Case of Elevated Inhibin with a Midtrimester Maternal Serum Screen

I have spent most of my free time this week, the little I seem to have anymore, catching up with all of the readers' comments that accumulated while I took my vacation. One thing that seems to be a constant in medicine is that you can turn off your computer, pager, and cell phone for a few days, but it will all be waiting for you and you WILL pay for it in the end! Not complaining, just a statement of fact. I REALLY do love what I do! Anyway, there were several excellent questions raised by our readers in their comments and I thought that I would share several with you over the next couple of days.

Mon Feb 18, 03:40:00 PM 2008 Kate said...

To Dr. T,
I have been reading everyone's comments and leared a lot. I have also abnormal quadruple screen 1:27 risk for Down syndrome (trisomy 21). I am 32 years old. I had two ultrasounds after that and both were normal. I was just diagnosed with a dermoid tumor in my ovary in this pregancy. From my quadruple screen, the inhibin was elevated at 2.24 multiples of the median (MoM). Everything else was close to 1 MoM. I wanted to see if you know of a case with dermoid causing abnormal quadruple screen. Is there anything associated with high inhibin during pregnancy.
Thanks!

Fri Feb 29, 07:32:00 PM 2008 Kenneth F. Trofatter, Jr., MD, PhD said...

To Kate Feb 18: Inhibin is one of the 'serum markers' that is included in the maternal serum 'quad screen (alpha-fetoprotein (AFP); hCG (the 'pregnancy hormone'); estriol; and inhibin)' performed in midtrimester to screen for certain birth defects, particularly those that involve defects in the body wall (especially, neural tube defects and abdominal wall defects) and also used to reassess risk for certain chromosomal abnormalities (especially trisomy 21 (Down syndrome) and trisomy 18). The primary advantage of including 'inhibin' in the test is that it can help to reduce the 'false-positive' rate of the screening.

Although inhibin is made by multiple tissues in the genital tract, there is not a lot of literature on elevated levels associated with ovarian tumors. I did stumble on one article, however, that described high levels of inhibin in an ovarian teratoma (like a dermoid) in an older woman (Itoh, et al., Pathol Int 2004;54:279-83). More often, high inhibin levels have been associated with hypertensive disorders (preeclampsia) during pregnancy (Sartori, et al., J Thromb Haemost 2008;6:352-8). There is some suggestion that certain patients have these elevated levels as early in midtrimester as the maternal serum screening is done (16-20 weeks) (Kim, et al., J Korean Med Sci 2006;21:452-6). I hope that's all this is and not an indication that your baby has a chromosomal abnormality. I always learn from extraordinary questions like yours, so PLEASE let me know how things turn out. Many of our readers will appreciate your feedback as well. Thank you for reading and so much for writing.
Dr T

Fri Feb 29, 07:32:00 PM 2008

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Grand Rounds Thanks to ScienceRoll

Many thanks to Bertalan Mesko at "ScienceRoll" for Grand Rounds 4.22: The Future of Medicine and for including a link to my post regarding "Abnormal Sperm Morphology and Recurrent Pregnancy Loss." When we evaluate the couple for recurrent early pregnancy loss, the focus usually is on the woman, however, it is a great disservice to leave the male partner out of the work up. He could be a carrier of a balanced translocation or other chromosomal abnormality, be the source of a genetic defect, or simply have very abnormal sperm morphology accompanied by a high percentage of aneuploid (chromosomally abnormal) sperm or a inborn or acquired condition that leads to abnormal DNA structure or integrity.

Labels: recurrent pregnancy loss, sperm morphology

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Cruise - 2 - A Lesson in Group Therapy

The last day of the cruise was overcast, rainy, and cold. For those who had gotten too much sun already, that was probably a blessing! We were not in sight of land and the open water was rougher than it had been – out came the Dramamine. Anyway, not having had time to partake of many of the on-board, below deck activities to that point, the nasty weather was the perfect opportunity to do so. One of those activities was a take-off on the old game show “The Newly Wed Game.” Only in this case, the couples selected to compete ran the gamut of time spent in wedded bliss: the first couple having been married only two days (they took the cruise to get married on Grand Cayman with 57 family members); the second 15 years; and, the third more than 50 years. The cruise director more-or-less randomly selected these couples from the audience, but they couldn’t have been better choices if there had been an actual preselection process.

The game was set up as on the old television show. The women were left on stage and the men were taken to a room off-stage where they could not hear the answers their spouses gave to a series of questions. They were instructed that they HAD to answer every question, they should not be shy nor try to ‘protect’ their spouses or themselves, and they should consider answering with the first thoughts that came into their heads after the question was asked. They were asked to “keep it clean” in a way that avoided nasty language but still conveyed the message, which for these couples could have been an obstacle because they were all traveling with close family and friends. To the credit of the ‘contestants’ in the end, they couldn’t have done a better job if they had had the opportunity to preview the questions and think about their responses. The actual questions were as follows:

• Remember when, where, and some details related to the first time you met your partner.
• What do you think is your partner’s most annoying habit?
• How would your partner complete the following phrase: You haven’t seen ugly until you’ve seen my wife’s….
• When your partner emerges from the shower, does he most resemble a stretch limousine, a Ford pickup truck, or a pink VW Beetle with two flat tires?
• If you had a parrot that lived in your bedroom, what phrase(s) would he be most likely to pick up on and repeat?
• Sex hasn’t been the same since…(when, where, details of surroundings, situation, etc.- leave out the actual intimate details and sound effects)
• The last time you made whoopee it was like which holiday: 4th of July (fireworks and sparklers), Halloween (Tricks and Treats), Thanksgiving (grateful for left over turkey), or Presidents’ Day (honoring the dead)?
• If your partner was suddenly stranded on a deserted island with another woman, would he say he would rather she be a hooker or a nun?

So, now, you may ask, why am I including this ‘game show’ on a website that is supposed to be devoted to ‘expert medical opinion’. The reasons are very simple. First, it was one of the most enjoyable and memorable moments of the cruise. I haven’t laughed so hard in quite awhile, and everyone in the audience (including the ‘contestants’ families, their children of all ages, and friends) would probably agree. Second, it was clear as the ‘show’ progressed that these were all questions that led to conversations that had never transpired between any of the couples over the days/years they had been together. Thirdly, it dawned on me as the atmosphere shifted from nervous laughter (even if “what goes on on the ship, stays on the ship”), and some unease about the position in which the contestants had been placed (AND GRATITUDE THAT IT WASN’T US!), to rapt attention and anticipation of the next responses, drawing the entire audience into the ‘game’ as participants themselves, that a catharsis of sorts was taking place. You could see everyone answering the questions in their own heads as if they had actually been up there on the stage.

What occurred to me at the time (in my 'expert medical opinion') was that this was an amazing form of group therapy. I have observed over the years, the greatest risks to relationships are poor (or, complete lack of) communication, loss of the ability to laugh at/with one another and together, and reluctance to share our personal concerns with other individuals we can trust. This ‘game’ successfully overcame all of those barriers and it did so during the course of only an hour. Even if they didn’t know why, I think everyone left that auditorium with a sense that something special had happened and also with a better appreciation and understanding of their own interpersonal relationships. Incidentally, the contestants were thanked with a standing ovation and I do not think I have ever seen one that was more sincere and from the heart!

So, take the challenge! If you haven’t done so already, answer each of the questions above by yourself and write down your responses. Follow the same rules: answer every question, do not be shy nor try to ‘protect’ your partner or yourself, and consider answering with the first thoughts that come into your head after reading the question (you don’t have to keep it clean!). See if you can get your partner to do the same and then share the results. Then, take the conversation wherever it leads you. If that is to somewhere you haven’t been before, or been to in awhile, keep on with the ‘game’ and please let me know if something really ‘special’ comes out of it!

By the way, one of the best answers was the very last response to the last question by the couple that had been married 50+ years. The woman answered that she thought her husband would prefer to be stranded on the deserted island with the ‘hooker’. Not knowing this, her husband responded, ever so tactfully, that he would prefer a “nun by day, and a hooker by night.” They both laughed until the tears streamed down their faces and so did we!
Ciao!
Dr T

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Dr T Takes a Cruise

Well, I have been gone about a week on a long overdue vacation. Did any of you miss me? I went on a cruise (for the first time) and stayed away from any contact with the internet and work. You guys are NOT work. You are a labor of love and I missed you! Pardon me for not warning you about the absence, but things were so crazy at work before I left that I didn’t have time to inform all of you, and besides it is definitely NOT cool to apologize for something that hasn’t happened yet! I did try to answer all of the 60+ new comments before I left and actually worked on that right up until the time I got in the car.

Incidentally, I checked my email today and saw absolutely NO comments. I KNOW that some of you have written comments/questions/concerns over the past week (since they seem to be expanding exponentially), and that only means the ‘comment fairy’ at Healthline hasn’t prescreened the ones you have submitted and posted them on the website. Don’t worry, when I finally receive them, I will answer as quickly as possible, so please don’t resubmit one if you already have and it hasn’t yet appeared on the site.

Anyway, to purposely avoid all things medical for at least another day, let me tell you about some aspects of the cruise. First, I have a whole new appreciation for DIMENHYDRINATE (marketed as Dramamine, Gravol, and Vertirosan). As I am sure many of you know, this is a medication used to treat ‘motion sickness’ (and it is very safe to take during pregnancy – oops, I already haven’t avoided ‘all things medical’!). Chemically, it is very similar to the antihistamine diphenhydramine (Benadryl) and it is actually a salt of both diphenhydramine and 8-chlorotheophylline (related to the stimulants caffeine and theobromine – CHOCOLATE), although the antihistamine effect predominates.

Motion sickness is the body’s natural response to conflicting reports from your senses (particularly your eyes and inner ears) to your brain regarding motion and women are about twice as susceptible to it as men for reasons I do not understand. Anyway, half the ship woke up seasick after the first night on the cruise and if it hadn’t been for the Dramamine, I don’t think I would have had much fun. Thank goodness it works FAST! Enough of that digression!

It was a short 5-day cruise. The first stop was in the Cayman Islands and while there I visited “Hell” (and returned safely). For those of you unfamiliar with “Hell”, it is a wetlands field that has jagged limestone rock structures covered with black algae that gives it a truly ‘out-of –this –world’ and hellish appearance. If I figure out how to post a picture on this page (I am technically challenged), I will do so in the future. Anyway, we went from “Hell” to 'heaven’ where we sampled many varieties of Tortuga rum cakes – VERY yummy! It would not have been hard to have spent the rest of the trip there! The rum samples (especially the ‘spice rum’) weren’t too bad either! Although the sea was not necessarily my best friend by that point, I did enjoy the beautiful water and the ambience of the people. No scuba diving for me yet because the left shoulder still has not healed. Before I left, I had to stop at the local Harley-Davidson dealership and get a Grand Cayman T-shirt with a pirate on it, of course – ARRRGGH!

The next stop was Calica, Mexico on the Yucatan peninsula. From there we went to see the Mayan ruins at Tulum. Our guide was Mayan, indeed that was his ‘first language’, and his family still lives in an open-sided thatch-roofed hut without running water and electricity in the middle of the country. Gilberto gave us a perspective on the history, culture, philosophy, and religion of the Mayan people that I am sure many of the other touristas didn’t appreciate by simply wandering the ruins on their own. When he found out that I was a physician, he related several tales of the ‘herbal’ cures passed down through the centuries and still used by his people today. He even educated me on the Mayan midwives’ method of predicting the number and gender of children a woman would have by ‘interpreting’ the number, spacing, and appearance of ‘knots’ in the umbilical cord of the first born child – will have to give that one a try! Gilberto was so good, he even made the ritual of ‘human sacrifice’ sound like it was something both understandable and acceptable. I was afraid to ask if his family had yet abandoned that practice, but if I ever go back to visit him again, we will be sure to clarify that point before heading into the mountains to say hello to his Mom and Dad!

Well, today, I won’t bore you with other more banal details of the cruise. In brief, I am currently withdrawing from both overeating and Dramamine (but not too much sun or alcohol). I already miss the vacation and the wonderful people (crew and passengers) we spent time with during the week. If you want to be spoiled, take a cruise! Tomorrow, I will tell you about one of the ‘activities’ on board that was not only entertaining, but gave me some insight into a technique that could be applied to improve relationships with significant others. So for now, and out of respect for the ship’s captain who was Italian,…Ciao!

Labels: dramamine, motion sickness

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Preterm Labor or Cervical Incompetence?: Unclear Diagnoses Complicate Choices for Therapy

Below are three comments from readers that appeared under my recent post on the safety of 17-hydroxyprogesterone caproate (17P) in the treatment of premature labor. They give us pause to reflect on the fact that the distinction between preterm labor and preterm labor and delvery secondary to cervical incompetence is often blurred, a fact that means selection of a therapeutic regimen is often not straightforward, sometimes delayed, and sometimes too late to improve the outcome in another pregnancy...

Thu Feb 07, 02:36:00 PM 2008 Anonymous said...

I have previously been pregnant 3 times and have delivered prematurely with all of them, 17 wks, 22 1/2 wks, and 7 1/2 wks. I am currently pregnant for the fourth time, and will be 16 wks this saturday. My doctors suggest that I have weekly injections of 17-hydroxyprogesterone to prevent preterm labor of this pregnancy, however, they are uncertain as to whether the cause is preterm labor or incompetent cervix. I am very skeptical when it comes to relying on drugs of any sort, and am not sure as to whether I should go through with this treatment or not, only to regret it later I have researched this and have not found enough inormation assuring its safety. I am currently on bed rest. Can strict bed rest keep me from delivering prematurely again, or will I need to have the injections administered? Are there any alternatives to this?

Thu Feb 14, 07:24:00 PM 2008 Kenneth F. Trofatter, Jr., MD, PhD said...

To Anonymous Feb 7: Personally, with your history, I would have placed the cerclage at 13-14 weeks, still followed your cervix with serial ultrasound examinations, starting at about 16 weeks, and considered the 17P if you had any evidence of uterine activity or cervical shortening. I think you would "regret" delivering early again much more than you will ever have cause for regretting the use of 17P. As an alternative, however, we have done a study with a vaginal progesterone compound (Prochieve) that seemed to be most effective in preventing early delivery in women with a short cervix (De Franco, et al., Ultrasound Obstet Gynecol 2007;30:697-705). Since this is a compound with the same 'natural' progesterone that your body and the placenta make, it should be completely safe for the baby. I do NOT trust bedrest alone under these circumstances for various reasons, especially if you have an incompetent cervix (and there are risks such as deep venous thrombosis and pulmonary emboli from prolonged bedrest). And I certainly do not trust progesterone alone in any form for a true incompetent cervix! Good luck and let us know how things turn out. Dr T

Thu Feb 07, 02:51:00 PM 2008 Anonymous said...

Dear Dr. T:

In your opinion, which is more beneficial, a cerclage or 17-hydroxyprogesterone injections? I was recently told What factors make me a candidate for either of these and determine their effectiveness? What are the risks and side-effects, long-term and short-term?

Thu Feb 14, 06:58:00 PM 2008 Kenneth F. Trofatter, Jr., MD, PhD said...

To Anonymous Feb 7: Your questions are straightforward and excellent and the answer is not so simple. At some point I will have to devote another whole post to cerclage. The answer depends on what your doctors think they might be treating and quite frankly, that depends, somehwat, on a detailed review of the previous pregnancy complications that have led you to this point. If you truly have an 'incompetent cervix', personally, I am a cerclage person. Placed early in pregnancy (13-14 weeks), a cerclage carries very low risks and is highly effective if the person who has placed it really does it right. Unfortunately, many cerclages are NOT well-placed and their efficacy has come into question more for this reason than anything else.

Your doctors probably have not been able to determine (based presumably on your past OB history) whether you had problems related to premature labor or whether you have an incompetent cervix. (It can be extremely difficult once the cervix has begun to change to decide which came first, the cervical change or the contractions). Under those circumstances, we will often follow you with cervical ultrasounds, consider using 17P if the history is strong enough, and then place a 'rescue cerclage' if and when the cervix starts to shorten (particularly if there is "funneling" of the membranes into the cervical canal), although this might not happen until 18-22 weeks (and sometimes even later). Of course, placing a cerclage at this point always carries more risk (primarily related to infection) than if placed earlier in the pregnancy, but again, in experienced hands, it is often successful in prolonging pregnancy, especially if very early preterm birth appears imminent if something isn't done (and there is no evidence of intrauterine infection already). The 17P appears to be relatively safe from midtrimester on, but I would suggest you read the blogs I have already posted on this subject. I wish you luck! Please let us know how things turn out.
Dr T

Fri Feb 08, 05:46:00 PM 2008 Anonymous said...

Dear Dr. Trofatter:

If I take 17P for one pregnancy, would I be required to take it for all future pregnancies, or will I be given the option?

Thu Feb 14, 07:29:00 PM 2008 Kenneth F. Trofatter, Jr., MD, PhD said...

To Anonymous Feb 8: If the 17P has a beneficial effect in your case, that will not carry over to another pregnancy. It has no long-term benefits. If you take it for one pregnancy, didn't really need it, and did well, you'll probably do well the next time whether or not you take it! The question is, do you want to take the chance of not taking it if you really do benefit it! Wish the answers were simple, but they are not! Thanks for reading!
Dr T

Labels: 17-hydroxyprogesterone caproate, 17P, cervical incompetence, preterm labor

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Heterozygosity for Homocystinuria and Heterotaxia Syndromes?

Although I have had a hard time keeping up with new posts lately because of added responsibilities at the job that feeds my family, I have tried to keep up with my responses to the many comments I have received.. However, today I opened my mailbox and found that I had fallen behind about 60 in the last 3-4 days. OUCH! Double-OUCH because I leave for a long overdue vacation at the end of this week and will not have internet access for the week I am gone. Anyway, as I have done before, occasionally, I generate fresh posts from interesting questions that make me think or dig into the medical literature. (Sorry, I am the first to admit that I can’t answer all your questions off the top of my head). The comment below from Talya is one of those questions…

Talya has left a new comment on your post "MTHFR Mutations and Congenital Heart Defects":

Hi, my name is Talya. I have a 16 year old son with homocystinuria. I have a 12 year old daughter who was born with a unique congenital heart defect - isolated ventricular inversion. She also has heterotaxia. I was religious about taking my prenatal vitamins before and during my pregnancies, which included folic acid. Early on in my pregnancy with my daughter the doctor recommended that I take high doses of vitamin B6. I do not have an elevated level of homocysteine although I am a carrier of homocystinuria. I would like to know whether my daughter’s heart defect may be related to folic acid/homocysteine.

Talya’s questions appeared under a post from about a year ago in which we reviewed a presentation by Dr. Katharine Wenstrom from Vanderbilt University School of Medicine regarding the association of fetal heart malformations with genetic defects (polymorphisms) in methylenetetrahydrofolate reductase (MTHFR), an enzyme involved in folic acid metabolism. MTHFR 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-adenosyl methionine that is an essential intermediate required to add methyl (CH3) groups to nucleic acids (DNA; RNA), proteins, neurotransmitters, and phospholipids, a process that plays an important regulatory role in the biological functions of each of these.

Dr. Wenstrom pointed out that certain complex 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 is also found in the offspring of women who have mutations in the MTHFR gene. It was also pointed out 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. (Neural tube defects are also more common in babies of women that have MTHFR deficiencies and elevated levels of homocysteine). To support the importance of these biochemical pathways in the normal development of the fetal heart, Dr. Wenstrom 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 complex heart abnormalities.

It is clear from the above that the buzz words of homocysteine and folic acid metabolism, combined with the complications of her children (one with homocystinuria and one with a complex and rare congenital heart defect), led Talya to consider an association that might be a common explanation for their problems. And, I am sure she took hope in the possibility that dietary supplementation with folic acid can often overcome the partial enzymatic defects associated with certain MTHFR polymorphisms. In her case, although the possibility of an association is intriguing, and cannot be entirely ruled out, there really may not be a relationship.

Homocystinuria is an autosomal recessive defect (requires one bad gene from Mom and one from Dad) in methionine metabolism that is caused by a deficiency in cystathionine synthase. It is a rare condition affecting about 1 in 300,000 children born worldwide with higher frequencies in certain countries such as Ireland and Denmark. The rarity of the condition increases the likelihood of consanguinity (known or unsuspected) in couples who end up with children that have homocystinuria.

This condition is associated with an accumulation of homocysteine in the serum and an increased excretion of homocysteine in the urine. Children born with homocystinuria often appear normal at birth, but generally will become “failure to thrive” and develop a very characteristic appearance similar to Marfan syndrome: tall, thin build: long arms and legs; nearsightedness; high-arched feet; knock-knees; depressed sternum (pectus excavatum); and varying degrees of mental and neurological impairment. If homocysteine levels cannot be normalized by therapy and diet, there is an increased risk for problems related to blood clots, atheroscerotic cardiovascular disease, and damage to connective tissue over time, however, for purposes of our discussion here, as far as I am aware, there is no significant increase in risk for congenital heart defects in children born with homocystinuria.

Talya’s other child had ‘heterotaxia’ and an unusual congenital heart defect. She does not have homocystinuria (but I do not know her 'carrier' status). But, the question remains, could maternal heterozygosity for the gene defect associated with homocystinuria (and perhaps a heterozygous state in the daughter) have contributed to her daughter’s conditions. Here I cannot be so sure whether or not there is a relationship! In reviewing the literature, I could find no association between heterotaxia (a condition characterized by cardiovascular malformations and intestinal rotation abnormalities – situs inversus (a mirror image of normal orientation of the stomach and intestines)) and elevated homocysteine levels or homocystinuria. But based on the suspected effects of abnormalities of the same folic acid/vitamin B12-dependent pathways noted above, as well as the observations on defective methylation and abnormal neural crest cell migration that appear to be present in congenital heart defects accompanying MTHFR polymorphisms, I am not closing the door on the possibility of an association that has not yet been recognized! However, there is also known familial predilection for heterotaxia syndromes and for certain types of congenital heart defects, so my greater concern in Talya’s case is that she and her husband may share more ‘bad genes’ than just those associated with homocystinuria!

Thanks for your question Talya. It really is a great one! For the time being, keep taking your folic acid and B12 and if you get pregnant again, let us know the outcome!
Dr T

Labels: congenital heart defects, heterotaxia syndromes, homocystinuria, MTHFR

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Diabetes in Pregnancy - 11 - Hemoglobin A1c and Diabetic Control

In our last post, we discussed the preconceptional evaluation of the woman with pregestational diabetes – this evaluation pertains to women with either type 1 or type 2 diabetes. As part of the evaluation, we mentioned screening for ‘hemoglobin A1c’ and one of my local readers asked me to explain that in more detail. She is, herself, a nurse, and I appreciate her reminding me that sometimes I get ahead of myself without providing adequate explanations to our readers, even those who are medical professionals themselves. I confess this is a common fault of our profession, so let me see what I can do to offer an explanation of what it is and why we suggest including it in the evaluation of diabetic women…

Hemoglobin is contained in red blood cells and is the oxygen-carrying component of red blood cells and, because of its iron content, it is that which makes blood appear red. In individuals without genetic abnormalities of their hemoglobin, hemoglobin A (which stands for ‘Adult’), is the predominant type of hemoglobin found in the red blood cells. In normal (nondiabetic) individuals, more than 92% of the hemoglobin A is simply hemoglobin A. However, a small percentage of the hemoglobin A molecules have sugar (glucose) that is attached to them. These ‘glycosylated’ hemoglobin molecules are called ‘hemoglobin A1c’.

The percentage of hemoglobin A that actually becomes hemoglobin A1c depends on the blood glucose levels over the long-term, generally six to eight weeks (although some believe that 3-4 weeks is more accurate). The higher the average blood glucose levels, the higher the percentage of hemoglobin A1c. Once a hemoglobin molecule becomes ‘glycosylated’, it stays that way for the life of the red blood cell (about 120 days) (Bunn, et al., Biochem Biophys Res Commu. 1975;67:103–9). Short-term fluctuations of blood sugar, such as those associated with meals, do not have much effect on the concentrations of hemoglobin A1c, unless of course, they are abnormal and contribute to an unusually high range overall. For these reasons, levels of hemoglobin A1c are a direct reflection of blood glucose control over time.

In healthy individuals, hemoglobin A1c comprises less than 7% of the total hemoglobin that is present. Conditions that can falsely elevate levels of hemoglobin A1c include kidney failure, hypertriglyceridemia, and folate and vitamin B12 deficiencies that are accompanied by slower rates of red blood cell turnover. Conditions that cause more rapid turnover of red blood cells, such as blood loss, sickle cell disease, or glucose-6-phosphate dehydrogenase (G6PD) deficiency, can falsely decrease levels.

Rahbar and colleagues (Biochem Biophys Res Commun 1969; 36: 838–43) first identified the presence of elevated levels of hemoglobin A1c in diabetics and others have correlated the levels with degree of blood glucose control (Koenig, et al., N Eng. J Med 1976; 295: 417-20). To give some perspective on this, average blood sugars of 90 mg/dL are associated with hemoglobin A1c concentrations of about 5%, blood sugars of 120 mg/dL with 6%, 150 mg/dL with 75, 180 mg/dL with 8%, and so on. The International Diabetes Federation and American College of Endocrinology suggest that ‘normal’ levels of hemoglobin A1c be considered values below 6.5%.

As pointed out in our previous post, poor diabetic control, as reflected in elevated levels of hemoglobin A1c during the time of embryogenesis, is associated with both early pregnancy loss and congenital anomalies. For example, as shown by Miller and colleagues (New Engl Med J 1981;304:1331-1334) a hemoglobin A1c level >8.5% confers a risk of birth defects of approximately 22% versus 3.4% in women with A1c levels <8.5%. On the flip side, normal hemoglobin A1c levels during this critical time in fetal development, even in long-term diabetics with other complications, are generally accompanied by a risk for birth defects close to that of the nondiabetic population.

It is important to note, however, that it is not the hemoglobin A1c level that causes the birth defects, it is the poor diabetic control (high maternal blood sugars). In other words, if a diabetic comes in for preconceptional counseling and has a hemoglobin A1c of 11.5% (very bad), quickly normalizes her blood sugar control according to our strict standards, then gets pregnant a week later and continues good control of her blood sugars during the period of her baby’s embryogenesis, the hemoglobin A1c level may be high, but the baby’s risk should be minimal. On the other hand, if she says “I have normal blood sugars” and she gets to 14 weeks and her hemoglobin A1c is 11.5%, check her glucometer and be on the look out for major congenital malformations!

Labels: diabetes, hemoglobin A1c

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Diabetes in Pregnancy - 10 - Preconceptional Evaluation of Pregestational Diabetics

Although I have left the discussion of pregestational diabetes until the end of our series on “Diabetes in Pregnancy,” that was not done with the intent of diminishing its significance with regard to maternal and fetal morbidity and mortality. Even though pregestational diabetes only comprises about 4-5% of the diabetes we manage during pregnancy, it probably contributes to more significant complications for mothers and babies and to the overall cost of medical care than all of the gestational diabetes detected early in the third trimester. We have often said that the best prenatal care begins prior to conception and almost nowhere is that more true than under circumstances in which a woman has pregestational type 1 (or type 2) diabetes.

I see several major goals of management of the pregestational diabetic:

• Reduce the risk of early fetal wastage
• Reduce the risk of fetal malformations
• Reduce the risk of progression of maternal ‘end-organ’ disease (e.g., kidney, eye, and cardiovascular disease)
• Reduce the risk of pregnancy complications such as preeclampsia, urinary tract infections, and premature labor and delivery
• Reduce the risk of epigenetic ‘programming’ of the baby’s metabolic pathways
• Reduce the risk of fetal damage and loss in later gestation
• Reduce the risk of fetal macrosomia
• Reduce the risk of traumatic delivery
• Reduce the risk of neonatal complications such as hypoglycemia, hyperbilirubinemia, and pulmonary immaturity

To have the greatest impact on all of the above, preconceptional counseling and care, aggressive, ongoing maternal management, and fetal assessment and surveillance throughout the pregnancy are required. A pregestational diabetic should not wait until she has a confirmed pregnancy to see her doctor. Fetal wastage (miscarriages) and major fetal malformations are directly related to the degree of mother’s blood sugar control in early pregnancy. Poorly-controlled diabetics can have 3 to 10 times the fetal malformation rates of nondiabetic women and numerous studies have proven that diabetic women with normal blood sugars during the embryonic period have no higher rate of fetal abnormalities than nondiabetic women.

Major fetal abnormalities now account for 20-50% of the perinatal deaths accompanying pregnancies of pregestational diabetics. Although there is no specific ‘diabetic syndrome’, the most common congenital malformations include neural tube, heart, skeletal, and abdominal wall defects. An unusual condition called ‘caudal regression syndrome’, associated with poor development of the lower fetal spine and severe structural abnormalities below the waist, is rarely seen in babies of nondiabetic women (Kucera, et al., J Reprod Med 1971;7:73-82). The reason preconceptional care is so important is that these malformations can occur as the result of poor control of blood sugars within two weeks after the first missed menstrual period signaling pregnancy (for example, the neural tube should be completely closed by day 26 following conception).

Another reason preconceptional evaluation and care is important is that it provides the opportunity to identify and optimize therapy for other medical problems, related and unrelated to the diabetes, that may put both mother and baby at risk for complications during a pregnancy. For example, long-standing, poorly-controlled diabetes is often accompanied by kidney damage (diabetic nephropathy), eye damage (retinopathy), atherosclerotic disease, hypertension, as well as peripheral and autonomic neuropathies. When these conditions are present, pregnancy can increase progression of these ‘end-organ’ problems and the presence of these underlying defects themselves are red flags for risks associated with pregnancy complications such as preeclampsia, intrauterine growth restriction, preterm delivery, stillbirths, and infectious complications during pregnancy. Type 1 diabetics are also at increased risk for thyroid disease (also autoimmune in origin) at a rate about three times that of the general population.

With all that said and done, in addition to the routine pregnancy laboratory studies, and counseling regarding nutrition, exercise, self-monitoring and expected levels of blood sugar control we have discussed in earlier posts in this series, any woman with pregestational diabetes should have at least the following studies done, preconceptionally, or as early in pregnancy as possible, to establish a reference baseline for counseling and follow-up evaluation during the pregnancy:

• Complete physical examination
• Ophthalmologic examination
• 24 hour urine for protein and creatinine clearance
• Hemoglobin A1c
• Thyroid stimulating hormone
• Fasting lipid profile
• Electrocardiogram with any evidence of vascular disease by history or physical exam and in all with diabetes > 10 years duration

If one is fortunate enough to see the woman for preconceptional counseling, once the laboratory results are available, any new problems (e.g., thyroid disease, hypertension) should be addressed medically in preparation for pregnancy. In addition, I will usually recommend a prenatal vitamin, supplemental folic acid (2-4 mg per day) as a means, perhaps, of reducing certain congenital birth defects, as well as low-dose aspirin (81 mg per day), particularly for those with long-standing diabetes or evidence of vascular disease.

Labels: preconceptional counseling, pregestational diabetes, type 1 and type 2 diabetes

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Abnormal Sperm Morphology and Recurrent Pregnancy Loss?

The following comment was recently received with the request to comment upon the possible association of "poor sperm quality" and recurrent pregnancy loss...

Posted by Concerned_in_Canada to Fruit of the Womb at Thu Jan 31, 11:59:00 AM 2008 "Early Pregnancy Loss - 2":

This is a great thread! Anyway, I have a question regarding recurrent miscarriage and sperm quality. I'm currently facing my third miscarriage in 8 months.(I'm having an ultrasound tomorrow to confirm things...HCG wasn't doubling, now it is but still not looking too good) Anyway, I'm 33 and had my first loss in June 2007 at 6 1/2 weeks, the cause unknown as they don't test first pregnancies. The second was in September at 7 weeks and turned up as a trisomy. Now I'm pregnant again, the levels have been rising but slowly, they've picked up the last few days to double correctly but considering my history I'm not holding my breath for a good result. So, considering we keep getting told by doctors that they are 'sporadic' and 'bad luck' I'm concerned there is more to these chromosomal problems than just chance. We have both had the karyotype testing and all is fine, however my husband has terrible quality sperm with extremely low morphology. His DNA fragmentation is fair. Why with such deformed sperm are our doctors not taking the chromosomal abnormalities more seriously? Can poor morphology increase the risk of miscarriage?
Sorry for the long post...but it’s been a frustrating few months and I'm really starting to lose hope for a healthy pregnancy.

To Concerned in Canada: I thought this was an excellent question and quite frankly I did not have a ready answer. I am not a specialist in Reproductive Endocrinology and even less of one in evaluation of infertility from the male factor (andrology) side of things. The obvious situation in which the male can contribute to recurrent early pregnancy loss is when he is the carrier of a balanced chromosomal rearrangement, such as a Robertsonian translocation, in which he has the correct total amount of genetic material but has a high risk of making sperm that have an incorrect amount and we have discussed this situation in previous posts. Too much or too little genetic material usually results in early miscarriage. We also know that males, who have low sperm counts or very high percentages of abnormal-appearing sperm, have lower chances for achieving conception with their partners. However, our reader asks the question, does the male who is chromosomally normal, but has a high percentage of abnormal-appearing sperm, also contribute to a higher rate of miscarriage in his partner once conception has occurred?

Although the medical literature has supported mixed opinions on this subject over the years, a recent review by Puscheck and Jeyendran (Curr Opin Obstet Gynecol 2007;19:222-28) suggests that “the male contributes to recurrent pregnancy loss due to genetic factors, semen factors, or due to other factors such as age” and sperm morphology may reflect these underlying deleterious conditions. In 1991, Kobayashi and colleagues (Hum Reprod 1991;6:983-6) demonstrated in in vitro fertilization cycles that low percentages of normal sperm morphology were associated not only with lower successful fertilization rates and pregnancy rates per cycle, but also with a greater risk for miscarriages even if embryo transfer was successful.

Egozcue and colleagues (Hum Reprod Update 2000;6:93-105) reported that among infertile couples in which the males were chromosomally normal and there was no identifiable source of infertility in the females, there were greater frequencies of chromosomally abnormal sperm produced by the males as the result of ‘meiotic disorders’ – meiosis being the final stage of sperm production in which the normal chromosomal complement of 46 (23 pairs) is supposed to be halved to just 23 different chromosomes. Among these males they found a greater percentage of sperm with two copies (or none) of single chromosomes, such as chromosome 21 or other autosomes (non-sex chromosomes), two copies (or none) of sex chromosomes (rather than just one X or Y), and sperm that were still diploid, containing 46 chromosomes rather than 23. Obviously, under any of these circumstances, if these abnormal sperm got together with an egg that had a normal number of 23 chromosomes, the resulting baby would end up with too many or too few and the likelihood of miscarriage in early pregnancy would be high.

The results and conclusions of this study were supported by Carrell and colleagues (Obstet Gynecol 2003;101:1229-35) who found the sperm aneuploidy (chromosomal abnormalities) rate in couples with recurrent pregnancy loss to be about twice that of the general population and this was accompanied by diminished percentages of sperm with normal morphology. Similarly, Bernadini and colleagues (Reprod Biomed Online 2004;9:312-20) reported that among men with recurrent pregnancy loss and poor semen quality, elevated frequencies of sperm aneuploidy were found in about 10% of these men who had, individually, sperm aneuploidy rates between 30-34%. In some instances, the high aneuploidy rate may be related to mosaicism (separate populations of cells, one chromosomally normal and the other chromosomally abnormal) that is confined to the germ lines (sperm-producing cells) in the testes (Somprasit, et al., Reprod Biomed Online 2004;9:225-30). Such individuals would appear to be ‘chromosomally normal’ except where it counts!

In addition to sperm aneuploidy, other parameters of sperm evaluation, DNA fragmentation and high DNA stainability, have also been correlated with both abnormal sperm morphology and recurrent pregnancy loss. Carrell and colleagues (Arch Androl 2003;49:49-55) found higher rates of sperm DNA fragmentation in couples with recurrent early pregnancy loss following spontaneous conception. Similarly, Borini and colleagues (Hum Reprod 2006;21:2876-81) found higher early pregnancy loss rates in couples undergoing assisted reproductive technologies, both by in vitro fertilization (IVF) and by conception with intracytoplasmic sperm injection (ICSI) when high sperm DNA fragmentation and abnormal morphology were present. In a very recent (as yet unpublished) study by Lin and colleagues (Fertil Steril abstract online September 2007), abnormalities of sperm DNA structure, high DNA fragmentation and high DNA stainability (HDS), were not correlated with IVF or ICSI fertilization rates, ‘good embryo’ rates or pregnancy rates, but did appear to be correlated higher postimplantation spontaneous abortion rates.

So, in conclusion and in response to our reader’s question, there is evidence to support the premise that in couples with recurrent early pregnancy loss, abnormalities of sperm morphology can reflect underlying abnormalities of chromosome number and DNA structure that may subsequently increase the risk of early miscarriage even after successful conception, spontaneous and assisted. What to do about that is truly outside my realm of expertise, but can probably be addressed by an REI or Andrology specialist! Thanks again for a great question and best of luck to you…
Dr T

Labels: aneuploidy, recurrent pregnancy loss, sperm morphology

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