Allison K. Rodgers, M.D.
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.
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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.
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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
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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.
Meike L. Uhler, M.D.
We continue our efforts to keep you updated on advances in reproductive medicine and the availability of the newest technologies at Fertility Centers of Illinois. This letter provides information regarding a program called Fertility Awareness Checkup, which offers patients basic tests about their reproductive potential regarding ovarian reserve and semen quality.
Infertility affects approximately 15% of the reproductive age population, which is currently estimated at about 7.5 million people. Because of the high prevalence of this disease, as well as the media and internet attention to this problem, young women and men are becoming increasingly more aware of their own fertility potential. The Fertility Awareness Checkup is a simple test comprised of day 3 FSH, estradiol, and antral follicle count to measure ovarian reserve and semen analysis to assess sperm parameters.
The single most important factor in predicting pregnancy is the age of the female partner. It is commonly known that as age increases, the chance of pregnancy decreases. At the same time, the rate of spontaneous miscarriage and the chance of having a child with a chromosomal abnormality increases with increasing age. Both the age at which women are having their first child and the age of marriage are noted to be increasing. According to the CDC, the average age of first-time mothers in the U.S. in large metropolitan areas increased from 25.9 years in 2007 to 27.7 years in 2017. The average age of marriage has similarly increased from 26 in 2008 to 28 in 2018. As women choose to delay marriage and childbearing, the likelihood of future infertility increases. The monthly chance of achieving pregnancy gradually but significantly begins to decline at age 32 and decreases more rapidly after age 37.
Ovarian reserve refers to the ability of the ovary to respond to treatment to ovulation induction to produce reasonable quantity and quality of oocytes, and therefore, to achieve pregnancy. It does not predict spontaneous conception. There are several methods to test for ovarian reserve, and the simplest include day 3 FSH and estradiol.
FSH is elevated due to the aging ovary not producing an adequate amount of inhibin, which in turn suppresses FSH. Estradiol is elevated due to an increase in FSH earlier in the menstrual cycle. An FSH<10 mIU/ml and estradiol <70 pg/ml are considered within the range for normal ovarian reserve. Antral follicle count is another test of ovarian reserve using transvaginal ultrasonography to measure small follicles <10mm on day 3 of the cycle. A total number of small follicles bilaterally between10-20 is considered within the range for normal ovarian reserve.
Since male infertility comprises approximately 40% of all couples with difficulty achieving pregnancy, a semen analysis is an important step in assessing malefactor, the Fertility Centers of Illinois reference range for normal semen analyses is: volume 1.5-5.ml, concentration >15 million/ml, motility > 40%, and strict morphology >14%.
An abnormal test will most likely result in a recommendation to repeat the semen analysis with further follow up as indicated.
Fertility Awareness Checkup is a simple combination of four tests to check for ovarian reserve and semen quality. This test may be utilized by patients who are considering their present fertility potential with possible family decision making currently or in the near future. The cost is $90, and a nurse will call the patient back with results within one week. If the patient decides to further consult with an FCI physician, the fee is credited towards future treatment services.
Patients’ Fears about Fertility Treatment—Ann and David’s Story
Marie Davidson, Ph.D.
Fertility Centers of Illinois (FCI) continues to bring you the latest information concerning advances in reproductive medicine and the available treatments for your patients. This letter discusses patients’ fears about fertility treatment from the perspective of patients Ann and David.
Ann and David were a married couple, both 34, who had been trying to start a family for about 18 months without success. They qualified as infertile because they had not achieved a pregnancy in over 12 months of unprotected intercourse. Ann’s gynecologist did some hormone testing without any significant findings and she recommended that the couple consult a fertility specialist because Ann was very anxious and worried that they would be childless. They came to Fertility Centers of Illinois. They had some concerns (let’s just call them fears) that were representative of most fertility patients.
FEAR #1: Something must be wrong and maybe it’s really bad.
This is a fear that begins in advance of a patient’s first visit to Fertility Centers of Illinois. When Ann and David arrived for an initial consultation, they were already anxious, Ann in particular. Women start worrying after a couple of months of not conceiving. Men are more patient, but they become concerned about their wives ’ upset, even if they are not upset themselves. Typically, meeting a specialist is a big step—it signals there is a problem, which is negative; and that they are taking a step to figure it out, which is positive.
It is unusual for a couple to get a firm answer about what is impeding their efforts to build a family in this first visit, but they will get a lot of information about what might be a problem, as well as an overview of diagnostic tests and probabilities of success with different treatment approaches. This first visit is intended to be an exchange of information between physician and patient, followed by some time for the patient to think through what they want to do next. Ann and David left the office with what I call “a virtual suitcase of new anxieties,” as well as feeling that they now had allies in their dream to have a baby.
FEAR #2: Whose fault is this?
Even before diagnostic testing on a couple is completed, both partners worry if it is a problem on their end. David wondered if the occasions in his single 20’s when he hadn’t used a condom but his partner didn’t get pregnant (lucky at the time!) meant that his sperm didn’t work. Ann worried that her often irregular cycle was the issue and whether the fact that her aunt hit menopause at age 39 meant anything for her.
Ideally, Ann and David could talk about this, but it is a hard conversation to have and even harder if the problem is identified as residing in one partner. It is difficult to be completely rational when the stakes are high. Of course, any fertility problem of wife or husband is a couple of problems, but what if they can’t see it that way, and it becomes a source of resentment for the fertile partner and a source of guilt for the partner with the fertility obstacle?
Fortunately, when Ann and David found out that their issue was likely an ovulatory dysfunction, David was able to say, “Look, we’re in this together. I married you, not your ability to ovulate on time.” This was very comforting to Ann, although she still saw herself as the one to “blame.” Perhaps the only thing worse than getting a diagnosis is getting no diagnosis and having your problem classified as “unexplained.” Something is getting in the way but we don’t have the scientific tools to uncover every impediment. Being “unexplained” drives fertility patients crazy. It is essentially human for people to know why something is happening and when it is unknown that adds another dimension to what all fertility patients describe as feeling out of control.
FEAR #3: Can This Problem Be Fixed? (And what’s It Going to Cost?)
Ann and David came back to Fertility Centers of Illinois for diagnostic feedback and to hear in more detail how their problem could be addressed—medications and monitoring to normalize Ann’s cycle and pinpoint when ovulation would occur, with timed intercourse; or all of that, but also with insemination with David’s sperm on the optimal day; or in vitro fertilization (IVF), using more medications and more monitoring but leading up to an egg retrieval, insemination of eggs in the lab, and an embryo transfer. IVF would also introduce the possible creation of multiple embryos, the possibility of doing genetic testing of the embryos to detect abnormalities, and concerns about the final fate of any embryos that would be frozen and stored in the IVF lab.
David and Ann had pretty good insurance for fertility treatment through Ann’s job, and they were pleased to find that they were benefitting from living in Illinois, a “mandated” state where infertility treatment is a covered expense. However, there would still be co-pays, out-of-pocket expenses for anything not covered (genetic testing of embryos, freezing cost), and maybe a large amount of money if they needed expensive fertility medications after their drug maximum was reached.
For many patients, Illinois law doesn’t apply. Employers who are “self-insured” (usually large companies,) religious employers (e.g., a Catholic hospital,) and businesses with less than 25 employees do not have to follow the state law regarding treatment and patients have “diagnostic only” coverage. Self-employed patients may have no coverage at all, although that has improved greatly with the impact of the Affordable Care Act. Infertility treatment may be simply unaffordable for many people, who might borrow from family, take out a second mortgage, or apply for fertility scholarships. Or, forego treatment.
How many of our patients take home a baby? That is the plan, for all the patients who come to us, but some people do not arrive at the dream we share with them. The live birth outcomes we have the best information about are reported to the Society for Assisted Reproductive Technology (www.sart.org.) They are usually two years behind, to allow time for reporting of live births after treatment. Putting all FCI’s treatment approaches together, our best estimate is 70% of our patients achieve parenthood with our help. Sometimes, a former patient will call to tell us they had a baby through, of all things, sex! As our founding physician, Dr. Aaron Lifchez, once said, “Sometimes our patients get pregnant despite our best efforts.”
FEAR #4: How will we handle the emotional and social struggles of treatment?
Ann and David started out with a solid marital relationship and were able to work, most of the time, as a team. It was not easy, and they ran into many ups and downs during their time with FCI. The costs of fertility treatment are not just financial.
Impact on work—Ann was a 4th-grade teacher in a Chicago suburb. Even though FCI offices open very early in the morning, there were times when she had to be late and have someone take over her class for a short time. She was lucky that her principal was very sympathetic and made it work for Ann. A downside was that Ann felt her fertility journey was common knowledge in the staff room. She said, “In an elementary school, there is no such thing as reproductive privacy.” Other female patients have a hostile boss or fear they won’t be considered for advancement, or value their privacy and want to keep their treatment a secret. That becomes nearly impossible if the treatment is IVF, with all the monitoring appointments and days off needed for egg retrieval and embryo transfer. David had a much easier time, as a sales representative who had a flexible schedule.
Impact on relationships—this might be the hardest area to navigate, at least as hard as dealing with infertility in the first place. Despite their strong marriage, Ann and David had some difficult times as a couple. When David’s younger brother’s wife was expecting a baby, Ann had a very difficult time with that and did not want to attend the baby shower. This is quite normal for a fertility patient, but David felt hurt that his wife couldn’t “suck it up” and just go and put on a fake smile. They worked out a compromise. Ann went to the shower, delivered a gift, and stayed for lunch. As gifts were about to be opened, Ann left, pleading a migraine.
Both David and Ann agreed that attending family gatherings was often not pleasant when they were going through treatment. They had decided to share the basics of their journey but dreaded all the intrusive questions and unwelcome advice. One Christmas, a very child-oriented holiday in their families, they opted to take a vacation in Florida. The family was aghast, but Ann and David hung tough and were glad they did. They needed to take care of themselves as a couple.
Fertility patients need to be careful about which friends they go to for support. Men tend to be less disappointed because they are more private and don’t share as much. David‘s best college friend was a good sounding board for David and cheered him on. Ann learned, to her dismay, that most of her girlfriends were not very sensitive when it came to her fertility journey. “They just don’t get it,” Ann said. She found her best support came from her single sister and from a Facebook group she joined.
Impact on self-image and emotional health—Fertility patients are vulnerable to feeling somehow defective, or “less than.” Ann struggled with the way her body didn’t work correctly. Was she an imperfect woman, incomplete if she couldn’t have a baby? David had normal sperm parameters, but he commented that he would have had a tough time if his fertility was compromised. When it is the male with the problem, it may throw them into a profound personal crisis. If someone finds out they have no sperm, for example, that is shocking news that takes time to adjust to.
Patients sometimes feel that they have met their “dark side.” Ann asked, “Am I really a bad person because I am so envious of every pregnant woman I see at the mall?” This is very much a temporary state of being, but it feels awful.
It is very common for our patients to suffer from high levels of anxiety and/or depression. They worry that their stress is a factor in their infertility or if they can keep going in treatment feeling a bad as they do. Women seem to suffer more, but their male partners suffer, too, often in silence. They want to be strong for their wife, even when they are frustrated that they can’t fix this problem and don’t know what to say. As David put it, “Infertility is not for sissies.”
FEAR #5: What if nothing works?
Patients spend some time dwelling on this thought fairly early in the treatment process. Women, in particular, think ahead and mentally rehearse all possible outcomes, often baffling their husbands, who are more willing to just see what happens. It is hard to contemplate the possibility that all of the time, all the money, all the disruptions to their life, and all the emotional capital they have expended might not result in the child they wish for so fervently. Sometimes, when patients are able to embrace this lack of any real control over the outcome of treatment, they are liberated from some of their emotional burdens and can look at their lives beyond infertility. For some, that might involve pursuing adoption; for others, it might be accepting a life that does not involve directly parenting children.
Countering the Fears: What does Fertility Centers of Illinois offer?
Fertility Centers of Illinois understands that our patients are not only on a medical journey and we offer all our patients support and counsel for their emotional and psychological well-being. We have three behavioral health specialists on staff who have expertise in the challenges of fertility treatment and who can offer help with decision-making, pregnancy loss, couple conflicts, and managing anxiety and depression.
Our behavioral health staff can see patients at four of our office locations and can call a patient in a crisis. We offer a complimentary first meeting for support, and an additional complimentary meeting for patients thinking of moving to IVF. If it makes more sense, we will help patients find a mental health provider in their local community.
Our social worker offers three on-going support groups—general infertility, single women pursuing parenthood, and patients who have had a pregnancy loss. We work closely with Pulling Down the Moon, our holistic partner who offers in-person classes and webinars on yoga, nutrition, acupuncture, and other approaches to helping make the fertility journey less difficult and more manageable. We will help our patients long after they have left, but now want advice about talking to their children about their donor-assisted conception or are seeking help about what to do with their frozen embryos.
Ann and David—the end of their story.
After two years and two months with FCI, they succeeded, having a successful pregnancy after an IVF cycle. They have frozen embryos so we expect to see them back to try for a second child. The other day, Ann, who is on maternity leave, came in to visit with baby daughter in her stroller. These “baby visits” are very special to FCI staff and remind us why we are here.
Fibroids & Infertility
Edward L. Marut, M.D.
At Fertility Centers of Illinois, we believe in staying current on recent literature and applying that knowledge to better care for our patients. We enjoy sharing that information with fellow physicians to help keep you informed on recent advances regarding infertility therapies. The Information letter from Fertility Center of Illinois this month deals with fibroids and infertility.
While many women conceive with leiomyomata and even go on to deliver vaginally at term, the likelihood of successful pregnancy is clearly reduced overall. The probabilities lie in the size and position of the fibroids. Most obviously, the biggest culprit to prevent implantation is the submucous myoma, and virtually any size can cause problems if in the fundal area. Also obvious are the intramural or transmural myomata, which extend into the cavity and have a submucous component.
Studies have been done to show that certain RNAs associated with implantation are reduced or absent with submucous myomata. The simple physical presence, as well as the attendant inflammation and abnormal endothelial surface, can explain the negative effects.
The next type of myoma that is problematic is one that does not have a submucous component but distorts the cavity, which may have more implications for the maintenance of pregnancy than conceiving. This type can also play a role in premature labor, obstructed labor, and complications at delivery.
Less obvious and not an absolute factor are subserosal fibroids. Strictly speaking, if they do not interfere with tubal function and are clearly away from the cavity, they can be left alone. But normal tubal function may be impaired by strategically placed subserosal myomata, which may not be obvious.
Lastly, the intramural myoma that has no submucous component and does not distort the cavity may be the most difficult to assess its effects. There are several studies that document the proximity of intramural myomata larger than 4-5 cm to the cavity to result in reduced pregnancy rates from IVF.
It is not a jump to assume that natural conception may be affected in a similar manner. It seems that conception may occur due to the good fortune of an embryo implanting on the wall opposite the myoma’s influence; thus, overall pregnancy rates are beholden to chance (which no one likes) as are the rates of normal progress of the gestation. There is good evidence that myomata may shrink, grow, or stay the same during pregnancy; even one that has not interfered with conception may degenerate and jeopardize the pregnancy. The inflammation of an ischemic fibroid can present as an acute abdomen and even a pelvic infection.
The diagnosis of fibroids can be made by plain pelvic ultrasounds, the vaginal probe usually being more reliable in determining position, but enhancing the visualization by a saline infusion sonogram or hysterosonogram, will characterize size and position better. Hysterosalpingography is not as helpful, and more elaborate methodologies like CT or MRI would usually be redundant, but often useful in certain cases.
Surgery is the mainstay of treatment, and hysteroscopic and laparoscopic techniques are widely used and are shown to have excellent results, with the least damage to normal uterine tissue. However, open myomectomy is often necessary with large or transmural myomata. The need for future Caesarean sections will depend on the entry into the cavity and integrity of the wall.
The medical management of fibroids seems to be most efficient for the intramural and transmural myomata; using GnRH analogs, both agonists and antagonists have been shown to reduce the volume, but the process tends to be reversible once therapy is stopped. Ulipristal and mifepristone are progesterone modulators that have shown promise in reducing myoma size, but again without certain lasting effects. Medical pretreatment prior to surgery has been shown to be quite useful in reducing blood loss and normal tissue disruption.
While at Michael Reese Hospital in the mid-80s, I published a paper demonstrating the efficacy of leuprolide acetate in the medical management of myomata. However, this was usually prior to surgery or for long term medical management. Thus, the decision to treat fibroids may be pre-emptive, or only after a time of infertility or a pregnancy loss. The sooner the better, for sure.
Jennifer E. Hirshfeld-Cytron, M.D./MSCI
Fertility preservation is an emerging area of reproductive medicine that empowers women to make well-informed decisions regarding their reproductive options. In October 2012 The American Society for Reproductive Medicine (ASRM) published practice guidelines that removed the experimental label from oocyte cryopreservation. To date, there have been over 2,500 live births achieved from oocyte cryopreservation without an increase in pregnancy complications or congenital anomalies.
It is commonly known that as age increases, the chance of pregnancy decreases. At the same time, the rate of spontaneous miscarriage and the chance of having a child with a chromosomal abnormality increases with increasing age. The monthly chance of achieving pregnancy gradually but significantly begins to decline at age 32 and decreases more rapidly after age 37. Other modifiable factors that are known to impact a patient’s fertility include tobacco use and obesity. These realities are driving many women to inquire about their ovarian reserve and consider oocyte vitrification as a means to extend one’s reproductive window.
We recommend women who are considering egg freezing, to undergo ovarian reserve testing. Ideally, women are off hormone contraception for at least a month prior to testing. We use this opportunity to also conduct preconception testing such as viral titers and genetic carrier testing. We view egg freezing as the ultimate in preconception and another opportunity to educate women regarding the value of this testing.
Interesting, studies following women that obtained ovarian reserve markers who had been trying less than 3 months, or in the context of a desire to learn about “reproductive potential”, did not find a relationship between abnormal ovarian reserve markers and fertility. In other words, ovarian reserve markers help to determine response to gonadotropins and egg yield for patients considering egg freezing but can’t predict reproductive potential in women who are not infertile.
Although the first successful birth from egg freezing occurred in 1986 by Chen et al, it wasn’t until 2012/2013 that ASRM/ACOG, removed the experimental label from egg freezing. Egg freezing was initially performed using a slow free technology, the use of vitrification has greatly improved success. Vitrification is a freezing method that encases a cell in a glass-like (vitreo = glass in Latin) ball of ice.
Vitrification does not cause ice crystal formation and therefore causes less damage to cells. At FCI, we have been using vitrification technology for embryos for 13 years with 95% survival rates upon warming. Oocytes that are frozen using vitrification technology have yielded similar survival rates.
Studies have suggested for women less than 38 pregnancy success from vitrified eggs is similar to fresh. For women older than 38, although embryo freezing is more successful it requires either a partner or a sperm donor. The approach of egg freezing has been to create a sufficient number of eggs for women of varying ages to allow for success. For instance, women less than 35 years old likely need 12-15 mature eggs to have an 80% chance of a SINGLE live born from those eggs.
Women who are 38 years old require 25-30 and women who are 40 years old require 50 mature eggs for similar success. Questions that still remain is what is a reasonable number if a woman desires many children? How do we best counsel women with low yields of oocytes from an egg freezing cycle regarding natural conception?
Data looking at children created from egg vitrification has been reassuring. There has not been shown an increase in aneuploidy or birth defects from these children. Although initial data is reassuring, a worldwide database would be ideal. The literature has demonstrated comparable pregnancy rates between fresh and frozen oocytes. Cobo and Diaz published a meta-analysis in Fertility and Sterility, August 2011, and combined data from the use of 22,741 frozen oocytes. Pregnancy rates in the vitrified oocyte group were 49.1% compared to 48.3% in the fresh group.
Our very own lab at FCI has demonstrated similar success rates with vitrification technology. At FCI, we have been doing egg freezing since 2004, initially for cancer patients. We have vitrified 10,845 oocytes to date from 921 patients with a mean age of 35.8 years. To date, we have warmed 720 oocytes with a clinical pregnancy rate of 45-48%.
Steiner et al. Associations between biomarkers of ovarian reserve and infertility among older women of reproductive age. JAMA. 2017:318(14):1367-76.
Goldman et al. Predicting the likelihood of live birth for elective oocyte cryopreservation: a counseling tool for physicians and patients Hum Reprod 2017 32(4): 853-859
Endometriosis & Infertility
Jane M. Nani, M.D.
Endometriosis is a relatively common disorder affecting women of reproductive again. It is estimated that 25% to 50% of infertile women have endometriosis and that roughly 30%-to 50% of women with endometriosis are infertile.1 However, the exact causal relationship between infertility and endometriosis remains controversial. In some cases, the development of pelvic adhesions and distorted pelvic anatomy, clearly demonstrate a cause and effect relationship with expected decreased fecundity. Still, the causality with mild endometriosis is less obvious, and expected enhanced fertility with hormonal suppression of endometriosis is not supported by the literature.
Several mechanisms have been proposed as explanations for reduced fertility with endometriosis. With severe endometriosis and major pelvic adhesions, this could result in impaired oocyte release and/or inhibited ovum capture or transport. The increased peritoneal fluid that occurs in endometriosis has been shown, in some studies, to contain elevated prostaglandins, and inflammatory cytokines, thus leading to systemic inflammation. Increased IgG and IgM antibodies that may be present in women with endometriosis, could alter endometrial receptivity. Decreased expression of ∂Vβ3 integrin during time of implantation has been suggested in some women with endometriosis. It has also been suggested that women with endometriosis may have unruptured follicle syndrome.2
In current clinical practice, a surgical procedure such as laparoscopy is required to make a definitive diagnosis of endometriosis. In addition, if the diagnosis is not immediately obvious at the time of surgery, histology may be used to make the diagnosis. The question of whether and when to suggest diagnostic surgery in the case of infertility is controversial. In the clinical situation of infertility alone, without any pain and/or dysmenorrhea, the likelihood of making the diagnosis of endometriosis and the benefit of surgery must be considered. According to recent ASRM guidelines, laparoscopy of asymptomatic women with infertility is unwarranted. In addition, since 1996 the ASRM offers a classification for the staging system of endometriosis that is widely used.
Unfortunately, the staging system does not correlate well with the chance of conception following treatment. However, a new classification system proposed in 2010, the Endometriosis Fertility Index, has been validated as a clinical tool that predicts pregnancy rates after endometriosis surgical staging.3 The EFI score takes into account the function of tube, fimbria, and ovaries on both sides, and accurately predicts pregnancy rates in patients with endometriosis, who attempt non-IVF conception.
Therapeutic options for the treatment of endometriosis-associated infertility, include medical and surgical approaches. For mild disease, stage I & II endometriosis, various medical approaches have been tried historically, with the goal of suppressing endometriosis. These have included combined estrogen-progestin therapy, progestin alone, danazol, and both GnRH agonists and antagonists. However, a meta-analysis that included 13 clinical trials and 800 infertile women, done by the Cochrane Review some years ago, concluded that no evidence exists that medical suppression was superior to placebo in women who wished to conceive.4
Newer agents such as aromatase inhibitors and SERMs have not been well studied in the medical management of endometriosis for fertility. On the contrary, in stage I/II endometriosis, laparoscopic ablation of endometrial implants has been associated with a small, but significant improvement in live birth rates.
With advanced disease, stage III/IV endometriosis, surgical management may increase fertility, especially when large endometriomas (>4cm) are completely resected rather than just drained. However, the risks of surgery and its potential damage to ovarian reserve need to be balanced against complications associated with the persistence of endometriomas during IVF.5 Indeed, the continued debate in the literature rages on about the initial approach to ovarian endometriosis, whether surgery or IVF.6
When it comes to the utilization of superovulation and intrauterine insemination (IUI) in endometriosis, the results in the literature are confusing. In most studies, superovulation and IUI are started after initial surgery to ablate endometriosis in mild disease. In this specific setting, of stage I & II endometriosis, surgical treatment, followed by ovulation induction/IUI may be a viable option as an alternative to IVF.
Particularly, in younger women mild endometriosis, expectant management after surgical therapy is considered an option. However, better data exists to suggest that in severe endometriosis, (stage III & IV), IVF likely maximizes cycle fecundity, especially in those with pelvic distortion. For women with stage III/IV endometriosis who fail to conceive following conservative surgery, IVF is an effective alternative.
Lastly, female age, duration of fertility, degree of pelvic pain, and stage of endometriosis should be considered when developing a management plan. Younger women (< 35) with mild disease, expectant management or ovulation induction/IUI can be considered as initial therapy. However, for women of advanced maternal age, more aggressive therapy, such as IVF should be considered.
- Missmer SA, Hankinson SE, et al. Incidence of laparoscopically confirmed endometriosis by demographic, anthropometric, and lifestyle factors. Am J Epidemiol 2004; 160: 784-96.
- Schenken RS, Asch RH, et al. Etiology of infertility in monkeys with endometriosis: luteinized unruptured follicles, luteal phase defects, pelvic adhesions, and spontaneous abortions. Fertil Steril 1984; 41:122-30.
- Adamson GD, Pasta DJ, et al. Endometriosis fertility index: the new, validated endometriosis staging system. Fertil Steril 2010; 94:1609-15.
- Hughes E, Brown J, et al. Ovulation suppression for endometriosis. Cochrane Database Syst Rev 2007:CD000155.
- Donnez J, Garcia-Solares J, et al. Ovarian endometriosis and fertility preservation: a challenge. Minerva Ginecol 2018; 70:408-14.
- Lessey B, Gordts S, et al. Ovarian endometriosis and infertility: in vitro fertilization or surgery as the first approach? Fertil Steril 2018; 110: 1218-1226.
How to Counsel Your Patients about Fertility & Family Planning
Asima K. Ahmad, M.D., M.P.H.
In the United States, the mean age of a woman having her first child has risen over the past several decades. Although there are many factors that could be contributing to this change, it does impact how we approach and counsel our patients about their fertility potential and pregnancy outcomes.
Females are born with the oocytes they will use during their lifetime and this number continues to drop over time. They have 1-2 million oocytes at birth, dropping to 400-500,000 by puberty and only ~1,000 by the time she is menopausal. In addition, the genetic quality of her oocytes decreases with age as these oocytes go through the final stages of meiosis – for a woman >42 years of age, >90% of her oocytes will be aneuploid. Therefore, even though she may still be menstruating regularly, the likelihood of that oocyte being euploid and it resulting in a live birth is extremely low. Her rate of miscarriage will be >40% per pregnancy and her chance of pregnancy per cycle will be 5% or less.
Given these changes in a woman’s fertility potential with age and increasing age with first pregnancy, sometimes our patients do not realize their fertility potential by the time they are ready to start building their families. And in some situations, it is already too late… Each one of their clinic visits presents an opportunity for us to assess their desire for childbearing in the near or distant future and their family-building goals.
One way to look at it is – fertility care – not just infertility.
We live in a unique time where fertility preservation techniques, such as oocyte vitrification, have been refined and present the opportunity for women to delay childbearing if they so choose – leaving potential to conceive at a later age. This allows women more freedom and flexibility to have their first child when they are ready. In addition, for those desiring multiple children, seeking treatment sooner and having embryos frozen at an earlier age increases their chance of live birth per embryo as compared to seeking fertility treatment at a later age.
For those women currently trying to conceive, but having difficulty, certain situations also warrant an earlier referral than the usual 6-12 months. These women include but are not limited to those with ovulatory dysfunction, severely diminished ovarian reserve (i.e., very low AMH), tubal dysfunction, or male factor. In situations where there is a delay to care, sometimes it is too late for women to use autologous oocytes for conception.
Every woman is unique in her fertility goals, and the conversation is not always easy to broach with patients. However, educating our patients on their fertility potential and presenting options for family building earlier on can bring them one step closer to their ideal family size.
Fertility Preservation Coverage for Illinois Cancer Patients
John J. Rapisarda, M.D.
As of January 1, 2019, a new law goes into effect requiring that fertility preservation be covered by Illinois health insurance companies for patients diagnosed with cancer or who experience iatrogenic infertility, also known as medically-induced infertility.
For the first time, Illinois patients will not have to choose between effective medical treatment and a future chance at a family. This change is a long time coming, and Illinois is the fifth state in the country to adopt this into law.
According to the Illinois Department of Public Health, a reported 5,800 Illinois residents of reproductive age – between age 14 and 45 – are diagnosed with cancer each year. The majority of cancer patients are at risk for medically-induced infertility as a result of their cancer treatment. Patients undergoing treatment for sickle cell anemia, lupus and other autoimmune diseases may also experience medically-induced infertility.
We’d like to explain what this new law includes, what is covered, who is eligible, and how you can access these new benefits.
What is covered: Standard fertility preservation services including the preservation of eggs, embryos and sperm for patients with cancer and certain other diseases.
Who is eligible: Those with IL-based health insurance who are at risk of experiencing medically-induced infertility as a result of treatment for cancer, sickle cell anemia, lupus, and other autoimmune diseases. Medically-induced infertility is defined as impairment of fertility by surgery, radiation, chemotherapy, or other medical treatment affecting reproductive organs or processes. Treatment may directly or indirectly cause infertility, meaning that there is a likely possibility that treatment will cause a side effect of infertility based upon current evidence-based standards.
The law also states that an insurer shall not discriminate based on an individual’s expected length of life, present or predicted disability, degree of medical dependency, quality of life, or other health conditions, nor based on personal characteristics, including age, sex, sexual orientation, or marital status.
Who isn’t covered: Keep in mind that this law offers very broad coverage, but not all will be eligible. Unfortunately, Illinois patients with health insurance that is not based in Illinois are not eligible. Health insurance that is regulated and overseen by the federal government also does not adhere to state law. This includes federal employees, those with an ERISA (Employee Retirement Income Security Act of 1974) plan, TRICARE for the military, and Medicaid.
For patients who are ineligible, Fertility Centers of Illinois offers discounted fertility preservation treatment. The Livestrong Fertility Program also offers discounted treatment and medication to accepted applicants, and the Heart Beat Program from Ferring offers free medication to women with cancer.
Determining eligibility: The best way to determine your coverage is to reach out to your HR department as well as your insurance company.
Keep in mind that coverage will vary – outside of this law, you may have coverage. For example, some companies such as Facebook and Google cover fertility preservation. Veterans Administration is not covered under this law but they have created their own plan that covers fertility preservation. Companies with ERISA plans may have opted for this benefit in their own plan.
Appointment requests: We see cancer patients within 24-48 hours of appointment request to discuss the fertility preservation process and begin treatment as soon as possible. The best candidates for freezing eggs or embryos are pre-menopausal women who have clearance from their oncologists to use injectable fertility medications and undergo the procedure.
The treatment process:
- Egg Freezing: The entire egg freezing process requires roughly three weeks to complete. A woman is placed on medication that stimulates the ovaries to create eggs, and is monitored via ultrasound regularly. Once egg development is optimal, a 15-minute egg retrieval procedure is completed and the result eggs are frozen.
- Sperm Freezing: A male provides a sperm sample which is then frozen for future use. Samples can be produced at home or in a dedicated private room at our offices.
- Embryo Freezing: Once eggs are retrieved, they are injected with sperm in our laboratory. The resulting embryos are cryopreserved for future use.
Working with your Oncologist: We work closely with your oncologist to ensure that we do things in a way that continues to make it safe for the patient to pursue fertility preservation without affecting cancer treatment. It is important to note that long-term studies have shown no decrease in the number of patients who survive if they have gone through fertility preservation. Patients who are unsure on whether to pursue treatment can set their minds at ease regarding this concern.
Choosing a center: It is overwhelming to receive a cancer diagnosis and navigate cancer treatment and preserving your fertility at the same time. When choosing a center to work with, select one that has extensive egg and embryo freezing experience and women who have returned to use their eggs or embryos and then had children. When there is truly one opportunity to preserve fertility, it is essential to work with an experienced team.
As you work with your insurance provider and respective medical teams, please reference and share the links below for background information on this new law.
Veterans Health Administration: VHA Directive 1332 Infertility Evaluation and Treatment – VA.gov
Preconception Checklist for Growing a Family
John J. Rapisarda, M.D.
As part of our continuing effort at Fertility Centers of Illinois to keep you up-to-date on important topics and advances in reproductive medicine, the following letter will provide a pre-conception checklist to help your patients prepare for growing their families in the New Year.
While your patients may complete a physical and routine screening with you prior to trying to conceive, we’d like to provide a list of other considerations to take into account.
Review updated insurance coverage:
The new year often comes with updates and changes to individual insurance coverage. As many as 20% of patients will have coverage for infertility services designated as diagnostic only. This means that only testing will be covered, but not treatment. In these patients, it is very important to do all testing first before any treatment is started, such as ovulation induction with clomiphene citrate. After treatment has started, no further testing will be covered. With diagnostic only coverage, the patient is considered self-pay for all infertility treatment.
Assess the reproductive health of both partners:
Fertility diagnoses are split with approximately one-third being attributed to the woman, one-third with the man, and another third due to combined factors, or unexplained. Completing a Fertility Awareness Checkup for only $90 is an affordable way to assess the reproductive potential of both partners. The checkup includes a blood test and ultrasound for women to evaluate ovarian reserve and a semen analysis for men to assess sperm count, morphology, and motility.
Review existing medication:
Many medications may interfere with conception or pregnancy. We recommend that you review your patient’s current medications and supplements and identify any that could be deleterious during pregnancy. When possible, the medication may be discontinued, or a safe alternative can be chosen.
Offer genetic carrier screening:
The American College of Obstetricians and Gynecologists recommends genetic counseling and offering preconception carrier screening for all women contemplating pregnancy. This includes screening for cystic fibrosis, spinal muscular atrophy and other conditions as indicated by family history and ethnic background.
Assess Body Mass Index and encourage a weight goal:
An elevated BMI can impact fertility in both women and men and lead to hormonal imbalances. A very low BMI (<20) may be associated with cessation of ovulation. It’s recommended to encourage a healthy lifestyle and achieve realistic weight gain or loss prior to attempting pregnancy.
Boost Vitamin D levels:
Normal Vitamin D levels may help optimize fertility and decrease complications during pregnancy. Midwesterners are at particularly high risk of having low Vitamin D levels and should undergo screening with recommended supplementation or dietary changes if found to be deficient.
Complete all necessary vaccinations:
This includes screening for immunity to Rubella and Varicella and having a flu shot during influenza season.
Start folic acid supplementation prior to conception:
400 micrograms of folic acid per day are recommended for those at average risk of having a child with a neural tube defect (NTD). High-risk individuals with a history of having a child with an NTD, or who have a seizure disorder, should take 4mg of folic acid daily.
Manage chronic conditions:
To optimize pregnancy outcomes and reduce the risk of complications, control of chronic medical conditions such as diabetes, hypertension and thyroid disorders should be achieved prior to pregnancy.
Counsel about travel:
Certain destinations increase the risk of exposure to infectious diseases which may impact a subsequent pregnancy. Patients should be counseled about Zika virus exposure and the appropriate interval to postpone pregnancy following travel to affected regions.