Ask Dr. Quaas Part II
As some or most of you read in my post a few weeks ago, I had sat down with Dr. Alexander Quaas to ask him a few questions that I thought might be helpful for those starting infertility treatments order anyone just needing to hear some answers directly from a medical professional's mouth.
If you didnt get a chance to read that blog post please make sure you check it out! But as a refresher, Dr. Alexander Quaas earned his M.D. from the University of Manchester in Manchester, England and his Ph.D. from the Albert Ludwig University in Freiburg, Germany. He completed his residency in Obstetrics and Gynecology at Harvard University and his fellowship in Reproductive Endocrinology and Infertility at the University of Southern California. Prior to joining Reproductive Partners Fertility Center – San Diego, Dr. Quaas was a physician and faculty member at Oklahoma University Health Science Center and at the University Hospital of Basel, Switzerland. He is a board certified in Reproductive Endocrinology (RE) and Infertility.
Dr. Quaas is constantly researching and is very involved in the teaching field of infertility as well. He always has a way of explaining everything to me until I completely understand it. And sometimes, if he doesn't quite know what to tell me, he will do more research before giving me an answer. So he's the best person to ask these questions to since he always takes his time and gives me the best possible answers.
Furthermore, since our first Q&A with Dr Quaas was so successful, I thought it would be nice to have another set of questions for him. A lot of you sent me a few questions and I had some myself with everything going on in the world today.
On that note, these questions were sent to Dr. Quaas via email because, well social distancing of course #covid19. I hope that soon we can sit with our doctors and nurses without masks and ask as many questions as our little hearts desire. But for now, this was a good "second best" option.
1. What is your take on baby aspirin? Why is it given or not given?
Aspirin is one of the most widely used medications in the world- it can relieve pain, fever and inflammation and acts as a blood thinner. It can save lives when given shortly after a heart attack.
In the IVF setting, a randomized trial was performed in Argentina on 298 tubal factor IVF patients to study the use of Aspirin versus placebo. It found that the ovaries of patients taking Aspirin were more responsive to stimulation, and that blood flow to the uterus and ovaries of the patients taking Aspirin was improved. Most importantly the implantation rate and clinical pregnancy rate of patients taking Aspirin were higher.
The problem with the study is that since it was done, there have been at least 10 other trials with a similar study design, and the Argentinian study is the only one that demonstrated a benefit. A meta-analysis by the Cochrane collaboration, an institution that pools study data to answer clinical questions, concluded that there was currently no evidence in favor of Aspirin in the setting of IVF. There is little harm to the use of Aspirin, but the potential harm is not completely zero, so I no longer recommend baby Aspirin for patients going through an IVF cycle.
2. During PGS testing, on average, how many embryos typically come back normal?
When a couple chooses to do PGT-A testing (pre-implantation testing for aneuploidy, formerly known as PGS), the main predictor of how many embryos will be euploid, meaning chromosomally normal, is the age of the eggs. That means the age of the female partner, or in the setting of egg donation, the age of the egg donor.
When I discuss this topic with my patients, I like to go over the results of a study by Franasiak et al. from RMA New Jersey published in “Fertility and Sterility” in 2014 entitled “The nature of aneuploidy with increasing age of the female partner: a review of 15,169 consecutive trophectoderm biopsies evaluated with comprehensive chromosomal screening”.
The authors of the study present data from over 15,000 tested embryos, and Figure 2 of their paper includes a graph depicting the relationship of age with the rate of aneuploidy (chromosomally abnormal embryos). In other words it demonstrates what the rate of abnormal embryos is for each age.
As an example the approximate rate of aneuploidy up to age 35 is somewhere around 30%. Over age 41 more than 70% of embryos are abnormal. Between age 35 and 41 the rates are somewhere in between.
It is important to emphasize that these rates are approximate, and that individual results will vary a lot, because the “sample size” (the number of tested embryos) for each individual couple is usually low, and outliers are common- a couple may have an unexpectedly positive or negative result that deviates from the expected rate.
3. When grading an embryo good, fair and poor, what are you looking for exactly?
The lab has multiple criteria for grading embryos that differ depending on the stage of development of the embryo. On day 3 after the egg retrieval, the embryo is at the “cleavage stage”, and the embryologist looks at the number of cells (it should be somewhere around 8), but also other “morphological” (appearance) factors such as the degree of “fragmentation” and whether the cells are equal size.
Most laboratories nowadays culture the majority of embryos to the “blastocyst” stage, which is reached between days 5 to 7 after egg retrieval. At this point the embryo contains more than 150 cells. A blastocyst has two parts: the “inner cell mass” (ICM) which is destined to develop into the fetus, and the “trophectoderm” which is the precursor of the placenta. The number of cells in both, but also the degree of expansion of the blastocyst factor into the grading of the embryo.
It is important to keep in mind that embryo grading is somewhat subjective, and that while an association between morphology and success rates exists, it is not a strict correlation.
A very favorably graded embryo may not be chromosomally normal, and may not implant. On the other hand there is a (very unscientific) saying that “sometimes the ugliest embryos make the cutest babies”.
4. Do most good embryos come back PGS normal? Or does one not have anything to do with the other?
There is some correlation between the morphology and the chromosomal status of the embryo, and as a general tendency, more favorably graded embryos are more likely to be euploid (chromosomally normal). However the correlation is not very strong, and the purpose of the PGT-A testing is to help us select the most promising embryo when there are multiple morphologically similar blastocysts. It is not uncommon that the “best-looking” embryo is not chromosomally normal, and that the PGT-A testing leads us to recommend transferring a euploid embryo that received a less favorable grading.
There is a big ongoing debate about the use of PGT-A in our field. Most infertility specialists use a strategy of transferring the morphologically best embryo amongst the chromosomally normal ones in patients who choose to have the PGT-A testing.
5. How many days is the average number that someone might be on hormones to grow their follicles? At what point would you stop the cycle?
The average duration of ovarian stimulation with injectable gonadotropins prior to egg retrieval is somewhere around 9-12 days. During that time we monitor the growth of the follicles closely with ultrasound, and also follow the hormone (estradiol) levels to assess the ovarian response. We try to find a happy medium between obtaining a good number of eggs and not hyperstimulating the patient. We usually “trigger” patients in preparation for egg retrieval when the lead (largest) follicle reaches a size of 18-20 mm, but many factors are being considered with regards to timing. The most common reason for cycle cancellation is a poor ovarian response to the stimulation. Rarely, it is necessary to cancel a cycle prematurely because of an excessive response, but this can usually be prevented with careful choice of medication dosing and close monitoring.
6. How do you determine how much medication is needed for each patient? Is there a typical starting point for egg retrieval prep? For transfer prep?
The main factor to consider when deciding on the stimulation protocol and dose of medications is the ovarian reserve of the patient. This can be assessed by looking at the patient’s age (most importantly), but also the number of follicles in the ovaries, and some specialized blood test, such as the AMH (anti-mullerian hormone) level. As a general principle, women with lower ovarian reserve need higher doses of medication, and women with high ovarian reserve lower doses. All of our treatments (egg retrieval cycles / transfer cycles / insemination cycles) usually start with the patient calling with her period (“cycle day 1”).
7. What should someone expect post egg retrieval?
After the “ovulation trigger” prior to the egg retrieval, which induces the final maturation of the eggs, the cells of the follicles in the ovaries undergo a transformation which induces physiological changes in the whole body. This manifests itself in water retention and increased bloating. I tell patients that the bloating, which is commonly already present prior to egg retrieval, usually gets worse before it gets better. This is especially true for women with high numbers of follicles and eggs retrieved. At its worst, patients can get “ovarian hyperstimulation syndrome”, a severe complication of IVF treatment, which fortunately is getting less and less common because of changes in treatment strategies in our field.
Another common occurrence after egg retrieval is constipation, due to a variety of factors, including rising progesterone levels, use of pain medications, inactivity etc.
I usually discuss strategies with my patients to prevent this, such as minimizing the risk factors for constipation, and being proactive about ambulation, hydration, and the use of stool softeners if needed.
Serious complications, such as excessive bleeding, are fortunately very rare after egg retrievals, but I tell my patients to err on the side of calling us with any questions or concerns regarding their symptoms.
8. When do you recommend a fresh transfer v. a frozen one?
Because of the improvements in laboratory techniques, and because of new research findings, our field is moving more and more towards frozen transfers and abandoning the use of fresh transfers.
With a strategy of freezing all embryos, the risk of ovarian hyperstimulation syndrome (OHSS) is decreased, because women at risk are even more at risk if they also get pregnant during the same cycle.
Additionally, the synchrony between the embryo and the lining of the uterus can be better controlled in a frozen transfer setting. There is also evidence that some complications of pregnancy are less likely with a frozen embryo transfer (FET).
This is an ongoing area of research and constantly evolving.
At our clinic, we have moved away from doing fresh transfers, and towards doing segmented treatment with a “freeze-all / freeze-only” strategy followed by FET in a separate step in all patients, with excellent success rates.
9. Post transfer, do you feel there are any signs things are working we could look out for?
Not really. It is tempting to read a lot into all sorts of symptoms that commonly occur- cramping, spotting, breast tenderness, fatigue etc. etc.
While there may be a small correlation with outcome for some of these, the picture is blurred by the medications that women are on at this stage. So my recommendation is to continue the medications and wait until the day of the blood test to figure out whether the treatment worked, even though it is understandably hard to be patient.
10. How do you determine someone’s diagnosis?
When a patient or couple first comes to see me, the vast majority of the time it is because of trouble getting pregnant (“Infertility”, most commonly) or trouble staying pregnant- this is called “recurrent pregnancy loss”.
In the initial basic infertility workup, I recommend assessing the following:
- the male partner (if there is one, some women come to see us with the desire to conceive using donor sperm)
- whether ovulation occurs regularly and normally
- anatomic factors, such as the uterus and the fallopian tubes
- the “ovarian reserve”- beyond looking at the patient’s age this may include ultrasound and blood tests (see question 6) above
If an abnormality is found, then we have a diagnosis, for example “male factor infertility” or “ovulatory factor”. In some couples more than one cause is found, and the infertility is multifactorial. In some couples no abnormality that can be detected by standard testing is found, in that case we talk about “unexplained infertility”.
11. When should someone change RE’s (if ever)?
Infertility is a very personal and very troubling disease. And the clinic / doctor that you see in order to treat it may affect outcomes in a major way. While a lot of doctors and clinics practice in similar ways, and while there are many good specialists out there, there is quite a lot of variation in the standard of care offered. There are also differences in how well doctors or clinics interact and communicate with their patients.
So my advice for patients with infertility is: be selfish. Do some research on the clinic and the doctor you are thinking about seeing. The IVF laboratory plays a big role in whether you will be successful or not, and the CDC publishes success rates according to age for each clinic.
When you are a patient of a particular clinic or doctor, I do not recommend constantly wondering whether you would be better off somewhere else or with someone else. But if it does not feel right, or if you feel like your treatment is not going in the right direction, it is totally appropriate and OK to switch clinic, or switch doctor. If you switch doctor within the same clinic, keep in mind that the lab will remain the same. In general I recommend not feeling a false sense of loyalty. It is your fertility that is at stake, and you need to look out for yourself. All of us (fertility providers) have had patients switch away from us to another doctor who is a better fit, or switch to seek care with us from another provider.
12. What role does health play in having a successful cycle and transfer?
A healthy lifestyle is very important for fertility in general, and in our practice we provide a lot of counseling on the do’s and don’ts while trying to conceive. In the first part of this blog we already went over the role of a healthy diet when trying to conceive naturally or with assistance (question 4). A good “sleep hygiene” is important, too, including trying to get at least 8 hours of sleep every night. We also recommend avoiding alcohol, especially after the embryo transfer, and cutting out other unhealthy habits such as tobacco use. Patients should try to minimize stress as much as possible, but not getting “stressed about being stressed” and adding another layer of stress. Ultimately, I advise couples to try their best to have a reasonable healthy lifestyle without being too hard on themselves- the experience of going through infertility treatment is hard enough!
13. On average, how long do fertility treatments take to work?
It really depends on the individual circumstances, and the reason why a patient or a couple is going through the treatment. Couples where the reason for the treatment are problems with sperm quality, ovulation or the tubes generally have a good prognosis, and the first cycle is often successful. When the egg quality and number are the problem, the situation is often a lot more challenging and multiple cycles may be needed. But every situation is a little different, and it is hard to generalize.
14 What are the risks of doing fertility treatments?
The risks of insemination treatments are relatively small, but because they are usually combined with medications to stimulate the ovaries prior to the insemination procedure, the main risk is multiple pregnancy. That’s why ultrasound monitoring during IUI cycles is so important, in order to be able to cancel the IUI if too many follicles develop.
For IVF, a major risk of treatment is ovarian hyperstimulation syndrome (OHSS), as mentioned previously, especially in younger women, those with polycystic ovarian syndrome (PCOS), and generally in those with higher ovarian reserve. However, with careful dosing and close monitoring, it is possible to almost eliminate this risk. The egg retrieval is generally very safe, but carries a small (<1%) risk of complications such as bleeding, damage to surrounding organs, and infection. Of these rare complications, bleeding is the most common. If it occurs, patients (rarely) have to be observed for a longer period of time and / or admitted to the hospital. Rarely a blood transfusion becomes necessary.
Multiple pregnancy used to be a major complication of IVF treatment. However with advances in our field we have largely moved to universal use of “elective single embryo transfer” (eSET). With eSET, the twin risk is only about 2%: if twins happen after the transfer of a single embryo it is because the embryo splits and produces monozygotic (identical) twins, which can occur naturally as well.
15. How do you feel COVID19 affects pregnant women? What about women still going through their cycles?
During this current pandemic, the recommendations and guidelines from professional societies are evolving on an almost daily basis. Therefore my main advice is to refer to the Centers of Disease Control (CDC, www.cdc.gov), the American Society of Reproductive Medicine (ASRM, www.asrm.org) and the American College of Obstetrics and Gynecology (ACOG, www.acog.org) for the latest updated guidelines.
As of now (April 2020), we are following the ASRM guideline to suspend all fertility treatments except emergent fertility preservation in newly diagnosed cancer patients. This recommendation came in March, so we completed the cycles that had already been started, but did not start new cycles.
The effects of Covid-19 on pregnancy are still being studied. As ACOG states: “At this time, very little is known about COVID-19, particularly related to its effect on pregnant women and infants, and there currently are no recommendations specific to pregnant women regarding the evaluation or management of COVID-19. Currently available data on COVID-19 does not indicate that pregnant women are at increased risk.” Just like everyone else, we are following this development very closely, and hope to get back to “normal” in the not too distant future.
16. What should women, who have had cancelled cycles due to covid19, do to prep their bodies while they wait for clinics to re -open?
Women who are waiting to start treatment once the pandemic precautions are lifted, should maintain a healthy “fertility lifestyle” (as outlined in question 12). With a lot of canceled work and social commitments, I recommend using this time to catch up on regular uninterrupted sleep if possible. Regular exercise is good for the body and mind, even if the opportunities are limited.
In general, maintaining mental health is at least as important as physical health at all times, but especially currently. The American Society of Reproductive Medicine (ASRM) has published extremely useful messages for patients on “Coping during the COVID-19 Pandemic” that can be found here: https://www.asrm.org/news-and-publications/news-and-research/announcements/coping-during-the-covid-19-pandemic--messages-for-patients/
Nobody can predict with certainty when the current crisis will be over. But I can assure you that fertility providers including myself are just as eager as our patients to resume treatments as usual once this is safely possible.