risk of breast and gynecologic cancers: a retrospective cohort study within the Israeli Maccabi Healthcare Services. Fertil Steril 2013;99:1189–96.
Cookingham et al. Successful treatment algorithm for evaluation of early pregnancy after in vitro fertilization. Fertil Steril. 2015 Oct;104(4):932-937
Londra et al. Ectopic pregnancy after in vitro fertilization: differences between fresh and frozen-thawed cycle. Fertil Steril 2015;104:110–8.
Roque M et al. Freeze-all strategy in IVF/ICSI cycles: an update on clinical utility. Med. 2019 Mar;61(1):52-57. doi: 10.23736/S0031-0808.18.03492-4. Epub 2018 Jun 28. Review
A.K. Ludwig et al. Perioperative and post-operative complications of transvaginal ultrasound-guided oocyte retrieval: prospective study of >1000 oocyte retrievals Hum. Reprod. (2006) 21 (12): 3235-3240
Nelson SM Prevention and management of ovarian hyperstimulation syndrome. Thromb Res. 2017 Mar;151 Suppl 1:S61-S64
Bates SM. Anticoagulation and in vitro fertilization and ovarian stimulation. Hematology Am Soc Hematol Educ Program. 2014 Dec 5;2014(1):379-86.
Zohav E, Et al. A New Perspective on the Risk of Hypercoagulopathy in Ovarian Hyperstimulation Syndrome Using ThromboelastographyReprod Sci. 2017.
Kasap E. Et al. Comparison between resveratrol and cabergoline in preventing ovarian hyperstimulation syndrome in a rat model. Gynecol Endocrinol. 2016 Aug;32(8):634-640.
Govaerts et al. Short-term medical complications of 1500 oocyte retrievals for in vitro fertilization and embryo transfer European Journal of Obstetrics & Gynecology and Reproductive Biology; Volume 77, Issue 2, 1 April 1998, Pages 239–243
Jacob SL, et al. A short course of metformin does not reduce OHSS in a GnRH antagonist cycle for women with PCOS undergoing IVF: a randomized placebo-controlled trial. Hum Reprod. 2016 Dec;31(12):2756-2764.
Dosouto C et al. . Gonadotropin-releasing hormone agonist (GnRHa) trigger – State of the art. Reprod Biol. 2017 Mar;17
Son WY, et al. Early hCG administration as an alternative prevention strategy of ovarian hyperstimulation syndrome during an IVF cycle. Minerva Ginecol. 2017
Valeria M.S. et al; Cabergoline for the prevention of ovarian hyperstimulation syndrome: systematic review and meta-analysis of randomized controlled trials Fertility and Sterility, Vol. 101, Issue 3, p664–675.e7 2014
Sahin N et al. Comparison of the effects of letrozole and cabergoline on vascular permeability, ovarian diameter, ovarian tissue VEGF evels, and blood PEDF levels, in a rat model of ovarian hyperstimulation syndrome. Arch Gynecol Obstet. 2016 May;293(5):1101-6
Kumar P et al. Ovarian Hyperstimulation Syndrome. J Hum Reprod Sci 2011 4 (2) 70-75.