Although we strive to practice “evidence-based medicine” when the evidence is good and the practice is sensible, there are many times when personal experience still plays a role in patient care activities. Nowhere does this seem to be more true in obstetrics than in situations where “thromophilias” potentially place a pregnant woman at risk or might be a contributing factor in recurrent pregnancy loss. Under those circumstances we must carefully weigh the risks and benefits of therapy vs. no therapy, and we must include in those equations a broader perspective, the emotional turmoil of pregnancy loss or the potential loss of a mother who has recently given birth to a child. The comments from the two readers below (my apologies to them for the modifications for the sake of clarity) and my responses may help put these thoughts into a better perspective, because my answers many not be what either expected, but they illustrate the various factors that must be considered when confronted by these sorts of issues.
• At Tue Nov 20, 12:48:00 PM 2007, Amber said… I have factor V Leiden (heterozygote) and had one normal pregnancy without knowing that I had it. With my current pregnancy the doctors started me on Lovenox. My original doctor said that I would be switched from Lovenox at 36 weeks and induced at about 38 weeks. Because I am military, I don't really have the luxury of seeing the same doctor because of duty station changes, etc. At my most recent appointment, the doctor I spoke with said they weren't going to change me to heparin until 38 weeks and that they would not induce early. My son was 3 weeks early, so if this pregnancy chances to follow suit, shouldn't they change me to the heparin at 36 weeks like my original doctor advised? And is being induced 2 weeks early normal? I tend to believe my original doctor because the other one changes his mind constantly about even the littlest things. Thank you…
• At Mon Nov 26, 06:58:00 PM 2007, Kenneth F. Trofatter, Jr., MD, PhD said… To Amber Nov 20: Sorry for the delay in responding but I just got your comment in my mailbox today. I need to have the answer to one VERY important question, before I can answer any of yours properly. What led to you finding out that you were a factor V Leiden heterozygote? Those tests usually don't get done on any routine basis! Anyway, personally, I would switch you to heparin at 36 weeks, especially if you delivered early before (and why was that delivery early? - another important question!) because if there is nothing else I have learned in this business, it is that obstetrical history tends to repeat itself. The reason for switching you is to decrease your risk of bleeding and anesthetic complications (bleeding at the site of an epidural or spinal) around the time of delivery. Most anesthesiologists would prefer that Lovenox be out of your system for 48-72 hours before you have a regional block performed. Heparin can be reversed easily with protamine sulfate, even if you present in labor just having taken a dose, whereas Lovenox cannot be reliably. Let me know the answers and I will see if I have any other thoughts. Thanks for reading! Dr T
To which Amber responded...
• At Tue Nov 27, 12:36:00 PM 2007, amber said… I found out because my grandmother has had clots her entire life, and was finally tested a couple years ago. She had clots after all of her pregnancies and was found to be a factor V Leiden heterozygote. My uncle had a pulmonary embolism in ‘91, and so he tested as well, and was positive. My mother has had some minor clots, and tested positive for it too and told me about it. She said it was genetic, so I requested to be tested because I had been on birth control and I have heard that hormonal birth control can add to the risk. I haven't had any problems with clotting thus far, it probably helps that I am military and usually fairly active. I was not aware of this family history until after my first child. My son was early naturally and I didn’t have any complications with him thankfully.
• At Thu Nov 29, 11:05:00 AM 2007, Kenneth F. Trofatter, Jr., MD, PhD said… To Amber Nov 27: Thanks for your answers. I figured there was more to the story! My first answer stands. Based on your family history and your previous early delivery, I would switch you to heparin at 36 weeks. However, if the baby is growing well, has normal fluid, normal nonstress tests, and normal Doppler flow studies, and you are not having any complications yourself, I would not deliver you before 39 weeks unless I first documented fetal lung maturity with an amniocentesis. This is the current recommendation of the American College of Obstetricians and Gynecologists. Late preterm delivery is now the number one cause of premature delivery and there is an increased risk of morbidity for both you and the baby if induced early when there is no good medical indication. After delivery, I would place you on Lovenox, starting 12-24 hours after having the baby, continuing that until at least 6 weeks postpartum. After that, you might consider taking one baby aspirin (81 mg) per day for the rest of your life in view of your very strong family history! Good luck my friend and let us know how things turn out! Dr T
The second patient was diagnosed with a different “thrombophilia” as the result of a workup for recurrent miscarriages, but otherwise has no medical history, family history, or past obstetrical history that would appear to place her at “high risk” for complications, or even necessarily implicate her thrombophilia as a cause of her recurrent early pregnancy loss…
• At Sat Nov 24, 11:06:00 AM 2007, Anonymous said… Dr. Trofatter, I was just diagnosed with 2 copies of the MTHFR C677T mutation (homozygous). I am 38 years old, have a healthy 2 year old boy and have had 3 miscarriages this year, all pregnancies with the same father. We are meeting with a genetic counselor next week. I am having several tests done and have gotten the MTHFR result so far. I miscarried at 8 wks, 11 wks, and 5 wks. No testing was done prior to the 3rd miscarriage. I have gotten pregnant each time I have tried, though my doctor is still going to test my estradial and FSH. Do you think this is neccessary?
Here is my question- I have done a ton of research and have a basic grasp of the blood disorder but am wondering what actually stops the baby from surviving? Is it always that there is a defect because of the lack of folate and vitamins B getting to the fetus? Or is it that there is blood clotting and the baby isn't getting what it needs? I also want to know, and I know the geneticist will tell us more once she has mine and my husband’s results, but should we NOT try for another? This year has been gut-wrenching and I selfishly want another child, not just for me but for my son. I always wanted more than one child but is it too risky??? I am on Vitamin B12, B6, 5 mg of folic acid and 81 mg of baby aspirin. I 'm assuming I will get my homocysteine levels checked before I get the green light to conceive? I don't want to wait much longer because I am 39 years old in March. Thank you for any and all information regarding these questions.
• At Thu Nov 29, 05:16:00 PM 2007, Kenneth F. Trofatter, Jr., MD, PhD said… To Anonymous Nov 24: You were homozygous for C677T when you had your first child and you did just fine. The presence of this homozygous MTHFR polymorphism only modestly increases your “risk” so that should only be a minor consideration with regard to your decisions regarding another pregnancy. To answer your questions, these polymorphisms may put you at slightly greater risk for clotting problems, particularly if you have other risk factors, but they are probably not a major cause of recurrent early pregnancy loss, especially once you have started supplemental folic acid. That probably also reduces the risk of having a baby with a neural tube defect or congenital heart disease as well.
First let me review why folate metabolism and the methylenetetrahydrofolate reductase (MTHFR) gene are important. MTHFR is an enzyme that requires folic acid to convert homocysteine to methionine (an important amino acid) and when this does not occur, homocysteine can accumulate. As we discussed in a previous post, when this occurs in a developing embryo as the result of either folate deficiency or certain mutations in the MTHFR gene, this may have a ‘toxic’ effect, increasing the risk for neural tube defects and certain cardiovascular abnormalities. This same biochemical pathway is also essential for the production of a substance called S-adeneosyl methionine that is an essential intermediate in pathways that add methyl (CH3) groups to nucleic acids (DNA; RNA), proteins, neurotransmitters, and phospholipids, a process that plays an important regulatory role in the biological functions of each of these. The MTHFR C677T polymorphism is associated with a reduced efficiency of these metabolic pathways, but this deficiency can be overcome by loading up on folic acid as you have done.
But, all that said and done, I would wager that your primary problems are more 'age-related' than anything else. Fertility drops with age for reasons that are not completely understood. Part of the contribution may be the increased risk for having a chromosomally abnormal fetus; part may be other medical problems such as diabetes, obesity, thyroid disease, autoimmune disorders, hypercholesterolemia, and hypertension; part can be anatomical changes within the uterus that impair implantation, such as fibroids, endometriosis, or endometrial polyps; part is simply that your body's ability to hormonally support an early pregnancy might not quite be what it was when you had your son.
Ovulation induction and progesterone support may be all that you need, but I would suggest you find a Reproductive Endocrinologist (if you haven't already) since he/she will be in the best position to move you through a thorough evaluation and treatment regimen, even if that ends up being just empiric therapy. As you are well aware, at your age, efficient and experienced medical care is very important if you hope to have another baby. Good luck to you and thanks for reading. Dr T