Plasminogen Activator Inhibitor-1 (PAI-1): Role in Adverse Pregnancy Outcome? - 2 - Late Pregnancy Complications

In our last post, we discussed the role of plasminogen activator inhibitor-1 (PAI-1) in helping to maintain the balance between the clotting and fibrinolytic (clot-dissolving) sides of the coagulation system. The primary function of PAI-1 is to inhibit plasminogen activators (t-PA and u-PA) from converting plasminogen to plasmin which is responsible for initiating fibrinolysis. The premise is that if there is too much PAI-1 activity, clots will tend to hang around longer and if there is too little, the individual would be at increased risk for bleeding problems. Before we can address possible roles of abnormalities of PAI-1 production and activity in adverse pregnancy outcome and recurrent pregnancy loss (RPL), it would be helpful to understand changes that might occur in these parameters during normal pregnancy.

Kruithof and colleagues (Blood 1987;69:460-6) reported that both plasminogen activators (t-PA and u-PA) and plasminogen activator inhibitors increased during pregnancy. t-PA and u-PA increased 50% and 200%, respectively, throughout normal pregnancy. They also found that PAI-1, produced predominantly by endothelial cells lining blood vessels, increased nearly 10-fold by term over that found in nonpregnant women and a second plasminogen activator inhibitor, PAI-2, not found in nonpregnant women, but produced by the placenta, was present in very high concentrations by term. The increase in both activators and inhibitors appeared to maintain the balance between the clotting and fibrinolytic systems during normal pregnancy because no changes in plasminogen or the overall fibrinolytic activity were found. Within “three to five days after delivery most parameters of the fibrinolytic system were normal again.”

In 1989, Estelles and colleagues (Blood 1989;74:1332-8) reported that women with severe preeclampsia in third trimester had significantly higher levels of PAI-1 than nonhypertensive women. Interestingly, PAI-2 levels were significantly lower in the preeclamptic women and a positive correlation between birth weight and PAI-2 levels was found (in other words, the higher the PAI-2, the greater the birth weight); and birth weight was inversely correlated with PAI-1 levels (higher the PAI-1 activity, the lower the birth weight). The presumption is that the lower PAI-2 levels correlated with a decreased placental mass or function in preeclamptic women. Regardless, the high levels of PAI activity in severe preeclampsia appear to be solely related to the increased activity of PAI-1. And, as many of our readers are aware, this might account in part for the coagulation abnormalities frequently accompanying the more severe forms of preeclampsia.

Unfortunately, these observations late in pregnancy don’t really tell us whether elevated levels of PAI-1 in preeclampsia are a cause, an effect, a response, or a contributor to the disease process itself. Based on several observations by other investigators, and the putative role of PAI-1 in placentation early in pregnancy (which we will eventually get to here), perhaps it is all the above. There does appear to be a genetic predisposition/association with abnormalities in PAI-1 production and later pregnancy complications. Yamada and colleagues (J Hum Genet 2000;45:138-41) evaluated the association between preeclampsia and deletion/insertion polymorphisms (4G or 5G) in the promoter of the PAI-1 gene. The 4G/5G polymorphism was assessed in 115 women with preeclampsia, 210 normotensive pregnant women and 298 nonpregnant controls. The frequency of the 4G allele (which results in increased production of PAI-1) and of 4G/4G homozygosity was significantly higher in the preeclamptic women than either the normal pregnant or nonpregnant controls, suggesting that the presence of 4G is one risk factor for preeclampsia and perhaps more severe manifestations of the disease.

Along the same lines, Glueck, et al. (Metabolism 2000;49:845-52) evaluated complications in 133 women with at least one pregnancy, and found a significant association of the 4G/4G PAI-1 polymorphism with prematurity, intrauterine growth restriction (IUGR), and “total complications of pregnancy” that was independent of the presence of other genetic thrombophilias (factor V Leiden, MTHFR C677T, and prothrombin G20210A mutations). In a subsequent study (Glueck, et al., Obstet Gynecol 2001;97:44-8), they reaffirmed the presence of the 4G/4G genotype as a risk factor for IUGR and extended their findings to include associations with severe preeclampsia, placental abruption, and stillbirth. They also reported that “the hypofibrinolytic 4G/4G mutation of the PAI-1 gene…is frequently associated with the thrombophilic factor V Leiden mutation” which would further increase the risk of problems related to clotting.

Over the years, PAI-1 made by vascular endothelial cells was found to be induced by angiotensin II which is produced by the action of the angiotensin I-converting enzyme (ACE). In a fascinating paper published in 2003, Xia and colleagues (J Soc Gynecol Invest 2003;10:82-93) reported that 18 of 20 women with severe preeclampsia were found to have IgG antibodies to the angiotensin II type 1 (AT1) receptor. None of 18 normotensive pregnant women had these autoantibodies. They also found that the serum from the same 18 of 20 women with these AT1 receptor autoantibodies stimulated PAI-1 secretion by trophoblasts (placental cells) in culture. Activation of the trophoblast AT1 receptors was also correlated with decreased trophoblast migration and invasion in tissue culture models and this, too, was directly correlated with PAI-1 production. We will return to this point in our subsequent discussion of the role of PAI-1 in recurrent early pregnancy loss. Bobst and colleagues (Am J Hypertens 2005;18:330-6) further reported that AT1 receptor autoantibodies found in preeclamptic patients stimulated PAI-1 (and the cytokine IL-6) production by human kidney (mesangial) cells in culture. Reversible ‘damage’ to the kidney is one of the events which characterize preeclampsia and the more severe the kidney impairment, generally, the more severe the preeclampsia with regard to hypertension and decreased urine production...(more to follow!)...

Labels: IUGR, PAI-1, preeclampsia, thrombophilias

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Plasminogen Activator Inhibitor-1 (PAI-1): Role in Adverse Pregnancy Outcome? - 1 - Introduction

In a post at the end of September, we summarized a series of questions from a 26 year old, otherwise healthy, reader who had had recurrent early first trimester pregnancy losses. Her ‘work-up’ to date had been relatively unremarkable, however, she was found to be a carrier for the plasminogen activator inhibitor-1 (PAI-1) 4G/4G polymorphism and her queries revolved around the possible role of PAI-1 polymorphisms in recurrent pregnancy loss (RPL), options for ‘therapy’, and the utility and safety of such therapy. In the last comment from her cited in that earlier post, she notified us that she had actually conceived again, but unfortunately, a few days later, she again miscarried. Is her PAI-1 polymorphism contributing to her early losses? To be honest with you, I don’t know at this point. I can think of other possibilities that may be just as likely, but her questions are very good ones, and it was well worth my time to look into the literature on the issue and perhaps draw some conclusions that may help her or another reader who is in a similar situation...

First of all, what is PAI-1? The best way to explain PAI-1 is to describe what it does. The blood clotting system is made up of many different factors, some which cause a clot to form and others which cause the clot to breakdown, and these coexist in a very delicate balance. When the blood clotting pathways are activated, fibrinogen, a soluble plasma glycoprotein, is polymerized to form fibrin which is then cross-linked by the action of factor XIII to form the ‘clot’. Under normal circumstances, as soon as a clot forms, it begins to be broken down by other plasma factors. Specifically, a substance called tissue plasminogen activator (tPA) converts an inactive plasma protein, plasminogen, to the active substance, plasmin, which then plays a critical role in the breakdown of fibrin (fibrinolysis), thereby ‘dissolving’ the clot. (Interestingly, and perhaps germane to our discussion at some later point, plasmin also plays important roles in ovulation, cell migration, and epithelial cell differentiation).

PAI-1 fits into this balance as the primary inhibitor of tPA and other ‘plasminogen activators’ in the blood. To put its role in perspective, by inhibiting tPA, PAI-1 prevents the activation of plasminogen, thereby controlling the rate and extent of fibrin degradation (clot break down, or fibrinolysis) that occurs. Overactivity of PAI-1 will therefore lead to a tendency to form (or maintain) clots and an underactivity will result in an increased risk for bleeding. (With regard to other known functions of plasmin mentioned above, overactivity of PAI-1 might then also impair ovulation, cell migration, and epithelial cell differentiation).

Control of PAI-1 production is complex, but it is at least partly determined on a genetic basis. Certain polymorphisms of PAI-1, 4G/4G and 4G/5G, are associated with increased blood concentrations of PAI-1. Elevated PAI-1 levels have been correlated with risk for both arterial and venous thromboembolic conditions (e.g., deep venous thrombosis, pulmonary embolism, and stroke) and atherosclerotic disease (.eg., coronary and carotid artery disease), especially if other genetic (e.g., factor V Leiden; prothrombin G20210A; MTHFR polymorphisms; protein C, protein S, and antithrombin III deficiencies) or inherited (e.g., antiphospholipid antibodies; lupus anticoagulant; anti-beta-1-glycoprotein) thrombophilias are also present. Individuals with insulin resistance syndromes and diabetes mellitus frequently have elevated PAI-1 levels. Obesity and hyperlipidemia are also associated with elevated PAI-1 and under certain circumstances, weight reduction and/or reduction in cholesterol and triglycerides, can lead to reduction in PAI-1 levels.

In our next post on this subject, we will begin to explore the possible association and mechanisms of PAI-1 activity with adverse pregnancy outcome and recurrent pregnancy loss…

Labels: PAI 1, pregnancy loss, thrombophilias

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Chromosomal Abnormalities and Multiple Gestations - 3

To bring those of you just jumping into this discussion up to speed, in our last two regular posts on the subject of “Chromosomal Abnormalities in Multiple Gestations,” we presented a case in which a 40 year old woman, who conceived twins by IVF after a long (and expensive) history of infertility, presented at 20 weeks for a ‘targeted’ ultrasound and was found to have one of the babies with multiple congenital anomalies. Subsequently, it was determined by amniocentesis that the baby with abnormalities had trisomy 18, confirming our initial clinical suspicion. Despite recommendations by her infertility doctors and her regular physicians, she had declined any assessment of the babies for chromosomal abnormalities earlier in the pregnancy. The other baby appeared perfectly normal and did not have chromosomal studies done. Her case is presented, because as the number of women delaying childbirth increases, as does the dependence of older women on infertility services for conception, this situation is becoming much more common. To have waited so long, and been through so much for a pregnancy, to have shared the excitement of a multiple gestation with friends and family, and then to be put in the position of having to deal with the emotions, and sometimes hard decisions, related to one “normal” baby and one baby with complications, can be extraordinarily difficult and at times quite devastating.

In the current case, our patient was told the baby had trisomy 18 on the basis of the rapid (FISH) studies that were done, but she elected to wait until the final fetal karyotype, based on the standard culture technique, was completed before she returned to discuss “where do we go from here.” At the time of that return visit, she was now about 23 weeks. Before performing another ultrasound, we reviewed the poor prognosis for babies with trisomy 18 – many will die in utero and most who don’t, succumb shortly after delivery. She asked if there was anything we could do to help the baby at this point, or to improve his chances for survival and quality of life and we told her that there wasn’t. She asked if this baby was lost in utero if that could deleteriously affect the outcome for the other baby and, without going into details here, she was told that it could, but that the prognosis for the healthy baby should be fairly good, if that occured, because the twins were dizygotic (from completely different eggs) and had completely separate placentas.

In the same breath, however, I told her that sometimes survival of an abnormal baby in multiple gestations actually jeopardizes the pregnancy. She looked at me quizzically and I went on to explain with several examples of women under similar circumstances (advanced maternal age; infertility; IVF pregnancies; multiple gestations) who had twins (or more) with one or more babies with chromosomal abnormalities in which the healthy babies were put at risk as the result of complications arising due to the abnormal babies. Babies with Down syndrome, for example, often have upper bowel obstructions, such as duodenal atresia, that result in the inability of the baby to return fluid wastes to the mother for disposal. As the result, excessive amniotic fluid accumulates around the baby (polyhydramnios), the uterus becomes overdistended, and premature labor and/or premature rupture of membranes can ensue. Similarly, babies that are severely growth restricted (whether or not they are chromosomally abnormal) increase the mother’s risk of developing preeclampsia that may also necessitate early delivery, thereby putting an otherwise healthy sibling at risk for complications of prematurity.

At that point, it was clear we had hit a nerve. “Oh,” she said, “I guess that would be a good reason to consider finding out early with twins if one of the babies has a chromosome problem ...” “That’s one reason,” I said, “and there are lots of others…Some people use the information to prepare for pregnancy complications and to gather information and support for their deliveries, some elect to have ‘selective termination’ of the chromosomally abnormal fetus, and others elect to terminate their entire pregnancies. What I have found is that most people do NOT know what they would do with the information before they actually have it! No matter what they bring to the table, they just do not know…and you know what? We don’t tell them what to do either…”

With regard to this discussion, recently, I received the following comment from a reader…

Thanks for putting so much effort into a fascinating and endlessly informative blog!

How reliable is the screening for multiple gestations? Isn't beta-HCG elevated in that case? Or is there sufficient info in the database on twins, triplets, etc. that the differences can be taken into account and reliable estimates of risk can still be made?

The query above is about the usefulness of first trimester screening for aneuploidy in the evaluation of multiple gestations. Its timing coincides nicely with the clinical situation we have been discussing and, indeed, was a point of conversation between the patient and me when she finally returned for follow-up and it was another impetus for this brief series on chromosomal abnormalities in multiple gestations.

As we have discussed previously, the basic approach to first trimester screening for aneuploidy involves a risk calculation based on a combination of fetal measurements (crown-rump length and nuchal translucency-NT), maternal serum screening for free beta hCG (pregnancy hormone) and PAPP-A (pregnancy-associated plasma protein-A), and pertinent ‘demographic’ information that is generated by comparison to a large database of other patients. Using this, the overall detection of Down syndrome (trisomy 21) and trisomies 18 and 13 in singleton pregnancies is in the range 90% with a false-positive rate of about 5%. Other chromosomal abnormalities may also be detected using this approach, but not as reliably. Thus, one shortcoming of first trimester screening is that it does not alert us to the risk of all chromosomal abnormalities. When cystic hygromas are found during the course of this evaluation, more than 50% will have some form of chromosomal abnormality.

Spencer in 2000 (Prenat Diagn 2000;20:91-5) analyzed the distribution of free beta-hCG and PAPP-A in 159 twin pregnancies and compared that to 3466 singleton pregnancies and found “on average free beta-hCG values are 2.099 times greater in twins than in singletons and PAPP-A some 1.86 times greater.” Using NT measurements and these results to provide statistical correction for these biochemical markers in the risk calculations for twin pregnancies, he estimated detection rates for Down syndrome in the range of 80%, which was higher than for using the NT measurements alone. In a subsequent study (Prenat Diagn 2001;21:715-7), he demonstrated the validity of the risk correction algorithm in both monochorionic and dichorionic twin gestations. In a summary of studies to date, Bush and Malone (Clin Perinatol 2005;32:373-86) concluded that “the best available data (based on modeling) show approximately 75-85% detection rates for Down syndrome, with a false-positive rate of 5%.” Thus, in the case of twins, it would appear that combined first trimester screening can be used reliably to assist women in their decisions regarding the options for additional fetal evaluation (screening and diagnostic). At this point, there is probably insufficient data to extend that reliability to higher order multiples, but fortunately, we do not have to deal with them that often as our Reproductive Endocrinology colleagues have become more efficient (and more cautious) in their efforts to achieve fertility!

Labels: aneuploidy screening in first trimester, Multiple gestations, twins

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Grand Rounds 4.5 at Pallimed!

Many thanks to Dr. Christian Sinclair at Pallimed for the efforts put into the organization and content of this week's Grand Rounds 4.5. Great job and wonderful reading! Thanks for the flattering comments and for including a link to my post on "Retinal Arteriole Occlusion in Early Pregnancy." We are never too old to learn from our patients!

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Chromosomal Abnormalities and Multiple Gestations - 2

…After talking with one of our genetic counselors, I went back into the room (see previous post). By this time, they had both used some tissues and were ready to talk more. They agreed to see the counselor and we walked across the hall to her office. (We are blessed with great genetic counselors). Over the course of 30-40 minutes, she explained ‘nondisjunction’ as the cause of increased risk for chromosomal abnormalities with advancing age, the actual risk for aneuploidy in midtrimester at age 40 in singleton (1/75 for Down syndrome; 1/44 for all aneuploidy) and twin pregnancies (about twice these risks that one of the babies will be abnormal in twins from different eggs), the diagnostic procedures that could be done to confirm the diagnosis, the benefits of knowing if the baby has a chromosomal abnormality with regard to decision-making during and after the pregnancy, and specific information with regard to the presumptive diagnosis of trisomy 18.

The patient was then asked if she wanted an amniocentesis and both she and her husband agreed that, based on what we had told them, they needed to know if the baby had a chromosomal problem, even though “we only want the procedure done on the baby that appeared abnormal.” (I wish I could accurately portray here the skepticism that was conveyed in the way the word “appeared” was inflected, but never being one to take away all hope, I just let it slide). I told them that under the circumstances, that was a very reasonable request. The normal ‘growth and appearance’ of the other baby probably reduced her risk for a chromosomal abnormality by as much as 90%. The procedure was then explained to them, including the small risks, and a consent was signed. As I always do under these circumstances, I made it quite clear that if the baby was lost following the amniocentesis, it would be much more likely due to the condition of the baby rather than to the procedure itself. She nodded that she understood. When asked if they had any questions, the only query was the inevitable, “I heard these things are awful…does it really hurt.” Welcoming the query, I gave her my patented reply that “it is going to be the most painful thing you have ever been through in your entire life and the large nurses in the room are here to hold you on the table.” She smiled and we did the procedure without any complications.

The amniotic fluid was sent for fetal karyotype studies by both fluorescent in situ hybridization (FISH) and routine culturing techniques. She was offered the FISH and told that a ‘presumptive diagnosis’ could be back within 48-72 hours and the routine culturing studies (results available in 10-14 days) could be used to confirm the FISH results and/or identify other chromosomal abnormalities not detected by the FISH assays; and, she readily accepted this approach. We would notify her directly as soon as any results were back and arrange for her to return to discuss the findings and options for follow-up depending on the diagnosis and her own needs.

A few days later, unfortunately, but as expected, the baby’s karyotype by FISH came back as 47XY,+18 (trisomy 18). When she was called, her immediate response was, “Some friends told me the FISH has lots of false-positives, so the baby could still be all right, right? Don’t we have to wait for the final results of the cultures?” Again, not to mince words, I told her that it was very unlikely the cultures would change the FISH results. In fact in 20 years, I have not seen a single FISH diagnosis of aneuploidy be overturned by the culture technique (although I have seen ‘negative’ FISH studies in circumstances where the final results demonstrated a chromosomal abnormality not included in the FISH profile). The silence that followed was deafening, and the crying that followed that was heartbreaking, but when she finally asked between tears, “Where do we go from here?,” I knew we were going to be alright. “Why don’t you come back to talk with us when you are ready; we’ll work you in on a moment’s notice if necessary…”

Labels: amniocentesis, aneuploidy, chromosomal abnormalities, FISH, trisomy 18, twins

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Chromosomal Abnormalities and Multiple Gestations - 1

In our practice, we see many cases of multiple gestations (mostly twins and not more, thank goodness) that come about as the result of the success of our colleagues in Reproductive Endocrinology and Infertility (REI). In general, these patients tend to be older, have underlying medical problems, and are at greater risk for a wide range of complications during pregnancy including diabetes, pregnancy-induced hypertension, cervical incompetence, and premature labor and delivery. Their pregnancies are also at greater risk for babies with congenital birth defects and chromosomal abnormalities beyond the typical risks associated with “advanced maternal age.”

Recently, we were asked to perform a “targeted ultrasound” to assess fetal growth and anatomy on a set of IVF twins in a 40 year old woman (who had had many years of primary infertility) at about 20 weeks gestation. After conception, and documentation of fetal viability by our REI group, she reestablished care in the office of her usual OB/GYN providers. Because of her age, the option for aneuploidy screening was discussed with her by our REI docs even before she left their care and apparently again once she crossed the threshold of her private doctors’ office. Her response of “What would I do about it anyway?” is one that I have heard too many times before to mention, but it usually leads to an immediate cessation of information exchange between patient and busy provider. I am sorry to say, I have come to realize that this is more related to denial mechanisms on the part of both patient and provider rather than a true lack of desire for information. Regardless, as part of her scheduled visit with us, a pre-ultrasound genetic counseling session was offered and also declined.

During the course of her ultrasound, it became readily apparent we had problems that required discussion. The baby girl was perfectly normal in size for her well-documented gestational age and had absolutely no visible gross abnormalities or soft markers for a chromosomal abnormality. The little boy, on the other hand, was two weeks behind in size, symmetrically ‘growth-restricted’, had intracranial abnormalities, micrognathia (small and recessed chin), and a complex congenital heart defect. The babies’ abdomens, side-by-side, were so strikingly different in size that the patient herself immediately recognized the difference and sat bolt upright in the bed the minute the image was displayed on the overhead monitor. “What’s wrong with my babies,” she asked? “Is this the twin-to-twin transfusion syndrome I have been reading about on the internet?”

In my position, the ‘buck stops here’, so I am not much for mincing words. I explained to her that her baby girl was normally grown and appeared to have no visible abnormalities. There was no evidence of a twin-to-twin transfusion sequence and that would be extraordinarily uncommon in babies from separate eggs, different genders, and completely separate placentas. Then I detailed the findings of her little boy. Before I could tell her why I thought the baby had these abnormalities, she interrupted and asked, “Can they be fixed inside or do we have to wait until after delivery?” It was at this point that I told her that it was very unlikely they could be fixed because the baby probably had a severe chromosomal abnormality – trisomy 18 – and was at high risk of either not surviving the pregnancy or dying shortly after birth. “How can that be?” she asked, “No one in my family has that or has ever had a baby with that kind of problem?”

“I’m sorry,” I said, “But this is something that you had no control over. The same conditions that increase your risk with age for having a baby with Down syndrome (trisomy 21), a process called nondisjunction, also can result in babies with other chromosomal abnormalities.” It was at this point that I saw in the dimly lit room, her husband, who had been completely silent to that point, gently sobbing in his chair. I picked up the ever-present box of tissues, walked around the examination table to him, held his shoulder, and told both of them that “I have just given you an awful lot of information. I am going to leave you alone for a few minutes and then we can talk some more. I would like to see if our Genetic counselor can spend a few minutes with you too….”

Labels: aneuploidy, Multiple gestations, trisomy 18

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Retinal Arteriole Occlusion in Early Pregnancy

The comment below was left on a recent post regarding "Readers' Questions Related to MTHFR Polymorphisms." The reader presents a very unusual complication early in her first pregnancy - retinal arteriole occlusion - and the response to her query does not have a ready answer, but it sure was fun to try to come up with one!

I'm now pregnant with my first child. At 9 weeks I developed an arteriole occlusion in the retina of my right eye with some vision loss. My OB did quite a lot of testing and I was found to be positive for homozygous MTHFR. My homocysteine level (not fasting) was normal and my doc doesn't think I need Lovenox or Heparin. I'm on baby aspirin alone but questioning if I should be on additional therapy or seek a second opinion. Any suggestions? Of note, I'm an otherwise healthy 29 year old with no history of lost pregnancies or other clotting problems.

One of the hardest things about responding to a question like this from afar is inadequate information and the inability to question the patient in person and to perform an adequate examination. The obvious concern is why did a “healthy 29 year old” pregnant woman develop occlusion of a retinal arteriole to begin with. We are told that she had “quite a lot of testing done” but without knowing what tests were done, it is hard to know what other tests should be done so that our reader’s question might be best answered.

Retinal arteriole occlusions are most common in older individuals, typically in their 70’s, and in that group, they are usually the result of embolic events – most often cholesterol emboli from atherosclerotic disease in the aorta or carotid arteries, calcific emboli from valvular disease in the heart or atheromatous plaques, and platelet/fibrin emboli from foci of thrombosus in the heart or vascular tree. It has been estimated that less than 1 in 50,000 patient visits to an ophthalmologist will be for the indication of retinal arteriole occlusion in someone less than 30 years of age (Greven, et al., Am J Ophthalmol. 1995;120:776-83).

Indeed, causes of retinal arteriolar occlusion in younger folks are typically NOT related to embolic events, although there are still circumstances when they still can be. Conditions that may increase the risk in this age group include sickle cell hemoglobinopathies, smoking, diabetes, hypertension, genetic and acquired thrombophilias (e.g., antiphospholipid antibodies, lupus anticoagulant, anti-β-2-glycoprotein-1, factor V Leiden, antithrombin III deficiency, protein C and S deficiencies, prothrombin mutation, hyperhomocysteinemia, and, perhaps MTHFR polymorphisms and plasminogen-activator-inhibitor-1), hyperlipidemia, cocaine and IV drug use, cardiac arrhythmias (e.g. atrial flutter) and valvular disease (e.g., bacterial endocarditis), hyperviscosity syndromes, as well as pregnancy and use of hormonal contraceptives. Other conditions that should also be considered are HIV infection, use of certain herbal products and prescription medications such as sildenafil citrate (Viagra) to increase libido, Behcet’s disease, and a host of less common infectious/inflammatory diseases. A history of migraine headaches is also very common among younger women who develop retinal arteriole occlusion.

So the first thing we need from our reader is a very good history, including family, dietary, and social, to query for risk factors and to select for further evaluation from the myriad of possible causes for this condition in women of her age detailed above. She needs a thorough physical exam with blood pressure, cardiac, vascular, and ophthalmologic evaluation, the latter of which she most likely has already had. Serious consideration should be given to both an electrocardiogram (or Holter monitoring) and an echocardiogram to evaluate the rhythm and structure of her heart. Unless some other physical finding such as carotid bruits dictate, carotid Doppler studies are probably unnecessary at her age. Consideration should be given to screens for syphilis (remember, false-positive results are associated with thrombophilias), general autoimmune disease (e.g., ANA, rheumatoid factor), selected genetic and acquired thrombophilias (choose from above!), homocysteine (although if she is on supplemental folic acid, or was at the time her initial homocysteine level was performed, this will probably be 'normal'), complete blood count with platelet count, hemoglobin electrophoresis, diabetes, lipid profile, HIV, and perhaps even blood cultures for bacteria that might be associated with endocarditis and valvular disease.

Interestingly, despite the association of the thrombophilias with venous and arterial thromboembolic disease, I am not aware of any good study that has correlated MTHFR polymorphisms (even in the homozygous state) with retinal arteriole occlusion. Lowenstein and colleagues (Am J Ophthalmol. 1997;124:840-41) were the first to demonstrate the presence of the MTHFR C677T polymorphism in a patient who presented with retinal vein occlusion. In a subsequent study (Ophthalmology 1999;106:1817-20) they reported that among 59 patients with retinal vein occlusions, 44% were heterozygous and 11% were homozygous for the same polymorphism. Around the same time, Saloman and colleagues (Blood Coagul Fibrinolysis 1998;9:617-622) reported an association between MTHFR C677T homozygosity and retinal vein occlusion in 102 patients (OR 1.9; 95% CI 0.95-3.81). However, a retrospective study of 174 patients in Ireland demonstrated no association between MTHFR homozygosity and either retinal vein or arterial occlusive disease (Cahill, et al., Br J Ophthalmol 2001;85:88-90). I am also unaware of any studies that indicate elevated homocysteine levels are associated with retinal arterial occlusion. Indeed, one study from Scandinavia found no association of either the MTHFR C677T polymorphism or homocysteine levels among 116 patients even with retinal vein occlusion (Larrson, et al., Acta Ophthalmol Scand 2000;78:340-343.

So, how do we counsel our reader. I suppose if nothing other than the homozygous MTHFR C677T polymorphism is found, most likely the baby aspirin, supplemental folic acid and prenatal vitamins may be adequate therapy. If some other risk factor is found upon subsequent evaluation, then her treatment should be adjusted accordingly. Admitting our limitations in current medical understanding due to the ‘unknowns’ that might have led to her retinal arteriole occlusion, and since this is such an unusual condition in young women, her pregnancy should be followed very carefully for evidence of complications related to abnormalities of placentation. Remember, thrombophilias in particular are associated with intrauterine growth restriction, fetal loss, pregnancy-induced hypertensive disorders, and early delivery.

I would suggest she have maternal serum screening done at 16 weeks, a ‘targeted sonogram’ at about 20 weeks, and a follow-up assessment of fetal growth and Doppler flow studies at 26-28 weeks. Understand, there is no standard of care here, but such an approach might help anticipate fetal complications and, thereby, allow for antepartum testing that might reduce her risks for an untoward outcome. She must also be made aware that retinal arteriole occlusion is associated with long-term risks for both cardiovascular disease and stroke and if she does have an underlying thrombophilia as the cause, other thromboembolic complications.

Thanks to our reader for sharing her story and for a most challenging question!
Dr T

Labels: MTHFR, retinal arteriole occlusion, thrombophilias

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Thanks Adam for Grand Rounds 4.04!

Thanks to Adam at NY Emergency Medicine for hosting this week's Grand Rounds 4.04. Love the pictures! And, no, the handsome guy next to the paragraph with my link is not me! If I looked that good, I'd be impossible to live with. While we are on subject, the topic of "Obstetrical Ultrasound and Lefthandedness" may not seem like an 'emergency issue' and it isn't, but then again, I'm not a pregnant woman walking in for my first ultrasound either, so thank you so much for including me anyway! Just wish after 25 years and 100,000+ scans that I would have improved my left-handed dexterity - just a little. Cheers, and go check out Grand Rounds 4.04.

Labels: grand rounds, nyemergencymedicine

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Concerns Regarding Methotrexate Therapy

In a recent post we discussed "A Complication of Methotrexate Use for Ectopic Pregnancy..." and in response to that post we had several excellent questions from our readers. The queries below should be of general interest to many women who undergo methotrexate therapy either for ectopic pregnancy or for other medical conditions, such as autoimmune or neoplastic diseases, that are not uncommon in women of childbearing age…

Hi Dr. T. I've been given conflicting answers by different gynecologists and rheumatologists in regards to methotrexate "wash out period" and pregnancy and frankly, I'm worried. Some say it's safe to get pregnant 3 months post methotrexate others say 4-6 months. Here's my scenario: I've been on methotrexate 25mg sc weekly dose, last dose being June 28, 2007. My LMP (last menstrual period) was Sept 8, 2007, and I just found out I was pregnant yesterday. Although it's been almost 4 months since my last dose of methotrexate, I'm very concerned about my child’s risk of teratogenicity. What are the chances of this happening? What would the best course of action be? Also, would folinic acid help, in my case, to decrease the chances of birth defects? Thanks

Chances are you will be just fine. When methotrexate is given by injection, peak serum concentrations are reached within 30-60 minutes. The drug is metabolized by the liver and excreted, mostly, by the kidneys. The half life ranges between 3 to 15 hours depending on the dose, chronicity of therapy and, obviously, liver and kidney function. Methotrexate does have some metabolites that may hang around “for an extended period of time” but the general consensus is that it is “safe” to get pregnant after at least one complete ovulatory cycle following the last dose. In your case, you are well beyond this recommended period and are, therefore, probably at no greater risk for fetal malformations than either the general population or other predisposing risk factors you and your partner bring into the pregnancy. There is no need for folinic acid, but since methotrexate is an antagonist of dihydrofolate reductase, I hope you started supplemental folic acid before conception and, if not, get some today! If you have regular cycles and your LMP was September 8, your baby’s neural tube should be closing even as we speak, and there probably is still time to decrease the risk for certain congenital heart defects! Best of luck to you and thanks for reading…
Dr T


Hello Dr. My question is regarding what is considered normal for betaHCG levels following MTX treatment for my ectopic pregnancy. On October 2, I was admitted to the hospital with abdominal pain and slight bleeding for the two weeks prior (last period was Aug 24). Tested positive for pregnancy with beta-hCG level at 960. Ultrasound showed nothing in the uterus. Beta-hCG tested again on October 5 was 1544 with ultrasound showing a small (1.1cm mass) in the right cornua (still nothing in the uterus). Beta-hCG tested on October 6 was 1797. Referred to OBGYN at ER for MTX treatment for ectopic pregnancy, for which an injection of 50mg was given same day (my weight 49.8kg). Beta-hCG tested on 10/10 was 2040 and I have not had the pain and abdominal cramping my Dr had prepared me for. My question is whether it is normal for the beta-hCG level to continue rising 4 days after MTX injection? Shouldn't it be falling? Scheduled for another blood test on October 13 but I was wondering when I should be worried that the MTX treatment is not working? I am 25 years old and would like to conceive in the next few years; thus, I would like to preserve both my tubes if possible and avoid surgery. Thank you kindly for your time and consideration.

This is an excellent question. You would certainly be a good prognosis candidate for methotrexate therapy with your relatively low hCG levels and no evidence of rupture or of an embryo with cardiac activity. Various studies have followed the course of hCG and progesterone over time after methotrexate administration for ectopic pregnancy. One study out of Brazil (Elito Junior, et al., Rev Assoc Med Bras. 1998;44:11-5) demonstrated an increase in beta-hCG titers between days 1 and 4 in 50% of women following methotrexate therapy. However, more than 85% of women had a decline of at least 15% by day 7. These findings were confirmed in a more recent study by Gabbur and colleagues (Am J Perinatal 2006;23:193-6). So what you described in your case is not at all unusual. Most studies demonstrate that it takes a mean of about 4 weeks before hCG levels become undetectable. Serum progesterone levels drop more quickly than hCG levels and some investigators have suggested using this as another parameter to predict the success of methotrexate therapy for ectopic pregnancy (Saraj, et al., Obstet Gynecol. 1998;92:989-94). Thank you for your question and I hope things turn out well for you!
Dr T

Labels: Ectopic pregnancy, methotrexate therapy

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Fever in Pregnancy

The same reader who asked if obstetrical ultrasound caused babies to be left-handed also wanted to know if fever during early pregnancy could hurt her baby. As is so much in this business, the answer, of course, is not straightforward. The simple answer is yes, but without qualifying that affirmative, I am sure that many pregnant women would be cast into an unnecessary panic. Any source of maternal hyperthermia - fever, hot tubs, saunas, electric blankets, excessive sun or other environmental exposure, and hyperthermia-inducing activities – that results in significant core temperature increase (generally considered to be above the threshold of 38.9 degrees C) could potentially affect the baby, but the consequences of hyperthermia depend on the extent and duration of the temperature elevation, the timing of the exposure with regard to fetal development and, perhaps, maternal nutritional status (e.g., folic acid), concurrent medical problems, medications, genetic background and, I am sure, many other factors.

Professor Marshall J. Edwards at the University of Sydney, Australia, is generally considered to be the individual who pioneered the discovery that maternal hyperthermia during pregnancy can be teratogenic (Birth Defects Res A Clin Mol Teratol. 2005;73:857-64). In animal studies over the course of 40 years, Edwards demonstrated that mechanisms for hyperthermia-induced fetal damage included “cell death, membrane disruption, vascular disruption, and placental infarction…” Modest elevations in temperature prior to implantation and more sustained elevations during early embryogenesis may cause fetal death and abortion. Embryos surviving maternal hyperthermia during early development are at risk for a host of congenital anomalies, including neural tube and central nervous system (CNS), micrencephaly, microphthalmia, cataracts, craniofacial, heart, renal, dental, and abdominal wall defects among others.

The most common cause of hyperthermia during pregnancy is fever related to viral illnesses (and other common causes include bacterial infections associated with pyelonephritis, tonsillitis, and appendicitis). Since we are heading into the cold and flu season, women who are either anticipating or already are in the early stages of pregnancy, should be especially cautious (start taking your folic acid now!). Over the years, several studies have confirmed that temperature elevations in pregnant women accompanying influenza and common cold virus infections are associated with greater risk for congenital anomalies, multiple and isolated, especially, neural tube defects.

A meta-analysis of 15 separate studies by Moretti and colleagues (Epidemiology. 2005;16:216-9) included 1,719 cases and 37,898 controls and found an overall odds ratio for neural tube defects associated with maternal hyperthermia of 1.92 (95% CI = 1.61-2.29). Acs and colleagues (Birth Defects Res A Clin Mol Teratol. 2005;73:989-96) evaluated 22,843 newborns or fetuses with congenital anomalies and 38,151 matched controls and found “there was a higher prevalence of maternal influenza during the second and/or third month of pregnancy for the group of newborns with cleft lip +/- palate (adjusted prevalence odds ratio (POR), 3.2; 95% CI, 2.0-5.3), neural tube defects (adjusted POR, 1.9; 95% CI, 1.1-3.3) and cardiovascular malformations (adjusted POR, 1.7; 95% CI, 1.3-2.3).” They also concluded that “a direct teratogenic effect from influenza viruses appears unlikely” and the higher prevalence of congenital anomalies “can be explained mainly by fever, because this risk was reduced by the use of antifever drugs.” These same congenital defects have been found at a higher prevalence in women with folic acid deficiencies and aberrations of folate metabolism, such as those associated with polymorphisms of methylene tetrahydrofolatereductase (MTHFR), so it was most interesting to see that the authors found that “periconceptional folic acid supplementation also showed some preventive effect…”

One other study worth mentioning, conducted by Suarez and colleagues (Birth Defects Res A Clin Mol Teratol. 2004;70:815-9), is interesting because it looked not only at febrile illnesses, but other causes of maternal hyperthermia as well. They studied a population of high-risk Mexican-American women who lived in 14 Texas counties bordering Mexico. To quote their results, the odds ratio (OR) “associated with maternal fever in the first trimester, compared to no fever, was 2.9 (95% CI, 1.5-5.7). Women taking fever-reducing medications showed a lower risk effect (OR, 2.4; 95% CI, 1.0-5.6) than those who did not (OR, 3.8; 95% CI, 1.4-10.9). First-trimester maternal exposures to heat devices such as hot tubs, saunas, or electric blankets were associated with an OR of 3.6 (95% CI, 1.1-15.9). Small insignificant effects were observed for activities such as cooking in a hot kitchen (OR, 1.6; 95% CI, 1.0-2.6) and working or exercising in the sun (OR, 1.4; 95% CI, 0.9-2.2).”

In closing, I would also like to point out that although the period of early fetal development carries the greatest risk from maternal hyperthermia, severe temperature elevations during the second and third trimesters may still put the baby at jeopardy, particularly for CNS damage, and might be responsible for some cases of behavioral and developmental compromise and even more severe neurological conditions, such as schizophrenia, autism, and cerebral palsy. In my experience as well, high fever associated with both viral and bacterial illnesses in late second and third trimester also dramatically increases the risk for subsequent premature labor and delivery and may precipitate preeclampsia!

Labels: birth defects, fever, folic acid, hyperthermia, neural tube defects, teratogenesis, viral infections

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Obstetrical Ultrasound and Lefthandedness?

In our last post, following a distraught patient’s request and one of our own reader’s queries, and at the risk of putting myself out of a job, we began to address the issue of safety of obstetrical ultrasound procedures for the developing baby. I will admit at the outset, that I do not know. We have used ultrasound in obstetrics for 40+ years throughout its remarkable evolution of technological advances. There has been, and currently is moreso, widespread use of ultrasound beginning in early first trimester (sometimes with multiple early scans during the critical periods of embryogenesis) and throughout pregnancy and yet there are no convincing reports (to date) of specific, reproducible, visible, physical birth defects associated with its use.

The overall impression has been and continues to be, in the eyes of patients and providers, that ultrasound is, generally, safe and the potential benefits of ultrasound-based procedures far outweigh the small risks and the downsides of other options currently available for fetal evaluation. But, it is also true that over the years, despite the fact that most babies don’t lose their fingers, toes, or genitalia following ultrasound procedures, questions have been raised about the possibility of more subtle ‘bioeffects’ of even the low-level ultrasound intensities used in B-mode scanning. Hence the question of our astute (and most loyal!) reader regarding lefthandedness and ultrasound exposures.

The first study of which I am aware that raised the issue of an association between ‘lefthandedness’ and in utero ultrasound exposure was published in 1993 by Salvesen and colleagues (BMJ 1993;28:159-64). This study reported the follow-up of 2161 eight and nine year old children whose mother’s participated in two randomized, controlled trials of routine ultrasonography during pregnancy in Norway from 1979-1981. Using questionnaires and an abbreviated version of the Denver developmental screening test, handedness and developmental milestones in this cohort of children were retrospectively assessed. Although they found “no clear differences…between the groups with regard to deficits in attention, motor control, and perception or neurological development during the first year of life,” they did find that the odds of lefthandedness “were higher among children who had been screened in utero than among the control children (odds ratio 1.32; 95% confidence interval 1.02 to 1.71). The authors were fast to point out, however, that even though their data suggested a “possible association…the observed results may be due to chance.” A subsequent report by this same group (Salvesen, et al., Ultrasound Obstet Gynecol 1999;13:241-6) presented a metaanalysis of two follow-up studies from their three randomized (ultrasound vs no ultrasound) trials of 4715 children and concluded that “there was no statistically significant difference in the presence of non-right handedness between the ultrasound-screened children and the controls, but there was a statistically significant difference…among the boys.” Again, they stated “the results …must be interpreted with caution.”

A subsequent study out of Sweden (Kieler, et al., Epidemiology 2001;12:618-23) looked at a cohort of men born between 1973 and 1978 and estimated relative risks for being born left-handed according to in utero ultrasound exposure. Risk estimates were based on 6,858 men born in hospitals “that included ultrasound scanning in standard antenatal care (exposed) and 172,537 men born in hospitals without ultrasound scanning programs (unexposed).” They found no differences between the groups during the early years (1973 to 1975) of ultrasound use, but “when ultrasound was offered more widely (1976 to 1978; multiple scans during pregnancy), the risk of left-handedness was higher among those exposed to ultrasound…(odds ratio = 1.32, 95% CI = 1.16-1.51).” Such a study cannot be completely ignored but, even if compelling by virtue of the number of individuals evaluated, it suffers from the faults of any retrospective analysis. For example, not analyzed is the ‘handedness’ and socioeconomic status of the parents of the children born at the different centers; nor are the indications for birth at an ‘ultrasound center’ adequately differentiated from those indications for birth at centers that did not have ultrasound.

Yet to be adequately explained is why this difference only was found in the subgroup of randomized males and not in the entire population of ‘exposed vs nonexposed’ children (Kieler, et al., Early Hum Dev 1998;50:233-45). It should also be noted that subsequent studies by this group involving 3,265 eight to nine year old children whose mothers participated in a randomized (ultrasound vs. no ultrasound) study between 1985-1987 showed no significant differences in behavioral disorders or impaired neurologic development (Kieler, et al., Obstet Gynecol 1998;91:750-6), nor in abnormalities of childhood growth, hearing, or vision (Kieler, et al., Br J Obstet Gynaecol 1997;104:1276-72). Furthermore, when Kieler and colleagues (Epidemiology 2005;16:304-10) focused on men born in Sweden between 1973 and 1978 and broke this down into ultrasound exposed (N = 7998) vs unexposed (N = 197,829) individuals enrolling in military service between 1991 and 1996, they “failed to demonstrate a clear association between ultrasound scanning and intellectual performance.”

To my knowledge, the only other group that has systematically evaluated ultrasound exposure and childhood outcome is that of Newnham’s in Western Australia. In their first study (Newnham, et al., Lancet 1993;342:887-91), they randomized women with singleton pregnancies at 16-20 weeks to receive either a single scan (18 weeks) or 5 scans (18, 24, 28, 34, and 34 weeks) with the latter including continuous-wave Doppler flow studies (higher intensity and longer ultrasound exposure). Interestingly, they found a higher rate of intrauterine growth restriction at both < 10th (RR = 1.35; 95% CI 1.09-1.67; p = 0.006) and < 3rd (RR = 1.65; 95% CI 1.09-2.49; p = 0.020) centiles. However, a follow-up study of these infants (Newnham, et al., Lancet 2004;364:2038-44) demonstrated no differences in physical size by age 1 and thereafter, and more importantly, no differences in “standard tests of childhood speech, language, behaviour, and neurological development.”

In summary, based on the relative risks estimated in the Swedish and Norwegian studies, males exposed to ultrasound in utero in the 1970’s and early 1980’s have a 32% greater chance of being lefthanded than those who were not. To translate this into real numbers and put the results in perspective, these results suggest that about one in 50 ultrasound-exposed males who were expected to be born righthanded came out lefthanded. Is this simply the result of chance? Is it the result of differences in the demographic characteristics of the children who were more likely to be exposed to ultrasound? Is it the result of subtle brain damage? Is it the result of some form of ‘reprogramming’ of the genetic predisposition to lefthandedness? The bottomline is, we do not know! If brain damage is a concern, the follow-up studies have not clearly shown a more global effect on behaviour and neurodevelopment.

Should we brush these results off and resume a cavalier stance toward ultrasound imaging during pregnancy? Absolutely not! As the number and intensity of ultrasound-based procedures has increased across all socioeconomic groups, we should be especially vigilant for adverse outcomes. But, I must admit, I am grateful for our reader and patient who piqued my interest in this subject, because I have come away from this review feeling much more comfortable about what I do every day and about the admonition of primum non nocere!

Labels: lefthandedness, obstetrical ultrasound and safety

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Obstetrical Ultrasound - A Sinister Cause for Concern?

A few weeks ago, a patient was sent to me for consultation with the new diagnosis of gestational diabetes detected at the time of routine screening at 26 weeks. After reviewing her history and performing a limited physical exam, I proceeded with my oft-repeated spiel about gestational diabetes, diet, self-monitoring, and the expectations for, and importance of, tight glycemic control. I gave her the prescriptions for a glucometer and test strips, told her we would see her back in a week, and left her with our nurse to review the protocol for using the glucometer and reporting her blood sugar results to us.

A few minutes later, our nurse came out of the room to tell me that the patient was VERY upset. Now, in our business, it is not at all unusual to discuss a pregnancy complication with a patient who maintains a stoic face throughout the discussion and then falls apart when left alone with the nurse, but I was a little surprised in this case because I thought the conversation had gone well, the condition was not serious, the baby was fine, and the patient herself had smiled and expressed gratitude for the clarity of the discussion. “It’s not what you think,” the nurse told me, “She wants to know why we didn’t do another ultrasound today because she always has one done at each of her OB visits in her doctor’s office...”

I had just reviewed her records, I knew she had had multiple ultrasounds performed in her provider's office, the most recent being just a few days before her visit with me, and according to her report and the office notes, “the baby was growing well and had no problems.” Now, you have to understand, as a specialist in Maternal-Fetal Medicine, much of my kids’ college educations are going to be funded by the many ultrasound-based procedures we perform on a daily basis. However, as part of my devotion to the admonition primum non nocere (above all, do no harm), I have always considered myself rather conservative in the number of ultrasound studies I perform and rarely will do one without some clinical indication. So, there was something that made me very uncomfortable about her request. And, to be honest with you, part of that discomfort was fueled by a recent query from one of our readers who asked me if it was true that ultrasound increased the risk that her baby would be lefthanded (we will return to that question in the next post).

Primum non nocere reminds us that we must consider the possible harm that any intervention might cause and that human acts with good intentions may have unwanted consequences. Although I do not have the statistics to back this up, I would wager that more than 80% of pregnant women in the U.S. today will have one or more ultrasounds done during their pregnancies. And this is not the first patient who has told me that an ultrasound was part of every prenatal visit. Ultrasound is so widely considered completely ‘safe’ that if you have enough money, like Tom Cruise, you can buy your own machine and use it every day; and “Fetal Foto” shops, employing 3-D and 4-D ultrasound imaging are springing up in strip malls all around the country for anyone who wants to pay cash to (possibly – no refund if they don’t get it) get a pretty picture of their baby before birth. But let me remind you that we also considered DES to be ‘safe’ and, indeed, many practitioners used it for years after it was recognized that it might not be.

In 2003 (Ultrasound Obstet Gynecol 2003;21:100), the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) reaffirmed an earlier “Safety Statement” in 2000 that “based on evidence currently available, routine clinical scanning of every woman during pregnancy using real-time B-mode imaging is not contraindicated.” This statement is predicated on the fact that ultrasound performed in the B-mode for routine 2-D, gray-scale imaging is conducted at very low levels of energy intensity and that in 40+ years of its use, no reproducible serious side-effects have ever been demonstrated.

However, ultrasound is ‘energy’ and its use is accompanied by the generation of heat (and other effects) and, indeed, it is widely used at higher intensities as a therapeutic modality in physical therapy (for which my left shoulder is very grateful, but my shoulder is not a baby). Furthermore, those of us who were trained during the era of ultrasound evolution tend to forget that not all ultrasound imaging for obstetrical purposes is created equal in terms of energy intensity. Our senses have been dulled by the mantra of ‘safety’ of B-mode scanning and have, without the data to back us up, extended the cavalier attitude to the routine and frequent use of both “spectral and color Doppler” for many diagnostic purposes in obstetrics that as the ISUOG statement reminds us “may produce high intensities…(and) because of high acoustic absorption by bone, the potential for heating adjacent tissues…”

It is true, we are given the admonition that “exposure time and acoustic output should be kept to the lowest levels consistent with obtaining diagnostic information and limited to medically indicated procedures, rather than for purely entertainment purposes.” But, by the same token, we have been given very little guidance over the years in terms of what that actually means. How many ultrasounds, how much exposure, how should exposure differ by gestational age? The human experiments have never been done, prospectively, and it is not realistic to think they will be at this point! But some observations related to ultrasound exposure fetal outcomes have been reported in obstetrical patients over the years and in our next post we will briefly discuss a few of those…

Labels: obstetrical ultrasound and safety

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MTHFR Polymorphisms and Schizophrenia?

The other day, tjtiger left a new comment on my post "MTHFR Mutations and Congenital Heart Defects". Her many questions made her comment worthy of a post of their own and the query related to the possible assocation of MTHFR polymorhisms and schizophrenia is not only quite intriguing, but taught me something new as well. That's what I love about this work!

Hi, I found out yesterday that I am heterozygous for the C677T and A1298C gene mutations. I had a baby girl last August and three days after I left the hospital my blood pressure spiked and I had massive swelling in my legs. My OB put me in the hospital and ordered an EKG and Sonogram of my heart. They ran a zillion different blood tests but could find nothing. The OB said I was just exhausted from having a new baby and was doing too much. Several months later at a check up with my family doctor I told him about the incident and he said it sounded like MTHFR. He said most doctors don't know about it and that it wouldn't just show up in the Cardiologist's tests. He ordered a full set of labs including the MTHFR test and it came back positive. I actually have a copy of all the labs but I don't quite understand all of this and have a few questions...

Kenneth F Trofatter, Jr., MD, PhD. Said…
Hi tj, thanks for writing. First of all, I doubt very much that your compound heterozygous state for those MTHFR polymorphisms caused your blood pressure problems and swelling after delivery of your baby girl. It sounds like you simply developed preeclampsia following delivery. About one-third of women will not show evidence of preeclampsia until after they have had their babies. In my reading of the current literature, there is at best a very weak, if any, association between MTHFR polymorphisms and preeclampsia. However, I would be curious to know about the other complications you had during your pregnancy, your gestational age at delivery, the size of your baby at delivery, and any problems the baby might have had after birth. I would also be very curious to see the results of the other laboratory tests done by your family physician. If you would like to send them to me privately, write through the ‘Heathline Feedback’ link and they will send them to my email address. Now, let me try to address some of your questions, because they are good ones…

1. Where can I find more information about MTHFR?

Methylenetetrahydrofolate reductase (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. This same biochemical pathway is also essential for the production of a substance called S-adenosyl methionine that is an essential intermediate required to 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.

Nutritional deficiencies of folic acid and/or mutations (polymorphisms) of the
MTHFR genes decrease the efficiency of these enzymatic pathways and increase the risk of accumulating homocysteine. Elevated levels of homocysteine and decreased production of methionine and S-adenosyl methionine may have toxicity for the developing embryo, resulting in increased risk for early pregnancy loss, congenital heart defects (particularly those involving the great vessels), and neural tube defects (e.g., spina bifida and anencephaly).

MTHFR polymorphisms are also included among the ‘genetic thrombophilias’ that place individuals at increased risk for developing vascular thrombosis (blood clots) and thromobembolic complications such as pulmonary emboli because they have either an increased propensity for developing clots or a decreased ability to break them down (fibrinolysis). The greatest risks for these complications are in individuals who not only have the gene mutation(s), but also have elevated homocysteine levels and/or other ‘risk factors’ such as smoking, use of estrogen-containing contraceptives, and other genetic or autoimmune thrombophilias.

As I have also discussed in another series of posts, there also appears to be an association between Down syndrome and MTHFR polymorphisms. Down syndrome results from the presence of 3 copies of chromosome 21. In 90-95% of cases, the extra chromosome is maternal in origin and results from a failure of normal chromosomal segregation (nondisjunction) during meiosis. “On the basis of evidence that abnormal folate and methyl metabolism can lead to DNA hypomethylation and abnormal chromosomal segregation,” James and colleagues (Am J Clin Nutr 1999;70:429-30) hypothesized in 1999 that young women with the most common MTHFR mutation (C677T) might be at greater risk for having a baby with Down syndrome than their peers who do not have the mutation. Indeed, the women with the C677T MTHFR mutation in this small study had a 2.6-fold higher risk for having a baby with Down syndrome than those who did not.

With the growing evidence of the importance of folic acid in the development of the fetal heart as well, and the high prevalence of the MTHFR gene mutation among women that may put their babies at risk, it appears we now have another good reason for insuring an adequate intake of folic acid, and may well be able to reduce the risk of specific, severe fetal heart malformations. One might also make the case for routine screening of women for elevated levels of homocysteine, prior to, or early in, pregnancy to identify those women who may be at increased risk, take steps to reduce their risk, and plan for proper evaluation of their babies during pregnancy.

2. I have several brothers, sisters and half brothers and sisters. Should they all get tested. Can this affect their children?

There is not an easy answer to this question. Many more individuals carry MTHFR polymorphisms than ever have complications related to the same. Indeed, the detection of your genetic state probably had nothing to do with the post-partum pregnancy complications you had as I have already pointed out. The most common gene mutations in MTHFR (C677T and A1298C) do not completely inactivate the gene, but reduce its efficiency in catalyzing the biochemical reactions of importance. We know that this deficiency can be overcome by supplementation with folic acid (hence ‘genetic predisposition’ and ‘environmental factors’) and greatly reduces the rates of neural tube defects and perhaps early pregnancy loss and congenital heart defects as well. I suppose, my suggestion for your family members would be to have their homocysteine levels checked, eat healthy foods containing folic acid and B vitamins, and for the women anticipating pregnancy, begin supplemental folic acid (1 to 4 mg daily) prior to conception and during early pregnancy to reduce the risk of embryotoxicity and congenital birth defects.

3. I have a 14 month old daughter, should I have her tested? Can this condition cause any health problems for a baby so young?

I am honestly not aware of any, but I think you should discuss this with your pediatrician – ask about testing, diet, and folic acid supplementation. Ditto to my comments above when she starts thinking about having your grandchildren!

4. Is there a possibility that I could also have Factor V Leiden? I don't know if that is a separate test or not.

The test for Factor V Leiden (G1691A) is a separate test for another of the gene mutations considered to be a genetic thrombophilia. Others include the prothrombin (Factor II) mutation (G20210A), protein C, protein S, and antithrombin III deficiencies, plasminogen activator inhibitor (PAI)-1 (4G/4G), and excess Factor VIII production. Autoimmune thrombophilias are associated with antiphospholipid antibodies and lupus anticoagulants.

5. Is there any link between MTHFR and Paranoid Schizophrenia? My father has Schizophrenia and I am wondering if maybe the underlying cause is this genetic condition.

This is a GREAT question and the answer appears to be YES! Although the world literature has shown some differences in results, a meta-analysis published by Gilbody and colleagues (Am J Epidemiol. 2007;165:1-13) demonstrated an association between the MTHFR C677T polymorphism and depression, schizophrenia, and bipolar disorder. The risk seems to be correlated with elevated homocysteine levels (Muntjewerff, et al., Mol Psychiatry. 2006;11:143-9). Male carriers of the MTHFR C677T and A1298C polymorphism may be at somewhat greater risk than women for schizophrenia (Sazci, et al., Prog Neuropsychopharmacol Biol Psychiatry. 2005;29:1113-23) and women may be at greater risk for bipolar disorders (Kempisty, et al., Eur Psychiatry. 2007;22:39-43).

6. My family doctor said I should consider not having any more children until this condition has been studied more. Is this condition so severe I should consider not having anymore children? I had a very hard pregnancy and was put on bed rest several times. I am diabetic and had to take insulin injections while pregnant.

I am afraid I have to disagree with your family doctor on this point. Your diabetes probably is a greater risk factor than your MTHFR status although the two could certainly act together to increase your risk for pregnancy complications. If you supplement your diet with folic acid and tighten your diabetic control prior to conception, you should be able to minimize risks for both fetal and maternal problems during pregnancy. On the other hand, if your diabetes is NOT in good control during the critical stages of embryologic development, your risks will be increased for fetal abnormalities, especially neural tube defects and congenital heart defects that are, as we have pointed out earlier, also associated with MTHFR polymorphisms.

Well, tj, thank you again for writing and for the great questions. I hope I have answered most of them in a way that you feel they’ve been answered. Best wishes to you and your family.
Dr T

Labels: congenital heart defects, Down syndrome, folic acid, MTHFR, neural tube defects, recurrent pregnancy loss, schizophrenia, spina bifida

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Grand Rounds 4.02 at Musings of a Distractible Mind

Compliments to Dr. Rob at Musings of a Distractible Mind for a most bodacious, though occasionally loquacious, Grand Rounds 4.02 tribute to Dr. Seuss. Ya gotta read it to believe it! And many thanks 'midst all the rhyme in semiperfect time for including a link to my recent post on "Multiple Pterygium Syndrome - A Rare Cause of Recurrent Pregnancy Loss". Anyone out there got a rhyme for pterygium?

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