Management of an Rh-Isoimmunized Pregnancy

In my last three posts we have set the groundwork for understanding complications related to maternal Rh-isoimmunization and fetal Rh-disease. Now let’s use a real-live patient to focus our discussion on the medical management of this condition…

We are caring for a young woman who is Rh-negative and became ‘sensitized’ during her first pregnancy. This probably occurred at the time of an emergency cesarean section for ‘fetal distress’ associated with ‘placental abruption’ (premature separation of the placenta) at which time she was probably exposed to a lot more of her baby’s blood than her provider’s realized. She had no Rh-antibodies found in her blood at the time of that admission and the baby had no complications related to anemia and ‘Rh-disease’ after the delivery. The woman was given Rh-immunoglobulin prior to discharge to help prevent sensitization, but only received the standard postpartum dose (sufficient to eliminate no more than about 15 cc of fetal blood from the maternal circulation) which was, as we shall see, probably, not enough in her case. When a larger than usual fetal-maternal hemorrhage is suspected, maternal blood can actually be screened for FETAL blood cells by a test (Kleihauer-Betke test), the amount of fetal blood in the maternal circulation can then be estimated, and sufficient Rh-immunoglobulin given to help prevent isoimmunization under these circumstances.

When she came in for her initial OB visit with her second pregnancy, she was found to have developed antibodies to TWO antigens of the Rh-system (I am not going into that discussion here, but things are never as straightforward as I might have led you to believe in an earlier post!). She had antibody to both the D and C antigens with ‘titers’ (see previous post for an explanation) of anti-D at 16 and anti-C at 32. The father of the baby (who was also the alleged father of her previous baby) was screened and his RBCs were found to have both the D and C antigens. If he did NOT have these, and he was indeed the father of this baby, then the baby could not have them either and our story could probably end here (even though Jerry Springer or Montel would then have an unhappy couple for their shows!). Because the father had the antigens, we now knew that the baby was at risk for having either or both as well, and was therefore at increased risk for ‘Rh-disease.’

The patient was given the option of having an amniocentesis done to find out for sure if the baby was D and/or C antigen positive, but she declined this test. She was followed with monthly antibody titers and at 22 weeks, the titers were found to have increased to 64 for anti-D and to 132 for anti-C. This rise in antibody titers increased the likelihood that the baby is D and C positive. Either of these antibody titers would be in a range that would increase our concern that the baby could develop complications related to Rh-disease, and the combination of two antibodies raised that concern even further.

In circumstances like this in the past, when we wanted to assess the degree of anemia in the baby of an Rh-sensitized woman, the standard approach was to perform an amniocentesis to determine levels of ‘bilirubin’ (see last post), a breakdown product of hemoglobin that is excreted in the fetal urine (amniotic fluid). We have standard curves for amniotic fluid bilirubin, based on years of experience when Rh-isoimmunization was a common problem, that tell us, fairly reliably, when the baby is at ‘low risk,’ intermediate risk,’ and very ‘high risk’ for being anemic. Based on the level of fetal risk, we could then plan when to check the bilirubin again (another amniocentesis), when to consider a ‘cordocentesis’ (a procedure in which fetal blood is sampled from the umbilical cord), when to consider a fetal transfusion (which can be coupled with a cordocentesis so the blood can be delivered directly into the fetal circulation through the umbilical vein if significant anemia is confirmed) or, even, when to just deliver the baby.

Nowadays, we have another alternative to these invasive diagnostic procedures for screening about which our needle-shy patient was delighted to hear. We have learned that by measuring the peak (systolic) blood flow velocity (PSV) in an artery in the baby’s brain (the middle cerebral artery, or MCA) using Doppler flow techniques (ultrasound), we can also identify, very reliably, the babies at increased risk for severe anemia before they have gone into heart failure. High PSV values correlate very well with fetal anemia, especially before 34 weeks, and this noninvasive technique has a very powerful ‘negative predictive value,’ so that when the baby’s PSV in the MCA is within the ‘normal’ range, it is extremely unlikely that the baby has life-threatening anemia.

We followed her weekly and the PSV steadily rose with advancing gestational age (in excess of the normal increase with advancing gestational age), suggesting some degree of fetal anemia, and then suddenly increased dramatically at 36 weeks. It should be noted that by 36 weeks the ‘positive predictive value’ of the PSV decreases significantly (i.e., higher values may NOT necessarily indicate severe fetal anemia), but the degree of the increase was still quite startling. There was no ultrasound evidence of fetal heart failure at this time. An amniocentesis was performed and the amniotic fluid was checked for bilirubin and also assessed for ‘fetal lung maturity’ (another post, another day). The bilirubin was only in the low-intermediate risk zone and the maturity studies were very “immature” suggesting that the baby could be at risk for respiratory problems if delivered at that time. Due to the immaturity of the lung studies, and not feeling pressed to deliver based on the amniotic fluid bilirubin, we gave the patient corticosteroids to help accelerate lung maturation (still controversial at this late gestational age, but proven effective below 34 weeks), and have continued to follow her with fetal heart rate testing and ultrasound. The patient’s due date was established by a first trimester ultrasound, and at this point we will probably simply deliver her by repeat cesarean section at 38-39 weeks.

I will admit up front that, even with four posts, I have left out a fair amount of information regarding Rh-isoimmunization and management during pregnancy. But, I also think I have given you a basic understanding of a very complicated condition and an appreciation for the steps we go through to help minimize risk and ensure a good outcome for both mother and baby. After our patient is delivered, I promise to give you some follow-up of the baby’s course. Thanks for reading....

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Thanks for the Oscar Nomination Dr. Jake: Grand Rounds 3.22

Many thanks to Dr. Jake Young and the Pure Pedantry team for including my post from December 3, 2006, entitled "The Human Value of Knowledge" in their Oscar line up of this week's Grand Rounds 3.22. I am so happy, I think I will go out and shave my entire body (or has Britney already done that?).

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Understanding 'Rh-disease'

When antibodies from an Rh-sensitized woman cross the placenta and enter the circulation of an Rh-positive baby, they attach to the Rh-antigens on the fetal red blood cells (RBCs). Once that occurs, the fetal immune system is fooled into believing the baby’s own RBCs are ‘foreign’ to its body and then, just as it would do in response to any invading virus or bacteria it has identified as ‘foreign,’ the immune system sets about systematically destroying the invader, in this case the baby’s own antibody-sensitized RBCs.

The immune system has various methods of destroying invaders and we will not go into detail regarding these pathways today. However, in the case of Rh-sensitization, the fetal RBCs are predominantly destroyed by cells that attack, nonspecifically, whatever antibody has attached to. Most of the destruction of Rh-sensitized fetal RBCs occurs by cells, such as macrophages, comprising what is termed the ‘reticuloendothelial (RE) system’ that is highly concentrated in organs such as the liver and spleen. Fortunately, these cells are not capable of mounting a permanent immune response to these antibody-sensitized fetal RBCs, which is a GOOD thing for the baby. (In other words, after birth, once the mother’s Rh-antibodies are eliminated, the baby will no longer attack its own RBCs, although the destruction can continue after birth until such time as the antibodies are gone). There are several consequences of the RE system’s response that contribute to the course and physical changes associated with what we then term ‘Rh-disease’ in the fetus.

First, the RE system begins to break down the fetal RBCs at a faster rate than RBCs usually turn over. RBCs contain the hemoglobin that is necessary for carrying oxygen throughout the body. When RBC destruction exceeds the ability of the baby to make sufficient quantities of new RBCs to keep up with the needs of the growing fetus, then anemia begins to develop. As the baby grows its need for more RBCs increases rapidly; and, as the placenta develops throughout gestation, it becomes more efficient at transferring maternal antibodies (including anti-Rh antibodies) to the baby. Unfortunately, in the case of Rh-disease, this accelerates the destruction of fetal RBCs. This combination of events places the baby at greater risk for severe anemia as the pregnancy progresses.

In addition to the destruction of fetal RBCs, the primary organs in which this occurs, the liver and spleen, also begin to enlarge. This enlargement is the consequence of several factors. First, the cells of the RE system proliferate (to some extent) and enlarge as the result of destruction and consumption of the fetal RBCs. Secondly, while the baby is in the womb, the liver, in particular, and the spleen are important sites for the production of fetal RBCs, an event that usually shifts more to the bone marrow as pregnancy progresses. As the baby becomes anemic, the production of RBCs in these organs (called extramedullary hematopoiesis) actually accelerates, rather than diminishes, and the proliferation of precursor cells responsible for the production of new RBCs contributes significantly to enlargement of the liver and spleen. As the liver and spleen increase, abnormally, in size, the growing cell mass begins to compress blood vessels (particularly veins) and lymphatic channels, resulting in 'congestion' (retention of blood and fluid) of these organs, contributing to further enlargement and accelerating the ‘congestion’ in a vicious cycle.

Severe anemia in Rh-disease rarely occurs before about 20 weeks, although the fetal RBCs strongly express the Rh-antigen by 30 days’ gestation. Many factors play into the risk for severe anemia including the maternal antibody titer, the type of IgG antibodies to which the baby is exposed, and the baby’s genetic background. Baby’s can usually tolerate very low RBC counts. However, when the anemia becomes so profound that the baby’s ability to supply oxygen to its tissues diminishes, the baby begins to accumulate lactic acid as the consequence of having to use metabolic pathways to support its tissues that do not require oxygen (anaerobic metabolism). The resulting ‘acidosis’ is probably one of the primary mechanisms by which the fetal heart begins to function less efficiently and, if this continues long enough, the baby goes into ‘heart failure,’ resulting in the terminal stages of Rh-disease (unless corrective measures are taken) in which the baby retains fluid throughout its body, a condition called hydrops fetalis. It is also thought that the congestion of the fetal liver, by impairing venous blood flow from the placenta to the heart (remember, it is the umbilical vein, not a high pressure artery, that carries oxygenated blood from the placenta and through the fetal liver before going to the heart) contributes to the heart failure as well.

There is at least one other event that occurs during Rh-disease that can put the baby at long-term risk for complications, or even death. When the baby’s RBCs break down and release hemoglobin, the hemoglobin is then also broken down, primarily into a substance called bilirubin. Indeed, elevated circulating levels of bilirubin can usually be detected even before the baby begins to develop anemia. Some of the bilirubin is converted into a ‘water soluble’ form that can be excreted in the fetal urine and, as we will discuss in the final post on this subject, the detection of this becomes the basis for assessing, indirectly, the degree of fetal anemia. Unfortunately, due to the immaturity of its metabolic pathways, the baby is not very efficient at converting bilirubin to this excretable form and a water insoluble form of bilirubin can begin to accumulate in the fetal blood. This form of bilirubin, called indirect bilirubin, has the ability to penetrate the lipid membranes of nerve cells and is toxic to them, causing cell damage and death. At extremely high levels of bilirubin, the baby can suffer permanent brain damage (kernicterus) and death as a result of that damage, but this is rarely seen today with the management protocols currently used to follow pregnancies and the babies who are the products of Rh-sensitized women.

I fully realize that today’s post is fairly complicated (it is even for most providers), but having a basic understanding of Rh-disease is essential to understanding the options (and importance) for evaluation and management of an Rh-sensitized pregnancy that will be presented in my next post on this subject…

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Rh-isoimmunization

In our last post we discussed what it means to be 'Rh-negative' in response to a patient’s concern that she is. We also mentioned that complications related to being Rh-negative have been greatly reduced over the past 40 years by the prophylactic use of Rh-immunoglobulin during pregnancy (and after delivery) to help prevent ‘isoimmunization’ in Rh-negative women. Isoimmunization, also known as ‘sensitization,’ refers to the development of antibodies to Rh-antigens when women who are Rh-negative are exposed to a source of Rh-positive blood, red blood cells (RBCs) that have the Rh-antigens on their surface and are, therefore, ‘foreign’ to the woman’s immune system. These antibodies do not affect the woman, but may cross the placenta and deleteriously affect the current, or a subsequent, baby.

The most common source of RBC exposure during pregnancy is from the baby. A woman can be exposed to her baby’s RBCs during spontaneous miscarriage (rare) or elective abortion (more common); placental abruption (premature separation of the placenta from the wall of the uterus); fetal-maternal hemorrhage as the result of disruption of the usual ‘barrier’ between the mother’s and the baby’s circulation, occurring with placental abruption, placenta accreta (growth of the placenta into the muscle of the uterus rather than just into the lining), or from other forms of damage or trauma to the placenta; and, most commonly today, as the consequence of exposure to large amounts of fetal blood at the time of a cesarean delivery. Women can also develop Rh-antibodies as the result of transfusion with mismatched blood. The latter is rare today, but is a common cause of maternal isoimmunization to other blood group system incompatibilities that are usually not screened for, particularly when blood is required in emergency situations.

When a person is found to be isoimmunized to Rh (or any other blood group system), the amount of antibody present, or degree of isoimmunization, is usually expressed as an antibody ‘titer.’ A titer is determined by how many times the blood can be diluted and still have the antibody detectable. In this context, the lower the number, the fewer antibodies are present. At the risk of oversimplification, in the case of Rh-isoimmunization, antibody titers less than 16 (or sometimes described as 1 to 16) are rarely associated with severe fetal complications during pregnancy; and, the higher the titer, the greater the likelihood of fetal complications. Baby’s are also at increased risk if the maternal antibody titer rises during the pregnancy or if the mother has previously had a severely affected baby. Usually, if a woman is found (or known) to be Rh-sensitized, she can expect to have monthly antibody titers performed during the course of her pregnancy. If maternal titers are low, and remain low, the baby may be Rh-negative, or may simply be at very low risk and no significant interventions may be required during the pregnancy. If the titers are rising, the baby is more likely to be Rh-positive and, therefore, ‘at risk’ and the pregnancy may require more intensive surveillance, including noninvasive or invasive assessment of the fetal status during the pregnancy.

In my next post, I will discuss the complications the baby may develop as the result of maternal Rh-isoimmunization, and also the options for fetal assessment of risk for these complications…

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Implications of a "Negative" Blood Type

Recently, a reader, Lynda, became pregnant and found out that her blood type is “Rh-negative” and was concerned about what that meant - ”I am really worried and no one has explained it to me.” Well, Lynda, let me explain that to you in a way I hope that you will understand and remain reassured for the time being…..

Blood type screening is one of the routine tests we offer to all pregnant women. Blood type is defined by the presence or absence of specific substances that are exposed on the surface of red blood cells (RBCs). At present, there are 29 different human blood group systems recognized by the International Society of Blood Transfusion. For sake of simplicity, the most significant of these are the ABO and Rh (Rhesus) blood group systems.

The ABO system defines the major blood group “antigens” (things to which the immune system can react if they are foreign to our bodies). The “O” part of this system represents, actually, the absence of either “A” or “B.” We inherit one copy of the genes for this blood group system from each of our parents and the presence of either (or both) “A” or “B” determines the individual’s blood type. Therefore, an individual can be A (= AA or AO), B (= BB or BO), AB, or O (= OO). Yes, therefore, it is possible to be an “O” blood type and have parents that are “A” or “B.” But, if both of your parents are O, and you are “A” or “B,” or if you have a parent who is AB and you are not “A,” “B,” or “AB,” then someone is not telling you something!

The Rhesus blood group system is a little more complicated and, again, for the sake of simplicity (forgive me on this one any ‘professionals’ out there), for the most part we are concerned about whether or not you have the “D” antigen of this system expressed on your RBCs. If you do have this, then you are considered to be Rh(D)-positive and if you do not, then you are Rh(D)-negative. The Rh(D) status determines whether you have a “positive” or “negative” blood type. Thus, when you combine this with the ABO typing, you are classified as one of the following: A-positive, A-negative, B-positive, B-negative, AB-positive, AB-negative, O-positive, or O-negative. In North America, about 15% of whites and about 7-8% of Blacks will be Rh-negative. But, there is dramatic worldwide and subpopulation variation on this. For example, only about 1% of Chinese and Japanese, but almost 100% of Basques, are Rh-negative.

So, why do we screen for this in pregnancy and what is our concern regarding Rh-negative women? When women are pregnant, they can be exposed to a blood type that is different than their own – the baby’s (remember, the baby is only half you, Mom); and, when our immune system is exposed to things that are foreign to our bodies (like somebody else’s blood), we can make antibodies against those things. For example, if a mother is Rh-negative and her baby is Rh-positive (thank the father of the baby), AND the mother is exposed to enough of the baby’s RBCs, she may make antibodies to the Rh(D) “antigen.” Certain antibodies (IgG) are actively transported across the placenta from the mother to the baby and provide a source of “immunity” for the baby during the first 4-6 months of life; other antibodies (IgM) are too big and cannot be transported across the placenta. Antibodies to the major blood group antigens (ABO) are usually (but not always) of the IgM class and therefore do not get to the baby or cause problems. Unfortunately, antibodies to Rh(D) are usually IgG antibodies that readily cross the placenta (with the rest of the protective IgG antibodies) and may be the source of problems, specifics of which and current management of the same, which we will discuss in subsequent posts.

When a woman develops antibodies to Rh(D), she is considered to be “sensitized” or “isoimmunized.” Rh-isoimmunization used to be a BIG problem in obstetrics. However, about 40 years ago we learned that if we gave an Rh-negative woman a small amount of the same anti-Rh(D) immunoglobulin (that we don’t want her to make on her own) during episodes of bleeding or, prophylactically, in early third trimester (around 28 weeks’) and within 48-72 hours after delivery, we could significantly reduce the risk of her becoming “sensitized” on her own, thereby, protecting the current and, especially, a future pregnancy.

So, Lynda, if you are Rh-negative and have a negative “antibody screen” (no abnormal antibodies to Rh or any other blood group system), there is nothing to worry about at this point. Your doctor will probably repeat that antibody screen around 28 weeks’ and administer “Rh-immunoglobulin” to help prevent isoimmunization during the third trimester when it is most likely to occur. (If the baby is found to be Rh-positive after delivery, you will be given the Rh-immunoglobulin again prior to discharge). Of course, if the father of the baby is also Rh-negative, then you don’t even really need that because your baby could not be Rh-positive. But, before you open that can of worms, be sure you know “who the Daddy is!”

And, in my next posts, I will continue the discussion on Rh and tell you about a patient we admitted to the hospital yesterday who had complications related to the fact that she had an Rh-negative blood type and did become sensitized during a previous pregnancy….

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More Highlights from the 2007 SMFM Meeting in San Francisco

Over the past several days there have been many more fascinating presentations at this year’s SMFM Meeting. In all the time I have attended this meeting, I have not seen research at this level presented. Unfortunately, much of the information would not be of much interest or use to the lay person who is reading this post. But, I want to mention briefly a few highlights that might give you some idea of where we are now from a research standpoint and what that might mean for the future.

Dr. Ursula Harkness (another former resident of mine while I was at the University of Minnesota) presented the results of studies (conducted during her fellowship in maternal-fetal medicine at the University of Cincinnati) in an animal model that consistently results in ‘intrauterine growth restriction’ of the fetus (rats). She and her colleagues were able to overcome the fetal growth problems by injecting a growth factor gene (IGF-1), contained within a virus (adenovirus vector), into the placentas of these babies, overcoming not only the intrauterine growth delays, but the growth and metabolic problems that these animals have following birth.

Dr. Kjersti Aagaard-Tillery presented very convincing evidence from nonhuman primate (macaque) experiments confirming the hypothesis that offspring from obese mothers are, themselves, programmed in the womb to go down the path of obesity, hypertension, and diabetes, that this ‘programming’ occurs not only in the liver (the site of the metabolic pathways that lead to these problems), but also in the brain, and is indeed the result of aberrations of methylation that alter normal DNA gene expression. She and her colleagues demonstrated quite elegantly that genes that ordinarily produce chemicals (Npas2) that regulate the part of the brain that tells us we are full when eating (the satiety center) can also be ‘reprogrammed’ in a way that reduces their expression (making us feel less hungry when we have actually had enough to eat). (I am so glad I finally have an excuse for craving the triple whopper with cheese in the jumbo-sized combo.)

Dr. Darine El-Chaar and coworkers from the University of Ottawa reported data from a large perinatal database that contained information about birth outcomes in patients who had undergone conception with the help of ‘assisted reproductive technology (ART).’ (We have mentioned in the past that these women are at increased risk for pregnancy complications such as preterm birth, cervical incompetence, hypertension, HELLP syndrome, placenta previa, low birth weight, diabetes, and chromosomal abnormalities, not to mention multiple gestations). The report confirmed that such women also have a prevalence of babies with birth defects that is overall almost twice that of the general population. In the year they reviewed the data, gastrointestinal, cardiovascular, and musculoskeletal defects were significantly higher in ART women than those who had spontaneous conceptions. Risks of birth defects for different methods of ART were 2.72% for intrauterine insemination, 3.35% for in vitro fertilization, and 2.23 for ovulation induction. Reasons for these increased risk rates are yet to be determined.

Lastly, here is something you don’t want to hear, although I have had my suspicion of this for many years now. Dr. William Dobak from Emory University (and colleagues from around the country) evaluated the effects of coital frequency and number of partners during pregnancy and pregnancy outcome. In brief, women who had more frequent sex and 3 or more partners were at greater risk for early delivery, intrauterine growth restriction and low birth weight babies. This effect was NOT the result of age, race, smoking status, history of preterm delivery, or presence of sexually transmitted infections. I always knew we weren’t doing much when we told patients to “get more bed rest” but now it appears we may actually be doing more harm than good. I mean, what else are you going to do if you are lying around in bed all day?

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More from the 2007 Society for Maternal-Fetal Medicine Meeting in San Francisco

There were several very interesting presentations today at the Annual SMFM Meeting in San Francisco. Two of these described animal experiments that will undoubtedly have an impact on how we approach the management of certain medical and genetic conditions in humans.

The first was an outstanding presentation by Dr. Kjersti Aagaard-Tillery who is currently at the University of Utah. She was a resident in OB/GYN while I was at the University of Minnesota and is a rising star in basic research in Maternal-Fetal Medicine. Let me be the first to predict that her work will result in major contributions to the understanding and treatment of many chronic medical conditions in humans and worldwide recognition for her accomplishments (hear me out Nobel prize committee; keep an eye on this young one). Anyway, she presented powerful evidence that confirms that the environment to which the fetus is exposed (in this case, decreased uterine blood flow resulting in intrauterine growth restriction) results in permanent ‘programming’ of the fetus that sets it down a pathway that culminates in adult metabolic diseases associated with obesity, diabetes, hyperlipidemia, and hyperinsulinemia.

This programming is the result of persistent changes in hepatic (liver) gene expression as the consequence of ‘epigenetic modification in DNA methylation’ that occurs under the stress of the intrauterine environment and, once this occurs, the condition can be passed on to the next generation of offspring. (This ‘methylation’ results from the same pathways we referred to in yesterday’s discussion of fetal heart malformations and aberrations of folic acid metabolism). Yes, Mathilda, in addition to your genetic background, in some ways we are the product of our (intrauterine) environments.

The most remarkable part of Dr. Aagaard-Tillery’s work (to date), however, is that she and her collaborators were able to completely reverse the phenotypic (fat rats) and biochemical abnormalities associated with these epigenetic modifications by simply placing the animals on a life-long diet rich in the micronutrients (folic acid, choline, vitamin B12, betaine, methionine, arginine, zinc) that are involved catalyzing the biochemical reactions in these metabolic pathways. Perhaps, if we are ever to get serious about attacking the current human epidemic of obesity and its consequences, we need to make sure all folks (from an early age) are provided with a diet rich in these substances. Of course, a little exercise wouldn’t hurt either!

Briefly, the other research that I also thought was absolutely fascinating was presented by Dr. Laura Toso from the National Institutes of Health, Unit on Perinatal and Developmental Neurobiology. Dr. Toso described a mouse model in which the animals carry a chromosomal abnormality that results in a medical condition analogous to Down Syndrome (trisomy 21) in humans. These animals end up with inadequate nerve myelination (myelin is important for rapid transmission of information along nerves), nerve degeneration, developmental delays, and eventually ‘early Alzheimer’s’ disease that is very similar to that seen in Down Syndrome and seems to be associated, at least partly, with insufficiencies of certain biochemicals (neuropeptides) that regulate the release of ‘neurotrophic peptides’ (NAP and SAL for sake of simplicity) that normally help protect nerve cells from this kind of degeneration.

Dr. Toso and her colleagues found that administration of these neurotrophic peptides to the mouse embryos, at a gestational age equivalent to the late first and early second trimesters in humans, resulted in animals with developmental milestones comparable to, if not better in some parameters than, the ‘normal’ and unaffected animals in the control group. Wouldn’t it be amazing if we could give every child with Down Syndrome a shot at a more ‘normal’ life! Makes another pretty good case for getting into a routine of offering ‘combined first trimester screening for aneuploidy’ available to all pregnant women so that we can find these chromosomal abnormalities early, doesn’t it?!?

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MTHFR Mutations and Congenital Heart Defects

This afternoon, I attended a ‘focus group’ devoted to congenital heart disease and fetal cardiology. As we have discussed on other occasions, fetal heart defects are the most common abnormalities a baby can have, affecting about 1% of all pregnancies, but more than 60% of these are not detected until after the baby is born. The cause of congenital heart defects is thought to be ‘multifactorial’ in many cases, involving some degree of underlying ‘genetic predisposition’ and certain ‘environmental factors.’ This is similar to the situation with neural tube defects (abnormalities in closure of the spine).

Dr. Katharine Wenstrom from Vanderbilt University School of Medicine presented a wonderful talk during this session on “MTHFR mutation and risk of congenital heart defect.” She pointed out that certain congenital heart defects, particularly those involving abnormalities of the great vessels (e.g. aorta; aortic valve; pulmonary artery; pulmonic valve) can have very high rates of recurrence. This same group of fetal heart abnormalities are also found in the offspring of women who have mutations in the MTHFR (methylenetetrahydrofolate reductase) gene. This particular gene requires folic acid to convert homocysteine to methionine (an important amino acid) and when this does not occur, homocysteine can accumulate and may have toxicity for the developing embryo. This same biochemical pathway is also essential for the production of a substance called S-adeneosyl 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.

Interestingly, it has clearly been shown in animal experiments that the normal development of the fetal heart requires proper migration of ‘neural crest cells,’ the same types of cells that must move normally to close the spine and abnormalities in MTHFR function increase the risk of heart defects. (Neural tube defects are also more common in babies of women that have MTHFR deficiencies and elevated levels of homocysteine). Dr. Wenstrom also presented evidence that babies with a certain severe cardiac malformation, hypoplastic left heart syndrome, have heart tissue that is clearly not as well ‘methylated’ as that seen in the hearts of normal babies. Therefore, impaired neural crest cell migration and impaired nucleic acid methylation may both play a role in the etiology of these heart abnormalities.

The most common gene mutation in MTHFR (C677T) does not completely inactivate the gene, but reduces 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. 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 prior to conception and during early pregnancy, 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.

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Report from the 27th Annual SMFM Meeting - 2007

Hey guys! I am really still alive. I have been traveling and now am in San Francisco for the 27th Annual Meeting of the Society for Maternal-Fetal Medicine. This is the first access to the internet that I have had in the past week. Yesterday, I attended an all-day course on “Suggested Guidelines for the Evaluation and Management of High-Risk Pregnancy Conditions.” In my next few posts, I will present some of the highlights and some of the disappointments from the course presentations as well as some of the new and interesting information that is presented in the plenary and poster sessions over the next several days:

• Dr. John T. Repke, Professor and Chair of OB/GYN at Penn State talked about “An evidence based approach to the management of mild and severe preeclampsia.” Great talk, but not much new information.

• We still do not know what causes preeclampsia, although in their various forms, hypertensive disorders of pregnancy account for 17.6% of all maternal deaths in the U.S.

• We still have no good screening test to define which women are at risk for preeclampsia, although we know many of the underlying conditions (chronic hypertension; kidney disease; autoimmune disorders; pregestational diabetes; obesity, etc.) that put women ‘at risk’ for developing it.

• Many forms of ‘empiric therapy’ have been tried to reduce the risk, but none have proven efficacy (e.g. low-dose aspirin; fish oil; zinc; calcium) and some are not only ineffective, but may actually be harmful (high-dose vitamin C and E supplementation).

• Despite the ‘bad press’ magnesium sulfate has received for management of preterm labor, it remains the ‘treatment of choice’ to prevent seizures associated with preeclampsia and to stabilize the patient in preparation for delivery, although its use in ‘mild preeclampsia’ is still of uncertain value.

• Expectant management (rather than immediate delivery) of women, even with severe preeclampsia, offers the best option for improving neonatal outcome, especially with early onset disease (24-25 weeks’), as long as maternal condition is stable and the baby does not appear to be compromised. Frequent assessment of both mother and baby is necessary under these circumstances since either/both can deteriorate rapidly once the condition begins to worsen.

• Women with severe preeclampsia associated with thrombocytopenia (low platelets) may benefit in the antepartum period by administration of a steroid (dexamethasone), but the primary advantage to therapy may only be that the platelet count can be raised to a level that bleeding risk is low and the anesthesiologist feels comfortable in administering a regional anesthetic (epidural or spinal) during labor or for cesarean delivery.

Women who develop preeclampsia are at life-long risk for hypertension, stroke, atherosclerotic cardiovascular disease, and possibly thromboembolic (blood clot) disorders and should be counseled regarding approaches to risk reduction during and after their pregnancies.

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