Plasminogen Activator Inhibitor 1 (PAI 1) and Recurrent Pregnancy Loss

Back in June, a reader I.R. left a comment on my post "Recurrent Early Pregnancy Loss - 7 - Immunologic a...". Her specific question related to the possible role of plasminogen activator inhibitor 1 (PAI 1) activity and polymorphisms in recurrent pregnancy loss. The question interested me so much at the time, that rather than answering it in cursory fashion, I promised her I would review the current literature and devote a full post to the issue “in the near future.” Despite my having been, repeatedly, sidetracked, I.R. has remained a loyal reader, and insightful patient, and updated me regularly on her progress. Today, in the paragraphs below, I am going to summarize (and modify for clarity) her story with excerpts from her comments and then summarize my thoughts on the issues she has raised in a follow-up post ….

Dr. Trofatter, I have been diagnosed with Recurrent Pregnancy Loss. I've lost three early pregnancies- 6 weeks, 7 weeks, and 4 1/2 weeks- over the last year. After the third loss, my husband and I went through testing in March 2007 and it's been determined that I have a PAI 1 (4G4G) genetic mutation… I am a healthy 26 year old. I have found a wonderful hematologist that goes above and beyond for me. However, I'd like to know your perspective of how PAI 1 correlates with early first trimester miscarriages… I am having a difficult time finding much information on PAI 1 and miscarriages. It seems that most blood clotting disorders cause second trimester miscarriages; however, I feel that scientists and doctors are still building correlations between clotting and early first trimester losses. Thanks for any advice! I.R.

In August, this was followed by another comment on my post "Diabetes in Pregnancy - 2 - Glucose Metabolism and...":

Dr. Trofatter, I have yet another question. My last miscarriage was in February. I have been trying to get pregnant all summer…using ovulation sticks. Does PAI 1 have anything to do with me not being able to conceive? I've mentioned to two of my doctors the connection of PCOS (polycystic ovary syndrome) and PAI 1 and they all agree that I do not fit any of the typical picture of PCOS; however, after asking for a glucose/insulin test, I am now scheduled to get one. Do you think this is a good step? I know that PAI 1 has something to do with insulin which has to do with the endocrine system which can affect ovulation. I've never had issues in the past getting pregnant, just maintaining my pregnancies. I do not have diabetes. Any advice would be greatly appreciated! No matter how much I try to research PAI 1 and recurrent pregnancy loss, I can’t seem to understand it. Thanks so much for your time! I.R.

A few weeks later, I.R. left another comment on the same post…"Diabetes in Pregnancy - 2 - Glucose Metabolism and..." (sometime I have really got to finish up that series too!)…

Hi Dr. Trofatter, Low and behold, after a few months of asking for an insulin/glucose test, my wish was granted last week. I received my results yesterday and both fasting tests were normal and my two hour glucose was normal as well; however, my two hour insulin levels were elevated which is evidence of insulin resistance…I have mentioned the correlation of PAI 1 and insulin to my doctors a couple of times before but was essentially dismissed because I don't fit the "criteria" of a person who has insulin resistance. I'm not overweight at all and I'm not inactive…I start glucophage with hopes of increasing the quality of my ovulation. I do ovulate "regularly" on CD 15. What are your thoughts of taking glucophage (Metformin) while pregnant?...I know that it is controversial either way. I would appreciate any insight about the connection of PAI 1 and early trimester pregnancy loss as well as its connection to insulin.
Hope you're doing well! IR

I actually did respond briefly to this query and my comment included the following thoughts: There indeed appears to be a need to increase insulin sensitivity in first trimester to aid in proper implantation and placentation...I bet you will be home free from the baby's standpoint if you can get past twelve weeks...You will still be at increased risk for gestational diabetes...While you're at it, why don't you throw the progesterone support, baby aspirin, extra folic acid, and heparin or Lovenox into the mix as well...The latter I would not begin until a pregnancy is confirmed chemically (just about the time you miss a period)... Hang in there girl. I wish you the best on this and think you are going to be a great MOM! Dr T

Then, within two weeks of the above, the following comment was received from I.R.…

Hi Dr. Trofatter, I am on calendar day (CD) 31 and had a positive pregnancy test on CD 27. :) I started Lovenox and am continuing low dose aspirin, my prenatal vitamin and because of the insulin resistance diagnosis, I began glucophage on CD 23. I talked with my nurse today about a calcium supplement and also mentioned the glucophage. She talked with my doctor and she said that he wants me to stop taking glucophage. According to him, since I never made it to the maintenance dose (the 3 pills each day), then it isn't doing anything to help me. I've read elsewhere though that it can help prevent MC. She said that they only wanted me on it to regulate my ovulatory pattern, which does make sense to me, even though I do ovulate regularly just at a later day than 14. My question/concern is that my doctor isn't giving any thought to his decision of stopping glucophage and my diagnosis with PAI 1. This is such a big deal to me…I want to call again tomorrow, but would like a second opinion about my feelings as to whether they're rational or not! I really do like my RE (reproductive endocrinologist) and know that he's performed miracles for many women… Thoughts??!! Thanks again for your insight and time! It means so much! I.R.

To summarize I.R.’s many questions and to throw in a few of my own…
1) What is PAI 1 and what are its roles?
2) What is the association between PAI 1 activity and recurrent pregnancy loss?
3) Should screening for PAI 1 be a part of our regular evaluation of the couple with recurrent pregnancy loss?
4) What is the association between PAI 1 activity and insulin resistance?
5) Could PAI 1 activity be associated with infertility?
6) What role might glucophage play in the management of women with recurrent pregnancy loss and abnormalities of PAI 1 activity?
7) If glucophage is used in women with ‘insulin resistance’, is there a benefit to continuing it during pregnancy or should it be stopped, and when?
8) In the absence of clinical indication other than recurrent pregnancy loss, should the other medications (Lovenox and aspirin) be continued or stopped and when?

Actually, if I had all the answers to the above questions (and I am sure I will come up with a few more as I try to answer these), I would probably be quite famous, but in our next post on this subject, I will at least give you my thoughts! And, to I.R., thanks for your loyalty and your patience and best of luck with this pregnancy!

Labels: diabetes; insulin resistance, glucophage, lovenox, PAI 1, PCOS, plasminogen activator inhibitor 1, recurrent pregnancy loss, thrombophilias

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Multiple Pterygium Syndrome - A Rare Cause of Recurrent Pregnancy Loss

The following comment and query was recently left on my post "Grand Rounds 3.52 - Thanks Kerri!" Although it had nothing to do with the subject of my Grand Rounds offering, it is still a fascinating condition most worthy of a post all its own – multiple pterygium syndrome...

Posted by to Fruit of the Womb at Tue Sep 18, 02:37:00 PM 2007
Hi,
My name is Nikky. I am 31 years old. I am currently 4 weeks pregnant for the 5th time. My first, third, and fourth pregnancies were ended due to the babies having multiple pterygium syndrome. It really surprised the doctors that this rare genetic syndrome has happened three times to me. The first baby was lost at 22 weeks, the third at 20 weeks, and the fourth at 19 weeks. I have a healthy 3 year old daughter (second pregnancy). Do you know if there are any ways to prevent this from happening in this pregnancy? Since we are the ones that educate the doctors about this, we are kind of stuck with just going for weekly ultrasounds until we notice the fetal abnormalities and lack of fetal movement. I am taking prenatal vitamins, 4 mg of folic acid, and vitamins B6 and B12. I also get a CVS (chorionic villus sampling) done at 11wks, but this cannot catch this abnormality. Do you think there are any tests to detect this? We were told that this syndrome can be found early second trimester or even in the third trimester. I just want to have a normal pregnancy. Thanks.

Hi Nikky. Thanks for writing and for sharing your story. Multiple pterygium syndromes (MPS) comprise a group of disorders characterized by multiple congenital anomalies typified by pterygia (webbing) of the neck, elbows, and knees and associated with limited fetal movement and joint contractures (fetal akinesia - arthrogryposis sequence), and many other abnormalities. MPS have been traditionally divided into lethal and nonlethal (Escobar) types. The lethal forms of the condition frequently exhibit facial clefting, intracranial abnormalities, large cystic hygromas, progressive fetal edema (hydrops) and death by midgestation and, as in your case, they have been found to be a rare cause of recurrent midtrimester pregnancy losses (Lockwood, et al., Am J Obstet Gynecol. 1988;159:474-6).

The inheritance of MPS appears to be variable, but the lethal form described by your history is most likely the result of either autosomal recessive inheritance or X-linked recessive inheritance. If the inheritance in your situation is autosomal recessive, that means that both you and your husband each carry one dose of the ‘bad gene’ (I am presuming neither one of you, nor your daughter, have characteristics of MPS) and 25% of your children (male and female) would be entirely normal genetically, 50% would be unaffected carriers, and 25% would develop the lethal condition and die prenatally.

If, on the other hand, the inheritance is X-linked recessive, then you must be the unaffected carrier (because your husband could not have the mutation or he would not be alive) and 50% of your daughters would be genetically normal, 50% would be carriers, 50% of your sons would be genetically normal, and 50% of your sons would die in utero. Sons who have the 'bad gene' on their X-chromosome cannot live and the genetically normal sons will not pass the ‘bad gene’ on to any of their children. Incidentally, if any of the children you lost were daughters, then you and your husband must have the autosomal recessive type of inheritance pattern detailed in the paragraph above.

So, to answer one of your questions, regardless of the inheritance, since this is a genetic problem, there is no way you can prevent it from happening. You just have to take your chances each time you get pregnant. But, the lethal forms of this condition can also often be detected earlier in pregnancy than 20 weeks in families known to carry the genetic mutation, thereby allowing them to make decisions about whether or not they continue to carry the pregnancy until the baby dies. The lethal condition is frequently associated with large septated cystic hygromas, or widened ‘nuchal translucencies’, frequently appearing to completely surround the body and in some cases the limbs, that may be visualized by ultrasound in late first trimester. Potentially, many of the other major physical abnormalities (such as diaphragmatic hernias, scoliosis, intracranial malformations, short forearms, and facial clefting), variably associated with the lethal syndrome, and hydrops fetalis may also be present well before 20 weeks.

You correctly point out that CVS cannot readily detect MPS because it is not a chromosomal abnormality per se, it is a genetic defect. Recent studies have shown that in a least some cases of MPS specific genetic defects have been identified as “germline-inactivating mutations in the embryonal acetylcholine receptor gamma subunit (CHRNG) in families with both lethal and nonlethal MPS” and have actually been mapped to the short arm of chromosome 2(2q36-37) (Morgan, et al., Am J Hum Genet. 2006;79:390-5). This finding does open up the possibility of earlier diagnosis by CVS and, possibly, even preimplantation genetic diagnosis, and with that is the potential for some form of interventive therapy.

In view of this information, Nikky, I suggest you review your history with a genetic counselor to find out if diagnosis of the condition can be established in your case on fetal tissues early in the pregnancy at some laboratory somewhere in the world - perhaps the one that did the study cited above! Again, thank you for reading and for sharing your situation with us. Best wishes for you and your family in the future.
Dr T

Labels: cystic hygroma, muliple pterygium syndrome, recurrent pregnancy loss

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Comment Regarding Prednisone Therapy for Recurrent Pregnancy Loss

Below are excerpts from a comment/query that appeared recently on my post Recurrent Early Pregnancy Loss -6- A Special Patient. In this post, I recount my first experiences with a woman who had pregnancy complications (miscarriages and severe preeclampsia) associated with a 'thromobphilia' - in her case, lupus anticoagulant. Her fascinating medical history stimulated my interest in both recurrent pregnancy loss and the role of an appropriate immune response in pregnancy success. The reader's comments below reminded me how far we have come in our quest to understand factors that contribute to pregnancy loss...and also, how far we still have to go...

Anonymous said...
I was happy to read your thoughts on the immune/thrombophilic connections to recurrent pregnancy loss. I have had 3 miscarriages and 1 ectopic pregnancy causing emergency laproscopy and the loss of my right fallopian tube. We have been trying to conceive for 2 years...I recently saw a specialist in NYC... who diagnosed me with high antinuclear antibody (ANA) 1:320, speckled. I am now trying o conceive for the first time since the diagnosis and am nervous about taking prednisone. Have you noticed any severe side effects from this? I was also advised to take one baby aspirin (81 mg), 40 mg of Lovenox twice per day (I have homozygous MTHFR, homozygous PAI-1, heterozygous factor XIII V34L), Vitamin E, Metanx(a Folgard-like drug), progesterone(always had low progesterone around 7 after ovulation). I will probably take Clomid because in the past, it has helped raise my postovulatory progesterone levels...I have high CD 19 and CD 19+ cell, CD5+ on the NK (natural killer) cell assay...

Kenneth F. Trofatter, Jr., MD, PhD said...
To Anonymous Sept 20: You are a mess, Girl! Just kidding. I have seen much worse! It sounds like you are in pretty good hands. Did your doctors find any specific autoimmune antibodies known to be a problem in pregnancy, ie, anticardiolipin antibodies, lupus anticoagulant, anti-Ro(SS-A), or anti-La(SS-B)? Not that any of those would change your therapy at this point very much.

Your primary question seems to be related to the prednisone therapy - how much are you taking each day? Many years ago, prednisone was the foundation of our therapy for women suspected of having an immunologic basis for their recurrent pregnancy loss. Over the years, the literature has shown no great benefit of that, and potentially some harm, over anticoagulation therapy with unfractionated and low-molecular weight heparin (Lovenox). I usually reserve the prednisone for women with diagnosed autoimmune conditions such as systemic lupus erythematosus (SLE), who need to be treated for acute flares in their disease, and for women who decline heparin therapy because of the need for daily injections. Incidentally, despite the "high ANA," you do NOT meet the criteria for SLE (from what you have told me so far) and, indeed, many individuals who have modestly elevated ANA have no identifiable autoimmune or pregnancy-related problems whatsoever!

Prednisone therapy during pregnancy is associated with increased risk for gestational diabetes, infectious complications, premature rupture of membranes, and early delivery. It also increases your appetite (and weight) and fluid retention at high enough doses. If you absolutely don't need prednisone, try to get off of it by 20 weeks gestation. It probably isn't going to help much beyond first trimester in your case anyway.

Incidentally, I have also found that women in your situation with homozygous PAI-1 are insulin resistant and often benefit from therapy with glucophage (metformin) prior to and during their pregnancies. Anyway, thanks for reading and writing and I wish you the best of luck!
Dr T

Labels: recurrent pregnancy loss, thrombophilias

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Anticoagulation Therapy Does Not Mandate Cesarean Delivery

The following comment/question appeared recently on my post Recurrent Early Pregnancy Loss - 7 - Immunologic and Hematologic Causes. Since anticoagulation therapy for recurrent pregnancy loss, as well as genetic and autoimmune thrombophilias, with unfractionated and and low-molecular weight heparins appears to be growing in popularity, many readers with pregnancy problems may have an interest in my response...

Anonymous said...
In 2004, after the stillbirth of my first child at 22 weeks gestation, I was diagnosed with APS (Antiphospholipid Antibody Syndrome). I have a very good reproductive endocrinologist and perinatologist to work with me when I decide to become pregnant again. I know that I will have to follow the twice daily heparin injections. My question is, is a woman on this therapy always forced to have a c-section? I understand that the drugs are stopped 24 hours before the delivery, however I want to know if I can attempt to have a natural childbirth even with APS. Thanks for the advice...

Kenneth F. Trofatter, Jr., MD, PhD said...
To Anonymous Sept 17: You do NOT have to have a cesarean delivery just because you have antiphospholipid antibody syndrome. However, many women with APS will end up with one simply because, even with therapy, they are at increased risk for abnormalities of placentation that result in poor fetal growth (intrauterine growth restriction), hypertensive disorders of pregnancy (preeclampsia), or decreased placental reserve which can lead to nonreassuring fetal heart rate patterns ("fetal distress"), especially with uterine contractions. Incidentally, you do NOT have to stop therapy with unfractionated heparin 24 hours prior to delivery. You can take heparin until you actually present in labor and, if necessary, its effects can be 'reversed' with a drug called protamine sulfate.

If your doctor chooses to use 'low-molecular weight heparin' (such as enoxaparin), that does need to be stopped at least 24-48 hours prior to delivery because its effects cannot be readily reversed and that could increase your risk for bleeding problems. Indeed, many anesthesiologists will not consider using a regional anesthetic (an epidural or spinal anesthetic) unless you have been off enoxaparin for at least 48 hours due to the risk of subdural and epidural hematomas. In our practice, we generally stop enoxaparin at 34-36 weeks gestation and intentionally switch to heparin to avoid the risks of these bleeding complications and to allow the patients the benefits of regional anesthesia during labor and delivery.

Many women with APS will also be on low-dose aspirin therapy. Aspirin blocks platelet function on the other side of the coagulation system. Even the typical dose of only 81 mg can impair platelets for several days. Given the opportunity, I will often try to discontinue this 2-3 days prior to delivery as well. Thanks for reading and for a great question. I will feature this query in one of my daily blogs! Best regards, Dr T

Thu Sep 27, 01:25:00 PM 2007

Labels: antiphospholipid antibody syndrome, APS, enoxaparin, heparin

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More Queries About Rh-Negative Blood

The following two comments recently appeared on my post addressing Implications of a Negative Blood Type. The first reader's question is worth repeating because MANY readers have asked the same question (in various forms) and the explanation is fairly simple. The second reader's questions revolve around potential complications of Rh-sensitization in someone who is attempting to conceive by in vitro fertilization with donor sperm. Her situation is NOT unique today and many other women may be interested in my responses to her queries as well...

Anonymous said...
Hi,I have a daughter who is
O negative. I also have a son who is O positive.
I am O positive and my wife is O negative. Is this possible?

Kenneth F. Trofatter, Jr., MD, PhD said...
To anonymous Sept 24: Yes, it simply means that you are heterozygous for the Rh D antigen. That means you have one chromosome that carries the gene for D and one that does not. Your wife has two that do not because she is Rh-negative and if she had even one dose of D, she would be phenotypically Rh-positive just like you because D is a dominant allele. Anyway, odds are that half of your kids (male and female) would be expected to be Rh-positive and half Rh-negative based on percentages alone (and no other extenuating circumstances). Sounds like that's what's happened so far in your family. Hope that helps. Thanks for reading! Dr T


lotsofdecisions said...
Hi. I became sensitized to Rh during my pregnancy with my daughter. My questions:

1) Does the fact that I was sensitized at my daughter's birth impact the problems I may have with a future pregnancy? I'm using donor sperm and know that the donor is O+ and heterozygous. How great is the risk? My titers are around 1:4.

2) After 2 unsuccessful IVFs to avoid having a second O+ child, I am about to admit defeat re: giving my daughter a full sibling. My question: should I consider only O- donors? It seems like using an A- or B- donor could result in as great of issues as if I used my daughter's donor.

3) How concerned should I be about CMV? I'm CMV negative. I've lived in the Northeast as well as the South. It seems like I'd have contracted CMV if I were susceptible to it.

Sorry this is so long. Thanks in advance.

Kenneth F. Trofatter, Jr., MD, PhD said...
To lots of decisions Sept 20:
1) Yes, your Rh-isoimmunization could have an impact on a future pregnancy. If your donor is heterozygous for Rh-positivity, there is a 50% chance your babies from that donor will be Rh-positive and potentially at risk for "Rh disease." You are currently at relatively low risk for complications with a titer of only 1:4. The risk begins to rise dramatically once your titer exceeds 1:16. During a pregnancy, I would recommend you have your titer checked every 4-6 weeks, especially if it begins to rise. In fact, if it does rise during a pregnancy, that probably confirms the baby is Rh-positive. We can currently assess risk for fetal anemia by a noninvasive study called Doppler flow velocimetry of the peak systolic velocity in the baby's middle cerebral artery. It's not as hard to do as it is to pronounce!

2) If you are using an Rh-positive donor, you cannot be sure that the baby is not Rh-positive until you test fetal cells by some sort of invasive procedure (chorionic villus sampling, amniocentesis, percutaneous umbilical cord blood sampling). You would be better starting off with an Rh-negative donor because then the baby CANNOT be Rh-positive. It does not matter whether that donor is A-, B-, O-, or AB-. The problem is with Rh, not the major blood group antigens.

3) CMV negativity is a BIG concern to me in your situation. (Check out a couple of my earlier blogs on that subject as well). You may be at risk for contracting that from your donor or you could simply contract it from someone else, especially your daughter, who is VERY likely to pick it up if she spends time around other kids. It is spread by all kinds of body fluids (e.g., blood, urine, and drool) and it is unlikely you are "not susceptible" to catching it; you probably have just been UNLUCKY enough not to have been exposed to it earlier in your life. I say unlucky, because if you did happen to catch it during a pregnancy, the results could be quite devastating to the baby. Thanks for reading and the great questions and BEST of luck to you too! Dr T

Labels: CMV, cytomegalovius, Rh-isoimmunization, Rh-negative blood type, Rhogam

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Readers' Questions - Cervical Dysplasia, Protein S Deficiency, and Recurrent Aneuploidy

These readers' comments/questions touch on a variety of issues of general interest - severe cervical dysplasia in pregnancy, protein S deficiency in a woman who lost a pregnancy at 24 weeks, and recurrent miscarriages associated with different chromosomal abnormalities. I want to thank all my readers for the wonderful queries that are coming in the door every day. I know there are many readers out there who greatly appreciate and will benefit from the fact that you have generously shared your stories, questions, and concerns.

The following comment appeared on my post Cervical Dysplasia and Cancer in Pregnancy-7

At Mon Sep 17, 08:00:00 PM 2007, Anonymous said…
I have been diagnosed with severe cervical dysplasia, and I have just found out I am pregnant. I'm very scared and would love to hear about what I may be facing in the weeks and months to come.

Kenneth F. Trofatter, Jr., MD, PhD said…
To Anonymous Sept 17: Different physicians have different approaches during pregnancy. The first step is to perform a thorough colposcopic examination of the cervix and biopsy those areas that are the most highly suspicious. This is usually a simple office procedure. If an 'adequate' exam can be performed, ie., the upper limits of the transformation zone in the cervical canal can be clearly visualized, and the biopsies show no evidence of 'invasion', it is usually safe enough to follow you through the pregnancy. Personally, I would repeat the colposcopic exams in each trimester, but as I said, different providers may have another approach.

If the upper limits of the transformation zone cannot be adequately assessed and/or the biopsies are suggestive of microinvasion or invasion, your doctor will probably consider performing a cervical 'conization' which is a large wedge-shaped resection of the transformation zone. Further recommendations for care will depend on findings of that surgical specimen. At the time of a conization, I will often perform a cervical cerclage prior to the actual conization, as a means of reducing risk of bleeding during the procedure and, possibly, premature labor later in the pregnancy. If nothing worse than high-grade intraepithelial neoplasia is found during the pregnancy, ie., there is no evidence of invasive disease, you will be more thoroughly evaluated 6-12 weeks following delivery. Even some high-grade lesions will regress spontaneously once you are unpregnant! Good luck and thank you for reading. Let me know how things turn out.
Dr T


At Thu Sep 06, 10:16:00 AM 2007, soumya said...
I lost my pregnancy at 24th week on July 17th. My GYN said that my protein S was low. She told me that it might be low because of the pregnancy and retested my 5 weeks after delivery - but I still had low protein S. My cousin who is a general practitioner said to wait for 3 months to test again for protien S and we would know for sure if there is a deficiency. If it turns out that I really have a protein S deficiency, what are the treatments and how many months should I wait before I get pregnant again? What kind of doctor should we visit the next time.

Kenneth F. Trofatter, Jr., MD, PhD said...
To soumya Sep 6: Sorry for the delay in responding to your query. I am so sorry to hear about your pregnancy loss at 24 weeks. It would be helpful if you could tell me a little more about the events surrounding that loss. For example, did the baby die before the delivery? Was the baby normally grown? Did the baby have any abnormalities? Did you have any bleeding or a fever before you lost the baby? Was your blood pressure elevated or did you have preeclampsia?

Regardless, protein S is important because it helps break down blood clots. It is often reduced during pregnancy and recovers to normal levels by 6-12 weeks after delivery. When your doctor checks it again, ask your doctor to have the laboratory perform a studies that look at the "functional protein S and protein C activities". This is a better way to assess the significance of an apparent protein S deficiency. By the way, did you have any other blood work done (e.g., antiphospholipid antibodies, lupus anticoagulant, factor V Leiden, prothrombin mutation, antithrombin III, MTHFR, factor VIII levels) and do you know the results?

If the protein S turns out to be low, or if you have any other laboratory evidence of a 'thrombophilia' (increased tendency to clot and/or reduced ability to break down clots), and your pregnancy history is consistent with the loss having possibly been the result of this, then my usual routine would be to begin folic acid (2-4 mg)and low-dose aspirin (81 mg) prior to conception and add either heparin or low-molecular weight heparin (e.g., enoxaparin) as soon as a pregnancy is confirmed. Thanks for reading and for a very good question. Best wishes for the future.
Dr T


At Mon Sep 17, 02:07:00 PM 2007, Anonymous said...
I just had my third miscarriage. The first one, I didn't have tested and the second one was a partial molar pregnancy. After the waiting period was over, I got pregnant for the third time and lost the baby in week 6. The baby was forund to have 47 chromosomes. My doctor thinks it's a fluke and that my husband and I just had bad luck. Do you suggest trying again or do you think I have a chromosome condition?

Kenneth F. Trofatter, Jr., MD, PhD said...
To Anonymous Sept 17: From what you describe, I would have to agree with your doctor at this point. You have probably just had a string of bad luck. The first pregnancy could have been lost either because it simply was a first pregnancy and your immune system didn't figure out how to help it hang on or that baby could have had a chromosomal abnormality. The last two pregnancies were clearly chromosomally abnormal, but they were also different abnormalities. If you are anxious enough, consider having chromosomal studies done on you and your husband. - but, I bet now they will be normal.

There may be some individuals who are at increased risk for recurrent aneuploidy for reasons that we don't thoroughly understand. Some genetic counselors will tell you that having a documented aneuploid pregnancy increases your risk to as much as 1% that you will have another. You did not tell me your age, but if you are less than 38, this is higher than your age alone risk. I would recommend to anyone who has had chromosomally abnormal pregnancies that when they conceive again, they seriously should consider having combined first trimester screening for aneuploidy, regardless of their age. Thank you for reading and I certainly wish you better luck in the future. Dr T.

Labels: HPV; cervical dysplasia and pregnancy, protein S deficiency, recurrent aneuploidy, recurrent pregnancy loss

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Grand Rounds 3.52 - Thanks Kerri!

Many thanks and congratulations to Kerri at Six Until Me for this week's Grand Rounds 3.52 and for including my recent post on a "A Complication of Methotrexate Use for Ectopic Pregnancy." My compliments on the nourishing selection of posts for both body and soul. The presentation is both unique and inviting. Great work, Kerri, and thanks again!

Labels: Ectopic pregnancy, grand rounds, methotrexate therapy

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Readers' Concerns Regarding Rh-immune Globulin and ABO-Incompatibilty

Anonymous said...
Great information! I just miscarried and I want to know why. I am 0- and received a Rhogam shot at 28 weeks with my 1st child. I did not receive a shot after delivery--I checked my records. Did this (not receiving a shot) contribute to my miscarriage? Wendy
Sun Sep 16, 12:10:00 AM 2007

Kenneth F. Trofatter, Jr., MD, PhD said...
To Wendy Sept 16: I am sorry for your recent loss. The most common cause of sporadic miscarriage in women who have had successful pregnancies is a fetal chromosomal abnormality. With regard to your other question, the routine would have been to give you Rhogam after you delivered UNLESS your baby happened to be Rh-negative as well. It is very unlikely that not getting the Rhogam after delivery caused you to miscarry your recent pregnancy. That doesn't even seem to be a problem with individuals who ARE clearly Rh-isoimmunized. It's dealing with those pregnancies after the first trimester that becomes the challenge! Regards, and thanks for your question.
Dr T

Sun Sep 17, Prefering Anonymity said...
My wife just delivered a baby girl 5 days ago who has elevated bilirubin levels with the cause thought to be ABO incompatibility. My wife is O-negative, I am A-positive and our daughter is A-positive/Combs-positive. My wife was not administered rhoGAM at any point during or after her pregnancy/delivery. Our pediatrician caught the jaundice fairly early and daughter is seems to be recovering, but I am also quite concerned with whether my wife and I can now safely have another child, as she did not receive rhoGAM. Is it possible for us to safely have another child and what would we need to do or screen for to do so? My thanks to you in advance.

Kenneth F. Trofatter, Jr., MD, PhD said...
To preferring anonymity Sept 16: Your wife did not NEED Rhogam if your daughter was Rh-negative. ABO incompatibility is another issue. All people with O blood types make antibodies to A and B blood groups. They are exposed to those antigens in the environment (bacteria) and do not even need to be exposed to another human's blood to generate these antibodies. However, usually these antibodies are of the IgM class of antibodies. IgM antibodies are very large and basically contain a pentamer (5 antibodies) joined together. They are TOO BIG to cross the placenta to the baby. Occasionally, individuals also make anti-A or anti-B antibodies that are IgG class antibodies. These CAN cross the placenta and, indeed, IgG antibodies are a major source of 'immunity (passive immunity)' against common pathogens for the baby during the first 3-6 months of life.

Unfortunately, the placenta doesn't differentiate between 'good' (protective) IgG antibodies and antibodies that might harm the baby. This is the same problem with Rh-isoimmunization when it occurs. The antibodies from the mother cross the placenta, attach to the fetal tissues that are foreign (in your baby's case blood group A red blood cells) and that signals the baby's immune system to destroy whatever the antibodies are attached to - at that point the baby's immune system cannot distinguish what uis 'foreign' and what is 'self'! With the destruction of the baby's own red cells, hemoglobin is released and its breakdown product, bilirubin, can cause jaundice and more serious problems if the bilirubin levels get high enough. When the baby has used up all the antibody it has gotten from Mom, it will not have anymore problems.

To answer your other question, yes it is safe to have another baby under these circumstances. Often ABO incompatibility isn't much of a problem until after the baby is born, unlike with severe Rh-isoimmunization. Your doctors can assess the degree of fetal anemia in utero, indirectly, by doing peak systolic velocity of blood flow in the baby's middle cerebral artery by Doppler flow velocimetry if you are worried about fetal anemia during the pregnancy. Let them explain that to you! Best of luck, congratulations on your new baby, and thanks for reading and the great questions.
Dr T

Labels: ABO incompatibility, rh-immune globulin, Rh-isoimmunization, Rhogam

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Recurrent Miscarriages and Empiric Use of Enoxaparin - A Reader's Queries

The reader below related her obstetrical history which included three miscarriages surrounding the birth (one before and two after) of a healthy child. Her doctor chose a course of empiric therapy despite a completely ‘negative’ work-up (which did not include parental chromosomal studies by the patient’s request because of the “expense”). This is a very common practice (and I readily admit to it myself) when dealing with the supercharged issue of recurrent miscarriages where there is a sense of “need” on the part of both patient and provider to “do something.” However, this reader has some excellent questions and concerns regarding her obstetrical history, the choice of therapy, and the prognosis for her current pregnancy now that she has gotten to the end of first trimester. I have paraphrased and condensed her comments…

Seema left a new comment on your post "Recurrent Early Pregnancy Loss - 5 - Introduction ... at Fruit of the Womb on Tue Sep 04, 08:35:00 PM 2007...

I am 31 years old. I have a son who is 4 years old and I have had a total of 3 miscarriages. With my first pregnancy, I had bleeding at 4 weeks for 3 hours and it stopped. At 8-9 weeks an ultrasound showed a twin pregnancy with fetal poles but no heartbeats. The doctors said it was a missed abortion and I had a D&C. The biopsy results came back as hydropic abortion. My second pregnancy was uncomplicated and I delivered a boy. The third pregnancy, I had severe cramping at 7 weeks and subsequently miscarried completely. The fourth pregnancy there was very good heart beat at 6 weeks 4 days, but when I went at 10 weeks for a scan, they said the fetus stopped growing at 7 weeks 4 days and they evacuated it. All of these pregnancies are with the same partner.

I had many blood tests done including antiphospholipid antibodies, anticardiolipin antibodies, lupus anticoagulant, thyroid function tests, antithyroglobulin antibody, serologic screens for toxoplasmosis, cytomegalovirus virus (CMV), and herpes simplex virus (HSV) and everything came back negative.

With my current pregnancy at 4 3/7 weeks, the doctor started me on folic acid, low-dose aspirin (81mg), and subcutaneous low molecular weight heparin (enoxaparin) 20mg subcutaneously per day. Now I am pregnant 10 weeks and 3 days. I had a scan which showed the baby growing very nicely corresponding to 11+ weeks. I haven't had the genetic testing done. My doctor said I may have some immune problems which causes these abortions and enoxaparin helps prevent this. But I still have many doubts and concerns. Can you answer some of these questions? Kindly answer my concerns. I will be extremely grateful to you. Thanks a lot in advance...

Is it possible that such an immune problem caused my first pregnancy to miscarry and then remained inactive during my normal pregnancy and then started acting up again with my 3rd and 4th pregnancies?

Anything is possible, but I think this is unlikely in your case. At this point, I don’t think your laboratory data support the diagnosis of “an immune problem” as the cause of your pregnancy losses. You could potentially have a ‘genetic thrombophilia’ associated with polymorphisms of certain clotting factors, such as Factor V Leiden, methylene tetrahydrofolatereductase (MTHFR), or prothrombin (G20210A), deficiencies in the activity of Protein C or S, antithrombin III deficiency, or an overproduction of Factor VIII. These can lead to an increased tendency to form blood clots and/or a decreased ability to break them down and they are thought to be associated with recurrent pregnancy loss and poor pregnancy outcomes (fetal growth restriction, fetal death in utero, preeclampsia, etc.) related to abnormal placental development. However, even one of these abnormalities is unlikely because of your history of the uncomplicated term pregnancy in between the early pregnancy losses.

If I am having such immune problems, how could I have delivered my son?

It is possible to develop “immune problems” at any time in your life, but, again, the laboratory data you have presented would not support that diagnosis at this point. Of course, there could be other ‘immune factors’ we have not learned about yet that have caused your losses.

My doctor said such problems could develop at any time and in my case I may have developed it after my son was born. If this is true, then what happened to my first pregnancy, before my son was born?

There seems to be a high risk for spontaneous losses of true first pregnancies. This may be a ‘self-limited’ immunologic problem in a woman’s initial response to a baby that is only half her. Many women overcome that immunologic ‘barrier’ during the process of losing a pregnancy or two (ie., they become properly ‘immunized’ to their partner) and then go on to carry normal pregnancies successfully as you did. Some women do develop ‘immune problems' to pregnancy only after they have had uncomplicated pregnancies. These women have sometimes been termed “secondary aborters” and they can be among the most difficult of patients to treat successfully.

There is also the possibility that one or more of your babies was chromosomally abnormal. This can happen by repeated 'chance' but it can also occur quite frequently if one of the parents carries a ‘balanced translocation.’ Since neither you nor your partner had chromosomal studies done on yourselves, this could still be the case. Approximately 1-2 per 1000 individuals carry balanced translocations and because they appear perfectly normal (and they are ‘normal’ because they have the correct total amount of genetic material; it’s just rearranged in a way that decreases the likelihood of normal gamete, egg or sperm, production) they do not encounter problems until they try to have babies. Incidentally, estimates as high as 2-3 per 100 individuals with recurrent miscarriages have one of the couple (more often the woman) as a balanced translocation carrier!

My doctor says enoxaparin helps increase the blood flow to the baby. If this is so, then how will it increase the blood flow before 8 weeks, when there is no umbilicoplacental circulation?

Exoxaparin does NOT directly increase the blood flow to the baby. In fact, its actual mechanism for reducing the risk of early miscarriages and of poor pregnancy outcome is not entirely clear. Enoxaparin is known to bind to and to accelerate the activity of antithrombin III. By doing so, it helps to potentiate the inhibition of coagulation factors Xa and IIa. Factor Xa catalyzes the conversion of prothrombin to thrombin so enoxaparin’s action ultimately reduces fibrin clot formation. It is thought that activation of thrombin (and clot formation) is one of the events that limits the invasion of the placental trophoblasts into the endometrium, however, if the thrombin system is overactive, it may also prevent normal placentation. Thus, in early pregnancy exoxaparin may help to achieve a better ‘balance’ in women who have increased activation of the clotting system for any reason (immune-mediated or genetic thrombophilia).

In certain animal studies, enoxaparin has been found to have some immunomodulating properties as well, decreasing inflammatory responses and complement activation that may also interfere with normal early placental development. In the end, enoxaparin can improve the placental development and vascularization that is so important to a normal pregnancy outcome, but by itself, it has no effect on fetal blood flow.

The enoxaparin is really expensive and I would like to know if there is any use in continuing it, in my case?

Enoxaparin is REALLY expensive; that’s why when I offer ‘empiric therapy’ to women in your situation, I usually suggest unfractionated heparin as an option. It is still administered by subcutaneous injection. You are on a very LOW dose of enoxaparin, below what is commonly used even for prophylaxis, and well below that used in therapeutic regimens. Since you have no identifiable laboratory risk factors, you probably do not need to continue it throughout the pregnancy.

There is no ‘standard of care’ in this regard, and to some extent, the duration of therapy depends on the individual patient’s level of anxiety. In circumstances like yours, I will frequently discontinue the drug at 20 weeks and simply continue the baby aspirin. At higher levels of concern, I will assess fetal growth and perform Doppler flow studies on the umbilical cord, middle cerebral artery and uterine arteries at 26-28 weeks to get a better feel for placental vascularization from both the fetal and maternal sides. If all is ‘normal’ at that point, it is usually ‘safe’ to discontinue therapy. If you and your doctor choose to continue it longer than this, it is recommended to stpo it at least 72 hour prior to delivery so that the anesthesiologist feels comfortable using a regional anesthetic (spinal or epidural). Patients who do have documented clotting problems should be switched to heparin in anticipation of delivery because its effects can be readily reversed unlike those of enoxaparin.

If I lose my pregnancies due to chromosomal abnormalities, what will be the chance with my current pregnancy as now it is 10 weeks?

At least 90% of aneuploid fetuses are lost in the first trimester, so every day that goes by improves your prospects for carrying the baby.

Up to which week can I miscarry if the baby has a chromosomal abnormality?

Some babies with chromosomal abnormalities aren’t lost until the second or even the third trimester. Obviously, some even survive through and after delivery. Most babies that are going to die from a chromosomal abnormality in utero grow poorly and/or have physical abnormalities that can be detected by ultrasound.

Anyway, Seema, thanks for reading and for a bunch of great questions! I hope I have helped and I also wish you the best for this current pregnancy...

Dr T

Labels: enoxaparin, miscarriage, recurrent pregnancy loss

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Another Reader's Questions Regarding First Trimester Screening for Aneuploidy

Anonymous has left a new comment on your post "Abnormal First Trimester Screening Results":

I received my screening results and was given a 1:86 chance of having a baby with Down syndrome (trisomy 21). I am 35 years old. Only my hCG levels were elevated. My PAPP-A was 1.4 and the baby's NT (nuchal translucency) was 2.4mm which I was told was at the 90%ile for the size of the baby and anything above 95% is considered elevated. Given that I don't "fit the pattern" with elevated hCG, decreased PAPP-A and elevated NT- am I facing better odds that the baby is fine? Could my hCG levels be elevated "just because" that's how I am?

Kenneth F. Trofatter, Jr., MD, PhD said...

To Anonymous Sept 14: I had a similar query from a reader and responded to her on that post on July 17. The answer is basically the same. The odds are what they are, regardless of the combination of measurements, serologic markers, and demographic information that led to them! You have a 1 in 86 chance of having a baby with trisomy 21. (That is about twice your 'age alone' risk and probably a more reliable 'risk estimate' as well because it is derived from real numbers based on your pregnancy and not just from the population-based risk of women at your age). That also means you have a 85/86 chance the baby does not have trisomy 21.

The important questions you must ask yourself are "How do I feel about those odds? Do I need some more information? Do I want to find out for sure whether or not the baby has a chromosomal abnormality before the baby is delivered?" If you would prefer not to have an invasive study done at this time, there are other options to consider. You could have an early anatomic survey of the baby done by ultrasound at 16 weeks and possibly couple that with a maternal serum marker panel ("quad screen") which will give you another asssessment of "risk." Some laboratories will combine the first and second trimester data into a single 'integrated' risk assessment. And/or, you could have a 'genetic sonogram' done at 18-20 weeks. If that is completely normal, your a priori risk (based on the screening tests, not your age) for a baby with trisomy 21 can be reduced 60-90% depending on the experience of the ultrasonographer.

Thank you for reading and my best wished for your pregnancy.
Dr T

Labels: first trimester screening

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Readers Questions About Du Blood Types and Cholestasis of Pregnancy

Below are two great comments/questions that were left on previous posts addressing Implications of a Negative Blood Type and Intrahepatic Cholestasis of Pregnancy which should be of general interest for readers...


Tue Sep 11, 07:24:00 AM 2007 beegley101 said...
I have been typed by the Red Cross as a volunteer blood donor as O+. I am now 21 weeks pregnant and have been typed twice by my OB's office and the results are calling me O-. My OB says I'm probably 'weak D.' I'm worried about taking Rhogam. What happens if an Rh-positive patient gets Rhogam?

Kenneth F. Trofatter, Jr., MD, PhD said...
To beegley101 Sept 11: If the Red Cross has typed you as O-positive, and your doctor's office laboratory has not, I would go with the Red Cross. They are about as good as one can get in the blood-typing arena! Your doctor is probably correct - you likely have the Du-variant of Rh, sometimes referred to as the 'weak' Rh D-antigen, and technically this makes you Rh-positive. Du-positive women cannot become sensitized to the D-antigen. Therefore, Du-positive women do NOT need Rh-immune globulin (Rhogam) during their pregnancies. If you got it inadvertantly, it would probably not cause any harm to the baby, but you just don't need it. But, your doctor needs to get this sorted out once and for all, even if he/she has to send you to a hematologist to do so, althoough usually it is simply a matter of notifying the laboratory that there has been a discrpeancy in blood-typing and they need to screen for the Du-variant. This was a great question that I have not addressed in any of my posts on this subject. Du is very common in Black women, so I am sure a lot of readers will be interested in my response to your question. Thanks for reading! Dr T


Tue Sep 11, 05:25:00 AM 2007 Anonymous said...
I have 3 sons all of which I was induced at 37 weeks due to cholestasis. During all 3 pregnancies I also had gallstones, after my third baby I had my gallbladder removed. I am now 28 weeks pregnant with a girl and have no gallbladder, am I likely to get cholestasis in this pregnancy the same as the others? or should I be ok as i have no gallbladder/stones this time?

Kenneth F. Trofatter, Jr., MD, PhD said...
To Anonymous Sept 11: True cholestasis of pregnancy is linked to genetic polymorphisms involved in bile acid metabolism in the LIVER, not the gall bladder. Think of the gallbladder as simply a storage sac for certain digestive enzymes produced in the liver and released when fatty foods are present in the digestive tract. So, true pregnancy cholestasis will probably NOT be improved by removal of the gallbladder. However, if your cholestasis was related to obstruction of the bile duct by gallstones (causing bile acids to back up into the liver), not by an enzymatic defect in the liver, then you just might do better this pregnancy. But, having your gallbladder removed is a heckuva way to confirm the diagnosis of true pregnancy cholestasis! Hope you don't itch this pregnancy. Thanks for reading and for a great question! Dr T

Wed Sep 12, 05:05:00 PM 2007

Labels: Du-positive blood type, intrahepatic cholestasis of pregnancy, Rh-negative blood type

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A Complication of Methotrexate Use for Ectopic Pregnancy

The comment from the reader below was published on one of my posts related to recurrent early pregnancy loss and illustrates one of the risks of methotrexate use in the treatment of ectopic pregnancy...


At Thu Sep 06, 05:52:00 PM 2007, Anonymous said…

Hi. Thank you for answering all these questions. I also had a question regarding Methotrexate. I was injected with a dose of Methotrexate on the 25 of July, 07. I was told my 6 week pregnancy was ectopic and needed to be terminated. One week later I was still pregnant with rising hCG levels. I went to the hospital, had an ultrasound done, and was told I did not have an ectopic pregnancy. I was about 8 weeks along with a living fetus in my uterus. They showed me the fetus with a strong heart beat. Two days later, on Aug 3, I was given a D&C to end the pregnancy. My husband and I would like to try again. We have three boys, I had one miscarriage with my second pregnancy, but the others have been normal. I started my period on September 5. It's pretty heavy. I was wondering if the Methotrexate is out of my system now. Can we try again, or should we wait until after my next period in October? I'm having such a hard time thinking about waiting, but I do know it's important to be careful. I also read taking one baby aspirin a day until conceiving can help the uterus is this true. Thank you.


At Sun Sep 09, 06:21:00 PM 2007, Kenneth F. Trofatter, Jr., MD, PhD said…

To Anonymous Sept 6: Ever since methotrexate became popular for treating ectopic pregnancies, I have seen the unfortunate scenario reported by our reader above played out time and time again. Methotrexate (MTX) is an analog of folic acid. It binds tightly to an enzyme called dihydrofolate reductase and when it does so, interferes with the production of tetrahydrofolates. In the end, this interferes with the normal production and repair of DNA by limiting the production of a key nucleotide, thymidine. Other metabolic effects are also known, but the take home message is that MTX can result in lethal damage to cells that are replicating, particularly those that are replicating rapidly, like certain cancer cells.

In the mid-1950’s, Li and colleagues (Proc Exp Biol Med 1956;93:361) demonstrated efficacy of MTX against choriocarcinoma. Choriocarcinioma is a cancer derived from cells of trophoblastic (placental) origin. Although choriocarcinoma only comprises no more than 1% of all gynecologic malignancies, it affects young, reproductive age women and is deadly if not treated. Indeed, before adequate chemotherapy was available, more than 90% of women with metastatic choriocarcinoma died from their disease, usually very rapidly. Thanks to MTX, and other chemotherapeutic agents, most women now survive choriocarcinoma and once remission is achieved, have a very low risk for recurrent disease, ie., they are CURED.

Because of its documented efficacy in the treatment of malignant trophoblastic cells, MTX, in recent years, has been employed as an alternative to surgical therapy in selected cases of ectopic pregnancy (Lipscomb, et al. NEJM 2000;343:1325-29). Ectopic pregnancies, by definition, implant ‘outside the uterus’ with more than 95% occurring in the fallopian tubes and about 2.5% in the cornua of the uterus (where the fallopian tubes enter the uterus). For that reason, they are frequently referred to as ‘tubal pregnancies,’ although they can also occur in the cervix, ovary and intraabdominally. The fallopian tubes cannot restrict the growth of invasive placental tissues, as can the endometrium, and they certainly cannot accommodate a growing embryo beyond a certain point before they rupture and hemorrhage. Indeed, ectopic pregnancies can be quite deadly if not treated appropriately. They are still a major cause of maternal mortality, accounting for 10-15% of all maternal deaths, and they are the leading cause of death in pregnant women in the first trimester. A ruptured ectopic pregnancy is a true medical emergency.

Because of the rising incidence of ectopic pregnancy, the risk (maternal and medical-legal) of not identifying and treating an ectopic pregnancy in a timely fashion, and the widespread acceptance and success of MTX therapy as an alternative to surgical management of an ectopic pregnancy if caught early enough, there has been a coincident increase in the inadvertent use of MTX in unrecognized early intrauterine pregnancies. The usual scenario is one in which the pregnancy is not quite as far along as anticipated and the patient happens to present with complaints of abdominal pain or some spotting and no clear intrauterine pregnancy is identified by ultrasound. This situation can be especially confusing if the pregnancy hormone levels (hCG) appear to be low for the expected gestational age or if a woman has a tender adnexal mass because a hemorrhagic corpus luteum (intraovarian bleeding at the site from which the egg was ‘hatched’) or torsion of an adnexal mass might be very difficult to differentiate from an ectopic pregnancy.

Since MTX is a category X drug, known to be teratogenic in humans, it is important to ascertain the presence of an ectopic pregnancy rather than simply to use it empirically. Unfortunately, its use in advertantly with an intrauterine pregnancy is most likely to occur during the time of neural tube and very early cardiac development, both of which rely on folate-dependent pathways. Various algorithms are in place that employ ultrasound imaging, quantitative hCG levels, and progesterone levels to differentiate abnormal from potentially normal pregnancies and these protocols can be useful in minimizing the chance of the inadvertent use of MTX and also in directing its use when appropriate for the management of an ectopic pregnancy. Perhaps the greatest risk of ectopic pregnancy is not suspecting that one could be present. Patients who are adequately counseled and followed closely are much less likely to end up in emergency situations.

Anyway, to finish the response to our reader’s questions, because the ‘half-life’ of MTX is measured in hours, and you received a very short course of the drug, you are probably 'safe' now to pursue another pregnancy from that standpoint. Whenever a D&C is perfomed, however, we often recommend waiting 3-4 months before attempting another pregnancy so that the inflammation in the uterus can die down and the endometrium fully reconstitute to improve the prospects for successful and normal implantation of another pregnancy. So, I would suggest waiting until after your next period and in the interim, starting supplemental folic acid 4 mg/day as well as a prenatal vitamin to reduce your risk even more. Before you start a baby aspirin, it is probably a good idea to discuss that with your doctor. Start all of this BEFORE you try to get pregnant and continue through the first trimester. Good luck next time and let me know how things turn out. Thanks again for reading and for a great question.
Dr T

Labels: Ectopic pregnancy, folate metabolism, methotrexate therapy

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Readers' Questions Related to MTHFR Polymorphisms

Several recent comments on my post "MTHFR Mutations and Congenital Heart Defects" worthy of a general response for our readers:

Anonymous said Sept 02, 09:30:00 PM 2007...
My daughter was diagnosed with MTHFR gene mutation during a blood test before putting her on birth control because of family history of blood clotting disorders (I have anitphospholipid antibody syndrome), lupus, and have had three strokes, 1 miscarriage, and I also almost lost her because of huge blood clots in the womb during pregnancy..My question is will she need to take foltex for the rest of her life (she is 18)... also, if she decided in the future to have children should she see a specialist?

Kenneth F. Trofatter, Jr., MD, PhD said...
To Anonymous Sept 2: Having the antiphospholipid antibody syndrome is MUCH different, and MUCH more serious than having a MTHFR mutation. YOU need to be on anticoaguation therapy the rest of your life. If your daughter was worked up because of your history, and the ONLY thing found at this point is a MTHFR polymorphism, she is probably at fairly low risk for the sort of complications you have had. I will caution you though, autoimmune conditions also run in families!

By the way, do you know if she had one or two MTHFR mutations? Many people carry one and have a low risk for problems, even on oral contraceptives. Also, do you know if they checked a homocysteine level on her? If that is also normal, again her risk for problems related to thrombosis and complications during pregnancy is probably no higher than the general population. Regardless, there is probably no harm taking the foltex. I wish more young women were on supplemental folic acid before they thought about getting pregnant.

Tell her to relax, and if you want a good 'second opinion' regarding her risks, find a local hematologist. She probably will not need to see a Maternal-Fetal Medicine specialist during pregnancy unless she develops complications. Women with single MTHFR polymorphisms do not need special treatment unless they have pregnancy problems that seem to be related to this. Thanks for reading!
Dr T


Phuong said Tue Sep 04, 08:06:00 PM 2007...
I had 2 miscarriages in 6 months (7 wks, and 8 weeks with 2 normal periods in between). I was told I was heterozygous C677T MTHFR...no elevated homocysteine level which I didn't test after fasting...doctor did not seem too concerned about preparing for my next pregnancy..did not advise to take baby aspirin, extra folic acid, or prenatal vitamins...he just said to do Lovenox injections daily once I find out I'm pregnant...should I take baby aspirin, extra folic acid, or prenatal vitamins as a precautionary thing prior to conceiving...I'd like to get pregnant in the next 2 months???


Kenneth F. Trofatter, Jr., MD, PhD said...
To Phuong Sept 4: I don't like to second guess your doctor under these circumstances. He/she may know more about you than you have told me (or they have told you). If you have been thoroughly worked up and no other risk factors were found except the single MTHFR polymorphism, and you were one of my patients, I would probably place you on the baby aspirin, prenatal vitamin, and extra folic acid (2-4 mg daily)BEFORE conception and ask you to consider trying a pregnancy on that alone. But, that therapy is purely empiric at this point and there is no evidence-based standard of care in that regard. Lovenox is VERY expensive! If you lost another pregnancy early, you could undergo a work-up for other 'risk factors' for which you have not yet been evaluated or simply add the Lovenox (or heparin - much less expensive)to the treatment regimen above and try again. Thanks for reading and for a good question. Best of luck to you next time!
Dr T

Labels: MTHFR

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Readers' Featured Comments/Questions - Why Wait to Conceive after Miscarriage and Rh-negative Concerns

Anonymous has left a new comment on your post "Early Pregnancy Loss - 2":

I found out from my OB today that I miscarried (I found out I was pregnant on 8/22, and began bleeding on 8/29, he ordered a hCG level test which went from 12 to 2 in a 48 hour period, therefore, confirming a miscarriage). I have had only two other pregnancies, which resulted in two healthy children (now 4 years and 21 months). Anyway he said I had to wait for my next menstrual cyle to start trying to conceive again - why do we have to wait?

To Anonymous Sept 2: I am sorry for your loss. Since you have had other normal pregnancies, the overwhelming odds are that this baby you lost was chromosomally abnormal. You lost this pregnancy so early (very low hCGs) that it probably wouldn't make any difference if you "tried again" during the next cycle. But, I too usually suggest that a woman wait for one normal period before trying again, just to give any 'inflammation' that was associated with the recent loss a chance to resolve to improve the probability of successful implantation the next time around. Waiting also gives your hormones and the endometrium a chance to get back in 'synch' and this too might improve the chances for a successful pregnancy. Thanks for reading and for a good question that, I am sure, is on the mind of many women who are in a similar situation! Best of luck on the next go-around! Dr T


Anonymous has left a new comment on your post "Implications of a "Negative" Blood Type":
I was recently pregnant and miscarried at 6 weeks. Since I am Rh-negative, I was given a shot of Rhogam and was told that it would last in my system for three months. I am pregnant again (5 weeks) and know that the Rhogam is no longer in my system. Will I need another shot ASAP?

To Anonymous Sept 2: Your doctor will perform an antibody screen on you as part of the standard 'new OB' labs early in this new pregnancy. If there is no evidence of sensitization, i.e., you haven't developed any antibodies against Rh-antigen (odds are you were entirely protected from becoming sensitized by having gotten Rhogam with your miscarriage), then you will not get another shot of Rhogam until about 28 weeks, unless you have an indication such as bleeding, trauma, or an amniocentesis with this pregnancy before then. Best wishes this time around and thank you for reading! Dr T


Anonymous has left a new comment on your post "Implications of a "Negative" Blood Type":
Hello! I am A- and my husband is O+. Will we have problems conceiving or problems during the pregnancy because of our different blood types?

To Anonymous Sept 3: Your different blood types should not increase difficulty conceiving. Because you are Rh-negative and your husband is Rh-positive, you are at a small risk of becoming 'sensitized' to the Rh-antigen during a pregnancy (if the baby is Rh-positive like your husband) or at the time of delivery. However, getting Rhogam (which contains anti-Rh antibody) during and after the pregnancy greatly reduces the chance of isoimmunization because it helps your body get rid of any fetal blood cells that have gotten into your circulation before your own body makes antibodies to them. In fact, it may actually suppress your immune system from making Rh-specific antibodies! I certainly wouldn't sweat the issue at this point! Go out (or stay in) and get pregnant and don't fret about this. Thanks for reading! Dr T

Labels: blood types and pregnancy complications, early miscarriage, Rh-isoimmunization

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Readers' Featured Comments/Questions - Late Preterm Birth and Abnormal Nuchal Translucency

Well, I returned from my Labor Day break to a very hectic day on Labor and Delivery and a bevy of great questions and comments from our readers. So many of these touch on important issues of general concern that it is worthwhile presenting them as a post so that other readers can benefit from the responses...


Anonymous has left a new comment on your post "Late Preterm Birth - AGAIN":

I had a late preterm baby almost 4 months ago now. It was my first pregnancy, I was over 35, and developed high blood pressure. I don't think I realized the seriousness of delivering at 35 weeks until it was all over....believe me, I did not want to go early, but everything happened so quickly that I was stunned. My daughter was in the NICU in a major US hospital for 5 weeks, and came home on her due date...we still have cardiac and respiratory issues that we need to follow up on for her, but she appears to be a happy and relatively healthy 4 month old now.

She has doubled her weight since she has come home with us. I am afraid to see the costs associated with her NICU stay-it is scary to see hom many children enter the world and spend their first days weeks or months in a NICU. The census in the NICU our daughter was in hit 60 for weeks at a time. I am grateful that the technology exists to help our children, but also troubled by the number of newborns that need it.

To Anonymous Aug 31: Thank you for sharing your story. I know that you did not expect a response, but I also know many other readers will benefit from your comments and, perhaps, learn from your experience. It is hard enough when someone needs to be delivered early, as was your case, and still has a baby with complications of prematurity. But, we need to be super vigilant as patients and providers that we don't place a baby in the NICU as the result of a delivery that was unnecessary, performed early by miscaclculation of gestational age, or done for convenience as are at least 30% of 'late preterm' births. It is very important to understand that not all babies born at 34-38 weeks will do just fine. I am glad your daughter graduated from the NICU successfully (just having to stay that long in the hospital is a risky proposition in this day and age!)and I certainly hope she does well in the long-term. Again, thanks for reading and for sharing. Dr T


Anonymous has left a new comment on your post "Fetal Cystic Hygromas in First Trimester":
Dr, My husband and I went for an NT scan yesteday in Boston. The ultrasound tech and the doctor both measured out 7mm of fluid in our baby's neck. We met with the genetic counselor, and she informed us that based on everything, we have a 50% chance of there being a chromosomal issue, and 50% of there being nothing wrong. The heart has been strong since my first ultrasound at 8 weeks, and the doctor remarked at how the heart seemed to be functioning properly. I am scheduled for a CVS on Tuesday. I guess my question is - have there been children who have been diagnosed with an excess amount of fluid on the neck, and have gone on to be delivered healthy with no issues? I know the risks and I know that it's hard to be certain. My husband and I are trying to deal with this as honestly as possible, and we know what we will do if the prognosis from the CVS proves to be dire. Thanks!
Jessica

To Jessica Sept 1: Did you have the NT done for any special reason, i.e., maternal age or previous pregnancy or family history of chromosomal problems, or simply as a routine study? Unfortunately, you do have at least a 50% chance of a baby with a chromosomal problem and/or a congenital heart abnormality. The prognosis for either of these problems will depend on the final diagnoses.

I am glad you are having the CVS done. That will answer the chromosomal question in most instances. However, even if this returns normal, your doctors might recommend that the baby have another study done during pregnancy or after birth to evaluate the possibility of mosaicism (two or more populations of cells, some chromosomally normal and some not. This will be especially important if any physical abnormalities are found. Also, the baby should have a very careful evaluation of its heart by 18-20 weeks, preferably, by a specialist in Maternal-Fetal Medicine, Pediatric Cardiology, or Radiology who has experience with the in utero diagnosis of congenital heart defects. The risk of a baby with a heart defect under these circumstances is proportional to the degree of NT width.

But the final answer to your question is this: YES, some babies with widened nuchal translucencies in first trimester end up being perfectly normal and with no apparent consequence of their 'abnormal' NT measurement. So, best of luck to you and your husband! Thanks for reading and please let me know how things turn out. I will be pulling for you guys - all three of you. Dr T

Labels: abnormal nuchal translucency, Late preterm birth

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Grand Rounds 3.50 - Parallel Universes

Many thanks to Dr. Emer at Parallel Universes for including my post regarding the association of "Low Pregnancy-Associated Plasma Protein A (PAPP-A) and Pregnancy Outcome" in this week's stellar Grand Rounds 3.50! This post was written in response to a reader's queries regarding her own pregnancy and it is a format I would like to continue over time - so keep the good comments and questions coming and, who knows, you could be the next 'featured guest' at Fruit of the Womb! And while you're at it, be sure to check out this week's Grand Rounds.

Labels: PAPP-A, pregnancy-associated plasma protein-A