Diabetes in Pregnancy -6 - Diet and Exercise as the Foundation for Management of GDM

Once we have established the diagnosis of gestational diabetes mellitus (GDM), the first step in management is to counsel the patient regarding the diagnosis, management options, potential risks to the pregnancy, antepartum assessment of the baby, and the importance of postpartum follow-up. All that said and done, there are about as many different ways to manage a gestational diabetic as there are Maternal-Fetal Medicine specialists in the U.S. Part of the reason for disparities in recommendations for care reside in skepticism regarding benefits to outcome, i.e., does aggressive management really decrease risks for fetal macrosomia, compromise in utero, shoulder dystocia and brachial plexus injury at delivery, or even cesarean delivery. Quite frankly, I have adopted the attitude that those issues may be important, but are not, necessarily, the most significant ones! Usually as late in the pregnancy as the diagnosis of GDM is made and therapy implemented, we will not significantly influence the occurrence of macrosomia. Similarly, it is the rare pregnancy with GDM in which respectable blood sugar control is established that will result in a fetal death in utero. And, since cesarean delivery rates around the country are almost uniformly above 30%, patients with GDM, even if they all underwent cesarean delivery (which is truly unnecessary), that would not add significantly to the problem!

The issues that concern me more are related to long-term care of the mother and short- and long-term outcomes for the baby. Due to the motivation to have a ‘healthy baby’ (and to be around to see her grandchildren!), pregnancy is about as good a time as we will ever have to provide information to the mother that may reduce her own future risks of diabetes and its attendant complications (e.g., hyperlipidemia, hypertension, cardiovascular disease, shortened lifespan). From the baby’s standpoint, complications related to hyperinsulinemia, hypoglycemia, hyperbilirubinemia, and respiratory distress in the newborn as a consequence of poor maternal blood glucose control can be significant, especially if the baby is delivered at an institution that is not in the mode to rapidly identify these complications or to manage them aggressively should the need arise. Furthermore, there is growing evidence that maternal hyperglycemia affects the long-term risks for the baby with regard to obesity, lipid profiles, cardiovascular disease and diabetes by a mechanism of in utero epigenetic ‘programming’ (a good subject for another series of posts). So, over time, I have generally taken a relatively aggressive approach to ongoing evaluation and therapy of GDM once the diagnosis is made.

The foundations of GDM management are diet and nutritional counseling, glucose monitoring, modest exercise, and medical therapy if the first three do not result in normalization of blood sugars. It is estimated that about 70% of GDM can be managed without medical therapy if attention is paid to the first three (Brody, et al., Obstet Gynecol 2003;101:380-92) and quite frankly, education and life-style modification in these areas will provide the most benefit to the mother for her long-term health if she is willing to accept responsibility for the same. Although almost everyone agrees in principle on the importance of these measures, there is no standard algorithm for care and, indeed, to some extent the care should be individualized to the patient. That does not mean we should ever lessen our desired standards for, or underestimate the patient’s willingness and ability to achieve, good glycemic control, but sometimes we may have to ‘bend the rules’ a bit to get to that point!

My first steps in counseling the newly identified woman with GDM is to review her past medical and obstetrical history and her current obstetrical course, explain in very general terms what diabetes is and the pregnancy/neonatal concerns, emphasizing at the outset the value of tight blood sugar control, assess her lifestyle and habits that might influence (for better or worse) her diabetic management, and explain that what she learns today, and over the remaining months of the pregnancy, may be important for the rest of her life. Prior to counseling about diet and nutrition, I try to pin down how much weight she has gained since conception. There are several reasons for this: If weight gain has been appropriate for her body habitus, then her caloric intake is probably appropriate and dietary counseling will focus on redistribution of caloric intake during the day and type of foods being eaten. If weight gain has been excessive, then counseling will emphasize not only the preceding points, but overall reduction in caloric intake as well. And, if she has had poor weight gain, and still has GDM, she is more likely to be a pregestational diabetic, or to be highly insulin-resistant, and require more than just dietary counseling alone. I have found that some women (unfortunately, often the most overweight) are absolutely terrified by what they may perceive as “dieting” during pregnancy, and the difference between ‘dieting’ and ‘good nutrition’ must be clearly explained. In most circumstances, they are also reassured that they will be expected (given ‘permission’) to continue to gain weight during the rest of their pregnancy – the actual amount determined by habitus. Indeed, in certain situations I have been known to tell extremely obese women that they may safely either gain no more weight, or actually lose weight during the last few months of pregnancy and, if done correctly, this should have no ill effects on their babies.

The next step in counseling is to explain the broader concepts of diet and nutrition (reserving the specifics for a visit to the dietitian). We place most of our patients on ‘3 meals and 3 snacks’ throughout the day – redistributing their total caloric intake. Patients are told that this approach, accompanied by adjustment of the type of calories they are ingesting, will curb their appetite and help to avoid wild swings in their blood glucose levels that might lead to abandoning their ‘diet’ for ‘comfort foods’. I also usually take this opportunity to explain that the baby basically ‘eats’ constantly, is constantly removing glucose from the maternal circulation in a manner reflecting maternal blood sugar levels, are ‘bottomless wells’ as far as blood sugar is concerned, and have the ability to make as much insulin as they need to use what they get, thereby leading to the problems related to excessive growth, too much insulin production, and low blood sugars after they are delivered (and no longer have the maternal ‘Willy Wonka Factory’ at their unlimited disposal).

The next part of the discussion revolves around the total amount and type of calories to be consumed. This will vary depending on weight gain to that point and expected for the pregnancy, maternal habitus, and general level of daily activity. In this regard, I am a firm believer in the general approach recommended by Jovanovic-Peterson over the years: 30 kcal/kg for women at 80-120% of their ideal body weight; 24 kcal/kg for overweight women; and 12 kcal/kg for morbidly obese women. Patients are told that these levels are at thresholds that will usually avoid ketonuria and are just a “place to start” and will be adjusted based on weight gain and glycemic control. They are also asked (and given instructions on how) to distribute calories as no more than 40% carbohydrate and about 20% protein and 40% fat; and they are asked to replace simple sugars with more complex carbohydrates. An alternative approach is to simply “count carbohydrates” but I usually leave this to the dietitian to explain. As an adjunct to these recommendations, I usually make it clear that we are asking that they should minimize intake of specific foods/drinks, especially candy, soft drinks, “sweet tea” (a mainstay of our South Carolina population), high sucrose/fructose juices, and sources of excessive caffeine. (In reality, the ‘caveman diet’ of lean meats, fish, nuts, vegetables, and fruit, avoiding dairy products, cereals, and refined fat and sugar would probably be ideal for many pregnant women with or without GDM).

As part of their dietary regimen, I also recommend to those that don’t that they begin a modest exercise program – suggesting to the ‘novices’ in this arena, simply walking 30-60 minutes 3 or more times per week. One incentive I use to promote these lifestyle changes (other than that it is just plain good for them and their babies) is that these efforts may reduce their need for medications, especially the dreaded INSULIN, to control their diabetes during (and, perhaps, after) pregnancy. In closing this part of the discussion, I like to make sure that they understand we are not asking them, nor is it good for them or their babies (and we will know if they are doing it), to STARVE themselves to achieve normal blood sugar levels.

I guess we should stop at this point, having spent more time on this part of the discussion than anticipated, but it truly is the foundation for GDM management and, as such, deserved the attention! Anyway, we will continue our discussion of the other components of GDM management with our next post in this series…And by the way, HAPPY NEW YEAR!!!!

Labels: gestational diabetes, pregnancy diet

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Diabetes in Pregnancy - 5 - Diagnosis of Gestational Diabetes

In our last post, we discussed the basic differences between type 1 and type 2 diabetes and concluded with the characterization of gestational diabetes mellitus (GDM), diabetes that is first expressed (or detected) as the result of pregnancy, as fitting more the picture of type 2 diabetes. Indeed, the World Health Organization now defines gestational diabetes as glucose intolerance in pregnancy, with normal or impaired glucose tolerance after termination of the pregnancy. The definition does not exclude the possibility that glucose intolerance might have been present before the pregnancy and it applies regardless of the therapy that is required to manage the diabetes during the pregnancy (Diabetes Care 2003;26:S5-S20). Although the risks of GDM for both mother and baby are generally less than that for pregnancy accompanied by type 1 diabetes, it comprises about 90% of the diabetes we see complicating pregnancy in the U.S. By virtue of the fact that GDM also now affects at least 4% of all pregnancies, the cumulative morbidity for women and their babies is significant. It is appropriate therefore to begin a discussion of diabetes in pregnancy with a focus on GDM.

Routine screening of all patients (except of course those who are already diabetic) for GDM has become a standard of care. GDM is associated with large (macrosomic) babies, risk of trauma during delivery (for both mothers and babies), neonatal hypoglycemia (secondary to hyperinsulinemia), hypocalcemia, hyperbilirubinemia, respiratory complications if delivered prior to term, and need for cesarean delivery. Poorly-controlled GDM also places the baby at risk for intrauterine fetal demise. Although over the years, some have argued that it is not necessary to screen all pregnant women, that has proven to be a battle not worth fighting. Screening is very simple and inexpensive to perform. If women were only screened based on ‘risk factors’ alone, about 50% of GDM would be missed (Jovanovic, et al., Diabetes 1985;34:21). If women who were not obese were excluded from screening, 10% of GDM would not be diagnosed and 16% of these women would have significant blood glucose levels that would require insulin therapy (Moses, et al., Diabetes care 1998;21:1803). Absence of diabetes with an earlier pregnancy is also inadequate to exclude GDM in a subsequent pregnancy, especially if a woman is significantly older or has gained weight since the previous pregnancy.

Different approaches to screening are employed around the world. In the U.S., the most widely accepted approach is to screen women at 24-28 weeks gestation who have not been shown or suspected to have hyperglycemia prior to this time. The glucose challenge test (GCT) is done by giving women a 50g oral glucose load, without regard to time of day or when they have last eaten, and then checking a plasma glucose level 60 minutes later. Although different institutions use different cutoff values to identify women for further testing, most use values > 140 mg/dL as an indication to perform a full 3 hour glucose tolerance test (GTT). Using this cutoff at this point in pregnancy will result in the need for a GTT in about 15% of women, but will detect 85-90% of gestational diabetics. Using a cutoff of 130 mg/dL for the GCT will pick up nearly 100% of GDM, but will be at the cost of having to perform a GTT on 25% or more of women.

The GTT is performed as follows: The patient is advised to eat her usual diet for at least 3 days prior to the test and to maintain her normal level of physical activity. Some suggest a diet that includes at least 150 g/day of carbohydrate. Then, after an overnight fast of at least 8 hours (but less than 14 hours), a fasting plasma glucose level is obtained and the woman is given a 100g oral glucose load. She is asked to limit her activity and not smoke during the test. Plasma glucose levels are then obtained 1 hour, 2 hours, and 3 hours later. Using either the recommendations of the National Institutes of Health Diabetes Data Group (NDDG) (Diabetes 1979;28:1039) or the values established by Carpenter and Coustan (Am J Obstet Gynecol 1982;144:768-73) shown in parentheses, abnormal values for each of the plasma glucose time points are as follows: fasting 105 (95); 1 hour 190 (180); 2 hour 165 (155); and 3 hour 145 (140). If a woman has two or more of these values abnormal, she is considered to have gestational diabetes. The attendant morbidity during pregnancy has been shown to be comparable regardless of the criteria set used. In all, 15-20% of women who end up requiring a GTT based on the initial GCT will be found to have GDM.

There are some caveats to screening that are probably worth mentioning although standard approaches under the circumstances described have not been universally adopted. Although routine screening is usually done at 24-28 weeks, women with significant risk factors can be screened earlier in pregnancy. These include women who are obese, previously had GDM or a macrosomic baby, previously lost a baby in utero (particularly if the baby was large for gestational age) or had a delivery complicated by shoulder dystocia or a baby who had neonatal hypoglycemia, have a strong family history of diabetes, glucose detected in their urine or an unexpectedly high blood glucose level at the time of a random determination. Women who pass their initial GCT at 24-28 can also be rescreened later in pregnancy if they have any of these risk factors or if they develop a large baby, excessive amniotic fluid (polyhydramnios), or excessive weight gain during their pregnancies.

Women who have a very high blood glucose level (> 190 mg/dL) on their 1 hour GCT, have a 90% chance of being diabetic. Under these circumstances, it is prudent to check the fasting blood glucose level prior to proceeding with the full 3 hour GTT, and if this is > 95 mg/dL, declare them to have GDM and treat accordingly. Women who are found to have one elevated value at the time of their 3 hour GTT, should probably have the GTT (not the GCT) repeated at 32-34 weeks because 10-15% of GDM will not develop until later in pregnancy. An alternative to screening in women who have previously had GDM and are well-motivated is to counsel them regarding diet and exercise early in pregnancy and, if they are familiar with the use of a glucometer for self-glucose testing from the prior pregnancy, to have them begin checking fasting and 2 hour postprandial (after eating) blood sugars periodically. (Specifics regarding self-testing will be discussed further in our next post). The advantage of this approach is that it allows early intervention when their blood sugar control begins to deteriorate during the pregnancy.

Once the diagnosis of GDM has been established, a management program should be implemented and that will be the subject of our next post in this series….

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Diabetes in Pregnancy - 4 - Window to Risk of Type 2 Diabetes

Back in August of this year, I started a series on “Diabetes in Pregnancy.” A recent reader reminded me that I hadn’t gotten around to finishing that series (which is true because I got distracted by other topics). In the first three installments of that series, we discussed general overviews of diabetes and the growing ‘epidemic’, glucose metabolism, and the changes in insulin sensitivity accompanying normal pregnancy that can complicate or precipitate diabetes. In this post, let’s discuss the different types of diabetes and see how gestational diabetes fits into the spectrum of disease.

Although glucose intolerance as manifested by high ‘blood sugar’ levels is the common denominator that defines an individual as diabetic, the two major groups of diabetes, type 1 and type 2, have very different underlying etiologies. Only about 10% of diabetes in North America is type 1. This form of diabetes is primarily an autoimmune disorder that is associated with the production of antibodies and auto-reactive T cells directed against and subsequent destruction of the pancreatic islet cells (β-cells) that produce insulin. Other conditions can also lead to the destruction of the pancreatic islets and type 1 diabetes, but these are much less common. Type 1 diabetes was formerly called juvenile onset diabetes (or insulin-dependent diabetes) and occurs before the age of 20 in about 50% of cases and most before the age of 30, although there is a life-long risk of developing this type of diabetes. There appears to be a complex polygenic inheritance pattern to the tendency to develop the autoimmune condition, and there is variable penetrance of expression suggesting a role for environmental factors in addition to the genetic predisposition. In this regard, a variety of different viruses (e.g., Coxsackie B4; cytomegalovirus) have been implicated, but not absolutely proven to play a role, in the precipitation of diabetes in certain individuals.

Twin studies support the contributions of both genetic background and ‘shared environment’ as sources for expression of type 1 diabetes. Monozygotic twins (identical twins from the same egg) have a 30-50% concordance for developing diabetes. Dizygotic twins (from separate eggs) have a higher rate of concordance than is seen in ordinary first degree relatives as well (Kyvik, et al., BMJ 1995;311:913-7). The earlier the onset of diabetes in the index twin, the greater the likelihood of the second twin (mono-or dizygotic) will eventually develop diabetes (Hyttinen, et al., Diabetes 2003;52:1052-5). Males seem to be at greater risk for developing diabetes and for concordance of disease in both monozygotic and dizygotic twins (Kumar, et al., 1993;42: 1351-63). Antibodies to the islet cells can be found in 90% of type 1 diabetics at the time of diagnosis and these are often directed against the glutamic acid decarboxylase enzyme as well as cytoplasmic antigens and insulin. Certain human leukocyte antigen (HLA) DQ haplotypes appear to have the strongest association with risks for developing type 1 diabetes and these are correlated with both autoantibody production and subsequent disease expression (Redondo, et al., J Clin Endocrinol Metab 2006;91:1705-13). Interestingly, there appears to be a predisposition to paternal treansmission of these haplotypes.

Type 2 diabetes is a more ‘heterogeneous’ condition than type 1 diabetes and represents about 90% of the disease seen in North America. It is characterized by both a decreased sensitivity to insulin in skeletal muscle and liver and a decreased production of insulin by the pancreatic β-cells in response to hyperglycemia, a condition that seems to worsen over time and with poor control of blood glucose levels. Typically, type 2 diabetes has been associated with genetic predisposition (family history), obesity, and advancing age. On a worldwide basis, it is clear that genetic predisposition is perhaps the greatest contributor to overt manifestation of type 2 diabetes. As in type 1 diabetes, there is a strong concordance of type 2 diabetes in twins in the range of 50% or more. In North America, and in other countries that are being affected by the ‘pandemic’, obesity is perhaps the single greatest cause leading to expression of the disease, particularly in younger individuals. About 10-15% of individuals with type 2 diabetes have specific gene mutations associated with autosomal dominant inheritance patterns. These conditions are currently classified as maturity onset diabetes of the young (MODY). The most common of these (MODY2) is related to a variety of glucokinase gene mutations and is commonly found in European populations. MODY1 and MODY3 are secondary to mutations of hepatic nuclear factors; heritable deletions or mutations of mitochondrial DNA can also lead to type 2 diabetes in and diabetes.

Although obesity has classically been correlated with both expression and severity of type 2 diabetes, a large proportion of individuals with type 2 diabetes in Europe and Asia are not obese. In these individuals, many have a disproportionately greater decrease in insulin production and less insulin resistance than that seen in obese type 2 diabetics. This suggests that the underlying predisposition to the development of type 2 diabetes is decreased insulin production and obesity contributes to the progression of disease by increasing insulin resistance. The latter may occur by a variety of mechanisms that may have differential expression and significance in certain individuals, contributing to the heterogeneity of presentation and severity of type 2 diabetes. For example, excess fatty acids can block insulin signaling in skeletal muscle and stimulate glucose production by the liver. In recent years, obesity has also been characterized by a chronic ‘inflammatory’ state with the increased production of tumor necrosis factor-α and interleukin-6 that can also contribute to insulin resistance in skeletal muscle.

However, the most exciting findings that have been widely published in the scientific literature within the past year may actually have identified the root cause of the genetic predisposition to type 2 diabetes. Genetic polymorphisms of the transcription factor 7-like 2 (TCF7L2) gene have been clearly correlated with type 2 diabetes around the world in individuals with different ethnic and genetic backgrounds (Chandak, et al., Diabetologia 2007;50:1-4; De Silva, et al., Diabet Med 2007;24:1067-72; Chang, et al., Diabetes 2007;56:2631-7; Hayashi, et al., Diabetologia 2007;50:980-4). These polymorphisms are associated with both decreased insulin production and increased insulin resistance in non-obese and obese individuals, but seem to play a greater role in the expression of diabetes in the former. This finding opens the door to novel and specific approaches to therapy that have eluded the management of type 2 diabetes to this point. For those readers who have an interest in this subject, let me commend to you several recent review articles (Vaag, et al., Appl Physiol Nutr Metab 2007;32:912-20; Florez, Curr Opin Clin Nutr Metab Care 2007;10-391-6).

So, where does pregnancy fit into the big scheme of things. As we discussed in one of those August posts, pregnancy in the second and third trimesters is associated with increasing insulin resistance that is correlated with the hormonal milieu of pregnancy. In that respect, the ‘stress’ of pregnancy can, and typically does, worsen control of women who embark on pregnancy with either type 1 or type 2 diabetes. Women who only overtly develop diabetes during pregnancy (gestational diabetes mellitus – GDM), however, have features that are most characteristic of type 2 diabetes. Indeed, the overall 2-14% incidence of gestational diabetes in different populations characteristically reflects the incidence of type 2 diabetes in the background population (and I will bet now, the genetic background as well). We now look at GDM as a crystal ball to identify women at risk for developing full-blown type 2 diabetes later (sometimes sooner than later) in life. Indeed, one of our major points of emphasis in counseling women with GDM is that the keys to diabetic control we provide to them to optimize pregnancy outcome should be carried forward in their lives after the pregnancy is completed to help minimize their future risks for diabetes. In the next post on this subject (hopefully not 3 months from now!), we will discuss the diagnosis and management of gestational diabetes…

Labels: diabetes; insulin resistance, gestational diabetes

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Low Early Pregnancy 'Hormone' Levels: hCG and Progesterone

The two recent readers shared their stories with us regarding early pregnancies complicated by “low hormone levels” and subsequently loss of their babies. Many questions arise regarding what it means to have low human chorionic gonadotrophin (hCG – the ‘pregnancy test’ hormone) or progesterone levels and what can be done about it, if anything? Do low levels mean you will lose a pregnancy? Can low levels indicate other potential problems with a pregnancy? All of these are frequently asked questions relevant to many of our readers and I will try to address them after responding to our readers’ questions below…

• At Thu Dec 20, 03:24:00 PM 2007, siniamejia said…

I am approximately 5 weeks pregnant, and had my levels of hCG checked (because I was bleeding). My doctor said my levels were really low and also my progesterone levels were low and that it looks as if this pregnancy will not turn out to be healthy. My levels were 114 Saturday and only 145 today (5 days later). He says that I should have a D&C but I refused, so he told me that I will miscarry or should. I am so upset right now because I do not want to be the one to make the decision to have that done. I feel like maybe there still is hope and maybe a couple of days from now the bleeding will stop and the numbers will increase. I am still praying and I still have hope that my baby could still make it, but my doctor really doesn’t think so. I am so hurt, I never even imagined this. I have a 8 year old son and a 5 year old daughter, which were both high risk pregnancies. My son was born at 24 weeks and weighed 1 pound at birth. He is completely healthy and normal. With my daughter, I had early contractions the whole pregnancy, not to mention that I couldn’t hold food down and needed an IV everyday in the hospital. Could this mean that my husband and I can’t have anymore children. I am still young and I lost a lot of weight. I exercise and maintain a healthy life, why could this be happening to me? It’s so painful, emotionally. Please help. Thanks.


• At Fri Dec 21, 05:54:00 AM 2007, Kenneth F. Trofatter, Jr., MD, PhD said…

To siniamejia Dec 20: There is always hope, but I am afraid your doctor is correct in telling you this pregnancy will not make it. Your hormone levels are not only low, they have not risen appropriately. You have had two other children, and even if those pregnancies were complicated, that probably has nothing to do with what is going on with this pregnancy. The most common cause of an isolated miscarriage in a woman who has previously had successful pregnancies is a chromosomally abnormal baby. Fifteen to 20% of all pregnancies miscarry and MOST of those are babies that are not chromosomally normal. It is still your baby, and I know you will be sad and you will go through wondering about what "could I have done to prevent this and what could have been", but this is certainly no reason to think that you cannot ever have another baby.

With regard to a D&C, as long as you are not bleeding heavily or have any evidence of infection, you are not in any danger and don't need to do anything else at this time. Waiting is just fine under these circumstances. My only other concern is with your history of weight loss and hyperemesis with your last pregnancy. Some women who lose an excess amount of weight (and I do not know if that is true in your case) will become nutritionally depleted and/or hormonally ‘imbalanced’ and not ovulate regularly. This could also deleteriously impact your pregnancy success but if you are having regular cyclic periods, then this is not likely to be the issue in your case. My best wishes to you and thanks for reading.
Dr T

• At Thu Dec 20, 10:58:00 AM 2007, Anonymous said…
Hi, my wife just miscarried our 7 week old baby. Her hCG levels were about 2,000 at that time. The doctors said that her levels were pretty low when we did the first the pregnancy test two weeks ago. My question is could we have been able to prevent this miscarriage if they placed her on progesterone supplements early on in the pregnancy? Could there have been anything we could have done to prevent this miscarriage?

• At Fri Dec 21, 06:00:00 AM 2007, Kenneth F. Trofatter, Jr., MD, PhD said…

To Anonymous Dec 20: Progesterone probably would not have helped at the point it was found to be “low” and may actually have been contraindicated. If you have had other children, the most likely reason for the miscarriage is that the baby was chromosomally abnormal. Most of those babies are lost in first trimester. If this was a first pregnancy, or if your wife has any other medical problems, there may be other explanations - usually hormonal or immunologic in nature. I am sorry for your loss, but this is one situation in which you should not kick yourselves for having done anything 'wrong.' Miscarriage is always sad - wondering what was, what could have been, and what could we have done different, but if there are no underlying medical conditions to have contributed to the miscarriage, then the odds are you will be successful in the future. My thoughts and best wishes are with you. Thanks for reading!
Dr T

*******

As a focus for further discussion related to these queries, let’s start with progesterone. Following ovulation, what’s left of the follicle (the corpus luteum) begins to make the hormone progesterone that helps to prepare (decidualize) the lining of the uterus (the endometrium) to receive the fertilized egg, aiding attachment and implantation of the early embryo. With implantation, the fetal trophoblast cells start producing the hormone hCG that sends a ‘message’ back to the corpus luteum to ‘stay healthy and keep making progesterone.’ Production of progesterone by the corpus luteum is necessary to support the development of the placenta during the first 7-8 weeks of the pregnancy. After that point under normal circumstances, the placenta itself takes over progesterone production at a level sufficient to maintain the pregnancy.

Decreased progesterone production following ovulation or inadequate production of hCG or placental progesterone has been found to accompany pregnancy abnormalities that result in miscarriage. Defective production of these hormones may precede by weeks the identification or loss of an abnormal pregnancy (Hahlin, et al., Hum Reprod 1990;5:622–626) or ectopic (tubal) pregnancy (Yeko, et al., Fertil Steril 1987;48:1048–1050; Ledger, et al., Hum Reprod 1994;9:157–160). Indeed, there is good evidence to suggest that serum progesterone measured in early pregnancy is the most reliable single predictor of pregnancy outcome in natural conceptions (Al-Sebai, et al., Br J Obstet Gynaecol 1995;102:364–369; Daily, et al., Am J Obstet Gynecol 1994;171:380–383) even in the absence of a pregnancy detected by ultrasound (Elson, et al., Utrasound Obstet Gynecol 2003;21:57–61). Ioannides and colleagues (Human Reprod 2005;20:741-6) demonstrated that even in IVF pregnancies supplemented with progesterone, a single serum progesterone on day 14 post-oocyte retrieval and fertilization (4 weeks gestation), could “highly (but not completely) differentiate between normal and abnormal pregnancies.” Women with viable intrauterine pregnancies “had significantly higher serum progesterone levels (median: 430, 95%CI: 390–500 nmol/l) compared to those who had either an abnormal pregnancy (72, 48–96 nmol/l; P<0.001) or failed to conceive (33, 28–37 nmol/l; P<0.001).” It is interesting to point out that as the result of their findings, they hypothesized “that endogenous progesterone is already sufficient in viable pregnancies and that exogenous progesterone administration will not rescue a pregnancy destined to result in a miscarriage.”

Although progesterone is highly effective at differentiating normal from abnormal pregnancies, it is still not routinely used at most institutions for this purpose because of the expense, inexperience of provider interpretation, and the more widespread availability and high reliability of quantitative hCG testing. hCG can usually be detected by routine blood assays within 10-11 days following conception (7-8 days by highly sensitive assays) and in the urine at 12-14 days (just preceding or coincident with the time of expected menstruation). Serial quantitative blood testing of hCG is a useful approach to evaluation of early intrauterine pregnancy viability and ectopic pregnancies. In 80-90% of normal pregnancies, hCG levels will double every 48-72 hours, peak at 8-11 weeks gestation and then fall off to a stable lower level for the rest of the pregnancy.

If hCG levels are low for a calculated gestational age, this can indicate a nonviable or ectopic pregnancy. However, it is generally recommended that decisions regarding viability not be made by a single hCG level alone. It could be low simply because the pregnancy is not quite as far along as expected (e.g., in circumstances when women ovulate later in their cycles than expected or are not “sure” of their last menstrual period) or as the result of normal variation in hCG levels in different women and different pregnancies. More ominous are situations in which the hCG is not rising appropriately over time.

However, at low levels of hCG, the woman is rarely in immediate danger, even if she has an ectopic pregnancy, so the prudent approach in situations in which the pregnancy is desired is to simply wait, repeat the hCG levels periodically, every 2-3 days, and perform an ultrasound to look for evidence of an intrauterine pregnancy when the hCG level is at the point where that becomes possible. Usually a gestational sac can be seen within the uterine cavity between 4 and 5 weeks and when the hCG is in the range of 1000-2000 mIU/mL. By 6 weeks, a ‘fetal pole’ is usually visible and the hCG is > 5000 mIU/mL; and by 7 weeks, fetal cardiac activity is readily detectable and the hCG is > 20,000. I can relate many personal experiences with patients who started out with an unexpectedly low hCG that went on to have normal, healthy pregnancies, so patience is a virtue under these circumstances.

Labels: early miscarriage, hCG, progesterone

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Readers' Questions Regarding Rh-immune Globulin

Like GBS (see our last post), another common source of questions and confusion in uncomplicated pregnancies is the significance of being an Rh-negative woman. It is another one of those things we screen for routinely, and when found, add to our 'problem lists', but rarely get around to explaining well enough to our patients that they understand why they are being given a 'shot' at 28 weeks and after delivery (and sometimes more often than that). In previous posts we have provided some explanations for all of the above, but questions still arise on a regular basis. Below are two recent comments from readers that include questions many pregnant women may have, but may be afraid to ask their providers, related to the use of Rh-immune globulin to prevent sensitization in pregnancies at risk because a baby may be Rh-positive. Again, to the readers who left the comments, I apologize for editing their posts to the best of my understanding so that others may appreciate their concerns...

• At Tue Dec 04, 01:43:00 PM 2007, Teri said…

I was 2 months along when I found out that I was pregnant. I went to the emergency room after my body rejected my baby (spontaneous miscarriage). They informed that I have Rh-negative blood. They gave me a shot that sounded like 'rogain' and told me it would prevent antibodies from attacking my baby in my next prgnancy. Is that what the shot is for? Will it affect me if my future baby's father is Rh-negative also?

• At Fri Dec 14, 12:50:00 PM 2007, Kenneth F. Trofatter, Jr., MD, PhD said…

To Teri Dec 4: Sorry about your miscarriage. You received Rhogam which is Rh-immune globulin that contains antibodies to Rh-positive blood cells. That helps your body destroy any Rh-positive red blood cells that might have gotten into your blood stream from the pregnancy and helps prevent you from developing antibodies of your own (just as the doctors told you in the ER). If the baby's father is Rh-negative too, then the baby could not be Rh-positive and you did not need the Rhogam, but it will not hurt that you got it either, now or with future pregnancies. In your next pregnancy, tell your doctor that you would like to have the baby's father's blood type tested as well. If he is indeed Rh-negative, then you won't need any 'Rhogam shots' during or after the pregnancy. Just be sure you "know who the Daddy is!" Thanks for your question!
Dr T


• At Thu Dec 06, 05:49:00 PM 2007, HAYAT said…
Hi. I'm 31 weeks pregnant. Today I had the Rhogam shot because I am O-negative. I didn't know what it is. I did search on the net and found out that I should have had it at 28 weeks? I am so worried. Is it too late for this shot? My doctor did take my blood before giving me the shot to perform an antibody screen? She gave me the shot after taking my blood. Does that mean I didn't develop the antibodies against the Rh-D antigen? I'm so confused and so sad. Can you please explain to me and tell me if my baby is at risk? And why didn't they give me the shot at 28 weeks. I'm sorry for my english if I made mistakes.
My name is HAYAT
THANK YOU

• At Fri Dec 14, 12:55:00 PM 2007, Kenneth F. Trofatter, Jr., MD, PhD said…

To Hayat Dec 6: See my explanation above to our first reader. The 'shot' is Rh-immune globulin that contains antibodies against Rh(D)-positive red blood cells. That way, if the baby is Rh-positive and any of its red blood cells get into your circulation, the antibodies will help to destroy those cells before you have a chance to make your own antibodies to them. If you do develop your own antibodies, that is called alloimmunization (or isoimmunization). We frequently refer to that as 'sensitization' as well.

If you had not developed any antibodies before you got the shot, then you can stop worrying. The shot will help protect you from becoming sensitized during the rest of your pregnancy. We generally recommend giving the shot at 28 weeks because very few women will become sensitized before that time and the Rh-antibodies usually hang around until about 40 weeks (full term). The shot does not have to be given right at 28 weeks! Some folks give it a little earlier, and some a little later. Women who have trauma, bleeding, or other invasive procedures (such as an amniocentesis) may receive several 'shots' during there pregnancies. One injection of 'Rhogam 300mcg' will neutralize about 30 cc of whole fetal blood. The important thing is that you did get it in time. You should be fine! After delivery, if your baby does turn out to be Rh-positive, your doctors may check your blood to see how much of the baby's blood got into your circulation and then adjust the amount of Rh-immune globulin to make sure you eliminate the fetal red blood cells. Good luck with the rest of your pregnancy and let us know how things turn out!
Dr T

Labels: rh-immune globulin, Rh-isoimmunization, Rh-negative blood type

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Misunderstanding Group B Streptococcus (GBS)

There is not a week that goes by when I don't get a bunch of questions regarding Group B Streptoccus (GBS) infections, either on this site or at the office. GBS is an endless source of stress, misunderstanding, and sometimes over-reaction. For example, when we told one of our patients recently that she had tested positive for GBS at the time of routine screening in third trimester (35-36 weeks) and that we would be treating her with antibiotics prophylactically when she went into labor to prevent transmission to the baby, all she could mutter was "I'm going to kill him." It did no good to explain to her that even though GBS might be passed back and forth by sexual contact, it is not a sexually transmitted disease. Indeed, this issue of transmission, colonization, "How did I get that?" and "How can I get rid of it?" is a recuuring theme as illustrated by the recent comments below from two of our readers...

• Mon Nov 19, 12:07:00 PM 2007, Anonymous said…

I am 23 years old and I just went for my yearly appointment. They told me I was Group B Strep positive. I was wondering how you get this and if you can get rid of it before you decided to have kids? I do know about the risk if you are to get pregnant but I asked my doctor and she said since I wasn't having any problems with the GBS that she wasn't going to treat it. So should I not treat it even if in the future I want to have children?

• Mon Nov 26, 06:17:00 PM 2007, Kenneth F. Trofatter, Jr., MD, PhD said…

To Anonymous Nov 19: Your doctor is absolutely correct under these circumstances. As many as 30-40% of people are GBS positive and are chronic carriers. There is no sense 'treating' it now, or even if you become pregnant unless you have a urinary tract infection with GBS, premature rupture of membranes, or are in labor. Even if you are 'treated' now, there is a very high likelihood that the treatment would be incomplete or that you will become recolonized in a short period of time. Indeed, the risk of complications from the antibiotics are probably greater than the current risk to you from the GBS! Your immune system needs to learn how to keep it in check (although some folks are immunologically hyporesponsive to certain strains of GBS) and both you and your baby (once you get pregnant) are at fairly low risk for complications if the accepted protocols for treatment and prophylaxis are followed. Besides, the next time you are checked, you may be GBS-negative! I am curious though, why were you checked for GBS at your annual exam, or did you have a GBS urinary tract infection? Thanks for reading, and let us know when you get pregnant! Dr T

• At Fri Dec 07, 10:23:00 AM 2007, Anonymous said…
Hi there. I am 32 weeks pregnant and have just tested positive for GBS with profuse growth! Can you tell me how I caught this please and tell me if my baby will be fine?
Thank you

• At Thu Dec 13, 11:43:00 AM 2007, Kenneth F. Trofatter, Jr., MD, PhD said…

To Anonymous Dec 7: As I have pointed out above, 30-40% of folks are simply 'colonized' with GBS. They carry it in their gastrointestinal tracts and can also have colonization of their vagina. So you didn't really "catch it" from anyone. You might have been a carrier since you were very young. Not all women who carry GBS place their babies at risk. However, it does appear that heavier colonization and urinary tract infections with GBS might indicate that your immune system has not responded well to the bacterium and MAY put your baby at greater risk.

If you have GBS at delivery, and are not treated with antibiotics, your baby has about a 50% chance of also becoming colonized, but even then, only a 1-2% chance of developing complications related to GBS. The important thing from your standpoint is that you KNOW you have tested positive for GBS and you should receive antibiotic prophylaxis if you go into labor or rupture your membranes, so that risk is even much lower by about 50-80%. Urinary tract infections with GBS during pregnancy should be TREATED and then you should be rechecked to make sure the infection has been cleared from your bladder. Good luck to you! Chances are that things will turn out just fine for both you and your baby! Let us know how you do!
Dr T

Labels: GBS and pregnancy

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Recurrent Pregnancy Losses: There are ALWAYS Causes, but They May Not be Related

The following comment was recently received and obsterical history the patient shares is a reminder that even though we would like to have a single 'problem' to treat, sometimes poor outcomes may be the result of a string of isolated events...

• At Thu Dec 06, 11:58:00 AM 2007, JS said…
Dear Doctor Trofatter,
Could you please tell me your opinion on this...

I had two missed abortions (first trimester losses) both pregnancies terminated with D&Cs. My OB did all these tests:
HSG
Hysteroscopy
Karyotype (Maternal chromosomes)
Protein C
Protein S
Leiden mutation (R506Q mutation)
MTHFR (C677T and A1298C mutations)
Cardiolipin IgG, IgM, IgA
Factor II (prothrombin) mutation (G20210A mutation)
Lupus anticoagulant
- PTT (LAC) Screen
- Hexagonal phase
- DRVVT
- Phospholipid Neutralization
Glucose and Insulin challenge test
Antithrombin III
- everything came back negative. My husband's karyotype was also normal.

My reproductive endocrinologist recommended to take baby aspirin and 600mg of progesterone. So I did and had a successful pregnancy then - full term, healthy baby born in 2006. I just had to be induced due to high blood pressure at 39 weeks.

The thing is that we just had another pregnancy loss - twins at 15 weeks. I didn't take any drugs during this pregnancy (no aspirin or progesterone) because I was still breastfeeding until 9 weeks of pregnancy. We lost our twins at 15 weeks of pregnancy after recurrent heavy bleeding. In ultrasound examination, there was a hematoma with a maximal size of 4cm. At the end of pregnancy, my amniotic fluid suddenly broke which caused subsequent contractions and miscarriage. In previous exams, no placental separation was seen and the placentas actually did never separate. I had to have a D&C to remove the placentas. The hematoma was under the membranes (not under the placentas).

So we've had three losses, all tests came back negative and I'm really scared and have tons of questions.

Should I take the baby aspirin, progesterone and/or prednisone next time?

Could the hematoma have been caused by any defects of my uterus (like polyps, poor endomterial lining)? Could it be a result of the previous D&Cs?

Could it be due to a sensibilisation towards a rare blood antigen (such as Kidd or Kell antigen groups)?

And the most important question:
What's the chance of happening this again? All doctors we've consulted think that there is no reason for our losses and that it was "just" bad luck. Do you agree? It seems like too much of bad luck... :( Should we keep looking for possible causes of our losses?

My husband and I are 30 years old with no chronic conditions.

I'm so sorry for such a long post. It's so hard to find a doctor who is an expert in this though and I really need to get answers to at least some of my questions to stay hopeful and to be able to try again...

Thank you very much in advance. This site is great!
Take care,
JS

• At Fri Dec 14, 12:05:00 PM 2007, Kenneth F. Trofatter, Jr., MD, PhD said…

Hi JS: I am sorry for your recent loss, but you have several very good things going for you. Despite your losses, you HAVE carried a baby to term and your 'work-up' to date has been completely negative. So, you really may be one of those folks who has just had a streak of unrelated 'bad luck.' Although I am the first to admit, there will always be other causes for which you have not yet been screened that could have contributed to all of your losses. But, let me make a few other comments.

With regard to the twins, that loss was probably the result of the bleeding. What caused the bleeding is uncertain. You could have had poor placentation, perhaps secondary to scar tissue from a previous D&C. Another possibility is that one or both of the twins was chromosomally abnormal. And, some women who carry nursing into another pregnancy, have less 'receptive' endometrium or increased uterine contractions (even if they don't feel them) because of the oxytocin released from their brains when they nurse. This isn't a problem for all women, but you may be more sensitive than others and that might have caused an abnormality of placentation that then led to the bleeding.

The bleeding by itself is not necessarily the problem, but most women who continue to bleed, eventually develop an ascending infection (blood changes the pH of the vagina and is a fertile culture medium for pathogenic bacteria to overgrow). Ascending infection potentiates the placental problems, usually leading to even more bleeding and contractions and eventually results in rupture of the membranes as happened with your twins.

With regard to next pregnancy, even though we don't know whether or not the aspirin and progesterone were the reason you carried your other baby to term, they certainly aren't a major source of risk for a pregnancy either. So, I would go back to that regimen. Rather than prednisone, if something else is needed, I would suggest heparin or low-molecular weight heparin. If you did take prednisone with the other pregnancy, though, that also would be reasonable; but I will usually stop that in my own patients (unless they have a known autoimmune condition and need it for that reason) by about 20 weeks. Some doctors stop it by the end of first trimester. One word of caution though. There is recent evidence that steroids may be associated with facial clefting, so that may be another reason to go with heparin instead.

Major defects of the uterine cavity were probably ruled out by the workup (HSG and hysteroscopy) your doctor already did, so mark that one off your list. Those procedures should have detected an endometrial polyp, a submucosal fibroid, or scar tissue from your previous D&Cs. Also, red blood cell isoimmunization is something you have probably already been screened for early in each of your pregnancies and even if you were sensitized, that is VERY unlikely to be associated with the problems you have had.

Could something bad happen again? Sure, but even though you have had a poor obstetrical history to date, the different losses may be the result of different, isolated, and unrelated (and less likely to repeat) causes. Other causes could be sought, but at this point, there is a point of diminishing returns and the risk of many 'red flags' that might still not point to a single cause. Based on what you have shared with us here, my sense is the odds are in your favor that you will successfully carry another baby. Good luck and thank for reading!
Dr T

Labels: recurrent pregnancy loss

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Molar Pregnancy vs. Hydropic Degeneration

As detailed in the reader's comment below, she had an early pregnancy loss and her doctors were concerned that she had a molar pregnancy. Sometimes it is very difficult to differentiate by ultrasound a true molar pregnancy from simple 'hydropic degeneration' of a pregnancy that did not get beyond the early stages of embryonic development. However, as I point out in my response, because of the risks of choriocarcinoma it is very important that the diagnosis under these circumstances is ascertained by histopathologic assessment of the products of conception. Many women who miscarry early in pregnancy may be placed in a similar situation, so I thought the reader's story and my response will be of general interest. I have taken the liberty of editing the reader's original comment.

• At Wed Dec 05, 08:20:00 AM 2007, Daisy said…

On Nov 5th, I suffered a missed miscarriage at 11wks 5days which required an emergency D&C due to a suspected molar pregnancy. This is my 1st pregnancy. I am 36years old, have regular 28 day cycles, periods that last 4 days with medium flow, and nothing significant to note other than 5 sisters - all very very fertile.

Besides the obvious shock at facing what I was told at the early pregnancy clinic, I now want to ensure I understand what the histology report says. The histology report results presented "no atypical features", but there are things I do not understand.

The clinical details: "Missed abortion @ 10/40. No foetal pole on ultrasound scan. ??Hydropic changes seen on scan."

The macroscopic report reads: "a bulky amount of haemorrhagic products, 70x40x20mm's. No membranes seen. No foetal tissue seen."

The Microscopic report reads: Chorionic villi, inflamed and degenerate decidua, blood and fibrin, in keeping with retained products of conception. No atypical features seen"

Can you tell me in plain english what this means? We desperately want to have a baby and I'm concerned about maximising my success rates given the gynaecological challenges I could face at my age.
Thank you for any help.
•

At Thu Dec 13, 02:31:00 PM 2007, Kenneth F. Trofatter, Jr., MD, PhD said…

Hi Daisy, sorry for your loss. From what you describe, you had a 'blighted pregnancy' that did not get past the very early stages of embryonic development, although the placental tissues continued to grow for awhile (which is not all unusual) and make pregnancy hormone (hCG) so that your body did not know the baby did not make it.

It is very unlikely that you actually had a 'molar pregnancy', although that is what your doctors were concerned about based on the ultrasound findings prior to your D&C. Hydropic degeneration (enlarged, fluid-filled, balloon-like) of the placental villi is characteristic of molar pregnancies, but also of pregnancies undergoing spontaneous abortion if it has been awhile from the time the baby was lost to the time of miscarriage or if the baby is chromosomally abnormal. First pregnancies have a high rate of miscarriage for reasons I have detailed in my posts, but at your age, there is also a greater chance that the baby had a chromosomal abnormality. These are not uncommon and most babies with aneuploidy are lost in the first trimester.

Your pathology report is not unusual under these circumstances - you had blood clot and the placental tissues were inflamed. The latter does NOT mean you lost this pregnancy as the result of an infection. It simply means that your immune system was reacting to the pregnancy tissues - that might be a good sign and increase your chance for success with a subsequent pregnancy.

True molar pregnancies occur in about 1 in 1000 to 1 in 1500 pregnancies. They are more common in very young women under the age of 15 and in women over the age of 40. Complete molar pregnancies usually result from a sperm fertilizing an egg in which the maternal chromosomes are either inactivated or lost. Occasionally, this results from two sperm fertizing the egg simultaneously. In most cases the maternal chromosomes do remain so the pregnancy tissues end up with three sets of chromosomes (a total of 69 chromosomes rather than the normal 46). No baby or fetal membranes develop in these situations, just the placental tissues. The placental villi may grow at a very fast rate and eventually become 'hydropic.' The uterus is usually enlarged for the gestational age expected for the pregnancy and the ultrasound appearance of the abnormal placental tissues is that of multiple small cysts, giving the classic 'grape-like appearance' of a molar pregnancy. Partial molar pregnancies in which there is an embryo, but also molar changes in the placental tissues can also occur, but these are less common.

Molar pregnancies can be accompanied by heavy bleeeding, very high levels of the pregnancy hormone (hCG), severe nausea and vomiting, hypertension (preeeclampsia-like, but prior to 20 weeks), abdominal pain/cramping and occaionally very large multicystic ovaries (theca lutein cysts) resulting from stimulation by the high levels of hCG. Women can have signs and symptoms of hyperthyroidism as well.

The primary concern of your doctors related to the possibility of a molar pregnancy is that as many as 20% can turn into choriocarcinoma (whereas simple hydropic degneration of placental tissues in a blighted pregnancy does not). Choriocarcinoma can be a very serious and rapidly progressing cancer, but today, almost all cases are entirely treatable if caught early enough. If a molar pregnancy is confirmed on the pregnancy tissues, we usually recommend serial measurements of hCG for at least six months (and in some cases a year) and also recommend that you do not get pregnant over that same time period. That will confuse the opportunity to make the diagnosis of choriocarcinoma and could delay early therapy. Women who have had a molar pregnancy are at increased risk (about 1%) for that to happen again.

Anyway, Daisy, I know you are sad over the loss of your pregnancy, but it appears you did not have a molar pregnancy - and that is good news. Once you have had a chance to recover, it should be safe to try again in a short period of time. Because of youir age, and this recent loss, I would recommend that when you do get to the latter part of the first trimester, you have 'combined first trimester risk assessment for aneuploidy' because you are at greater risk for having a baby with a chromosomal abnormality - but remember the odds are still in your favor that you will not!

Hope this helped. Thanks for reading and good luck to you!

Dr T

Labels: early miscarriage, hydropic placenta, molar pregnancy

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Recurrent Pregnancy Loss and PAI-1: Thrombosis vs. Hypofibrinolysis as the Pathogenic Mechanism?

Well hello again readers! It appears that the 'comment screening' process has been rejuvenated and we are back in business. As feared, however, now I've got to respond to the 50 comments that miraculously appeared in my mailbox yesterday after a week's void. I will do the best I can, but please bear with me while I play catch up between my physical therapy, post-op doctor's appointments, and work!

Below is a great comment from a reader who had the motivation (and fortitude) to tackle my recent series regarding polymorphisms of plasminogen activator inhibitor-1 (PAI-1) and poor pregnancy outcome. I am offering my response to our general readership because it summarizes concisely the major point of enlightenment I had myself during my reasearch on this subject...

Anonymous said...
Dr T.,
Thank you for this very interesting series on PAI-1. From my own personal experience with this defect (4G/4G mutation), I have found that most doctors are still not sure what to make of the experimental data to date. In general, I have received the following comments: 1) I don't think you have a blood clotting problem because you have no history of blood clotting even when you were on birth control pills. 2) I don't test for PAI-1 because regardless of the result I would suggest a person with repetitive miscarriages of your type try Lovenox therapy. 3) I think you do have blood clotting concerns but I don't think this is because of PAI-1. I suspect you have a yet-to-be-discovered variant of Factor V Leiden.

As for the first comment, my only thoughts are that somehow the interaction of PAI-1 and PAI-2 might be responsible for the blood clotting concerns during pregnancy. During one prior miscarriage, it was documented that my Protein S level plummeted in the early weeks of pregnancy, suggesting clotting activity was occurring. I continue to watch for news about PAI-1 and other clotting-related causes of pregnancy loss. I am hopeful that your series will encourage others to look more closely at this interesting gene.Fri Dec 07, 04:20:00 PM 2007


Kenneth F. Trofatter, Jr., MD, PhD said...
To Anonymous Dec 7: Thank you for your thoughtful response. What led to your being tested for PAI-1 in the first place? Was it repetitive early pregnancy losses or other pregnancy-related complications? Anyway, one of the things that dawned on me while writing this series is that the issues related to thrombosis (clotting) and those related to hypofibrinolysis, though related, may actually be SEPARATE issues when it comes to pregnancy complications. What I tried to point out is that even though hypofibrinolysis can lead to thrombosis, it might also lead to other defects (impaired ovulation and/or implantation) that are not related at all to thrombosis! I think this is a subtle point that most providers have missed. Of course when both occur, you've got the double whammy to contend with regard to suboptimal pregnancy outcome.

Incidentally, your doctor may be correct - you could have some other problem that we have not gotten smart enough yet to figure out and, he/she is also correct that an empiric course of therapy is often warranted even if we don't know what we are treating! By the way, protein S levels usually do drop, even during normal pregnancies, although usually this is after the first trimester. You might want to read a post that I wrote earlier this year regarding my first experience (many years ago) with a patient with repetitive miscarriages who only developed a 'lupus anticoagulant' after she conceived. After she got over that 'immunologic hurdle', she did just fine. I have often wondered if activation of the clotting system and the complement system early in pregnancy reflects a suboptimal immune response to pregnancy that can be overcome with time. Could that be your problem as reflected in the rapid drop of protein S activity? Again thank you for reading and best of luck to you!
Dr T

Wed Dec 12, 06:38:00 PM 2007

Labels: PAI-1, recurrent pregnancy loss

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Thanks to Odyssees of George for Grand Rounds 4.12

Thanks to Dr. George at Odyssees of George for this week's colorful Grand Rounds 4.12 and for including a link to my recent post Post-op Dr T. In this post, I relate my own personal (painful, but humorous) experiences as a patient in the post-operative period. It's sometimes beneficial and enlightening for us to view things from the patient's perspective! And now that I have (and still am) I am more anxious than ever to never have to do this again... :)

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

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

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

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

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

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

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

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

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

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

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

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

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

Thanks Sarah •

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

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

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

Dr T

Labels: MTHFR, recurrent pregnancy loss, RPL

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Comments in Cyberspace!

I want to apologize to all my readers, although that for which I am apologizing, I absolutely have no control over! Many of you have left (or tried to leave) comments on Fruit of the Womb over the past week, but none have appeared. I wanted to let you know that they have not gotten to me either. I think the 'comments process' works something like this:

1) You write and submit a comment.

2) Someone at Healthline (not me) reviews the comment and decides if it 'acceptable' to be posted on the site. Mind you, it does not have to be well-written, have good spelling, or even be flattering; it probably does need to be relatively devoid of overt obscenities! The hang-up over the past week or so has occurred at this step; hence my inability to respond.

3) After the comment passes initial screening, it actually gets posted (most of the time, sometimes not!) in the 'comments section' under the post from which it was originally submitted.

4) Simultaneously (most of the time), the comment gets sent to my email box.

5) Only then do I have the opportunity to respond to your comment. I will usually do so somewhere beneath where yours appears in the post, but sometimes will incorporate it into an entirely new post if I think it may be of interest and provide worthwhile information for a good number of other readers. If I do the latter, I will usually leave a comment under your post to let you know where to look for the answers to some of your questions.

6) I try to respond to as many comments as possible, but there are some for which I have no response.

7) The drawbacks to this system are the built-in delays, the occasional 'missed' comments, either posted to the site without my knowledge, or sent to me without having been posted to the site, and most importantly, I never know (unless you write back) whether or not you have actually found your way back to the initial post and seen my response!

Anyway, I certainly hope this situation is rectified soon. Please bear with us until it is. I am sure there will be tons of catching up to do on my part once the 'system' is operative again. In the meantime, thanks to all of you for reading!
Dr T

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Repetitive Miscarriages: Engender Fear and Require Patience

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

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

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

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

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

Dana

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

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

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

Dr T

Labels: recurrent pregnancy loss, RPL

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Thanks MedHelp for an Awesome Grand Rounds Selection!

Many thanks to Enoch Choi, MD at MedHelp for a full-plate of nourishing offerings (gotta get into the Holiday spirit a little bit now that we've finally digested, though not worked off, Thanksgiving dinner) and a lot of hard work at this week's edition of medical bloggers' Grand Rounds! Humble thanks for including a link to my recent post entitled "Late Preterm Birth - Patient and Provider Education is Still Needed." I wish this problem would just go away, but changing attitudes regarding this issue is like trying to climb Mt. Everest dipped in Crisco.

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Post-op Dr T!

Well, it has been exactly a week since my shoulder surgery and let me tell you how much I am NOT enjoying being a patient. I am also not a very good one. Things went pretty much as expected. After placing a ‘scalene block’ in the shoulder, the anesthesiologist had me asleep before I could worry too much about the surgery. As for the procedure itself, I am just as glad I wasn’t a fly on the wall in the O.R. listening to all that shaving, grinding, debridement, and reattachment of ligaments. It was bad enough looking at all the pretty pictures of the operation the orthopedist gave to my wife to show me afterwards. And, for awhile anyway, whenever I go to Home Depot or Lowe’s, I am going to avoid the aisles where my doctor does most of his shopping. That’s okay, he probably looks at what I do with the same jaundiced eye; and, I have to wonder what analogy he would use to describe where I buy the equipment for what I have to do every day! To each his own.

All I remember about the procedure is being wheeled into the O.R., having the mask placed over my face, and being told to “breathe the oxygen.” Yeah, right! The next thing I remember after my “oxygen therapy” is waking up in the recovery room after some unknown period of time (and who knows what I might have said) with a very different smelling oxygen on my face, my shoulder immobilized by a huge cushioned sling, and ice water flowing through the exoskeleton of the whole complex apparatus. All I could think about was what am I going to do if I have to go to the bathroom and is there anyone who would be able to help me out of this thing if I had to scratch my back. The recovery room nurse was very nice although it was clear she was working off a well-rehearsed script. “Breathe deeply, move your legs (also ensconced in waist high hose and compression boots), you are almost ready to go home, let’s review your discharge instructions…” All this was going on while my head was bouncing in and out of la-la land, and I kept wondering why they had to make the recovery room so ‘bright and cheery’, so I rudely interrupted by telling her “I think I am getting a little nauseated.” I guess the thought of me possibly throwing up on the new bionic me was more than she could handle, because she returned in about two seconds with BOTH Zofran and Reglan, for which I was eternally grateful. Mind you, I was feeling NO PAIN at that time.

When the initial wave of nausea passed, and my body had had a few more minutes to mobilize anesthetics from my subcutaneous fat stores and exhale them back into the ambient environment (geez, hope I wasn’t contributing to global warming or the dissolution of the ozone layer), my attention level returned to semi-conscious. At that point, the nurse was obligated to continue with my ‘discharge instructions’ none of which I remember to this moment. Guess that’s why they told my wife to be there with me the whole time. (I also clearly understood why they had forbidden me from riding my motorcycle to the outpatient surgery facility as well. That really would have been tricky! But, I also knew that that was one luxury I was going to h