Fertility Q&A #1: Methyfolate vs Folic Acid?

This article is a round-up of some of the most interesting questions submitted to my Q&A session that I held on my Instagram account on the week of June 27, 2023.

“Can you talk about methylfolate vs. folic acid? What did you do when pregnant, personally? “

I used Nature Made prenatal vitamins containing 400mcg folic acid for both of my pregnancies. Folic acid (a minimum of 400mcg per day) is recommended as part of your prenatal vitamin (ideally taken for 3 months preconception) in order to prevent or minimize the risk of birth defects called neural tube defects (ie. spina bifida). The only studied form of folate for this purpose is folic acid. Many aspects of the American diet (ie. cereals) now come fortified with folic acid to prevent deficiency and neural tube defects (as many people may not know they are pregnant until the neural tube and spine begin to form). Folic acid is heat stable and reliable and the form that the evidence is based on – and therefore is the type of folate recommended by all the major health organizations and societies that provide recommendations on women’s’ health. People began introducing the idea that methylfolate was superior back when MTHFR mutations (which are actually now known to be benign variants) were thought to be problematic and a common cause of infertility and pregnancy loss. This has been dis proven and we now know that a large proportion of the population have MTHFR mutations and there is a lot of redundancy and alternate pathways for the metabolism of folate, regardless of variants in the gene which code for the MTHFR enzyme which processes folate. Please refer to Dr. Jen Gunter’s deep dive on this issue.

“HSG shows proximal blockage, all else normal. Redo? Do I need IVF?“

The hysterosalpingogram (HSG) is a X-ray of the pelvis, taken after instilling radio-opaque (meaning it shows up on X-ray) dye into the cervix – and waiting to see how it fills the uterine cavity (providing a silhouette of the uterus’ inner contour) and how it highlights the caliber of the Fallopian tubes and whether there are any blockages on either side. If the dye doesn’t enter the tube, that is referred to as a proximal blockage (a blockage at the entry point/junction between the uterine cavity and the Fallopian tubes). This can be because of scar tissue – but because the uterus is a big thick muscular organ, it can also be a false finding due to a muscular spasm of the uterus. The uterine muscle can spasm in response to the dye filling the uterine cavity (this is why HSGs tend to be so crampy)- leading to a ~60% chance of any finding of proximal blockage on HSG being a false ‘positive’ finding. Many who repeat HSG will find that there in fact is not a blockage. Repeating it is the only way to know. I will often order a repeat test with a radiology center that is comfortable trying to open up a proximal blockage in a process known as ‘re-canalization’ which is done using a guide wire under visualization with fluoroscopy. 

If a blockage is distal, or at the end of the tube, that is likely a more reliable or ‘real’ finding as there is no muscular tissue near the end of the fallopian tube. If the dye doesn’t flow past the end of the tube, after filling the length of the tube, it is likely truly blocked. If both tubes are truly blocked (either distally or proximally) then I would say IVF is the only good option. Back in the day, before IVF was as successful and efficient as it is today, tubal surgeries were often performed in an effort to repair the tube and bypass the blockage. Nowadays, tubal repair surgeries (Tuboplasty) is seldom done as scarred tubes tend to re-scar within months, and it involves an invasive surgery that may or may not be successful and can be undone with the recurrence of scarring. 

“Thoughts of fertility preservation for cancer patients?“

Cancers are rapidly dividing cells that proliferate without any regulation – leading to the growth of tumors. Cancerous (malignant) tumors are invasive and can spread and infect other organ systems, aside from the prior organ where the cancer originated. Chemotherapy works by attacking the most rapidly dividing cells (which allows it to affect cancerous cells more than the other background cells) – which is also why it can cause hair to fall out. The ovaries and testes are VERY sensitive to the effects of chemotherapy and radiation (which can damage and kill cancerous and normal cells in it’s field of exposure). For patients with ovarian and other gyn cancers, treatment may require removal of one or both ovaries, or part of the ovary. Since the ovaries cannot make new eggs over time, chemotherapy/radiation/ovarian surgery can irreversibly impact female fertility. The stem cells in the testes of men with cancer can be damaged by treatment, leading to permanent loss of fertility in men. Because of these reasons, if faced with a cancer diagnosis, it is of utmost importance to take a quick pause before initiating treatment and to meet with a Reproductive Endocrinologist & Infertility specialist and get some baseline testing and learn about your options to preserve your fertility. For men, this means freezing several vials of sperm (collected by masturbation) and then frozen in a process called vitrification. For women this means taking a minimum of 2 weeks to stimulate the ovaries for 8-10 days to grow as many mature eggs as possible and then extracting the eggs under anesthesia. The eggs can then be frozen or turned into embryos and frozen. Your fertility doctor and oncologist should communicate and come up with a cohesive plan and an agreement on how much time you realistically have to do the ovarian stimulation and egg retrieval. If they give more than 2 weeks before needing to start chemotherapy, it might be wise to consider doing more than one cycle depending on how conservative and careful you want to be. Duo stim (doing overlapping cycles with 2 retrievals within short time frame (you begin stimulation medications 4-5 days post egg retrieval #1) may be warranted as it could allow for more eggs to be retrieved over a short period of time. I think everyone should have the opportunity to learn about and access the option of fertility preservation before undergoing cancer treatment. This is why I am passionate about working with organizations such as The Chick Mission – a not for profit which provides grants for egg/embryo freezing before patients undergo cancer treatments that could cause infertility.

“What are the pros vs. cons to doing ‘natural’ FET timing with HCG trigger to timed ovulation?“

A ‘natural’ FET cycle is a frozen embryo transfer timed with your ovulation. Patients with regular, predictable cycles are regarded as good candidates for natural cycle FET. I will usually still intervene (to a minimal degree) by using HCG trigger to trigger final maturation and ovulation of the dominant follicle, after doing a mid cycle scan to confirm an egg is ready to be ovulated. This helps to time things a little more precisely (as we know the HCG trigger takes approximately 2 days to cause ovulation). I will also give a small amount of progesterone support in addition to the progesterone we know the ovulated follicle makes after ovulation. This can be provided in the form of vaginal progesterone. The pros of natural cycle FET are that less medications are required. For patients who cannot tolerate using estrogen pills (ie. due to migraines etc) it can be beneficial to do natural cycle FET. It also obviates the need for using progesterone in higher amounts (either as intramuscular injections or a combination of vaginal and oral progesterone pills – which can be more bothersome than using vaginal progesterone alone). The downside of natural FET preparation is that the timing can be unpredictable and lead to missing the ovulation window and cancellation of the cycle (which means waiting til your NEXT cycle to try again). In order to avoid this, natural cycle FET involves more monitoring visits than a medicated FET preparation cycle where the estrogen works well to prevent ovulation and therefore the transfer can be timed reliably and flexibly. With natural FET, the timing revolves around when you ovulate, so you cannot guarantee that your doctor will be able to do the transfer on a certain day. With medicated FET, I can always tell my patients I will be the one to do their transfer, which brings them great comfort. 

Another potential (and not yet well proven) benefit to natural cycle FET is the theory that factors (ie. Relaxin) that are secreted by the ovulated follicle can lead to secondary benefits (ie. better implantation of the placenta and lower risk of issues like Preeclampsia) – there is little data to show a marked impact on the rates of Preeclampsia but some studies have shown an association between medicated FET and hypertensive disorders of pregnancy. When comparing most studies (a Cochrane Review pooling studies), there does not seem to be a better approach in terms of chance of implantation and live birth or risk of miscarriage. 

“At 38, am I more likely to have a healthy baby from IVF from PGT-A versus ‘naturally’?”

No, doing IVF (at any age) does not guarantee you will have a healthier baby, than if you conceived on your own, unassisted (or without treatment). At 38, approximately 50% of embryos that are PGT tested will be abnormal – which means either those embryos won’t implant, or they will result in miscarriage, and a small subset of embryos (that have chromosomal errors that still allow for live birth ie. Down’s Syndrome/Trisomy 21) could result in the live birth of a child with significant medical issues. However, if a normal healthy egg is ovulated at 38 – and the egg turns into an embryo which implants and results in a live birth – that child is not more or less likely to be healthy compared to a child born to a 38 year old who did a transfer of a euploid (genetically tested and normal) embryo. At 38, using a genetically screened embryo will get you pregnant (60-70% chance per cycle) faster and more easily than relying on ovulation of a single healthy egg in a given cycle (~10% chance of pregnancy). But it is important to know that the health and other features (ie. IQ, general well-being) is not thought to be modified by whether the child came from a 20-something year old egg versus a 38 year old egg.

Just a reminder that the contents of this blog are not intended to substitute for professional medical advice, diagnosis, or treatment. Please consult a healthcare provider if you have any questions about a particular health condition or any answer I’ve given above.