Sunday, August 2, 2009

Metformin and Pregnancy

This is a post I've been meaning to write since my last ob visit.

My Ob was not wild about me staying on metformin at our first appointment. I think I'm probably the first patient she's had come to her after conceiving on metformin and whole heartedly wanting to stay on it.

First, I just want to say that met was one of the best things that has ever happened to me. I love it. I don't think I'd be pregnant right now with out it. When I started it, it was like I was a new person. The spark came back into my life again. I had energy. For the first time (in a long time) I actually felt the effects of adding the calories into my body. And it never mattered how well I dieted before, they just didn't work, I couldn't loose weight without massive amounts of exercise. But since the met, I have been eating sensibly and loosing weight like a normal person does (amazing). I didn't really have any digestive issues other than a little extra gas (really only lasted for the first 6 weeks). I really like my dosage- 750mg Extended Release twice daily. If you feel a little knocked around/light headed on met, I highly recommend you try extended release. If you have digestive problems, see if going low carb helps while your body adjusts.

But back to pregnancy and met... my Ob wasn't sure and we decided to discuss it again at my 13 week appt and she would pull some research to review before then. And I pulled some research of my own of course.

First, check out Bird's list of papers on met during pregnancy. Their are some excellent papers listed there. And I have a few more papers listed below too.

Basically, when me and my Ob met again at my 13 week appt. she had read enough and knew that I was well informed on the risks and had read the research to support me in this. Neither she nor I had seen any research indicating complications from using it. HOWEVER, the research is not complete. There needs to be more, larger, long term studies showing the safety of metformin during pregnancy. Both she and I agree on that. But, I have weighed the research and am comfortable taking that risk because the benefits appear to outweigh the risk at this time. And she agrees with me and is going to support me in this decision.

In general, women with PCOS tend to face a significantly higher risk of complications during pregnancy (including miscarriage, preeclampsia, and gestational diabetes, to name a few). In comparing control groups (non pcos women) to pcos women on placebo and pcos women on met, the risks of these complications tend to be significantly reduced to levels meeting or even exceeding those of the non pcos women (even when controlling for weight). I haven't seen any reported increases of congenital defects from taking met. The last study on here shows that children of women who took met during pregnancy show no signs of abnormal development at 18 months.

The first and second papers on my list appear to conflict on whether met decreases in utero exposure to testosterone. If it does decrease exposure to testosterone, that is something really interesting to consider. PCOS appears to be an inherited condition... but no one has been able to determine if it is genetic yet. Also, PCOS symptoms can appear so differently between women... so what if exposing baby girls excess testosterone in the womb is a factor contributing to the development of PCOS? I'm just pulling this out of my ass, but wouldn't it be incredible if they determined that in utero exposure to testosterone causes PCOS 5 or 10 years from now, and this cheap and widely available drug prevents your daughter from developing it? How great would that be? But this is just Amanda's wishful thinking brain here and not really based on scientific facts at all (but it makes you think).

Conversely, if 10 years from now, they determine that kids exposed to met in the womb all develop type II diabetes at 13 that would not be good at all. I am taking a gamble here, and I hope I don't loose.

Well, if you are TTC and on met, I really recommend that you do some research. Stick to peer reviewed papers in actual journals and don't just believe the crap on blogs (particularly this one) or in chat rooms.

Metformin during pregnancy reduces insulin, insulin resistance, insulin secretion, weight, testosterone and development of gestational diabetes: prospective longitudinal assessment of women with polycystic ovary syndrome from preconception throughout pregnancy
C.J. Glueck , N. Goldenberg , P. Wang , M. Loftspring , and A. Sherman
Hum. Reprod. Advance Access published on March 1, 2004, DOI 10.1093/humrep/deh109.
Hum. Reprod. 19: 510-521.

BACKGROUND: In a prospective observational study of 42 pregnancies in 39 Caucasian women (age 30 ± 4 years) with polycystic ovary syndrome (PCOS), we examined effects of metformin on maternal insulin, insulin resistance (IR), insulin secretion (IS), weight gain, development of gestational diabetes (GD), testosterone and plasminogen activator inhibitor activity. We assessed the hypothesis that diet–metformin (MET) lessens the physiological gestational increase in IR and reduces gestational weight gain, thus reducing GD. METHODS: Preconception, in an out-patient clinical research centre, MET 1.5 (eight pregnancies) to 2.55 g/day (34 pregnancies) was started. Women with body mass index <25 or 25 kg/m2 were given a 2000 or 1500 calorie/day, high-protein (26% of calories), low-carbohydrate (44%) diet. Calorie restrictions were dropped after conception. RESULTS: On MET, GD developed in three out of 42 pregnancies (7.1%). Median entry weight (94.5 kg) fell to 82.7 on MET at the last preconception visit (P = 0.0001), fell further to 81.6 during the first trimester, was 83.6 in the second trimester, and 89.1 kg in the third trimester. Median weight gain during pregnancy was 3.5 kg. The median percentage reduction in serum insulin was 40% on MET at the last preconception visit; insulin did not increase in the first or second trimesters (P > 0.05), and rose 10% in the third trimester. The median percentage reduction in HOMA IR was 46% on MET at the last preconception visit; IR did not increase (P > 0.05) in the first, second or third trimesters. HOMA insulin secretion fell 45% on MET at the last preconception visit, did not increase in the first trimester, rose 24% in the second trimester, and rose 109% in the third trimester. Testosterone fell 30% on MET at the last preconception visit (P = 0.01) and then rose 74, 61 and 95% during trimesters 1, 2 and 3; median testosterone during the third trimester did not differ from pre-treatment levels. CONCLUSIONS: By reducing preconception weight, insulin, IR, insulin secretion and testosterone, and by maintaining these insulin-sensitizing effects throughout pregnancy, MET–diet reduces the likelihood of developing GD, and prevents androgen excess for the fetus.

Metformin reduces pregnancy complications without affecting androgen levels in pregnant polycystic ovary syndrome women: results of a randomized study
E. Vanky , K.Å. Salvesen , R. Heimstad , K.J. Fougner , P. Romundstad , and S.M. Carlsen
Hum. Reprod. Advance Access published on August 1, 2004, DOI 10.1093/humrep/deh347.
Hum. Reprod. 19: 1734-1740.

BACKGROUND: Investigation of a possible effect of metformin on androgen levels in pregnant women with polycystic ovary syndrome (PCOS). METHODS: A prospective, randomized, double-blind, placebo-controlled pilot study was conducted. Forty pregnant women with PCOS received diet and lifestyle counselling and were randomized to either metformin 850 mg twice daily or placebo. Primary outcome measures were changes in serum levels of dehydroepiandrosterone sulphate, androstenedione, testosterone, sex hormone-binding globulin, and free testosterone index. Secondary outcome measures were pregnancy complications and outcome. Two-tailed t-tests and 2-tests were used. RESULTS: Maternal androgen levels were unaffected by metformin treatment in pregnant women with PCOS. While none of the 18 women in the metformin group experienced a severe pregnancy or post-partum complication, seven of the 22 (32%) women experienced severe complications in the placebo group (P=0.01). CONCLUSIONS: Metformin treatment did not reduce maternal androgen levels in pregnant women with PCOS. In the metformin-treated group we observed a reduction of severe, pregnancy and post-partum complications. Metformin treatment of pregnant PCOS women may reduce complications during pregnancy and in the post-partum period.

Pregnancy outcomes among women with polycystic ovary syndrome treated with metformin
Charles J. Glueck , Ping Wang , Naila Goldenberg , and Luann Sieve-Smith
Hum. Reprod. 17: 2858-2864.
BACKGROUND: We sought to determine whether metformin, which had facilitated conception in 72 oligoamenorrhoeic women with polycystic ovary syndrome (PCOS), would safely reduce the rate of first trimester spontaneous abortion (SAB) and increase the number of live births without teratogenicity. METHODS: Seventy-two oligoamenorrheic women with PCOS conceived on metformin (2.55 g/day). They were prospectively assessed in an outpatient clinical research centre. Outcome measures included number of first trimester SAB, live births, normal ongoing pregnancies 13 weeks, gestational diabetes (GD), congenital defects (CD), birthweight and height, as well as weight, height, and motor and social development during the first 6 months of life. RESULTS: Of the 84 fetuses, to date there have been 63 normal live births without CD (75%), 14 first trimester SAB (17%), and seven ongoing pregnancies 13 weeks with normal sonograms without CD (8%). Previously, without metformin, 40 of the 72 women had 100 pregnancies (100 fetuses) with 34 (34%) live births and 62 (62%) first trimester SAB. In current pregnancies on metformin in these 40 women (46 pregnancies, 47 fetuses), there have been 33 live births (70%), two pregnancies ongoing 13 weeks (4%), and 12 SAB (26%) (P < 0.0001). There was no maternal lactic acidosis, and no maternal or neonatal hypoglycaemia. Fasting entry serum insulin was a significant explanatory variable for total (previous and current) first trimester SAB, odds ratio 1.32 (for each 5 µU/ml rise in insulin), 95% CI 1.09–1.60 (P = 0.005). On metformin, GD developed in 4% of pregnancies versus 26% of previous pregnancies without metformin, P = 0.025. There have been no major CD in the 63 live births or CD by sonography in the seven fetuses 13 weeks. In the 63 live births, neither weight nor height differed from the normal neonatal population. At 6 month follow-up, height was greater (P = 0.008) and weight did not differ from the normal paediatric population; motor and social development were normal. CONCLUSIONS: Metformin therapy during pregnancy in women with PCOS was safely associated with reduction in SAB and in GD, was not teratogenic, and did not adversely affect birthweight or height, or height, weight, and motor and social development at 3 and 6 months of life.

Height, weight, and motor–social development during the first 18 months of life in 126 infants born to 109 mothers with polycystic ovary syndrome who conceived on and continued metformin through pregnancy
C.J. Glueck , N. Goldenberg , J. Pranikoff , M. Loftspring , L. Sieve , and P. Wang
Hum. Reprod. Advance Access published on June 1, 2004, DOI 10.1093/humrep/deh263.
Hum. Reprod. 19: 1323-1330.

BACKGROUND: We prospectively assessed growth and motor–social development during the first 18 months of life in 126 live births (122 pregnancies) to 109 women with polycystic ovary syndrome (PCOS) who conceived on and continued metformin (1.5–2.55 g/day) through pregnancy. METHODS: The lengths and weights of PCOS neonates were compared with gender-specific Centers for Disease Control and Prevention (CDC) infant data. Gestational diabetes (GD) and pre-eclampsia in women with PCOS were compared with 252 healthy women without PCOS who had 1 live birth (262 live births). RESULTS: There were 101 out of 126 (80%) term (37 gestational weeks) PCOS births, which was not significantly different (P = 0.7) from controls, 206 out of 252 (81.7%). There were two (1.6%) birth defects. GD occurred in nine out of 119 PCOS pregnancies (7.6%) versus 40 out of 251 (15.9%) controls, P = 0.027. The prevalence of pre-eclampsia did not differ in PCOS versus control pregnancies (4.1 versus 3.6%, P = 0.8). The birth length and weight of the 52 male neonates did not differ (P > 0.05) from those of CDC males; the 74 female neonates were shorter than CDC females (48.9 ± 5.4 versus 50.6 ± 2.7 cm, P = 0.006) and weighed less (3.09 ± 0.85 versus 3.29 ± 0.52 kg, P = 0.04). There were no systematic differences in growth between PCOS and CDC infants over 18 months. At 3, 6, 9, 12 and 18 months, of a potential 100% motor–social development score, scores (±SD) were 95 ± 13, 98 ± 8%, 95 ± 10, 97 ± 8 and 94 ± 16%; no infants had motor–social developmental delays. CONCLUSIONS: Metformin reduced development of GD, was not teratogenic and did not adversely affect birth length and weight, growth or motor–social development in the first 18 months of life.

Glueck has probably been the leader in researching metformin in PCOS women and here is a handy link to most of Glueck's research if you would like to read more.


Celia said...

I went off met. But I am not happy about it. To be honest, I have been almost too freaked out to think for myself. So I am just doing what they tell me to do. I have been really afraid that I am going to turn into a sea cow without it. I lost 37 pounds in a year. And I know I am not supposed to gain much pregnancy weight.

Michelle said...

I think it would be interesting to see if that does, years from now, show that it helped prevent baby girls from this. I'm not on Met, and in the past when I tried to take it I got really sick. But I don't have the IR part of PCOS either so maybe that's why I had such a horrible effect from it? Either way, it's good your doctor is understanding and backs your decision.

The Wife said...

I've been kind of blah about metformin. And since last Tuesday I've also been really lax about taking it. It just did nothing for me, I didn't lose weight, have stomach problems or headaches or any other side effects and I don't have PCOS so I don't really see the point anymore. The RE wants me to keep taking it though. So the past 6 months of taking it hasn't caused me to ovulate/get pregnant while taking really powerful fertility drugs, but now that I'm not taking them anymore, somehow only using metformin will? Come on.
Kudos on being so informed. Someof us, I don't think, do enough *real* research on our own and just take what the RE/OB/GYN tell us as the final word.

Anonymous said...

Ooh you found more great journal articles! I'm glad you were able to convince your doctor with all of your research. I know there is some risk with continuing it, but like you said, the benefits appear to outweigh the risks for us. I really think the met is why I have managed to only gain 6-7 pounds at week 20.

I'm a little scared about trying to change obstetricians, because while my current one is a douchebag, he at least is okay with me staying on the met.

Suraita said...

Thanks for posting these - I am waiting to get a final word from my perinatologist on rather to continue the met or not so it is good to have this information!

Chelle said...

I have never taken met, but maybe I will when this pregnancy is over... Very interesting and informative post. Considering I have PCOS and I was just in the hospital at 24 weeks with preeclampsia scare. I am dreading my glucose test..

Sophie A. said...

It's interesting because one doctor wanted me to go on Metformin and the other didn't. I was diagnosed with hypoglycemia (low blood sugar) about a year and a half ago and wonder if that has anything to do with insulin resistance? The second doc is convinced I'm not IR b/c I'm kind of a stick, but I've heard skinny girls can have it too. This is why I wonder if the hypo. has anything to do with would be interesting.

Dianne said...

Wow, Thanks! I have been wanting to ditch the Met for sometime know since I have had alot of tummy issues, but after reading your post I can see why my doc wanted me on it. I dont have PCOS but they put me on it just in case. So I have been fighting it every step of the way!! But I will definitely have more of an open mind after reading this, thanks!

froogle said...

i have not been diagnosed with pcos, but i have unexplained infertility, i due ivf next month and im on metformin now to reduce risk of ohss, i have been taking it for only 6 days and already feel better and lost a couple of pounds which is great! as i have been exercing loads in the last 3mths and lost nothing.
i hope to achieve my dream and will keep you posted

Jellibells said...

I was on Met for PCOS and ovulation, and did get pregnant quickly (was not able to get pregnant before going on met) two times. I stayed on metformin through week 20 of my pregnancy with my daughter, she is now two years old, 90% for height, 70% for weight, and super healthy and happy little girl. We participated in an IQ study at the University of Il Chicago and she scored off over 90% in every area at age 18 months. Clearly there could be long term affects we don't know about yet, but she seems completely unaffected by the met use. Her blood sugar levels, as a side note, are fantastic.

I DID end up developing GD with her - but later than usual, not until week 30. It seemed my IR went downhill after going off the met in combination with the pregnancy progressing, and I passed my early test but not a later one. I did go on insulin, which wasn't a big deal except that in the nine weeks on it they never got the dosage right and I felt constantly ill from weird spikes and lows in blood sugar, it was awful.

Now I am 27 weeks pregnant with baby #2, and still on met as agreed upon with my doctor. I have been monitoring my glucose myself and it has been okay (not amazing, high side of average as the pregnancy progresses), but have the official 'challenge' tomorrow so we'll see. My OB consulted with several Endocrinologists on the matter, and all were okay with staying on met except one who said there is a new study from this year (2009) that has seen some long term insulin resistance issues in children whose parents stayed on met. I am trying to get a copy of the study to read myself, and my doctor did not feel the study was compelling enough for me to go off the met with the high risk of GD in my case, but again we'll see.

Anyhow, as someone who has been through it and going through it, just wanted to share my story. Good luck!

Anonymous said...

I recently came accross your blog and have been reading along. I thought I would leave my first comment. I dont know what to say except that I have enjoyed reading. Nice blog. I will keep visiting this blog very often.


Jennifer said...

Hello I thought I would share my experience with PCOS and pregnancy. After having our first child 4 1/2 years ago without problems we discovered I had PCOS. I was very unhappy with the infertility specialist who decided that I needed to go on birth control for my polycystic ovaries. I did finally become pregnant without any special treament only to lose the baby during my first trimester. My husband and I were devastated. I was 41 and it appeared unlikely we were going to have another child.

In a casual conversation with a friend who is a nurse practioner she asked why I wasn't on metformin. I was shocked that none of my doctors had suggested this. After 9 months on 500 mg three times daily I was pregant at 42. Our second son is due in 4 months and after extensive testing all looks perfectly fine! My OB was resistant to staying on the metformin but I too did the research and have peace that it is best to continue. I'll keep you posted-Jennifer

Lyndal said...

Hi there, thank you for your post. I'm currently TTC for about 2 years now (on and off; my husband and I are in a commuter marriage) and we're now starting to tackle this PCOS thing head-on. My doc just called and confirmed my blood work - I'm now placed on metformin. While I am excited about the prospects of getting pregnant, I am also drawn to what you had said about increased energy levels and losing weight normally. I too have had much trouble losing weight - even though I'm on the high end of the "normal" range - and I am hopeful that this will help make things easier for us.

Thanks again for sharing your experiences with others. This is helpful information.

alleclercq said...

Hello... I'm 26 now and me and my Husband been TTC since 7 months... 8th is coming... And I went o 2 Gyn. one of them said I needed to take contraception pill for 42 days in a raw to try to reduce the size of my cyst on the right ovaris... but my husband got upset, because this "treatment" would mean that for 2 months I would FOR SURE NOT get pregnant, so we went to another doc and he put me on Metphormin... I started yesterday 850mg and in 10 days I can take 850x2 a day... Was reading this blog and these few positive stories after Metphormin make me so excited about getting pregnant! HOPE it will work for us very soon.
(though I have a daughter of 3,5 from another marriage and I got pregnant without any problem by myself... I don't know if I had that cyst those days or not... but it worked out from the first cycle)...
Thank you for reading me

MaladroitBride said...

I have been TTC for about a year and a half now with my husband. I'd tried the BCP's and the Clomid to no avail. I have been on 850mg 2x's per day for about a month and already love it! I am a nurse and had to ask my Gyn. to put me on it! I have yet to get pregnant, but I'm hopeful, this will be my first cycle, so I have high hopes. Thanks for your blog.

LaLa said...

I took 1000 mg metformin the entire pregnancy and had a healthy, very intelligent baby girl. She is a bit bigger than average but so are her parents.