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- [00:01]
Commercial Narrator
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- [00:38]
Dr. Chapa
Podcast Family in this episode, we're going to cover something that we've talked about many, many times before on the show, which is PCOS. We've talked about the four phenotypes of PCOS. We've talked about THE 2023 International Guidelines for PCOS, which we covered at that time. And we're going to review some of those in this episode. But there's new information as of 1st December 2025 from the Gray Journal, that's the American Journal of OB GYN. Now, the title of this systematic review and meta analysis is Preconception and First Trimester Metformin on Pregnancy Outcomes in Women with pcos. Okay, so let me, let me set the stage here. In patients with pcos, some of them may be on metformin because they meet metabolic criteria. They've got really bad lipids, they've got a certain hip to waist ratio that's off. You know, their BMI is elevated, they've got high blood pressure or whatever, so they get placed on metformin. That's okay, that's a check mark. You can do that. Or some patients with PCOS are on metformin in combination with clomiphene for ovulation induction, which is totally fine. That second line, since Letrozole alone is first line for ovulation induction. Now, Letrozole doesn't seem to need a partner like metformin, unlike Clomid. But there is some new and small evidence that maybe metformin with letrozole is helpful, although it's very unclear. So right now, Letrozone is a lone pilot, is a lone ranger for ovulation induction, whereas metformin and clomiphene can be used for ovulation induction. So those patients get pregnant and the question is when to stop the metformin. Is it immediately with a positive pregnancy test? Should we continue throughout the first trimester? This is what this new publication addresses in a meta analysis format. Okay, now we're going to talk about what continuing through the first trimester, which is what this New study talks about may benefit. In other words, what it may do. We're going to talk about what it does not do according to the international consensus from 2023, and the potential concerns of metformin in pregnancy. The. Not just in this format as a carryover from preconception, but even for gestational diabetes. Right. The first line for gestational diabetes therapy when they need medication is insulin. We've talked about that many times before. That's gold standard. However, in patients with poor health literacy, it may be an option to do an oral medication, since if somebody has very poor health literacy, the last thing we want to do is them work the gun incorrectly, the pen incorrectly, and they give themselves a whopping dose of insulin and become hypoglycemic or. Okay, so in those with poor health literacy, possibly metformin is an option, and we use metformin for gestational diabetes in our patient population as needed. Okay, but there are some concerns there. So we're gonna talk about that. Even though. And I'll say it right now, guys, even though those concerns are more of an association and not necessarily have proved causation. Okay, so that's where we're going. We're gonna talk about this new systematic review and meta analysis about when to stop metformin in the first trimester. Should we do it at the pregnancy test or do we continue until the end of the first trimester? Brand new data. It's very interesting. Even though we still need more information. This can help you counsel patients in this regard. Now, before I get into the intro, I found a little funny clit. He's actually Scottish. And Michael, in all disclosure, Michael said, I'm not putting that in there. I said, yes. He said, no. I said yes. And we went back and forth. So, yes, this is my idea. It's just a joke. Laugh. It's good for you. You longer. Michael is absolutely excused from this portion.
- [04:26]
Michael
My wife suffers polycystic ovarian syndrome. Have you heard of this? It's to do with women's hormones, and it causes mood swings, low sex drive, and psychotic episodes, so it's hard to detect.
- [04:48]
Going to be honest, that was risky.
- [04:52]
Dr. Chapa
At the end. He says, I got to be honest. That was risky. Yeah, it's a little risky. Just a joke, guys. And no, PCOS does not cause psychosis. It's just a joke. Yeah. Causes mood swings, low sex drive, and psychosis, so it's hard to detect. Just a joke. Although, of course, PCOS is linked to some mood issues, for sure. Anxiety and depression. Is real. Guys, it's just a joke. Plus I just. Everything in the Scottish accent just sounds better.
- [05:18]
Michael
Ovarian syndrome. Have you heard of this? It's to do with women's hormones and it causes mood swings, low sex drive and psychotic episodes.
- [05:27]
Dr. Chapa
Right.
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Michael
So it's hard to detect.
- [05:39]
Gotta be honest, that was risky.
- [05:42]
Dr. Chapa
All right, Michael is shaking his head. Yes, that was my idea. I'll take that heat. It's just a darn joke. Geesh. All right everyone, that's what we're going to talk about. We're going to talk about this new systematic review and meta analysis from the Gray Journal about when to stop metformin for PCOS in the first trimester. Fantastic stuff. We'll be right back.
- [06:26]
This is Dr. Chapa's obgyn no spin podcast.
- [06:56]
Me and Vincent would have been satisfied with some freeze dried taste. His choice, right? Podcast family, you never have to settle for anything in life. Nor should you. And that includes your cup of coffee. We're super thankful still for our partnership with the Strong Coffee Company that is striving to reach our natural greatness. Strong Coffee Co. With 20% discount code unique to our podcast family, found in our show notes. Again, go to our show notes for a 20% discount whatever you buy through the Strong Coffee Company and kick up your cup of coffee a notch. Again, thankful for the Strong Coffee Co. 20% discount with the link in our show notes. All right, let's get to it. Yo. So in the ASRM 2023 international update on the guidance, there's a little section called Metformin in pregnancy. Woohoo. It's exactly what we're talking about very quickly. So let me tell you here. Let's start off with what it does not seem to do. And look at how they look Again guys, words mean something. Look what they tell you here because this is a good lead way a good segue into what this new publication is suggesting, even though we need more data. But this is helpful information. Okay, so metformin in pregnancy. It is section 4.11 in the 2023 international update on PCOS. Quote. Healthcare professionals should be aware that metformin in pregnancy in women with PCOS has not been found to prevent gestational diabetes, hypertension in pregnancy, preeclampsia or macrosomia, which is a birth weight greater than 4,000 grams. Now listen to this. It has not been shown to prevent late miscarriage, defined as greater than 12 weeks all the way to 21 weeks and six days, close parentheses. Now you're like, huh? Because you should go, huh? Because remember, this is international, so everybody has different rules. But here they say, oh, late miscarriage, 12 weeks. Yeah, I get that. That's still within the first trimester. Up to 14 weeks. But up to 21 weeks and six days. We wouldn't call a 21 weeks and six days a miscar. Cause it's over 20 weeks. But whatever. Remember international, everybody's different. Everyone's playing on the playground and we have to respect everybody. So I just wanted to throw that out. It does not prevent gestational diabetes, hypertension in pregnancy, preeclampsia, or late miscarriage. The question that you should think is, okay, it doesn't Prevent late miscarriage, 12 weeks and beyond. Get that? But what about early miscarriage? What about miscarriage under 12 weeks? Isn't that interesting? Notice what it says. It doesn't say anything here about early miscarriage. This is where this new publication fills the gap. Beautiful. Do you get that? So again, 2023 ASRM, the update says, hey, you got clinicians need to tell patients on metformin. If you're gonna take it, just be, just be aware it doesn't prevent gestational diabetes, hypertension in pregnancy, preeclampsia, late miscarriage over 12 weeks, or macrosomia. Okay, interesting. Now they also say, quote, metformin could be considered in some circumstances, like for preterm birth reduction. How about that? And to limit excess gestational weight gain in those with pcos. End quote. Yes, it is true. In some studies in PCOS patients, sorry, patients with pcos, metformin may reduce the risk, the likelihood of preterm birth, although that also is a little controversial. But that is in section 4.11.2. So if you're asked, hey, what do you tell patients who are on Metformin? Well, let me tell you what it doesn't do, first of all, but let me tell you now what it may do. According to this brand new data from the Gray Journal, which is the systematic review and meta analysis covering a total of 12 trustworthy, end quote. Studies trustworthy like the others aren't trustworthy. Trustworthy meaning, you know, low risk of bias. Well designed, but I love that trust, trustworthy studies, you other studies were not trustworthy, therefore you were not included. Total number of n was 1,708. So 1700 women. Okay, not huge, but still it's respectable. That's what was included in the meta analysis. I'm just going to say this very quickly. Even though.
- [11:32]
The results are what they are, which is very reassuring, I'm going to give you the odds ratios here so we can put things in proper perspective. Okay? So again, based on this systematic review and meta analysis, it seems to be. Let me just give you what, tell you the synopsis and I'll let you put this into proper perspective with the numbers. It seems to say that in those women who have pcos who are on metformin, who conceived and continued the metformin throughout the first trimester. Right? So keep taking it. Quote, showed higher clinical pregnancy rates and a possible reduction in miscarriage compared to placebo or those without treatment. End quote. Now it goes on to say, whereas those who stopped metformin once pregnant had an indication, meaning a trend of increased miscarriage rate. How about that? So while the ASRM says, hey, it doesn't seem to help with late miscarriage, this new study says, well, that's fine, but it actually may help for earlier miscarriage. So that is a potential advantage. They concluded continuing metformin throughout the first trimester of pregnancy may reduce the risk of miscarriage and increase live birth rates in women with pcos. Continuation of metformin seems to have greater clinical benefit than discontinuation of metformin after a positive pregnancy test, Although there's a need for further high quality research.
- [13:05]
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- [13:37]
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- [14:04]
Dr. Chapa
End quote. So we know what it does not do. Doesn't help prevent cessation of diabetes. Doesn't seem to help with hypertensive disorders of pregnancy. Preeclampsia doesn't seem to help with late miscarriage. Ah, but maybe early miscarriage is a thing. Now remember, we have to balance this exposure with metformin in the first trimester and the potential association with anthropometric issues in the child, even extending to age 5 and 10, meaning they tend to have higher BMI. Maybe some metabolic imprinting, although causation has never been clear. I'm going to read you that in a minute. Okay, well, the question that you should have, and we're going to answer here is what does this look like? What do the numbers actually mean? What are the odds ratios here? And that's where things are like, that's why we need more data. So the short answer is it might could help. Might could help in the first trimester, why not? But we need more data. So here's the actual numbers and then you can talk amongst yourselves. Quote Women who received preconception metformin that was continued throughout the first trimester showed higher clinical pregnancy rates. The odds ratio was 1.57. Now, let's stop there. We've talked about this before. Anything above 1 is great, but you really want it above 2 to be really helpful. But 1.57 outtakes like 50% higher. Okay, great. But the confidence interval is what you should be asking. What is that odds ratio confidence interval? Remember, you don't want it to cross one. And if it crosses one, you at least want it to cross one, just barely. And this one did. The confidence interval for that odds ratio of 1.57 for a higher clinical pregnancy rate was 1.1 up to 2.23. So again, not a lot of scattered. It's very tight confidence interval and it is on the side of, you know, towards benefit greater than one. But.
- [15:56]
It did include one. So just take that with a little grain of salt. It also says there was also a possible reduction in miscarriages and that even though the odds ratio was 0.64, that confidence interval, remember, for a reduction in something, it means it has to be under 1. Well, the confidence interval was 0.32. Yes, that's under 1. But it went all the way up to 1.25 crossing 1. Do you see that? That's where, like, I don't know, it's possible, but the confidence interval kind of crossed one and into the maybe no help zone. So again, the reduction in possible miscarriage, 0.64 with a confidence interval that crossed 1 up to 1.25. Still helpful as you tell a patient. It didn't seem to hurt and it might help. Although the imprinting issue is something we can't ignore and we'll talk about that in just a minute. Now, the third conclusion was. So again, first conclusion is higher clinical pregnancy rates. Number next was a possible reduction in miscarriage. Number next was a possible increase in live births with that odds ratio of 1.24. And yet again, that confidence interval did cross 1. So these numbers aren't great, but they didn't show that it increased miscarriage and it maybe could help. So that's why it says, hey, even though it's a systematic review meta analysis, it only did 1700 patients participants as a total N and the numbers here aren't phenomenal. Okay, but this is why things like which way is it trending? Is it trending towards a benefit? When you do a trend analysis, you're like, this may be there's something there. And that's what they found. Indirect comparisons between metformin continued throughout the first trimester and metformin stopped once pregnant demonstrated a trend favoring the continuation of metformin with a clinical pregnancy odds ratio of 1.16. Woo hoo. Not great, but fine. Miscarriage odds ratio of 0.44. Okay, that's better. But again, confidence intervals crossed one and life birth odds ratio of 1.14. And again the confidence intervals did cross one. So these are suggestive that continuing metformin until the end of the first trimester and it's not all the way to 14. If you can get them to 12, you can stop it at 12. It's pretty much first trimester is done okay at that point. So the point is you don't need to stop it immediately with a positive pregnancy test unless the patient wants to. This is a perfect example podcast family of shared decision making. So here's how I would approach this. Hey, you're trying to get pregnant because you're taking metformin and Clomid. Good for you. You got a positive pregnancy test. If you're gonna ask me when to stop it, it really depends on what you want to do. It seems to be helpful in the first trimester to at least get you through, but it's really not going to help you prevent pregnancy diabetes, it's not going to help you prevent high blood pressure, it's not going to help you with baby's overall weight of macrosomia, and it's not going to help you with miscarriage after the first 12 weeks. But that's the whole technically most miscarriages happen in the first trimester and the first 12 weeks anyway. So this is why this I still think is helpful with shared decision making, knowing that the benefit is probably small but there could be some benefit. Which is why the authors state, quote, there is a need for further high quality research, end quote. I have no problem doing this, guys. I keep my patients on it with shared decision making for 10 weeks at times, or sometimes 12 weeks if they desire to Continue. Because I believe that the benefit is there knowing that metformin has not been shown to increase any malformations in the first trimester. Now, the catch is, is there a potential imprinting because they've been exposed to this medication in pregnancy? And the truth is for sure that's a concern. But it's a concern that hasn't really proved causation. And it's hard to tease out this data because some of that potential imprinting epigenetic changes in the child is when metformin has been used for gestational diabetes, which is later on, right when the CNS is developing. They're putting down their, now it's not just organogenesis, but their systems are now putting together their function. So that's a big question is, is that exposure in the first trimester the same as exposure in the mid second trimester onward when it's used for GDM control? And that again, that again is a big unknown. That is section 4.1, 1.3 in the 2023 ASRM guidance. Let me read it to you. Quote, women should be counseled that the consequence of metformin exposure on long term offspring health unclear. And there is a suggestion of increased childhood weight, although causality is not certain. Now, some of these studies that have looked at this like one of them was from the pregmet study, that's pregnancy and metformin exposure showed, hey, kids at five to 10 years, yeah, they're fatter, dude. It's been five to 10 years since they took that. That could be a bad diet. That could be exposure, it could be genetics. There's a lot of stuff in there. And this is why this is, this is very tricky. Okay, so that study specifically that was called a pedmet, that's pediatric outcome in metformin exposed offspring, which is a follow up of the pregmet study. Again, pregnancy and metformin trial. So pregmet and pedmet. So pregnancy and metformin or pediatric outcomes after metformin did show higher BMIs and higher weight to height ratios, including waist circumference at ages 5 to 10 compared to those not exposed. But it's very hard to figure that out because there's so many CO variables that are very hard to control. That's why ASRM says it's an association. Right now we don't know. We don't know if that is causation. Okay. The good news is, is that neurodevelopmental issues doesn't seem to be a thing. It's more Again, metabolic imprinting, even though we have very, very limited and inconsistent data and a lot of the study protocols and study outcomes have a lot of heterogeneicity. So the good news is that it doesn't seem that metformin exposure affects neurodevelopment. Most of the impact on the child seems to be metabolic and metabolic imprinting, though it is not clear if that is real or not. Hence why we still give Metformin in our patient population to those with poor health literacy. Because I don't want them to get hypoglycemic coma because that's kind of worse. So again, this is fast. You know, our commitment here is to try to let you know quicker what's going on. This just came out in the Gray journal. This is a systematic review and meta analysis of preconception and first trimester Metformin on pregnancy outcomes in women with pcos. Now this is not women on metformin because they've got, you know, pregestational diabetes. And then you can extrapolate this. This is specifically for the biochemical, the, the, the, the genetic condition and metabolic condition of PCOS pre pregnancy. So please don't extrapolate. You know, somebody's on Metformin for, you know, pre, for class B diabetes and then they get pregnant. That's a different issue. This is for Metformin in PCOS patients who, you know, non diabetic and then who get pregnant. How to counsel these patients. So the short answer is based on this brand new data that's pretty limited. Again, only 12 trustworthy studies with an N of 1708. At least it's not harmful and it may possibly be helpful to get them out beyond 12 weeks. But also those limitations on not helping reduce preeclampsia, hypertensive disorders in pregnancy, macrosomia or gestational diabetes, okay, that's what it does not do or prevent late miscarriage. But again, even in the ASRM guidance it says, hey, in some patients, especially if they got a history of preterm labor, maybe there is some data that metformin in PCOS patients may possibly, possibly help reduce the risk of preterm delivery. Even though you know that that's a little controversial, but that's part again of shared decision making. So Podcast Family, I think we're going to wrap it up here. Again, this is out of the Gray journal December of 2025. Preconception and first trimester metformin on pregnancy outcomes in women with polycystic ovarian syndrome. Podcast Family, as always, we're thankful for you. Hey guys, we just got a 2025 Spotify award. Woohoo. Even though we're on different platforms and channels, Spotify is our home platform. And thank you. Thank you for your continued again, your faithful friendship, your. Your loyalty. Because, man, we got some pretty great stats from 2025. All right, now that we've done all that, we'll see you on the next episode of the no Spin Podcast. Michael, let's take it home.
- [25:34]
This has been Dr. Chapa Zobichi yn no Spin podcast.
- [25:41]
Podcast Family. Thank you for your support. Thank you for listening. And as always, we'll see you on another episode of the no Spin Podcast.
- [26:03]
It.