Metformin Use During Conception and Pregnancy
Friday, September 25, 2009
Kenneth F. Trofatter, Jr., MD, PhD
Dr. T,
Quick opinion if you don't mind. As you may recall, I miscarried on 9/12. I have since seen my PCP for a regular check-up. He prescribed me Metformin….he believes based on my history, weight, blood work and family history, my body may have issues with the breakdown of sugars (i.e., type 2 diabetes but I'm not diagnosed with that). He said that it also may have some positive side effects for me including weight loss and assistance in helping me to conceive (although that doesn't appear to be a problem since I WAS able to get pregnant even though I miscarried). He says it is completely safe.
I have read mixed things online about Metformin and potential effects on babies. Namely that no known birth defects have been caused from it but that there are not many studies either. Additionally, I have read some things about it potentially causing miscarriage.
Could you please give me your opinion on this? I would like to take it as I have for a week now, because I physically feel better. I'm very scared of the effect it may have of a pregnancy and if I were to stop taking it during my pregnancy (as my doctor said this is elective as he feels it would benefit me but is not imperative for me to take). Do you know of any potential miscarriage issues with this prescription?
Thanks again for EVERYTHING!
Christe
Women with insulin resistance are at increased risk for hyperinsulinemia, type 2 diabetes, polycystic ovary syndrome (PCOS), and hyperandrogenism (increased levels of ‘male hormones’). They also are at risk for reduced fertility secondary to ovulatory dysfunction and a suboptimal hormonal milieu that may impair conception, implantation, and placentation. Pregnancy complications include higher rates of miscarriage, gestational diabetes, hypertensive disorders, preterm delivery and operative deliveries, excessive maternal weight gain, fetal macrosomia as well as growth restriction, and admission of their babies to neonatal intensive care units for a variety of reasons (Boomsa, et al., Semin Reprod Med. 2008;26:72-84). In my own experience, they also appear to be at increased risk for complications related to cervical insufficiency.
Metformin is an oral hypoglycemic (blood sugar lowering) agent whose primary affect seems to be mediated through its ability to reduce insulin resistance, thereby leading to a reduction in blood glucose and insulin levels. Metformin has also been found to have other beneficial affects, some of which appear to be independent of its hypoglycemic activity. Included among these are its effects on lipids, inflammation, hemostasis, and endothelial cell and platelet function (Anfossi G, et al. Curr Vasc Pharmacol. 2010 Jan 1. [Epub ahead of print]; Matsumoto T, et al., Am J Physiol Heart Circ Physiol. 2008;295:H1165-H1176).
In women with PCOS, “reduction of hyperinsulinemia with metformin and diet is associated not only with improvement of the biochemical endocrinopathy, but, commonly, with restoration of menstrual cycles and fertility (Goldenberg, et al, Minerva Ginecol. 2008;60:63-75).” When used in infertile women with PCOS in combination with clomiphene citrate, an ovulation-inducing drug, metformin was shown to improve improve conception rates and, perhaps, live-birth rates compared to either drug alone (Legro, et al., N Engl J Med. 2007;356:551-66). In a recent small study of 66 women with PCOS who were clomiphene resistant and underwent in vitro fertilization, those who “received metformin (until conception) showed a significantly higher number of good quality embryos and implantation rate when compared with the placebo controls (Qublan, et al., J Obstet Gynaecol. 2009;29:651-5).” They were also found to undergo fewer spontaneous abortions in early pregnancy.
Very few studies have been done in which metformin therapy has been continued throughout the pregnancy, but in those that have, the results have been encouraging. Khattab and colleagues (Gynecol Endocrinol. 2006;22:680-4) studied 200 nondiabetic women who took metformin while undergoing assisted reproduction, of which 80 stopped the drug once they conceived and 120 continued it throughout pregnancy. Demographically, both groups were similar. Miscarriage rates “in the metformin group were 11.6% compared with 36.3% in the control group (p < 0.0001; odds ratio = 0.23, 95% confidence interval 0.11-0.42).” Similarly, Nawaz and colleagues (J Obstet Gynaecol Res. 2008;34:832-7), found that “In women with PCOS, continuous use of metformin during pregnancy significantly reduced the rate of miscarriage, gestational diabetes requiring insulin treatment and fetal growth restriction.” Furthermore, no significant congenital anomaly, intrauterine death or stillbirth in any of the woman who took metformin during in this study.
To support the observations in humans and, perhaps, to provide a mechanism of action, Luchetti and colleagues (J Steroid Biochem Mol Biol. 2008;111:200-7) found in mouse studies that hyperandrogenization, such as that which occurs in PCOS, induces embryo resorption in early pregnancy and that this is correlated with reduced production of progesterone-induced blocking factor (PIBF) and increased production of cyclooxygenase-2 (COX-2) - the overall effect of these changes creating a pro-inflammatory environment. Coincident treatment with metformin is able to reverse such changes and prevent early pregnancy loss in this animal model. To further support the overall beneficial effect of metformin in human pregnancy being the result of its overall anti-inflammatory properties, Orio and colleagues (Eur J Endocrinol. 2007;157:69-73) found in nonpregnant PCOS women that metformin treatment significantly reduced WBC count and C-reactive protein (CRP), reduced androgens, reduced low density lipids, and increased high-density lipids – all contributing to a reduction in the “proinflammatory” status of those PCOS women receiving metformin.
Finally, to answer our reader’s final concerns, in all the studies we have reviewed, in no instance did taking metformin, either during conception or throughout any time frame of pregnancy, appear to have a serious deleterious affect on the babies. Although the studies have been small, there does not appear to be a greater risk for spontaneous abortion, later pregnancy loss, or congenital anomalies (Goldenberg, et al., Minerva Ginecol. 2008;60:63-75; Nawaz, et al., J Obstet Gynaecol Res. 2008;34:832-7; Qublan, et al., J Obstet Gynaecol. 2009;29:651-5; Elizur, et al., Fertil Steril. 2008;89:1595-602; Bolton, et al., Eur J Pediatr. 2009;168:203-6; Ekpebegh, et al., Diabet Med. 2007;24:253-8). Furthermore, Bolton and colleagues (Eur J Pediatr. 2009;168:203-6) have reported that metformin is actually associated with beneficial effects of fewer growth restricted (< 10th percentile) and macrosomic (> 90th percentile babies) and fewer cases of neonatal hypoglycemia requiring glucose infusion.
Labels: diabetes, insulin resistance, metformin
27 Comments:
At Sun Oct 11, 12:44:00 PM 2009,
Anonymous said…
Dr. T.,
I'm looking for some information regarding AVMs. I had a missed miscarriage and D&C at 11 weeks last year. Earlier this year I had an ectopic pregnancy and a ruptured fallopian tube. I had surgery to remove my tube. I am now pregnant again. I am about 5.5 weeks along and had an ultrasound to rule out another ectopic. The u/s did reveal an intra-uterine gestational sac, yolk sac and fetal pole, so things seemed to be on the right track. However, the u/s also revealed what my Dr. suspects is a uterine AVM. She told me that it wouldn't interfere with the pregnancy, but could cause complications at delivery. However, when I started researching uterine AVMs, everything I read seemed to indicate that a full term pregnancy with this condition was highly improbable, and that my future fertility was also in doubt. I really don't know what to believe now or what to do.
Any advice?
Many thanks!
-RNM
At Wed Oct 14, 07:39:00 PM 2009,
Monika said…
Thanks for your article on metformin and pregnancy. I have been on metformin for just over a year, to treat PCOS. I wondered if you have seen studies that link Metformin to increased risk of blood clots during pregnancy, especially placental abruption caused by clotting. Or if there was added risk with Metformin when a patient is heterozygous for MTHFR.
I was on metformin during my pregnancy, but lost my son at 24 weeks. The tests on the placenta showed that there was a clot that appeared to have been developing for a couple of days. Placental abruption was considered to be the ultimate cause of the preterm labor. (I also had a shortened cervix, but it was still over 2cm a week before I delivered.) I tested positive for one (not both) of the MTHFR genes, which the nurse told me was typical of 50% of the US population. An HSG ruled that my uterus showed no abnormalities.
I've been told that I may receive a cerclage or may be put on progesterone suppositories longer into the next pregnancy, but nothing has been said regarding the blood clot.
I am trying to conceive again, but am a little nervous about remaining on the Metformin throughout the next pregnancy. (I was told different things about the Met by my OB and MFM.) Are there specific things my MFM should check for? Should I ask for my homocysteine levels to be checked?
Thank you so much! I appreciate that you take the time to write these articles and provide answers to some of the comments.
At Sun Oct 18, 06:40:00 PM 2009,
Kenneth F. Trofatter, Jr., MD, PhD said…
To RNM: Sorry, but that's a new one on me. I would love to see the pictures that led to the suspected diagnosis of the AVM. I think you should not panic at this point and just wait to see how things turn out. By the way, in this day and age of assisted reproductive technologies, even if you lost your uterus, as long as your ovaries were retained, you could still have a baby of your own via a surrogate carrier. Please let me know what happens and sorry I can't be of more help. Best wishes.
Dr T
At Mon Oct 19, 12:17:00 AM 2009,
Anonymous said…
Hi Dr. T.,
I wondered if you had seen any studies related to Metformin use in pregnancy and the risk of placental abruption?
I lost my son due to a placental abruption at 24 weeks, have been and am still on Metformin for PCOS, and am trying to conceive again. I would like to know if taking metformin could have led to the blood clot that caused the abruption.
Thanks for any insight you might have.
At Mon Oct 19, 03:24:00 PM 2009,
Anonymous said…
Hello, Doctor. I am really hoping you can give me some insight.
I had two miscarriages before my daughter and had another miscarriage in July due to Triploidy XXY 69, which I was told is very rare and a fluke.
I am now pregnant again and am currently 6 weeks along. This past weekend I experienced brown spotting and then red this a.m.
I went to the dr and he performed an u/s. He said the baby has grown, but it's very small and very low in my uterus. He told me he is 95% sure I will miscarry. He suggested that I have Karyotyping done on myself and my husband after I miscarry.
I am under the impression that if you have a genetic disorder, your only chances of conceiving are through IVF. I don't believe this to be the case for us because we have one healthy daughter who is 2.
Is this true or am I wrong? I do have a thrombophilia that I take heparin for when pg. I also take 25 mg of progesterone once a day along with Folgard, baby aspirin and prenatal vitamins.
At Tue Oct 20, 06:03:00 PM 2009,
Kenneth F. Trofatter, Jr., MD, PhD said…
To anonymous Oct 19: A couple of points: 1) Triploidies are NOT a rare cause of early miscarriage. See my recent post on this subject. 2) You CAN have normal children because you already have one, but that does NOT rule out the possibility that either you or your husband carries a balanced translocation (see other posts in my archives on this) 3) Do not confuse chromosomal abnormalities with genetic disorders - they are very different entities 4) IVF does not eliminate the risk of having a baby with either a chromosomal abnormality or a genetic disorder although it can be coupled with preimplantation genetic diagnosis (VERY EXPENSIVE) that may help reduce your risk for either. 5) What sort of "thrombophilia" do you have? Thanks for writing.
Dr T
At Tue Oct 20, 06:07:00 PM 2009,
Kenneth F. Trofatter, Jr., MD, PhD said…
To anonymous Oct 19: PCOS is a greater risk factor for hypertensive disorders, poor placentation, placental abruption, and early delivery all by itself. I am not aware of any independent association between metformin and those complications.
Dr T
At Tue Oct 20, 07:30:00 PM 2009,
Anonymous said…
Dr. T:
Thank you for answering my question from Oct. 19. I guess I am confused. Is Triploidy a genetic or chromosome abnormality? When my dr. told me what the testing from the D&C showed he said that it was rare case and it rarely happens to the same person twice.
I guess what I am looking for is reassurance that I still have a good chance in the future to carry another pregnancy. I was hoping since I already had one healthy child that my chances are still good. I am 31 years old.
At Wed Oct 21, 06:41:00 AM 2009,
Anonymous said…
this is just an inquiry, how long does it take for one's posts to appear and how do i check out for the answers? I posted a question recently but i don't know where to find the answer.
At Wed Oct 21, 05:22:00 PM 2009,
Kenneth F. Trofatter, Jr., MD, PhD said…
To anonymous Oct 20: Triploidy represents a condition in which the baby has 3 complete sets of chromosomes (69) rather than two sets (46) (23 from mom and 23 from dad). Triploidy occurs in 1 of every 12-15 early miscarriages (so it is very common). There are different origins of triploidy (see my post of August 31, 2009). I have known many women who lost more than one triploid pregnancy early or later in their pregnancies. At your age, there is an excellent chance you will have another normal pregnancy. Best wishes!
Dr T
At Wed Oct 21, 05:24:00 PM 2009,
Kenneth F. Trofatter, Jr., MD, PhD said…
To anonymous Oct 21: I cannot answer all the questions I get but try to answer as many as I can. The response will appear somewhere following your own on the same post at which you left your comment! I wish it wasn't so, but that's the way things work!
Dr T
At Fri Oct 23, 10:37:00 AM 2009,
Anonymous said…
A brief update to my Oct 11 post regarding AVMs. We had another u/s today, and found a strong heartbeat. The gestational sac was measuring about 1 week smaller than the fetus, but the Dr. wasn't concerned about this. They also saw a small hematoma behind the gestational sac, which also didn't worry her (I haven't had any spotting).
The Arteriovenous Malformation, however, is still there. The sonographer said is shows as a mass or leision with increased blood flow and doppler shows it has characteristics of both venal and arterial blood flow. It appears to be inside the uterine wall, rather than in the uterine cavity. It has not changed in size or appearance since the initial scan 2 weeks ago. Unfortunatley, I don't have copies of the u/s pictures for you, but based on this update, do you have any further insight?
At Fri Nov 06, 12:26:00 PM 2009,
Anonymous said…
Dr. T:
I've written in the past regarding my miscarriages. I am now currently going through my second miscarriage after the birth of my daughter. So far I have been able to pass everything naturally, but my levels are dropping slowly. Currently today my hcg level is at 227 compared to 346 three days ago. My ob/gyn is letting me go another week to see if it hits 0 and if it doesn't, he wants me to do a d & c.
I am against a d & c because I've had three in the past and I am worried about scar tissue and it affecting my ability to get pg again and/or cause miscarriage.
What are your thoughts? Should I proceed with the d & c or should I hold out and wait a couple more weeks to see if my levels drop?
I started miscarrying three weeks ago.
At Wed Nov 18, 05:41:00 AM 2009,
Mandy said…
Dr. Trofatter,
I stumbled upon your blog while searching for information on recurrent miscarriage. I enjoy reading what you have to say.
I just finished your March/April 2007 series on recurrent miscarriage. I have a question on the topic, and I didn't want to leave a comment on such an old post.
I am 24 years old and I recently had my second miscarriage (first one at 6 weeks, this one at 5 weeks). I am Rh-negative and I understand that there is a risk of sensitization with each pregnancy, so I really want to start and finish childbearing as soon as possible.
I have hypothyroidism and there is a history of lupus in my family. What tests should I be asking for? Should I insist that my doctor do it now rather than wait for a third miscarriage, as he said he would prefer?
Thank you!
At Sun Nov 22, 09:11:00 AM 2009,
Lana2179 said…
I am searching for answers...On Nov 14 I went to the ER b/c I had been bleeding for 10days. I assumed it was my cycle until I decided to take a pregnancy test which revealed me as pregnant. They ran test which reveal my Beta at 936 but saw nothing on the ultrasound. They then told me I miscarried. On the 17th b/c of cont. cramping I went back to the ER which Beta was now 1638 however still no signs of gestational sac and cervix is closed. On 19th Beta was 2148 and on 21 Beta was 2960. My last cycle was Sept 29 but could only have concieved on Nov 17 or 24th when my husband was in town. I am worried about this abnormal rise in my bhcg levels and since ultrasounds reveal no gestational sac,no embryo in uteral nor in tubes and my cervix is still closed I need definite answers before I just abort a pregnancy. I was also diagnoised with HIV in 2005 after being raped. I have since married and have a health husband and two year old daughter. Do you have any info to offer me?
At Fri Nov 27, 07:47:00 AM 2009,
Robin said…
Dr.T.,
I would like to start by saying Thank You for taking the time to answer all "our" questions. Reading your blog and subsequent comment responses has given me more usable info than I have found any where else on the web. With that said I have a question. I was recently pregnant I had a Ultrasound on 10/27 which showed a 10 week fetus with a heartbeat at 163 bpm. I was estatic as my OB had said once we saw the heartbeat my miscarriage risk went down to about 3% however my happiness was short lived as two weeks later I woke up Spotting after having a severre pain in the middle of the night. I went to the ER they said it was a threatened miscarriage . The next day I went to my OB who did a abdominal and vaginal ultrasound. There was no heartbeat he sent me home and said I would have a "heavy period" for a couple of days however I just kept spotting. On Wed.11/18 i went to the toilet after having horrible pain and suddenly had a gush of liquid I looked and there was my baby girl in the toilet. Fully formed the size of two of my fingers. I broke down . Sparing you the rest I had a D & C done last thursday 11/19. My OB said I am not high risk for future miscarriages. However my husband and I had been trying for three years and this was the first pegnancy. I am 24, overweight (hypothyroidism) and have endometriosis, but had lost 16 lbs during preganancy.I did all I was supposed to prenatal vitamins, folic acid, no caffiene.I am distraght and want to know why did this happen? Why did I deliver a fully formed baby (as I have not heard of this at 13 weeks)? Will having the D & C help with the endometriosis and my ability to get pregnant? And will it (miscarriage) happen againI know I was a bit long winded but wanted to give you as musch info as possible. THANK YOU So Much, Robin
At Mon Nov 30, 06:22:00 AM 2009,
Yusuf said…
Dear Doctor,
My wife had stopped using metformin after six weeks into pregnancy. She had PCOS issue and we went through IVF process to conceive the baby.
Can you please tell me, if stopping Metformin (after six weeks) has caused any problems for the mother and the baby?
We continuously took her diabetes test and they were in the normal range.
Please Advice
At Sun Dec 13, 11:59:00 AM 2009,
Anonymous said…
Hello Dr. T. I hope your recovery is going well! We were all worried about you when you hadn't posted anything for so long. Glad to have you back.
I wanted to give you an update on my progress since my last post. about the uterine AVM.
I am now at 15 weeks and have been seeing a MFM specialist since about 9 weeks. He is monitoring me by u/s every 2 weeks. Everything to date looks perfect with the baby, good heartrate, lots of movement etc... and the only complication continues to be the AVM. It is in the posterior myometrium, about 4cm x 4cm x 2cm. It has been growing at about the same rate as the uterus, so my Dr. thinks that it is essentially "stretching" as the uterus grows. There have been complications to date - no bleeding or pain - associated with it. He said that the placenta is also posterior, so he will keep monitoring me every 2 weeks by u/s to make sure that the AVM doesn't grow too quickly or that it does not somehow connect to the placenta. Other than that, he basically had the same advice as you did when you first responded to me, which was to just watch it and see what happens. He said there isn't much else to do. If all goes well, he'll make a decision about whether I have a vaginal birth or C-section when the time comes.
My biggest worry now is whether the baby, as it grows and starts kicking, can kick the area around the AVM and cause it to bleed. And if it does start to bleed, is there anything they can do to stop it while still protecting the pregnancy? My Dr. didn't really have an answer to this other than that we'll deal with anything that comes up as it happens. Any thoughts?
So few Dr.'s have actually seen this, so I guess I just continue to watch and wait.
Thanks for listening!
RNM.
At Mon Jan 11, 07:42:00 AM 2010,
Sharpiegirl said…
I am 42,just starting to try to conceive and I have had 2 missed m/c (8 wks and 7 wks respectively) and a chemical pregnancy in the last year. I had a d&c with each of the missed m/c and testing was done on them but nothing was found.
After the second one they ran all kinds of blood tests on me for clotting issues etc. Everything came back ok except one the "not so bad" clotting issues, as my doctor put it, came back indeterminable. I am now taking a baby asprin a day along with prenatal, dhea, vit B6, fish oil, vit E.
I don't have PCOS but I am hypo ( take 2 - 90 mg desicated thyroid at bedtime.) have high cholesterol and I am also overweight (225 and I can't even lose it when I don't eat I had the flu and didn't eat much more than chicken broth for a week, still gained 4 lbs. aaarrrggghh.) I have family history of diabetes and heart disease on both sides. Would I be a candidate to use Metformin?
At Mon Jan 18, 06:46:00 AM 2010,
Anonymous said…
Dr. T,
A question if you don't mind. I'm 31 and suffer mild PCOS - only one ovary is effected, although I do have other PCOS symptoms (irregular periods, infertility, 30lb weight gain). I started taking Metformin 5 weeks ago, after 2 years of infertility and became pregnant. My question is do I continue the Metformin therapy during pregnancy? I've only been on it for the short period of time, but I also know that having PCOS, even though not severe, will increase my chances of miscarriage. Will the Metformin help to prevent that?
I've got my first prenatal appt. this week, but wanted to get another opinion.
Many thanks!
- ER
At Tue Feb 02, 11:35:00 AM 2010,
Anonymous said…
Hi Dr. T - I wrote to you 2 years ago as a 38 year old woman who was evaluating the risks of an amnio, after having 2 early losses. That pregnancy ended in a cord loss at 18 weeks. You wrote a blog entry on our amnio discussions.
More than a year after losing my daughter, I went on to have a normal pregnancy and, at 40.5 years old, gave birth to a normal, healthy son. No amnio, just good screens.
I wanted to comment on the metformin issue. I was on metformin for this pregnancy, and I was fine. In fact, a maternal-fetal person told me that there could be an increased risk of loss if metformin was stopped during pregnancy. Is that correct?
I wanted to thank you for the support that you and your blog have given me through my recurrent pregnancy losses to where I am now. No more kids are planned, but I wanted to say that you are awesome and thanks.
Liz
At Wed Feb 03, 07:17:00 AM 2010,
Anonymous said…
Dr. T.,
I see in your article that you have seen an connection between insulin resistance an complications like cervical insufficiency. I am now pregnant for the third time, the two previous pregnancies I lost at 16wks due to cervical insufficiency. Prior to this conception I've used metformin and wonder if it's a good idea for me to continue to use this, and if so in which doses? I'm getting a cerclage this time around, but not until week 11 (am now 4 wks).
Thanks for your advice
Ingrid (from Norway)
At Sun Feb 07, 01:43:00 PM 2010,
Kenneth F. Trofatter, Jr., MD, PhD said…
To RNM Dec 13: I have not seen this note until now - was in the middle of my own recovery from surgery when you sent it. I truly doubt the baby is going to create problems with the AVM but have to concur with your doctor's assessment to continue to wait and see and to deal with problems as they arise. If severe bleeding occurs during the pregnancy, the only solution might be delivery, in which case I hope you are far enough along to get a good outcome with the baby. Please let us know how everything turns out and best wishes!
Dr T
At Sun Feb 07, 01:45:00 PM 2010,
Kenneth F. Trofatter, Jr., MD, PhD said…
To sharpiegirl Jan 11: At your age, my suggestion is that you ask your doctors for a consultation with a specialist in Reproductive Endocrinology and Infertility to help with the decision regarding metformin and any other evaluation and treatment to help you get a successful pregnancy. Thanks for writing and good luck with things!
Dr T
At Sun Feb 07, 01:50:00 PM 2010,
Kenneth F. Trofatter, Jr., MD, PhD said…
To ER Jan 18: There are those who discontinue it if the only indication was infertility and those that recommend continuation. I don't have the right answer at this point. Personally, in women with PCOS who are truly insulin-resistant, I have the tendency to continue the metformin. It could reduce your risk of gestational diabetes and complications related to the same and might also have other effects that might benefit outcome. There are concerns about potential effects of metformin on the baby related to fetal 'hypoglycemia', but to this point I have not seen good evidence in that regard. Best wishes and let us know what you decide to do and how things turn out!
Dr T
At Sun Feb 07, 01:53:00 PM 2010,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Liz Feb 2: Thank you for the update and for letting us know about your successful pregnancy. I know that was a long hard road! Generally, i leave folks on metformin if they have started it before conception, but in all honesty, I don't think the final word is out about its effects on the baby in the short- or long-term. On the whole it seems to be relatively safe to continue even if it does cross the placenta. Thanks for touching base with us and have fun with your baby!
Dr T
At Sun Feb 07, 01:56:00 PM 2010,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Ingrid Feb 3: If you have insulin-resistance, or frank type 2 diabetes, my inclination is to continue the metformin (at whatever dose you are currently on) throughout the pregnancy although you will hear arguments on both sides of the issue. I have not seen complications with it and believe it might reduce the risk for gestational diabetes and the complications related to that condition. Best wishes and let us know what you decide to do and how things turn out!
Dr T
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