Your Fertility Pharmacist

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This study followed three women who were 28, 38, and 32 years old. All three had sought reproductive assistance (ART) and could produce a low quantity of oocytes. The quality of their eggs was low and none could produce a viable embryo. After two key interventions, all three women made top quality embryos and two had babies!

A few months ago, a study was published in Fertility and Sterility that looked at whether or not there is an association between how a baby was conceived and the impact this mode of conception has on serious infections through childhood. This episode reviews the results and what they may mean for women using fertility treatments to conceive.

This podcast discusses the first U.S. study of seven COVID-19 infected pregnant women who presented to a NYC hospital. Below are the details provided about these seven women.

There has been an update since the podcast was originally recorded on April 2nd. The authors of the first study are publishing a new article on 43 COVID-19 infected pregnant women admitted to NYC hospitals between March 13-28, 2020. See the full article by clicking here.

Ten of 18 (55%) of pregnant women had a normal uncomplicated vaginal delivery.

Resources

ASRM Patient Management and Clinical Recommendations during the Coronavirus (COVID-19) Pandemic, Update #1. (2020). Available from: https://www.asrm.org/globalassets/asrm/asrm-content/news-and-publications/covid-19/covidtaskforceupdate1.pdf

Breslin N, et al. COVID-19 in pregnancy: early lessons. American Journal of Obstetrics & Gynecology MFM (2020). Retrieved from: https://doi.org/10.1016/j.ajogmf.2020.100111.

Center for Disease Control and Prevention (CDC, 2020). People who are at higher risk for severe illness. Retrieved from: https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-at-higher-risk.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fcoronavirus%2F2019-ncov%2Fspecific-groups%2Fpeople-at-higher-risk.html

Dashraath P, et al. Coronavirus Disease 2019 (COVID-19) Pandemic and Pregnancy, American Journal of Obstetrics and Gynecology (2020). Retrieved from: https://doi.org/10.1016/ j.ajog.2020.03.021.

This episode centers around the drugs being used experimentally to treat COVID-19 and what we know about how these drugs impact pregnant women. The links to the studies and drug information discussed on this episode can be found at “yourfertilitypharmacist.com.”

Before delving into the drugs, let’s touch base on the limited information we have on how pregnant women are impacted by coronavirus, which is the virus manifesting as the respiratory illness called “COVID-19.”The good news is, there have not been any confirmed cases of mothers transferring coronavirus to the baby in utero. Having said that, the limited information we have about delivery outcomes is concerning. A recent article in the Journal of Infection detailed the delivery outcomes from thirteen Chinese women who were pregnant and tested + for coronavirus. They ranged in age from 22 to 36 years old. They had no other pre-existing health conditions. Two women were in their second trimesters, and the other 11 were in their third trimesters. Six of the eleven women who were in their third trimester went into early labor related to fetal distress, premature membrane rupture, and even one stillbirth. The two women who were in their second trimesters did NOT go into early labor or have any other fetal consequences noted – I really hope that the researchers keep close tabs on those two pregnancies so we can learn more information on the impact of second trimester coronavirus infections. Since a lot of these pregnancies had complications, having a treatment for COVID-19 could improve the health of infected mothers and babies.

Regarding medications to treat COVID-19, there are a few drugs that seem promising for an illness that doesn’t yet officially have a cure.

A drug that’s been receiving a TON of press lately is chloroquine, as reports from China and France suggest that it’s effective against COVID-19. Chloroquine was originally approved by the FDA in 1949 to treat malaria, and it was later approved to treat lupus and rheumatoid arthritis. Since chloroquine has been used and tested for so many decades, we have information on how this drug impacts pregnant women and their babies. Chloroquine does go through the placenta and into breastmilk; in mice and monkey babies, this crossing led to vision problems and blindness. These eye problems were not seen in human studies conducted a decade ago in Thailand and in New Guinea on pregnant moms requiring malaria prophylaxis. Thus, the reference book Drugs in Pregnancy and Lactation considers chloroquine to be the unlikely cause of birth defects in humans. It also states that the benefits of preventing and treating malaria outweigh the risks. This permission could potentially be extrapolated to treatment of COVID-19… but before getting too gung-ho about stockpiling chloroquine, a more promising sister drug to chloroquine should be considered.

Hydroxychloroquine is chloroquine with a slightly different molecular structure that makes it less toxic yet just as effective as chloroquine for malaria and for immune-mediated disorders. It was FDA approved in 1955 and also goes by the brand name Plaquenil. Scientists, and therefore the mainstream media, have gotten very excited about using this drug because of a small study from southern France on treating coronavirus. In this study, 14 infected patients received hydroxychloroquine alone, 6 patients received hydroxychloroquine plus an antibiotic called azithromycin, and 16 patients, serving as the control group, who didn’t get hydroxychloroquine at all. After six days, the virus was cleared from the system of all six patients taking both hydroxychloroquine and azithromycin, from 8 out of 14 patients taking hydroxychloroquine alone, and from just two of the sixteen patients who didn’t receive hydroxychloroquine. Those encouraging results were only published five days ago. Since then, hoarding of the medication has become a national issue. It’s such an issue that the FDA is permitting a factory in India that was recently cited for quality issues to ramp up supply of hydroxychloroquine to import to the U.S.

This study inspiring the hydroxychloroquine shortage specifically excluded pregnant women. Given that it is safe to use in pregnancy in other conditions, plus it is generally considered to be a safer drug than chloroquine, it would be reasonable to assume that it would be safe in pregnant women infected with COVID-19. Of the drugs being tested to treat COVID-19, hydroxychloroquine is the drug I feel most confident endorsing for safety and efficacy in pregnant women at this time. I’d also recommend taking it with azithromycin to increase chances of clearing the virus.

Though I’ve given my endorsement, I would be remiss as a pharmacist if I didn’t discuss another promising drug that’s gotten a lot of attention lately. It’s an antiviral called remdesivir, which is NOT officially FDA approved for any illness in the U.S. It is allowed for “compassionate use,” meaning that a patient may be able to gain access to the drug if in a life-threatening condition and there isn’t a good alternative treatment available. The manufacturer of this drug has seen such a surge in requests to use remdesivir during this pandemic that they just cut off new requests to use this drug EXCEPT for pregnant women and in children.

So, while it remains available for pregnant women, is it actually safe and effective? In 2018/2019, remdesivir was given to six pregnant Congolese women infected with Ebola who were enrolled in a clinical trial looking at four investigational drugs to potentially treat that illness.

This trial was published in Dec 2019 in the New England Journal of Medicine; unfortunately, after looking over the study and all of the published information, there is very little detail on how these six pregnant women responded to remdesivir. We don’t know their ages, how far along they were in their pregnancies, etc. One reason that the trial may have given so little focus to so few pregnant women taking remdesivir is because two other drugs in the study were found to be more effective at treating Ebola, so they stopped giving remdesivir in favor of other drugs. I gleaned the study for details and read in the supplementary index about the adverse events broken down by patient and drug. One of the other experimental drugs mentioned one baby born with hydrocephalus and one with a shortened umbilical cord. Because these adverse outcomes were mentioned in a drug that was NOT remdesivir, can we assume that remdesivir does not cause fetal harm?

We still have too little information - six pregnant women taking a drug is simply not enough to draw useful conclusions. In the short-term, we will have to look at press releases for pregnant women who took remdesivir through compassionate use. According to upcoming U.S. studies listed on clinicaltrials.gov, only one of the three remdesivir trials is specifically excluding pregnant women from participating, so hopefully we will have some concrete data once the two inclusive trials have ended. To see the studies included in this podcast, please check out “yourfertilitypharmacist.com.”

Today’s episode centers around the impact on fertility treatments due to coronavirus, which is the virus manifesting as the respiratory illness called “COVID-19.”

On St. Patrick’s Day, the American Society for Reproductive Medicine (for short known as ASRM) released recommendations for managing fertility treatments during the pandemic. These recommendations came from the evidence we currently have on COVID-19. ASRM will update their position by March 30th or earlier as more information comes in. The link to the recommendations is available on my website, “yourfertilitypharmacist.com”

After listing their major recommendations from the eight-page document, I’ll go over the rationale for these momentous statements.

#1, no more new treatment cycles for the foreseeable future. By new treatments, they explicitly call out ovulation induction, in vitro-fertilization – including retrievals and frozen embryo transfers, intra-uterine inseminations, and non-urgent gamete cryopreservation.

#2, in quotes, is “consider cancellation of all embryo transfers whether fresh or frozen.”

#3, keep caring for a patient is already “in cycle” or requires urgent stimulation for cryopreservation. Now, caring for is a gray area, which I will come back to later in this episode.

#4 stop any non-urgent diagnostic procedures and elective surgeries.

And the last one, #5, minimize in-person interactions in favor of telehealth.

These recommendations are… extreme, but not shocking, given the surreal times that we are now living in. ASRM laid out how COVID-19 is more contagious and kills 10-15 times more people compared to the flu. There is a scary shortage of personal protective equipment for healthcare workers, so there is a suggestion that the gloves, masks, and other personal protective equipment used by the staff at fertility clinics could be rerouted to healthcare systems directly addressing COVID-19. Since the U.S. is severely deficient in testing and screening capabilities for coronavirus, staff at reproductive centers could unknowingly come into contact with the infection; if reproductive staff come down with the illness, this could easily impair the quality of care needed to treat patients. Most importantly, we still don’t know how COVID-19 infection will impact pregnant women; it’s unclear if a mother can directly pass the virus onto a baby in utero. A recent publication discussed the outcomes of nine pregnant Chinese women who tested positive and showed symptoms for COVID-19. Six out of ten babies born to these COVID-19 infected moms experienced intrauterine fetal distress and met criteria for critical illness. (More details about this publication from China can be found on the study link located on this episode’s webpage).

With the concern for negative impact to babies, women, and healthcare staff, ASRM’s recommendations to stop any non-urgent fertility treatments makes sense. I live in an area where coronavirus has really taken hold, and I’m seeing the uptake of the ASRM recommendations vary based on the local reproductive clinic. Deciding what is urgent and what is not is such a gray area. While a couple of sites haven’t seemed to alter their practices significantly, others are going on a case-by-case basis on whether or not to proceed with a stim cycle or transfer. Many women are feeling heartache over having to delay treatment in the face of a ticking biological clock. Other women are nervous that their cycle will be cancelled at the last-minute as more restrictions come into play. My advice to any active patients at a reproductive clinic would be to touch base with your clinic to know their stance on treatment during this pandemic and how they personally plan to attend to your case. For women who may have the possibility of conceiving naturally, please practice social distancing and keep taking your prenatal vitamins!

That’s the end of today’s episode of “Your Fertility Pharmacist.” In the next episode, I’ll discuss the medications being used experimentally to treat COVID-19 and what we know about how they impact pregnancy. All related links discussed in these episodes will be posted on the website “yourfertilitypharmacist.com.”

Despite the many advancements in science and technology that have been game-changers in the fertility field, there is still so much that is unknown. Even now, roughly 30% of couples seeking reproductive assistance have unexplained fertility. It’s extremely frustrating to not know why you can’t conceive, so I’m thankful to the lady scientists behind this week’s fertility article who posed some good questions. These questions were, how long lasting are the effects of the levonorgestrel IUD after its removed, and how does this IUD impact the future fertility of women who’ve never before had a baby?

Hello, this is “Your Fertility Pharmacist.” This podcast is for women who are trying to overcome infertility. If you keep a pulse on late-breaking fertility research, it could positively alter the course of your fertility journey, as it has for me.

This week’s article was written by Erin Dinehart, Ruth B. Lathi, and Lusine Aghajanova. It was published in the Journal of Assisted Reproduction and Genetics in November 2019.

The Mirena was the first levonorgestrel IUD approved in the U.S. in late 2000. Since then, other levonor IUDs have come out, including Liletta, Skyla, and Kyleena. They all look and act essentially the same. These IUDs will send out a low-level of progesterone, which will make the uterine lining thicken in the cervix. Kind of like a super stuffed up nose in which nothing seems to go in or out easily, the cervix is so plugged up with mucus from this IUD that the sperm can’t easily swim around. Beyond doing its job as a Sperm Stopper, the levonorgestrel IUD also can impact ovulation for up to one year after insertion.

Research has shown that the levonor IUD’s impact on fertility is reversible, BUT there are questions on how quickly fertility returns and to what extent. A 1992 study spent almost two years tracking 140 women who had used a Levonor IUD for an average of 19 months. After the IUD was removed, the pregnancy rates after twelve months of trying were 75.4%, which is lower than the general population, which is 85-92%. Moreover, the 1992 study combined women who had already conceived with women who had never conceived, which makes it harder to tease out the results for women who were trying to have their first baby. A more recent study from 2017 showed similar results - after removing the IUD, 71.2% of women conceived within twelve months. This 2017 study also lumped together the women who had previously given birth with women who hadn’t. So, we still don’t really know how levonor IUDs impacts women who have never had children before and/or women who used the IUD for closer to five years, which is how long Mirena and Kyleena can safely stay inserted.

I just searched clinicaltrials.gov to see if any new studies will be coming out soon with answers to these questions. There were 144 clinical trials related to levonorgestrel intrauterine devices, and NONE of the trials are studying the impact on fertility in women who would be first-time moms. There were studies looking at the satisfaction of women using levonor IUDs, but these studies were also limited to twelve months after IUD insertion.

To conclude, it’s possible that the IUD has a lasting impact on the tissue of the endometrium even after being removed, which may impact fertility. It’s also possible that the IUD impacts fertility differently for women who have already conceived vs. women who have never conceived. We don’t know, so I’m glad that the scientists publicly posed these questions.

I wish I had thought to look into the potential long-term consequences on my fertility before signing up for five years of the Mirena. If I was going to repeat getting an IUD now, I would probably select one that is indicated for three years, given that the data is more closely comparable to three-years vs. five or six years of keeping a levonor IUD in.

The study was published in February 2020 in Reproductive Physiology and Disease, and a link to learn more about the study will be posted on the podcast’s website, www.yourfertilitypharmacist.com.

There was a lot to like about this study. It focused on low ovarian reserve, which is also sometimes called “poor ovarian reserve” or “diminished ovarian reserve.” In pre-menopausal women, this means having a lower quantity or lower quality of eggs that could be used to conceive a baby. Some women can still conceive with these eggs, though it often takes fertility treatments to help make this happen. Results from using this particular PRP treatment are discussed in this episode.