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...