Recurrent Early Pregnancy Loss: To Treat or Not to Treat...

The readers who sent in the comments below related to recurrent early pregnancy loss (RPL) have what we could consider to be 'borderline' indications for 'treatment' and several questions related to their therapy. But, the fact remains, they have both repeatedly lost babies early. Many of you with with RPL have or will find yourself in similar situations and will be likely to have similar concerns. In my responses, I express my approach to their management given the circumstances detailed in their comments. Let me remind you up front, there is no 'right' (or proven and agreed upon) and no 'wrong' way to manage their care. Under these circumstances, you could put two Maternal-Fetal Medicine or REI physicians in the same room and come up with 10 different approaches!

• At Thu Nov 29, 06:12:00 AM 2007, Anonymous said…
Doctor,

I have written in the past about 2 miscarriages I had this year...and now I'm having my 3rd. I have a single mutation C677T MTFHR. My LMP (last menstrual period) was 10/12 and I was tested positive for hCG around 11/7 and my doctor prescribed 40mg of Lovenox. I was also taking Advanced natalcare prenatal vitamin. On 11/21 my doctor did an US and did not see anything in sac. The doctor said to not be concerned yet since I could have my dates wrong, but I know I conceived on 10/25 using fertility monitor. On 11/21 I was started on 200mg of prometrium. 11/28 they did another ultrasound and still no embryo, just empty sac. Do you have any advice you can give me for a future successful pregnancy? Who should I see next as a specialist? Are there anymore tests I need to get done? My doctor did bloodwork and found no issues except the MTFHR mutation which he said may not even be a cause.

I have had D&Cs in March and July of this year following the loss of my other two pregnancies. My doctor wants to see me again to confirm this loss on 12/6. Should I have another D&C? I find it mentally helps me get over it faster than waiting for it to happen naturally, but have concerns what a third D&C will affect the uterus and future pregnancies...Please help...I'm so desperate to find hope and a cause.

• At Sun Dec 02, 08:25:00 AM 2007, Kenneth F. Trofatter, Jr., MD, PhD said…

To Anonymous Nov 29: I am so sorry again for your losses. I am also sorry that I have no way to easily find your earlier correspondence to me or my responses. That's one disadvantage of the way this blog is set up.

I will be honest with you, it is highly unlikely the single MTHFR C677T polymorphism alone is causing your miscarriages this early, although I don't disagree with the attempt at 'empiric therapy' either. I generally will start the prometrium in mid-luteal phase after ovulation (even before conception is confirmed)rather than at '4 weeks' into the pregnancy and then continue it until 8-12 weeks after confirming a viable embryo. Refresh my memory if you can on what other tests have been done and then I will be in a better position to tell you what could be done. Are you seeing any sort of specialist at this point?

As far as the D&C goes, I have mixed emotions. It is a natural response to just want to get this over and move on, but I sometimes wonder if there might not be some advantage to future pregnancies from an 'immunologic response' standpoint until waiting until your body begins to reject the current pregnancy and you start bleeding. You are at very low risk for complications at this point and might consider that.

Repeated D&Cs can cause damage to the cervix at its internal opening and that could increase your risk for cervical incompetence when you finally do successfully get through first trimester. D&Cs can also cause damage to the lining of the uterus (the endometrium) resulting in scarring and adhesion formation that can also impair fertility. In its most severe form (Asherman’s syndrome), this scarring can cause your endometrium to stop cycling so that you don’t even have periods even if you are ovulating normally. However, the endometrium is also very resilient and it is unusual for this to happen in the absence of infection. To reduce the risk of infection with early miscarriages, I usually suggest having either a medical evacuation of the uterus (using misoprostol) or a D&C if you haven’t completed the miscarriage spontaneously within 48-72 hours after starting to bleed and cramp.

Thanks again for reading and feel free to get back to me with your answers to my questions.
Dr T

• At Thu Nov 29, 03:41:00 PM 2007, Sarah said…

I've had three early miscarriages and I tested positive for two copies of MTHFR A1298C. I have also tested borderline positive for anticardiolipin anitibodies. I have seen a hematologist who thought that my miscarriages would not have been caused by that. However a fertility doctor does think so. I am taking folic acid, vitamin B6, vitamin B12, low-dose heparin from cycle day 5, low-dose aspirin, and 10 mg prednisone. I am feeling very anxious because of the disagreement between the two doctors and I just wondered if the things I have tested positive for could have caused the miscarriagess at 5-6 weeks. Or am I taking all of this medication for no reason?

Thanks Sarah •

At Sun Dec 02, 08:45:00 AM 2007, Kenneth F. Trofatter, Jr., MD, PhD said…

To Sarah Nov 29: The honest answer is WE DON'T KNOW! That's the usual cause of disagreement between 'experts.' We don't know if your losses are the result of the individual factors for which you have screened 'positive', the combination of the individual factors, or something else entirely different (or combined with those other factors!) for which you have not yet been tested! The important fact is that you have lost 3 pregnancies very early and the 'empiric therapy' upon which you have been placed is relatively low risk to a developing baby.

But, I would suggest, in the absence of any other history or 'risk factors', if you successfully get through the first trimester on the current treatment regimen that your doctor consider getting you off the prednisone and the heparin by 20 weeks. Any beneficial effect on the development of the baby’s placenta should have been accomplished by that time and prednisone increases your risk for other complications in pregnancy such as gestational diabetes, premature rupture of membranes, and early delivery as a consequence of the latter. If your baby is showing normal growth at 26-28 weeks by ultrasound and is having no trouble pushing blood through the placenta as determined by Doppler flow studies, you are probably well on your way to a successful outcome. By the way, are you seeing the REI doctor for any reasons other than your miscarriages? Best of luck to you, thanks for reading, and let us know how things turn out!

Dr T

Labels: MTHFR, recurrent pregnancy loss, RPL

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Repetitive Miscarriages: Engender Fear and Require Patience

I received the comment below from one of our readers and my response, though abbreviated, is relevant to many of our readers who have suffered unexplained pregnancy losses. She has lost two early pregnancies and, understandably, is "scared" about losing a third. Although the immediate response is to want do everything possible to avoid another loss, there is still a sequence of evaluation and 'therapy' that is both practical and reasonable. As I have said before, and conclude in my comments to her, the odds are in her favor that she will be successful, based on the information she has provided to us at this point, regardless of any specific or empiric intervention...

Hello-
Thank you so much for the work that you do for RPL (recurrent pregnancy loss). I have read Fruit of the Womb and the segments on RPL. My question is: I am a 29 year old with no successful pregnancies and my husband is 31. We are both in good health. I have had two very early miscarriages within the last 6 months. One was natural (aborted spontaneously and completely) and the other was completed by a D&C. Both times no fetal pole (embryo) was found and my doctor said the second was a possible blighted ovum. Since in both there was no fetal pole found, would this be more of a immunological issue or hormonal one. Or still, could it be random chromosomal issues?

I am concerned and scared to try again and have been going to a reproductive endocrinologist (RE) who said he will treat me with baby aspirin, estrogen in the first half of the cycle to help my uterine lining and progesterone in the second half of the cycle. No other issues have been found except for that I am a possible carrier for Group B Strep...would the Group B Strep be causing the miscarriages? I am at a loss as to why this happening and since everything has come back normal it does scare me. I also went to see a herbalist and they tested my saliva for thyroid antibodies and I did have those, but they were not evident in the blood test that the RE performed.

I have regular menstrual cycles, check my temperature (basal body temperature) every day and ovulate. I read your suggestions on what you do for women with unexplained pregnancy losses. Would you suggest that same plan for some one like me? I don't want to have a third miscarriage as I know my percentage from there increases to have subsequent miscarriages. I am sorry this was so long, I am just so worried and don't know if my RE path is covering all my bases?

Thank you again for all your help to so many women.

Dana

To Dana:
Let me start with a couple of questions back at you: Specifically, you said that “no other issues have been found” and it would be helpful to know what specific studies have been done and, if possible, the results? Also, how did you find out that you are “a possible carrier for Group B Strep?” Was GBS detected in a urine culture? Is there any family history of recurrent pregnancy loss, blood-clotting disorders, or autoimmune diseases? You have regular periods but are they usually painful?

Regardless, my assessment of your situation is as follows: If you have regular cyclic menses and ovulate regularly in midcycle, the likelihood is that you do NOT have a significant hormonal problem. So, to answer your first question, your losses are most likely the result of an inadequate or inappropriate immune response to pregnancy (i.e., your immune system has not quite figured out yet that it’s supposed to help the baby survive) or the result of conceiving babies that were chromosomally abnormal. In the latter instance, this could be either ‘random’ aneuploidy or the result of either you or your husband carrying a balanced chromosomal rearrangement. Other possibilities include abnormalities of the uterine cavity, such as fibroids, polyps, or a congenital uterine defect and/or endometriosis which may be a more common cause of RPL than previously recognized, particularly in women who have delayed child-bearing until their 30’s. In the reading that I have done over the years, I have never seen an association between GBS carrier status and recurrent early pregnancy losses. However, chronic GBS carriers may not have an adequate immune response to the bacterium and, hypothetically, that might be the result of a subtle underlying defect (hyporesponsiveness?) in the immune response and be reflected in similar problems when it comes down to recognizing a pregnancy appropriately.

In the absence of finding specific abnormalities to ‘treat’, your RE doctor is taking a sensible empiric approach to therapy. I understand how hard it is to undergo repetitive miscarriages, since my first 3 babies ended up the same way, but at this point the hormonal support and aspirin are a reasonable first step. You could add a prenatal vitamin and extra folic acid to the mix as well. If your next pregnancy is lost, you will probably need a more thorough evaluation before conceiving again and/or a more aggressive approach to empiric therapy. How about if we cross that bridge if we come to it? Remember, the odds are in your favor that you will be successful, regardless of what we do as physicians!

Dr T

Labels: recurrent pregnancy loss, RPL

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Cytomegalovirus (CMV) Reprise

There is not a week that goes by in my practice that I do not have to address questions regarding cytomegalovirus (CMV) infections and pregnancy. Since we have also been discussing recurrent pregnancy loss in various contexts over the past year, I thought her questions were particularly timely and would be of interest to a good number of other readers. This is a good opportunity to reprise some of the information about CMV that we have provided in the past…

Anonymous has left a new comment on your post "Cytomegalovirus (CMV): Common and Confusing":

I have had reoccurring miscarriages and my OB did a TORCH blood test which showed my CMV levels were slightly elevated. I’m supposed to go back in two weeks for another test to recheck the levels. Could this virus have caused my miscarriages? Is there a period of time I should wait before trying to conceive again? If I do become pregnant again am I at risk of having a baby affected by CMV?

To Anonymous: All of your questions are answered at the very end of this post. You can jump to there if you would like or read on for more information…

The TORCH test looks for antibodies in your blood specific for TOxoplasmosis, Rubella (German measles), Cytomegalovirus, and Herpes simplex virus. It is not unusual to include a screen for syphilis and human immunodeficiency virus (HIV) at the same time. All of these can cause infections of a baby during pregnancy (congenital infections) but by far, CMV is the most common. If antibodies to a specific organism(s) are present, this indicates you have been infected with that organism at some time in the past. Let me elaborate on that point a bit so that you have a better understanding of the tests when you discuss them with your doctor.

Usually, when we contract a virus infection like the flu, our immune systems react by first producing specific antibodies of the IgM class. These usually hang around only for no more than 2-4 weeks after the infection has been cleared. Shortly after IgM antibodies begin to be made, our bodies switch to the production of a second class of specific antibodies called IgG. IgG antibodies generally hang around for a long time after the infection is cleared and provide us with a source of 'permanent immunity' to the organism, helping to prevent reinfection, or decrease the severity of a secondary infection, with the same or similar organisms with which the antibodies might 'cross-react.' It is these IgG antibodies that also afford protective immunity to the baby because they can cross the placenta whereas IgM antibodies cannot.

We can use this information to help us to characterize the status of an infection. If neither IgM nor IgG is present, the individual has probably never been exposed to the organism of concern (or is too early in the course of the infection to have mounted any antibody response). If IgM is present and there is no IgG, then the infection is probably a 'primary' infection, indicating first time exposure to the organism, usually very early in its course. If both IgM and IgG are present, this also usually reflects a primary infection, but later in the course of the disease. And, if only IgG is present, then this indicates a state of permanent immunity established from an infection that occurred at some time in the past. In any of the first three circumstances, if an infection with a specific organism is suspected and could be of concern for a pregnancy, it is probably worth repeating the antibody titers in 4-6 weeks.

Things can be a little confusing with CMV infections. CMV grows very slowly and the incubation period from the time of exposure to onset of symptoms, or asymptomatic excretion of the virus, is on the order of 4-12 weeks. IgG antibodies usually can be detected by 1-2 weeks after the onset of symptomatic infections, but because of the long incubation period of CMV, this might be a month or more after actual exposure to the virus. The presence of IgM in the absence of IgG and in the presence of symptomatic disease (or a history of recent exposure to a known carrier) is highly presumptive of a true 'primary infection.' Similarly, the findings of both IgM and IgG with a significant rise (four-fold or more) in IgG titers (with or without a fall in IgM titers) on a follow-up screen 4-6 weeks later, usually (but not always in the case of CMV) indicates a recent primary infection. Also useful, the presence of IgG in the absence of IgM, is highly suggestive of a remote exposure to the virus, often greater than 6 months previously.

The rub with serology in classifying CMV infections comes in most often when IgM is present but IgG titers are relatively stable or mildly fluctuating. Unlike most common viral infections, CMV-specific IgM can sometimes persist 6-9 months following its appearance. And to make things even more confusing, IgM has been found to reappear on occasion with reactivation of latent CMV infections. In other words, except in the circumstances detailed above, we may not be able to use the presence of IgM in our counseling to tell patients that they have had a primary or recurrent infection during the pregnancy or if the infection might have occurred even prior to the current pregnancy.

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CMV is the MOST common congenitally (fetal) and perinatally (newborn) acquired virus disease in humans and the single most important infectious cause of mental retardation and congenital deafness in the U.S. and other industrialized nations. CMV is a member of the herpes family and human CMV is restricted to humans with no known animal reservoir. At least 80-90% of all individuals are infected with CMV during their lives, but infection may occur in the absence of clinical symptoms or without recognizing that an illness is the result of CMV. As with other herpes viruses, once an individual is infected with CMV, 'recurrences' can result from periodic reactivation of virus replication at various sites in which the virus is latently harbored in the body. During periods of reactivation, the virus can be more readily transmitted to individuals who have not been previously infected. Although probably not that common, secondary infections can also occur with other strains of CMV.

Transmission of CMV can occur from exposure to just about any body fluid, most commonly via saliva, respiratory, and venereal routes or by contact with infected urine or breast milk. Exposure tends to occur at earlier ages in lower socioeconomic groups, promiscuous individuals, and children at day care centers. Antibodies to CMV (seropositivity), indicating a history of infection with the virus, in women during the common childbearing years (18-35) can be found in about 50% of those in middle and upper, and 90% in lower, socioeconomic groups. Among previously noninfected (seronegative) women, the chance of becoming infected with the virus (seroconversion) is about 1-3% per year, however, this is as high as 10-20%in women who work in day care settings and 50% in women with infected children under two years of age!

Congenital infections with CMV occur in 1-2% of ALL pregnancies, accounting for 40-50,000 cases per year, indicating the virus can cross the placenta with relative ease compared to other herpes and most other common virus infections. Transmission of CMV to the fetus can occur with both primary and recurrent infections despite maternal immunity and has been documented in consecutive pregnancies. However, congenital infection rarely results in a poor outcome unless the congenital infection is the result of a primary (first time) infection in the mother during the pregnancy. Overall, among seronegative women, there is about a 0.5-1% risk of a primary CMV infection in each pregnancy, although this is much higher in 'at risk' groups such as day care workers, health care providers, and women with young children. Primary maternal infections carry an overall transmission risk to the baby of 25-50% and recurrent infections about 2-3%. Maternal antibody to CMV is incompletely protective against transmission to the baby, but it does play a major role in reducing the severity of infection in both fetus and newborn.

A high percentage of primary maternal infections are asymptomatic, or simply confused with another illness, or even written off as normal symptoms of pregnancy, so usually the diagnosis is not considered. Indeed, perhaps, the hardest part of making the diagnosis of CMV infection during pregnancy in mother and baby is simply suspecting that it might be a problem. If a woman develops a prolonged (weeks) illness with fever, resembling infectious mononucleosis (caused by another herpes virus, Epstein-Barr virus (EBV)), and the latter cannot be confirmed by routine testing, then CMV should be high on the differential diagnosis. The ante goes up considerably if the mother is a young teen having her first baby (especially if she conceived shortly after becoming sexually active or changing partners), or if she works, or has another young child, in a high risk setting such as a daycare center.

Serologic testing, as we discussed at the outset, can often help to confirm a primary infection when it is obtained coincident with maternal symptoms. Virus detection by culture, immunofluorescent, or polymerase chain reaction (PCR) techniques, best done by sampling maternal urine, may be positive (and almost always will be for months after a primary infection), but this alone does not tell us if this is a primary symptomatic CMV infection or a recurrent infection accompanying another illness. Unfortunately, in most cases maternal infection with CMV is usually not suspected until the baby is found to be growth restricted or has subtle physical abnormalities, or a thickened placenta, to suggest it has either a chromosomal abnormality or a congenital infection, sometimes months after the maternal exposure. Under these circumstances, maternal serologic testing might not be helpful in establishing either the fetal diagnosis or the diagnosis of a primary maternal infection during pregnancy.

Congenital CMV infections associated with primary maternal infections early in pregnancy and accompanied by growth restriction and detectable abnormalities by fetal ultrasound, generally, have a very poor prognosis, but even then, the outcome is not entirely predictable. Establishing the presence of fetal infection, when fetal abnormalities are identified, requires an 'invasive' procedure. Performing a simple amniocentesis, and using a CMV-specific PCR or shell vial culture technique, can confirm fetal infection with CMV in nearly 100% of cases. (Remember, the amniotic fluid from midtrimester on is mostly fetal urine, and CMV is excreted in large amounts from the kidneys following congenital infection, and often for years afterwards, even in 'asymptomatic' cases). However, unless we have confirmatory maternal serologic information, or symptomatic infection confirmed to be the result of CMV during the pregnancy, we still may not know if the congenital infection is the result of primary or recurrent maternal disease. If the diagnosis of CMV is not suspected until late in pregnancy, or not until after the birth of the baby, detection of CMV in a urine sample taken from the baby within the first two weeks'(preferably, the first 48-72 hours) of life also suffices to confirm congenital infection. CMV is a VERY slow growing virus, so any detection of virus in this time frame most certainly represents intrauterine infection.

Congenital CMV infections are asymptomatic or unrecognized in about 90% of cases, including 85-90% of babies acquiring the virus as a consequence of primary maternal infection and 99% of those resulting from recurrent infections. Most of the asymptomatic infections pose no immediate life threat, but 10-15% of these babies are at risk for long-term complications such as sensorineural hearing loss, chorioretinitis, and dental abnormalities, usually apparent by two years' of age. Of these, the hearing loss is by far the most significant because delay in its detection can contribute to psychomotor retardation. More than 90% of congenitally infected infants, regardless of the severity of their infection, will shed infectious virus at birth, and may do so for 6 or more years longer, even in the presence of specific immunity.

About 5-10% of congenitally infected babies will have significant evidence of infection at birth. Approximately half of these will have classic 'cytomegalic inclusion disease (CMID)' (described below) and half will have atypical involvement. Virtually 100% of these infants excrete CMV at birth and will continue to do so for many years afterwards. Infants in this group have a 20-30% eventual mortality and account for 90% of the significant mental and psychomotor retardation associated with congenital CMV infections. The most severely affected children are usually the result of primary maternal infections during pregnancy and should be suspected in instances of unexplained intrauterine growth restriction and fetal death beyond 20 weeks' gestation.

The most common findings in babies with CMID include symmetrical growth restriction, multiple small skin hemorrhages (petechiae), enlargement of the liver and spleen (hepatosplenomegaly), jaundice, microcephaly (small head), abnormalities of the dental enamel, and chorioretinitis. They can have numerous associated birth defects involving virtually any organ system, a catalog of which is not necessary for our discussion today. Prenatal detection by ultrasound of fetal growth delay and gross or subtle, nonspecific physical abnormalities of the baby may be the only clues that a congenital CMV infection has occurred. Unfortunately, these often manifest themselves only weeks or even months after fetal infection has occurred because the virus is very slow growing, and it is relatively nondestructive, compared to other herpes viruses.

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With the above information as background, let me answer our reader’s questions:

Could this virus have caused my miscarriages? It is unlikely. Although I did not address this specific point above, many people over many years have tried to implicate CMV in recurrent miscarriages and I have never seen an article that found good evidence to do so.

Is there a period of time I should wait before trying to conceive again? The TORCH screen and your CMV seropositivity should not preclude your getting pregnant again soon. You already have ‘protective immunity’ and you will probably have the virus for the rest of your life. However, if you have had recurring miscarriages, perhaps you should wait to conceive until you have had a more thorough evaluation for that.

If I do become pregnant again am I at risk of having a baby affected by CMV? Yes, you have a 2-3% chance of having a baby with a congenital CMV infection. But, the presence of your antibody to CMV will decrease the risk of serious complications from the infection. Most (99%) babies who get CMV as the result of a recurrent maternal infection are asymptomatic, but 10-15% of these babies are at risk for long-term complications such as sensorineural hearing loss, chorioretinitis, and dental abnormalities, usually apparent by two years' of age. Your baby can be screened within 48-72 hours of birth by simply checking his/her urine for CMV to determine if there was a congenital infection. Almost all babies with a congenital CMV infection will excrete the virus in their urine. If CMV is present, the baby simply needs to be followed more closely for the hearing and eye problems noted above to prevent correctible sources of developmental delay. These children usually do not have problems with growth or mental retardation.

Labels: CMV, cytomegalovirus, RPL

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Plasminogen Activator Inhibitor-1 (PAI-1): Role in Adverse Pregnancy Outcome? - 5 - Implantation and Placentation

Things have been so busy at work the last few weeks that it has been hard to find the time to write here, but I would like to finish up the series we started on plasminogen activator inhibitor-1 (PAI-1) and role in pregnancy outcome and recurrent pregnancy loss (RPL) before moving on to any other major topic. I will admit that the review of the literature on this topic has been somewhat tedious and at times confusing, but it has also been very educational from my own standpoint, and I figure, it’s okay to be a little selfish every once and awhile, especially if a few of our readers might also benefit from the results of the efforts. Anyway, in our last post we reviewed observations that have been made regarding the role of PAI-1 in ovulation and development (and regression) of the corpus luteum and posited possible deleterious effects on these events, under circumstances in which PAI-1 is elevated, that might lead to ovulatory defects and RPL in early pregnancy. Today we are going to turn our attention to observations that have been made regarding the role of PAI-1 in implantation and placentation.

During the first part of the menstrual cycle, prior to ovulation, the hormone that stimulates the growth and the development of the lining (endometrium) of the uterus is estrogen. As we discussed in our last post, following ovulation, the corpus luteum produces progesterone that prepares ('decidualizes') the endometrium to receive the fertilized egg; and, if implantation of the embryo occurs normally, the hormones (mostly hCG) that are produced by the developing placental tissues (trophoblast cells), stimulate the corpus luteum to continue to make progesterone until the placenta gets big enough to take over that function. In 1996, Lockwood and Schatz (J Soc Gynecol Investig 1996;3:159-65) reported that progesterone stimulation (decidualization) of estrogen-primed endometrial cells (estrogen up-regulates endometrial cell receptors for progesterone), both in vitro and in vivo, results in “a marked increase in the expression of tissue factor (TF) and type-1 plasminogen activator inhibitor (PAI-1) and an inhibition of tissue-type and urokinase-type plasminogen activators (tPA and uPA,respectively), matrix metalloproteinases (MMP), and endothelin-1 (ET-1) expression…” Thus, even prior to implantation, the fibrinolytic balance is shifted toward preservation of the extracellular matrix (ECM) structure and prevention of hemorrhage that could be imagined to occur as the embryo implants and the trophoblasts start eating their way into the maternal endometrium. Indeed, progesterone withdrawal shifts the fibrinolytic balance in the opposite direction and this is thought to be one of the factors that permits the shedding/bleeding from the endometrium with menstruation if pregnancy has not occurred successfully.

During the course of normal placentation, some trophoblasts invade the maternal endometrium to anchor the placenta, some migrate through the endometrium and then invade and remodel (open up) the maternal blood vessels (spiral arterioles) that will be the source of blood to the ‘placental bed’ from which the baby will extract oxygen and nutrients (and into which it will transfer its own waste products), and other trophoblasts develop into the frond-like villi that eventually dangle into the placental bed of maternal blood and actually perform these latter functions (transferring oxygen, nutrients, and wastes between the fetal and maternal circulations). Proliferating and invasive trophoblasts produce urokinase-like plasminogen activator (u-PA) and this helps to degrade the ECM and facilitates their migration within the endometrium. One of the primary roles of PAI-1 in normal placentation appears to be in controlling the degree to which trophoblastic cells actually invade the maternal tissues. Graham (Placenta 1997;18:137-43) found that a substance produced by maternal decidual cells, transforming growth factor-beta (TGF-beta), stimulates fetal trophoblasts to make both PAI-1 and the inhibitor of metalloproteinase-1 and also down-regulates trophoblast production of u-PA. This suggests that the trophoblasts, under the direction of maternal cells, may limit their own invasiveness by the secretion of these inhibitors that inactivate u-PA and prevent the degradation of the ECM.

This hypothesis is supported in a study by Floridan and colleagues (Placenta 2000;21:754-62). Beginning with the observation that “trophoblast invasion…in normal intrauterine pregnancies appears to be strictly regulated…whereas tubal and molar pregnancies seem to be characterized by uncontrolled excessive placental invasion,” PAI-1 localization was evaluated in both maternal and fetal tissues under these conditions. In normal pregnancies, PAI-1 was localized, predominantly to trophoblasts that were in closest proximity to maternal tissues: the basal plate of the placenta; the extravillous interstitial trophoblasts comprising the placental anchors in the endometrium; and the trophoblasts that replace maternal vascular endothelial cells as the result of the remodeling of the spiral arterioles. In the basal plate at the deepest layer of placental invasion, PAI-1 (secreted by the trophoblasts?) was noted to be associated with the surface membranes of maternal decidual cells “or confined to the extracellular matrix (ECM) facing the invasive front of anchoring villi.” In contrast, there was a paucity of PAI-1 expression by fetal trophoblasts and maternal cells in both tubal ectopic and molar pregnancies that accompanied uncontrolled trophoblast invasion and damage to maternal tissues.

So, if normal placental invasion of both the decidua and maternal spiral arterioles is at least partly the result of controlled and ‘normal’ expression of PAI-1 activity, we can easily speculate on the potential consequences of excessive PAI-1 production without defining the underlying cause. This could lead to very shallow invasion of the endometrium and inadequate migration to and invasion and remodeling of the spiral arterioles. If severe enough, this could result in early pregnancy loss and if less severe, could result in an abnormal placenta, typical of that seen in preeclampsia, accompanied by increased resistance to fetal and/or maternal perfusion and restriction of fetal growth.

There are many factors that might contribute to the increased expression of PAI-1 under these circumstances. In other posts we discussed the genetic polymorphisms such as 4G/4G that are associated with increased PAI-1 production and activity and this could possibly contribute from both the fetal and maternal sides. Since PAI-1 expression by trophoblasts is at least in part influenced by TGF-beta production by maternal decidual cells, then anything that contributed to increased TGF-beta production by either decidual cells, or cellular components of the maternal immune system, might also result in the fetal trophoblasts producing excessive PAI-1. Indeed, one could imagine that if an abnormal maternal immune response to the pregnancy, either innate or specific, was accompanied by the production of factors that up-regulated PAI-1 expression, this could also contribute to inhibition of trophoblast migration and invasion.

Personally, I believe that aberrations in the maternal immune response are a major cause of abnormalities of placentation that result in pregnancy loss and preeclampsia and there is some evidence indicating that modulation of PAI-1 expression is indeed one mechanism by which these deleterious affects are mediated. Bauer and colleagues (J Clin Endocrinol Metab 2004;89:812-22) reported that the cytokine, tumor necrosis factor (TNF) alpha, inhibits both invasion and migration of trophoblasts in tissue culture experiments. Furthermore, this inhibition is correlated with increased production of PAI-1 and can be reversed by specific antibodies against PAI-1, restoring normal trophoblast migration. In subsequent studies, Renaud and colleagues (Biol Reprod 2005;73:237-43) demonstrated that activated macrophages (components of the innate immune system) also inhibit trophoblast migration. They showed that this inhibition is clearly the result of TNF-alpha production by the macrophages, requiring specific binding of TNF-alpha to the trophoblasts, and that it is accompanied by decreased production of u-PA and increased production of PAI-1 by the trophoblasts themselves.

In our posts to this point, we have built the case that aberrations in the fibrinolytic balance, associated with increased production of PAI-1, accompany adverse pregnancy outcome both late in gestation and in early pregnancy, and have presented several mechanisms by which early pregnancy success might be impaired by increased PAI-1 expression. The questions then remain: can PAI-1 expression be down-regulated in individuals with increased PAI-1 and/or a genetic predisposition for the same and, if so, is this accompanied by improved pregnancy outcome? In our final installment in this series, we will present evidence that it can be and does!

Labels: PAI-1, placental abnormalities; spiral arterioles, recurrent pregnancy loss, RPL

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Grand Rounds 4.8 at Dr Anonymous!

Thanks to Dr. Anonymous for including my last minute submission regarding the role of endometriosis in recurrent early pregnancy loss (RPL)in this week's Grand Rounds 4.8. Many women associate infertility with endometriosis, but are not aware of the connection with RPL as well, so it should be of general interest to a good number of readers who have had miscarriages. Check out Grand Rounds - the selection of topics will keep you entertained for the next week!

Labels: endometriosis, grand rounds, recurrent pregnancy loss, RPL

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