Many people of size take metformin (a.k.a. Glucophage). They might take it for insulin resistance/PCOS issues, or they might take it for blood sugar issues....or both, since the two are often related.
This post is of particular concern to those women of childbearing age who take metformin, but anyone on metformin should know about it.
I recently ran across some research linking metformin with low levels of B vitamins, particularly vitamin B12 and Folic Acid.
Although the worst effects seem to happen with years of treatment and higher dosages, even short-term treatment (16 weeks) reduced the levels of folate and B12.
These lowered levels of folate and B12 also seem to be linked to an increase in homocysteine levels, which is commonly seen after metformin is started. Now, what significance this has, if any, is still being debated. In terms of general health, homocysteine levels may be tied to heart health; high levels are considered a risk factor for cardiovascular disease. There is some research indicating that administration of B-group vitamins reduces homocysteine levels in non-pregnant PCOS patients treated with metformin. But we don't really know yet if lowering homocysteine levels results in any meaningful reduction in long-term endpoints like decreased heart attacks or mortality.
However, we do know that some people on metformin do develop megoblastic anemia at some point during treatment. So certainly, it's seems like it's something that anyone on metformin should be aware of and monitored for periodically.
It might even be sensible to take extra B vitamins (B group complex, presumably) while on metformin, although formal studies on the value of that seem to be lacking so far. There is also one study that found that supplemental calcium may help blunt or reverse B12 malabsorption with metformin.
Implications for Pregnancy?
All this information about metformin impacting B12 and folic acid levels makes me wonder if there are special implications for women of childbearing age. We know that folic acid levels are important for preventing birth defects like neural tube defects (NTDs, like spina bifida or anencephaly). If a woman with PCOS has been on metformin for years and her folic acid levels are chronically low when she conceives, does this increase her risk for NTDs?
As far as I can tell, no one knows. There doesn't seem to be any increase in birth defects in women on metformin so far, but research is limited. Because preliminary research on metformin in pregnancy indicates that it cuts the risk for miscarriage and gestational diabetes in women with PCOS, it's likely to be used more and more often in the future, provided the research continues to be supportive.
So the question becomes, should women on metformin who are considering conceiving (or who are of childbearing age at all) be supplemented with extra folic acid and B12 (or B vitamins in general)? And if so, by how much? What about calcium, if it helps reverse the malabsorption of B12? Should levels of B12 be monitored during pregnancy?
At this point, I don't think anyone knows for sure. Anecdotally, many women on metformin do seem to be taking additional folic acid at least. Consult your care provider about this topic and what dosages might be appropriate beyond a normal prenatal vitamin. (And if you do decide to take supplemental vitamins in addition to metformin, you should probably take them at different times of day.)
15 comments:
could prolonged use of metformin make a mild case of anemia worse?
Wow - thank you for this post. I've been taking Metformin to help me conceive and since starting it, I've actually had anemic symptoms. This is the first thing I've seen connecting Metformin, folic acid/vit B and anemia!
My sister passed on your blog post about met and b vitamins. I just went to the OBGYN yesterday b/c the met seemed to not be "working" like it had. 2000 mg a day isn't doing what it used to. I used to lose a ton of weight but have actually gained. I asked for a free t3 and t4 and was given the brush off when I suggested maybe it isn't JUST PCOS anymore! Looking forward to more posts about this!
I was put on metformin in January - I was "prediabetic" After 4 weeks on it, my fasting blood sugar was up to 122 from 113, my blood sugar one hour after eating pancakes and maple syrup was 76, and the machines at the gym complained that my heart rate was too high (above 140 BPM) and shut themselves down. Previously I regularly spent an hour on the treadmill without going above 125 BPM. My Dr said that this was an abnormal reaction and is referring me to an endocrinologist, but I'm thinking a cardiologist might be a good idea...
Interesting. I have been on 1700mg/day for the last 8 month, and 1000mg/day for the 8 months before that for PCOS. I have high fasting insulin levels, but my blood sugar has always been normal. Before pregnancy, I was taking 800mcg of folic acid each day, and since I found out I was pregnant (2 weeks after conception), I have been on the 1mg of folic acid a day. Just found out, at 11 weeks gestation, that our baby had anencephaly, which is a fatal neural tube defect.
I'm now taking 5mg/day of folic acid in prepartaion for the next pregnancy, but the drs don't think that the metformin had anything to do with the NTD.
Grrr...it seems like even though the chances are low, I wish is it was more standard practice to give Metformin ladies a higher dose of folic acid when TTC, or pregnant. Wondering if I could have avoided it by doing so...
What about if you AREN'T wanting to get pregnant, but still wanting to be healthy? It is still important to have solid levels of B vitamins and Folid Acid in your body, right?
What you are focusing on is birth defects, but I also wonder what effects it has on women in general.
I am going to be starting Metformin later this month, and I am not going to TTC. Should I just go ahead and get some B vitamin complex, as well as calcium? Folic acid anyway?
I wish there were more providers out there who had more knowledge on these basic vitamins and minerals. It is appalling to me how little they know.
Don't know why, but I just ran a search for metformin and spina bifida. I was on metformin and chlomid 3 months before conceiving. My dr. kept me on metforming for 16 weeks into pregnancy with twins and one of my twins was born with L3-L5 myelo spina bifida. I've always wondered if there was a connection.
To the women who have experienced a birth defect: My heart goes out to you. This is a very difficult situation.
It's not clear in such situations whether the problem was the condition for which the metformin was used (PCOS, insulin resistance issues, blood sugar issues) or the metformin itself. It may have happened even without metformin use. OTOH, if you've been on metformin for a long time and it has affected your folic acid levels, then it's possible that could be implicated too.
We know that women of size have a higher risk for birth defects, especially NTDs. No one knows why (we'll be discussing this in the future) but it may be related to metabolic abnormalities, blood sugar, insulin resistance, or decreased absorption/storage of nutrients.
We don't know if treatment of these things can lessen the risk for birth defects, or if the treatments themselves can cause problems as well (i.e. if metformin causes folic acid deficiencies). The problem may well be the underlying condition rather than metformin, but it's possible the two could act synergistically in the case of a build-up of nutrient deficits.
My point is that we should be aware of these possibilities but we can't jump to any conclusions yet. Bottom line is to make sure your care provider is monitoring your folic acid and B12 levels over time if you are on metformin.
I was on Metformin prior to and during pregnancy for PCOS. At 20 weeks we found out that the baby had spina bifida (directly associated with folic acid, a Chiari II malformation in the brain, and club feet. We did an amnioscentisis and all genetics were normal. I was never told about that Metformin depletes folic acid or Vitamin B and didn't take any precautions.
I was only taking metformin for 4 months prior conceiving my son. I was taking 2200mg of met. at 18 weeks my son was diagnosed with spina bifida, chiari malformation and hydrocephalus. No one ever told me about it depleting folic acid either, and I was taking so I could conceive a baby.
I just had my fourth child and sh ed has spina bifida...all my other children are healthy...taking metformin prior to this last pregnancy and during the first trimester was the only thing different than the other pregnancys.. :( she is 2/mo and goes in for surgery next mo..I am convinced the metformin caused this NERD. Good luck with u and urs. God bless
I think she meant, "caused this NTD."
I also was taking metformin prior to conceivING and kept on them during pregnancy. My daughter Was born with s5 s6 mylomeningacil spina bifida! This has to stop.. we need awareness..
Again, we don't know what is causing this. It could all be coincidental. Research so far does not seem to connect metformin during pregnancy with birth defects. It could be weight instead, it could be insulin resistance, it could be that women with PCOS have difficulty absorbing nutrients properly, who knows? I don't think we should jump to conclusions, but I certainly would like to see more directed research on this topic.
My main suggestion is that women and their care providers should be aware that metformin can deplete certain vitamins and might want to consider testing a woman's stores of those vitamins before she tries to conceive. It seems sensible to take some extra Bs and esp folic acid just before and during pregnancy too, but what dosage is a matter of strong debate and little research. Discuss it with your care provider.
Here's a cut-and-paste link to a meta-analysis of studies on metformin use and risk for birth defects:
https://www.ncbi.nlm.nih.gov/pubmed/24861556
First-trimester exposure to metformin and risk of birth defects: a systematic review and meta-analysis. Cassina 2014. Human Reproduction Update.
Conclusion: "There is currently no evidence that metformin is associated with an increased risk of major birth defects in women affected by PCOS and treated during the first trimester. However larger ad hoc studies are warranted in order to definitely confirm the safety and efficacy of this drug in pregnancy."
The problem with the studies so far is that they are fairly small and birth defects are rare, so it's hard to have enough power to really detect a relationship without a large study. In addition, I don't think they've studied how LONG someone was on metformin previously and whether that had an impact on birth defect incidence.
So you can't really say that metformin use is connected to birth defects, but neither can you really rule it out yet either. We need more studies that have the power to detect real differences and that differentiate between someone who has taken metformin for a few months vs. someone who has taken it for years.
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