Recurrent Cystic Hygromas

Kristi has left a new comment on your post "Fetal Cystic Hygromas in First Trimester":

Dear Dr.T,

With my first pregnancy a cystic hygroma was found at 13 weeks. I had an amniocentesis done which came back normal for all genetic and chromosomal abnormalities. We went through all other tests that were offered and at 35 weeks the cystic hygroma was gone. My daughter was born perfectly healthy and now is 17 months and even a bit advanced for her age.

I am now pregnant with baby #2. Today I went for the 1st trimester ultra screening and yet again the baby was diagnosed with a cystic hygroma of 6mm. Have you ever heard of this happening twice? I'm so nervous because I feel like we beat the odds once. Can it happen again? The doctors can't give me an explanation and are providing nothing better than the first time. I will be having the CVS test on Feb 8th and the waiting period is the hardest part.
Any advice would be greatly appreciated.
All the best,
Kristi


As we have reviewed previously, cystic hygromas result from abnormal development of lymphatic tissue between the 6th and 9th weeks of gestation so that the normal drainage pathways either do not develop or are delayed in development. About 80% of cystic hygromas are found in the neck and appear as septated or nonseptated fluid-filled spaces along the back and sides of the neck – often in a somewhat asymmetrical fashion – and highly variable in size. If the drainage pathways eventually develop, the fluid collections will resolve and the baby may only be left with redundant skin in the neck area, classically relected in the ‘webbed neck’ seen in Turner’s syndrome (45 XO). If the drainage pathways never form, the baby may go on to develop obstruction of the internal jugular vein and eventually fetal heart failure associated with hydrops fetalis and diffuse fluid accumulation in the skin and body cavity spaces around the lungs (pleural effusions) and in the abdomen (ascites).

Most cystic hygromas are found in babies with chromosomal abnormalities – the most common being Turner’s syndrome (50%); trisomy 21 or Down syndrome (6.6%); trisomy 18 (5%); trisomy 13 (3.3%); and 47 XXY (1.6%). However, in recent years, we have also discovered that cystic hygromas may be an indirect indicator of major heart malformations and diaphragmatic hernias even in chromosomally normal children. Cystic hygromas may also be found in certain genetic conditions, such as Noonan and Roberts syndromes and in some cases of fetal alcohol syndrome. It is estimated that 15-25% of babies with cystic hygromas are actually chromosomally normal, but not all of these will do well. Indeed, if hydrops fetalis develops in a baby with a cystic hygroma, it is almost uniformally fatal.

Now to get down to Kristi’s question...”Can it happen again?” The answer is yes. It can happen by chance in subsequent pregnancies, and be caused by completely unrelated events, and there appear to be rare instances when it is the result of a familial inheritance pattern – most likely autosomal recessive. In 1990, Watson and colleagues (Prenatal Diagnosis 1990;10:37-40) described the case of a woman who had three consecutive fetuses with cystic hygromas and hydrops – two of which were confirmed to be chromosomally normal – however, none of these babies survived. Teague and colleagues (Matern Fetal Med 2000;9:366-9) reviewed the limited literauture on this subject in their discussion of another instance in which a 19 year old woman had three consecutive chromosomally normal babies that she lost with cystic hygromas and hydrops. More recently, however, and on a more upbeat note, Rotmensch and colleagues (Prenat Diagn 2004;24:260-4) described 18 families in which 18 pairs of siblings were affected by transient, nonseptated cystic hygromas detected during pregnancy. All women underwent amniocenteses and ALL babies were chromosomally normal. Furthermore, all babies had normal hearts, normal growth, no other physical abnormalities, and were reportedly developmentally normal following delivery.

So, Kristi, since you have had a baby with a cystic hygroma who has subsequently turned out ‘normal’, and you now have another baby with a cystic hygroma, my prayer for you is that this is simply the result of a familial inheritance pattern rather than a chance event (because if it is chance, then the risk of chromosomal abnormality is high). If you are fortunate enough to be one of those folks with a ‘familial pattern’ of inheritance where the outcome for the baby is good, then don’t be too hard on your doctors about not answering your questions because this is an extremely rare event! Best of wishes for the rest of the pregnancy, and let us know what happens, please!
Dr T

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When to Start Anticoagulation Therapy for Recurrent Early Pregnancy Loss

For many years now, we have placed women with recurrent early pregnancy loss on low-dose aspirin (81 mg) and heparin, or low molecular-weight heparin such as lovenox, to help them improve their prospects for pregnancy outcome. In some instances this regimen is used because an acquired (e.g., lupus anticoagulant; antiphospholipid antibodies) or genetic (e.g., Factor V Leiden; MTHFR polymorphism; protein C, protein S, and antithrombin III deficiencies; prothrombin G20210 mutations, etc.) ‘thrombophilia’ (tendency to form or maintain blood clots) has been identified. In other instances it is used simply as ‘empiric therapy’ because no particular reason has been identified and, quite frankly, we know that we do NOT have all the answers, because patients request that “anything be done that can be,” and because on the whole it is a fairly safe regimen, although it can be somewhat expensive.

Under these circumstances and, particularly, when used as ‘empiric therapy’, even when a successful pregnancy results, we cannot be entirely sure if our treatment was the deciding factor or it if was simply the result of chance. The original thinking was that somehow the anticoagulation properties of these agents prevented abnormal clotting of the placenta that was preventing the early pregnancy from developing normally. In recent years, we have discovered that other factors may be equally, if not more, important in early growth and development of the placenta as I allude to in my response to our reader’s questions below…

• At Sat Jan 19, 02:46:00 PM 2008, ONE OUT OF SIX said…

Dr. T - what are your thoughts on starting lovenox prior to implantation - either right before, or right after ovulation? And is your opinion the same in regard to a natural cycle as opposed to an ovulation induction cycle in which ovulation is then triggered with HCG? Also - does the patient already being on a daily baby aspirin have an impact one way or the other?

It has been suggested to me that being on both baby aspirin and lovenox (40mg/once a day) could actually inhibit implantation by causing a bleed at implantation site.

Others have said this is not the case at all - and in fact the opposite is true - healthier blood flow to uterus will assist with implantation (that may have been prevented in the past by diagnosed clotting disorders - homo MTHFR C677T and hetero Factor V.)

Last question - can you move to Pittsburgh, PA so I can become a patient? ;-)
Thanks for your insight.

• At Fri Jan 25, 10:53:00 AM 2008, Kenneth F. Trofatter, Jr., MD, PhD said…

To One out of Six: Flattery will get you an answer EVERY TIME! Personally, I rarely will start lovenox or heparin before midway through the luteal phase after spontaneous ovulation or ovulation induction (about day 20-21) unless you have documented antiphospholipid syndrome or another condition that requires chronic anticoagulation. The reasons for that are it may increase bleeding from the ovarian ovulatory site (and, personally, I have taken two young women, who were not even on lovenox or aspirin, to the operating room in the past month with bellies full of blood from that very thing) and I sincerely doubt it does much good until the embryo has reached the uterine cavity and attachment has actually taken place. With all that said and done, on prophylactic doses of lovenox such as you are taking, it probably would not hurt or put you at much risk.

With regard to recurrent early pregnancy loss, however, the anticoagulation properties of lovenox and aspirin may be LESS important than their roles in improving trophoblast invasion and migration! This may be especially true under those circumstances in which 'thrombophilic antibodies' such as lupus anticoagulants, antiphospholipid antibodies, and anti-β2-glycoprotein-1 antibodies are present. These antibodies can bind to the trophoblasts in association with β2-glycoprotein-1 and impair both trophoblast invasion and migration that are necessary for early pregnancy success. Interestingly, heparin and lovenox can reverse the effects of these antibodies by blocking their binding to β2-glycoprotein-1. Anyway, I will put your question and my answer into a brief post on this subject soon (and perhaps a larger series later on) so, thanks for reading, for the excellent questions, and best of luck!

Dr T

Labels: heparin, lovenox, recurrent pregnancy loss, thrombophilias

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Choroid Plexus Cysts - Again!

The following comment was left on my last post in which we responded to a patient's concern that she should have an amniocentesis done because her baby might have a chromosomal abnormality due to her age alone risk despite the fact that she also had very reassuring first trimester risk assessment for aneuploidy. No one can make the final decisions in these circumstances except for the patient, but for her to do so in a way that makes her comfortable with the final decision, we must be careful as counselors to provide accurate information. The situation below reflects a common one (a daily event in my practice) in which the presence of one of the VERY 'soft' markers for fetal chromosomal abnormality creates considerable (and, in mind, unnecessary) anxiety for this woman and countless other patients...

Anonymous said Fri Jan 25, 10:21:00 AM 2008...

Just read the previous message with regard to previous lost pregnancies and age. My situation is similar in that I am 42 with 3 lost pregnancies in the last 10 years. We were not really trying to conceive except for the 1st pregnancy in 1997 which resulted in about 18 hrs of labor in an ER in my 3rd month. Anyway, surprise to us we became pregnant however the baby turns out, having an amniocentesis or any other genetic testing is irrelevant. Now at 19 weeks we had a 2nd ultrasound and my baby was found to have a Choroid Plexus Cyst – one measuring approximately 11 x 7 mm. The doctor told my husband & I that it is relatively a small cyst and located in the skull/brain area that is where fluid usually resides but this fluid developed tissue around it forming a cyst. She said that if the next ultrasound in 2 months shows any other genetic markers (as no other markers were found at this time) then she would insist on full genetic testing, ie amniocentesis, etc. I don't know much about that sort of testing as I have never gone through it. But how can she insist on it??? It's my baby. If I want to know in advance then that would seem to be my decision. The baby will come out either healthy or not and my husband will love & take care of him (it's a boy by the way) the best we can afford to. So who is she to say that she will insist?? All she is doing by running those extremely $$$ expensive tests is to take money out of our pockets that we will need for our new baby. Unfortunately, like many Americans we have very lousy insurance. It was great when we lived in CALIF and even in AZ, but here in Nebraska where insurance companies don't care to compete, the insurance plans just are lousy-unless one works for the railroad or the hospital. *** Just wanted to know your thoughts on this matter and I don't know much about Choroid Plexus Cysts. Thanks from a Housewife in Scottsbluff, NE

Kenneth F. Trofatter, Jr., MD, PhD said...

To Anonymous Jan 25: Your doctor cannot INSIST that you have an amniocentesis (or any other testing) done and you always have the option to find another one if that's the way she/he deals with sensitive situations like this. I have said this before and I will say it again, the diagnosis of 'choroid plexus cysts' and labeling these as an "ABNORMALITY" is one of the greatest disservices ever done to obstetrical patients. I have known women who have terminated perfectly healthy babies (without even having an amniocentesis done to determine the fetal karyotype!) simply because they were told the baby had CPCs and could be at higher risk for a chromosomal abnormality. Personally, I consider 99%+ choroid plexus cysts to be a NORMAL DEVELOPMENTAL VARIANT and many around the world have come to the same conclusion (Bethune, Australas Radiol 2007;51:324-9).

Early studies did show that babies with trisomy 18 have a high rate of choroid plexus cysts (CPCs), but the opposite is NOT TRUE - in other words, MOST BABIES with CPCs do NOT have chromosomal abnormalities (and most babies with trisomy 18 have LOTS of other things wrong with them that would have led to that diagnosis anyway). I counsel patients in whom we find CPCs (and frankly, I wish we didn't even have to tell them, and sometimes I don't) that in the presence of normal fetal growth and in the absence of a MAJOR fetal abnormality or a significant 'marker' for chromosomal abnormality (such as a thickened nuchal skin-fold) the overwhelming odds are that the baby is chromosomally normal and no amniocentesis or other genetic testing is necessary (Ouzouniau, et al., Am J Obstet Gyneecol 2007:196:155). That does not mean, however, I won't do it if that's what they want to have done. Incidentally, most CPCs will be gone by 24-26 weeks and no one has ever shown that the common CPCs that we see are associated with ANY long-term problems for the baby by themselves (DiPietro, et al., J Perinatol 2006;26:622-7).

Take a deep breath, relax, and enjoy the rest of your pregnancy. Stress is more likely to harm your baby than the CPC! Thanks for reading and let me know if I'm wrong!
Dr T
Fri Jan 25, 11:50:00 AM 2008

Labels: aneuploidy screening in first trimester, choroid plexus cysts

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Invasive Diagnostic Testing after Reassuring First Trimester Screening for Aneuploidy?

Attached is a comment from a reader who has written to me before because of a history of recurrent early pregnancy losses. She is now pregnant, has successfully gotten through first trimester, and has had very reassuring combined risk assessment for aneuploidy. She is now wrestling with the decision regarding whether or not she should undergo an amniocentesis for fetal chromosomal analysis anyway, mostly because of her age. In the end, she will have to make that decision herself, but in my response, I offer a perspective, occasionally, overlooked, to her and to others who are facing this decision...

Dr. T - I wrote to you a few months ago on your recurrent loss blog regarding my two 2007 1st trimester losses - I followed your advice to see a good RE (reproductive endocrinologist), we found impaired glucose tolerance, I started metformin, and I am happy to report that I am 15 1/2 weeks pregnant with what seems to be a healthy baby! So, thanks for that.

Here's my new question: I just turned 39. I had a NT done, and my risk for Downs is 1/2000 and my risk for Trisomy 18 is 1/3700 - which is reassuring. I scheduled an amnio anyway, because I am 39, and because of the possibility of the chromosomal problems with my lost pregnancies last year. Now, I am a week away from the amnio, and I am getting paranoid about the risk from the amnio of losing this baby. What I don't quite understand is how a history of previous losses impacts the risk of amnio. Does it make a difference if your previous losses were not spontaneous miscarriages, but missed ones? I was ok with my decision to have an amnio until yesterday, and now I can't get past the thought that something bad might happen. I know that my doctor doesn't care either way if I do the test or not, but I don't want to talk myself out of (or into) something if I am being overly cautious. Thanks in advance.
Liz
Tue Jan 22, 09:25:00 AM 2008


Kenneth F. Trofatter, Jr., MD, PhD said...

To Liz Jan 22: Liz, I am not going to tell you what to do. But, let me put this in perspective. The risk of the amniocentesis in experienced hands is still about twice that of your a priori risk for having a baby with Down syndrome or trisomy 18 (and probably several other chromosomal abnormalities as well) based on your first trimester screening results. In less experienced hands, the amniocentesis risk can be 10 times your first trimester screening risk! With those odds, if you did happen to be the 1 in 1000 (or 1 in 200) who lost their baby as the result of the amniocentesis, the overwhelming odds are that you will lose a completely NORMAL baby.

You are doing very well, you have been through a lot to get to this point, odds are this baby is normal, and you are 39 years old. You may not have many more opportunities if this one is lost. One option to consider, rather than jumping into the amniocentesis now, is to simply have a genetic sonogram done at 18-20 weeks. If that is normal, your a priori risk (based on the first trimester screening results, NOT your age) is reduced by at least another 50% (I generally quote folks 60-80%). So, answer me this...how does a 1 in 4,000 risk sound to you? If something really suspicious is seen at that point such as poor fetal growth, congenital heart defect, or a major marker for aneuploidy (and I am NOT talking about an echogenic intracardiac focus, or even a choroid plexus cyst alone), you could still opt for the amniocentesis with a FISH (fluorescent in situ hybridization) analysis for the more common types of chromosomal abnormalities. This can give you highly reliable results within 72 hours. Using first trimester screening, coupled with this approach, we have not missed a chromosmal abnormality in more than three years, nor lost a baby from an amniocentesis. By the way, CONGRATULATIONS! Again, best wishes to you and please let us know how you do with the pregnancy!
Dr T

Tue Jan 22, 05:27:00 PM 2008

Labels: amniocentesis, aneuploidy screening in first trimester

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Diabetes in Pregnancy - 9 - Use of Oral Hypoglycemic Agents

Gestational diabetes mellitus (GDM) and type 2 diabetes comprise more than 95% of the diabetes complicating pregnancy. Both are characterized by a relative (not absolute) deficiency in insulin as the result of inadequate production/secretion, peripheral insulin resistance, or a combination of the two. The mainstay of medical management of type 2 diabetes for about 40 years has been oral hypoglycemic agents. It is only logical then that their use should be considered in treatment of GDM. If they could be proven to be effective and safe for both babies and mothers, the ease, convenience, patient acceptability, and relatively low cost compared to insulin would favor their widespread use and perhaps use under circumstances of ‘borderline’ glucose intolerance as a means of reducing fetal risks related to macrosomia where intervention with insulin might meet with resistance by both providers and patients alike. Although there are five classes of oral hypoglycemic agents currently in use, sulfonylureas, biguanides, meglitinides, α-glucosidase inhibitors, and thiazolidinediones, my familiarity with the use of these agents in pregnancy is limited to only the first two and I will not venture beyond my level of experience to discuss the others.

The sulfonylureas were the first hypoglycemic drugs that reached approval in this country (for nonpregnant women) and were available even during my training. These drugs appear to exert their beneficial effects by acting directly on pancreatic beta cells to enhance the secretion of insulin from the pancreas. The use of first generation sulfonylurea compounds, such as chlorpropamide and tolbutamide, in pregnant women was discouraged in the U.S. based on limited scientific evidence. These drugs do cross the placenta and their use was associated with severe, prolonged hypoglycemia in neonates whose mothers were taking them throughout pregnancy (Zucker, et al., Pediatrics 1968;42:824-25; Kemball, et al., Arch Dis Child 1970;45:696-701). However, it is not clear from these early studies if the neonatal hypoglycemia might have simply been the result of very poor maternal blood sugar control.

Animal studies in mice and rats also suggested that these agents were teratogenic (caused birth defects) when given during critical stages of embryogenesis (Freinkel, et al., Am J Clin Nutr 1986;44:986-95; Eriksson, et al., Diabetes 1991;40(suppl 2);94-8; Styrud, et al., Teratology;1992;46:473-83). A small retrospective of only 20 women with type 2 diabetes who were taking these agents early in pregnancy reinforced these concerns (Piacquadio, et al., 1991 Lancet;338:866-69). When compared to 40 other pregnant women with type 2 diabetes who were not taking these drugs, 50% (10) of the exposed babies had congenital malformations compared to only 15% in the control group. However, again, poor blood sugar control alone in diabetics during the embryonic period is well-known to be associated with the same birth defects (including, anencephaly, cardiac defects, vertebral abnormalities, and single umbilical artery) that were reported in this small study. Frequently ignored, when the concerns noted above were raised, was a large, randomized, controlled trial published in 1971 and conducted in South Africa that compared the use of first generation sulfonylurea compounds versus insulin in the management of women with type 2 diabetes in pregnancy (Notelovitz, S Afr Med J 1971;45:226-29). In this study, no differences in the rate of birth defects were noted between the two groups.

Over the years, some degree of comfort has been achieved with the use of the second generation sulfonylurea drug, glyburide, in the pregnancy management of pregestational type 2 diabetics and GDM. In contrast to the first generation drugs, very little glyburide appears to cross the placenta to the baby. Furthermore, glyburide carries an FDA category B classification (in contrast to the first generation agents category C) suggesting minimal risk for human teratogenicity. The low risk for birth defects seems to be supported by multiple trials of sufonylureas (and the biguanide drug, metformin, to be discussed later) in early pregnancy in which the risk for major congenital malformations is correlated with poor maternal blood sugar rather than the use of any specific hypoglycemic agent (Hellmuth, et al., Diabet Med 1994;11:471-74; Towner, et al., Diabetes Care 1995;18:1446-51; Langer, et al., J Matern Fetal Med 2000;9:35-41; Hellmuth, et al., Diabet Med 2000;17:507-11; Gutzin, et al., Can J Clin Pharmacol 2003;10:179-83).

In addition to appearing very safe for use in pregnancy, glyburide is also very effective in many women with pregestational type 2 diabetes and GDM. Langer and colleagues (N Engl J Med 2000;343:1134-38) reported a randomized trial of glyburide versus insulin therapy in a randomized trial of 404 pregnant women with GDM. The mean gestational age at which therapy was started was 28 weeks. No significant differences between the groups were found for blood sugar control, fetal macrosomia, or neonatal hypoglycemia. Umbilical cord blood studies at delivery demonstrated no detectable concentrations of glyburide in women who received the drug. Remarkably, only 4% of the women on glyburide in this trial failed to achieve good glycemic control and were changed to insulin. Other smaller studies have demonstrated higher failure rates (generally ranging between 15 and 20%) and greater risk of failure in women identified to have GDM before 25 weeks and older than age 34(Conway, et al., J Matern Fetal Neonatal Med 2004;15:51-5; Kahn, et al., Obstet Gynecol 2006;107:1303-09). Furthermore, a nonrandomized, retrospective cohort trial by Jacobsen and colleagues (Am J Obstet Gynecol 2005;193:118-24), while demonstrating better efficacy of glyburide compared to insulin in achieving good blood sugar control, and similar rates of fetal macrosomia, did also note a greater risk for preeclampsia, birth injuries, and neonatal hyperbilirubinemia in the glyburide group. Confirmation of these findings will have to await future outcome studies.

When using glyburide, we usually begin at a low dose of 2.5 mg once or twice per day. Personally, I prefer the twice per day regimen. It generally takes 4 to 5 days or longer before an impact is seen on fasting and two-hour post-prandial blood sugar levels, but if the response has been inadequate within a week, it is usually safe to double the initial dose. If glycemic control is inadequate during the day, but fasting blood sugars are normal, the morning dose can be increased independently of the evening dose, just as we do with insulin. It is generally recommended that the total 24-hour dose of glyburide not exceed 20 mg and if adequate glycemic control is not achieved within 3 weeks, consider changing over to insulin. Side-effects are usually minimal but women will complain of episodic hypoglycemia and, in some cases, the use of glyburide is accompanied by excessive weight gain unless dietary intake (and exercise) is adjusted to compensate for the increased efficiency of utilization of the ingested calories! In my own experience, glyburide, coupled with diet and exercise, can achieve adequate blood sugar control in about 60-80% of pregnant women.

The other class of oral hypoglycemic agents which has received considerable attention in recent years is the biguanides group of which metformin (glucophage) is the only drug with which I have any familiarity. Metformin appears to work primarily by increasing the sensitivity (reducing the resistance) of the liver and peripheral tissues (muscle and fat) to insulin. To a lesser extent, it also appears to decrease absorption of glucose in the gastrointestinal tract. The actions of metformin have the combined effects of reducing glucose production by the liver and enhancing peripheral glucose utilization. Like glyburide, metformin is also classified by the FDA as a category B drug, however, it does have the disadvantage of being transferred across the placenta to the baby in which levels can be found that are comparable to those in maternal blood (Vanky, et al., Fertil Steril 2005;83:1575-78) and this has contributed to delayed acceptance in the management of the obstetrical patient with diabetes.

Most of the data to support the safety and efficacy of metformin in pregnancy has come from the ‘infertility’ literature, particularly that involving women with polycystic ovary syndrome (PCOS). PCOS is frequently accompanied by insulin resistance. In 2000, Glueck and colleagues (Fertil Steril 2000;74:396-7) presented a case report of a 32 year old woman with amenorrhea and infertility associated with polycystic ovary syndrome (PCOS) who had failure of 7 out of 10 IVF embryo transfers, 1 premature live birth, and two pregnancy losses at 8 and 17 weeks. She was obese, had high fasting serum insulin, androstenedione, and testosterone levels. Although not overtly ‘diabetic’, she was begun on metformin (2.55 g/day) and a weight reduction program and over the course of 4 months, her weight fell from 109 to 91.3 kg (16%), her insulin, androstenedione, and testosterone levels normalized (as did her PAI-1 activity levels).

As a follow-up to this case report, Glueck’s group (Fertil Steril 2001;75:46-52) reported preliminary results from an ongoing pilot study to determine whether metformin could reduce the rate of first trimester pregnancy loss in women with PCOS. They identified 19 women with PCOS who did not have overt diabetes and placed them on metformin (1.5-2.55 g/day) throughout pregnancy. Ten of the women had previously conceived but had miscarried 16 of their 22 pregnancies (73%). “While receiving metformin, these 10 women had 6 normal live births (60%), 1 spontaneous abortion (10%), and 3 normal ongoing pregnancies (30%)” all > 13 weeks. Up to the time of the report, among all 19 women receiving metformin, 9 (47%) had normal term live births, 2 (11%) had normal, but preterm births at 33 and 35 weeks, 6 (32%) had normal ongoing pregnancies beyond 1 weeks, 2 (10.5%) had first trimester miscarriages. For purposes of our discussion here, it is important to note that no adverse maternal side-effects, nor birth defects were attributed to metformin in this small study. Thus, metformin alone appeared to improve pregnancy outcome in a group of PCOS patients who had either had, or were at increased risk, for early pregnancy loss.

In subsequent studies, Glueck and colleagues (Fertil Steril 2002;77:520-25) demonstrated in 72 nondiabetic PCOS women that the use of metformin preconceptionally and continued throughout pregnancy not only reduced the risk of early pregnancy loss, but also reduced the risk of developing gestational diabetes (3% in the treated group vs 23% in controls). Again, though the total number of patients was small, they demonstrated no increased risk for congenital malformations in the metformin-treated patients (Glueck, et al., Hum Reprod 2002;17:2858-64). In follow-up evaluation over the first 18 months of life of 126 infants born to 109 women with PCOS who received metformin throughout pregnancy, these investigators also found no significant abnormalities of growth, motor, or social development compared to matched controls (Glueck, et al., Hum Reprod 2004;19:1323-30). A recent meta-analysis of pregnancy outcome after first trimester exposure to metformin actually has demonstrated a statistically significant protective effect for fetal malformations among metformin recipients (1.7%) compared to disease-matched controls (7.2%) (Gilbert, et al., Fertil Steril 2006;86:658-63).

Recently, preliminary results of a prospective, randomized trial comparing metformin and insulin in the management of GDM have been reported (Moore, et al., J Reprod Med 2007 52;1011-15). Although only 63 patients (32 metformin- and 31 insulin-treated) were included to date, fasting and two-hour post-prandial blood sugars were comparable between the groups and there were no differences in fetal birth weights, respiratory distress syndrome, neonatal hypoglycemia, hyperbilirubinemia, or neonatal intensive care unit admissions. None of the patients enrolled to date failed metformin therapy and required insulin and most were controlled on the initial dosing regimen of 500 mg twice per day. Maternal outcomes also did not differ between the two groups. Against this background, it should be noted that at least one older study (Helmuth, et al, S Af Med J 1984;65:635-7) reported a significantly higher prevalence of preeclampsia among 50 women treated with metformin compared to 68 treated with a sulfonylurea compound and 42 treated with insulin during pregnancy (32% vs 7% vs 10%, respectively; P < 0.001). In the same study, there was also a higher rate of perinatal mortality (11.6% vs 1.3%; P < 0.02) in the group treated with metformin in the third trimester. More recent studies do not support these earlier findings. Glueck and colleagues (Diabet Med 2004;21:829-36) found no higher risk for preeclampsia in 90 PCOS women treated throughout pregnancy compared to 252 healthy women with no history of PCOS.

When dosing metformin, we usually begin at 500 mg twice per day. Usually a beneficial effect on glycemic control will be seen within 3-5 days. Again, if the response has been inadequate within a week, the dose can be increased by 500 mg per day on a weekly basis until 2,000 (occasionally 2,500 mg) per day is reached. My first increment above the initial dosing regimen is to 500 mg three times a day, and then if necessary, 1,000 mg twice per day. If adequate glycemic control is not achieved within 3 weeks, one can either change to or add insulin to the current metformin regimen. Due to its insulin ‘sensitizing’ effects, required doses of insulin, when used in conjunction with metformin, are usually about half those necessary to achieve good blood sugar control without metformin. Side-effects of metformin include gastrointestinal intolerance and, even though food decreases its absorption, it is still suggested that metformin be given with meals during pregnancy to minimize this complication. Hypoglycemia is generally rare with metformin, but it can occur and in rare circumstances (0.03 cases per 1,000 patients) lactic acidosis has been described.

In our next post in this series, we will discuss complications related to and management of type 1 diabetes during pregnancy…

Labels: gestational diabetes, glucophage, glyburide, metformin

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Diabetes in Pregnancy - 8 - Basic Approach to Insulin Therapy

In our last two posts on diabetes in pregnancy, we discussed the importance of diet and exercise and the value of self-monitoring as the foundations of blood sugar control. If these measures fail to achieve normalization of blood sugars (fasting values < 95 mg/dL and 2 hour after meal values of < 120 mg/dL), then medical therapy should be started. Although there are various opinions regarding approaches to medical therapy and endpoints for adjusting and monitoring efficacy of therapy, most will agree the primary goal should be normalization of blood sugars. Secondary goals include, among others, minimizing fetal overgrowth (macrosomia), avoiding intrauterine fetal death, reducing the risks for fetal damage during the delivery (e.g., shoulder dystocia, nerve palsies, bone fractures) resulting from fetal macrosomia, and preventing neonatal complications related to hypoglycemia and hyperbilirubinemia, as well as admissions to the neonatal intensive care unit.

During my training (too many years ago), insulin was really our only option for therapy for the woman with gestational diabetes mellitus (GDM) and it is still the ‘gold standard’ against which other approaches to therapy must be measured. Despite the fact that insulin is comparatively expensive, requires multiple injections during the day combining different types of insulin to optimize control, requires frequent adjustments in dosing regimen (requirements change and usually increase as the placenta grows, hormone production increases and pregnancy progresses), is prone to greater risks for complications related to self-administration dosing errors, variability of response, and hypoglycemia, and often seems to terrify patients, in my experience its use can be learned by most patients (with or without the help of other family members) and, when well-understood by the patient in terms of her own responses, offers remarkable flexibility in management, accommodating variability in dietary intake and activity levels.

When estimating a starting dose for insulin, we use a combination of maternal weight (in kg) and pregnancy trimester. First, a 24-hour total insulin dose is calculated using 0.7 units (U)/kg in first trimester, 0.8 U/kg in second trimester, and 0.9 U/kg in third trimester. (To quell the usual concerns of our patients that this is “too much,” I usually tell them that others recommend starting doses as high as 0.8 U, 1.0 U, and 1.2 U, respectively, in each trimester). Two-thirds of the total dose is given in the morning before breakfast and one-third at night (half of that before supper and half prior to bedtime). Two-thirds of the morning insulin dose is then given as an intermediate-acting insulin (such as NPH) and one-third as a short-acting insulin (such as Regular insulin or Humolog) with both being given in a single injection. The goal of the combination therapy is to distribute the insulin action throughout the day, minimizing the number of injections that are required, and accommodating for the meals and snacks that will be consumed during that period of time. The insulin used just prior to supper is again the short-acting type alone, and prior to bedtime, the intermediate acting type alone. To give an example of how this works, suppose we have a 100 kg woman who is diagnosed with gestational diabetes at 30 weeks gestation:

_The TOTAL 24-hour insulin dose is 100 kg X 0.9 U/kg = 90 U insulin;

_The prebreakfast dose then totals 60 U (two-thirds of 90 U), with 40 U (two- thirds of 60 U) given as intermediate-acting insulin and 20 U as short-acting insulin;

_The evening dose then totals 30 U, divided as a presupper dose of 15 U of short-acting insulin; and,

_A bedtime (qhs) dose of 15 U of intermediate-acting insulin.

Some women can be adequately controlled by combining both of the evening doses of insulin prior to supper (just as before breakfast), but we have found over the years that, generally, distribution of dose and insulin type as detailed above achieves a more stable, physiological control of blood sugars and minimizes risks for large swings in glucose levels over the 24-hour period.

The combination of short- and intermediate-acting insulin allows for altering doses in a way that readily accommodates the patient’s eating and activity habits. Within a week (if not sooner) after starting insulin, adjustments in the insulin regimen can be made that are based on the fasting and 2-hour after meal blood sugar determinations (detailed in our last post on this subject). For example, if the blood sugars two hours after breakfast are still elevated, but the 2-hour after lunch levels are normal, then the morning dose of short-acting insulin can be increased independently of the intermediate-acting insulin to improve control earlier in the day with very little, if any, effect on control later on. Similarly, if the after breakfast blood sugars are good to start with, but the afternoon ones are elevated, increasing the morning intermediate-acting insulin alone might adequately improve control. I think you get the picture without belaboring all the alternatives! Other options for administration of insulin exist, for example insulin pumps, more frequent injections of short-acting insulin, and ‘sliding scales’ based on individual calculated responses to various foods, or to cover unexpectedly (and intermittently) elevated blood glucose levels, but most women are well-handled on the regimen detailed above.

One of the big fears (other than that of the shots themselves) that women starting insulin have is that they will get low blood sugar (hypoglycemia). As we discussed earlier in this series, gestational diabetes is, usually, more akin to type 2 diabetes than to type 1 diabetes. Women with GDM, therefore, tend to be relatively ‘insulin-resistant’, especially if they are overweight to start. Indeed, many women with GDM require much higher doses of insulin than is calculated as a ‘starting’ dose based on weight and gestational age. Hypoglycemia, therefore, is not a frequent problem in most cases of GDM and when it does occur, it is usually accompanied by symptoms (such as shakiness, palpitations, sweating, anxiety, weakness, difficulty talking) and it is rarely as profound, or as unpredictable, as it is in women with long-standing type 1 diabetes. Since the ‘symptoms’ of hypoglycemia are so common in pregnant women anyway, we encourage our patients on insulin not to overreact when they think their blood sugars are getting low, but to recheck their blood glucose levels before ‘self-medicating’ with additional caloric intake. Most women with GDM do not need prescriptions for glucagon to manage periodic lows in their blood sugars. However, as a word of caution, I always do worry if a woman’s insulin requirements begin to drop dramatically over what has been needed to maintain good glycemic control. This may be a sign of ‘placental insufficiency’, signaling a baby or a pregnancy at risk for complications but it is, again, more of a concern in type 1 diabetics than in women with GDM.

Although the primary reason for starting medical therapy in women with GDM is control of blood sugar levels, others have suggested that maternal blood sugar control alone, even if it appears adequate, may not prevent complications of pregnancy. Buchanan and colleagues (Diabetes Care 1994;17:275-83) identified women between 29 and 33 weeks with GDM that appeared to be well-controlled on diet alone, whose babies had abdominal circumference measurements that were greater than the 75th percentile, suggesting risk for fetal macrosomia , and hence risk for many of the other complications detailed in the first paragraph above. These women were randomized either to continue on diet alone or to have insulin added to their diet treatment. Interestingly, despite no significant differences in blood sugar measurements between the two groups, the insulin-treated women had only a 13% rate of fetal macrosomia compared to the 45% rate seen in the women treated with diet alone.

I have begun the discussion of medical therapy for GDM with a basic review of insulin therapy simply because of its historical significance, because it remains the ‘gold standard’ for care, and because it is the final resort if other approaches to therapy fail. However, in recent years the safety and efficacy of oral hypoglycemic agents have also been well-documented and, indeed, in many institutions they have become the treatment of first choice in women with GDM. A discussion of these drugs will be the focus of our next post on the topic of diabetes in pregnancy…

Labels: fetal macrosomia, gestational diabetes, insulin therapy in pregnancy

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A Case of Robertsonian Translocation and Turner Mosaicism

The reader below recently lost a pregnancy early in gestation. During the course of her work-up afterwards, she was found to have not only a balanced Robertsonian translocation of chromosomes 13;15, but a low level of mosaicism for Turner syndrome (cells that contained only one X chromosome) as well. All the cells, including the ones containing only one X chromosome also contained the balanced 13:15 Robertsonian translocation. Her questions regarding her prospects for having a “normal baby” are excellent and I have tried to interject my answers into the flow of her comments/questions. For the sake of readers not familiar with Roberstonian translocations, I would refer you to my previous post on this subject, but I will include pertinent information from that previous post to clarify my comments. Before we start, let me review what a Roberstonian translocation is.

Five of our chromosomes (13, 14, 15, 21 and 22) have ‘short arms’ that are very small and which contain no essential genetic material. These 5 chromosomes are called acrocentric chromosomes, or ‘acrosomes.’ Acrosomes have a tendency to fuse at the centromeres with other acrosomes, thus producing a ‘single’ larger chromosome made up of the ‘long arms’ of the chromosomes of origin, connected by a single centromere. When this occurs it is known as a ‘Robertsonian translocation.’ If no essential genetic material is lost (or gained) in the process, the individual with such a chromosome is said to have a ‘balanced’ translocation and appears ‘normal’ although they now have only 45, rather than 46, chromosomes in each cell...

Fanny has left a new comment on your post "Robertsonian Translocations" Sun Jan 06, 06:08:00 AM 2008

Hi Dr Trofatter,

I am very grateful to have found your website since I live in Singapore and the statistics/study on chromosomal translocation are scarce and I am feeling helpless. My gynecologist is still locating for genetic counseling for me. I am 32 and got pregnant after trying to conceive for two months. I eventually suffered a missed abortion at 10 weeks. My baby had a heartbeat at 7 weeks and the heartbeat stopped at 7 weeks 3 days. I requested to do a chromosomal analysis and test result was as follow: “Chromosome analysis on this peripheral blood specimen demonstrated the presence of Robertsonian translocation between chromosomes 13 and 15 and an apparent low level mosaicism for Turner syndrome (2 out of 50 cells)”. From my visual layman explanation, one chromosome 15 has gone over to attach one chromosome 13.

Karotype: 45,XX,der(13:15)(q10;q10)[48]/44,X,der(13;15)(q10;q10)[2]. I was given the hardcopies of two test specimens, one with only one X chromosome and the other with two X chromosomes. Both the two specimens contained the (13;15) abnormality.

My first set of question is: Are my chances of conceiving a baby with the right total amount of genetic materials similar to the more common (13;14) translocation in Gina’s case? Can I assume that the gametes analysis you did for Gina is similar to mine and my success rate is 33% with about 15% chance of my baby being a carrier? Or is my (13:15) translocation a very rare case and I have a very low chance of giving birth to a healthy baby? My husband has a normal karyotype.

Robertsonian translocations can occur between any of the acrosomes although this is not entirely random and the most common forms of these occur between chromosomes 13 and 14 (75%), 14 and 21 (10%), and 21 and 22. Robertsonian translocations of chromosomes 13 and 15 are less common, but the math plays out the same way as I detailed for our reader in our previous post. I will substitute Fanny’s 13;15 translocation into the scheme so that our other readers can follow the explanation:

Because of the two chromosomes that are connected to each other, when individuals with Robertsonian translocations produce eggs (which normally involves halving the total chromosomal complement from 46 down to 23 in preparation for fertilization with Dad’s 23 chromosomes), some of these will not contain a ‘balanced complement’ of chromosomal material. In the case of our reader, who apparently has a balanced 13;15 translocation, the possible eggs she will produce during meiosis may contain:

• 1) One free copy of chromosome (chr) 13 and one free copy of chr 15.
• 2) The translocation (chr 13;15) chromosome alone (which contains one copy of chr 13 fused with one copy of chr 15).
• 3) Chr 13;15 + one free copy of chr 13 (essentially, an egg with TWO copies of chr 13 rather than just one).
• 4) One free copy of chr 13 (and NO copy of chr 15).
• 5) Chr 13;15 + one free copy of chr 15 (TWO copies of chr 15 rather than just one).
• 6) One free copy of chr 15 (and NO copy of chr 13).

Obviously, 3 through 6 are eggs that have the incorrect number of chromosomes (either too little or too much genetic material) rather than the normal number or equivalent complement of 23 different chromosomes. When these eggs get together with the ‘normal’ sperm from her partner (which contain 23 chromosomes, that include one free copy of chromosome 13 and one of 15), the following possibilities result (in the same order as above):

• 1) Two free copies of chr 13 + two free copies of chr 15 = NORMAL
• 2) Chr 13;15 + one free copy of chr 13 + one free copy of chr 15 = translocation ‘carrier’ (just like Mom) with NORMAL TOTAL amount of genetic material
• 3) Chr 13:15 + TWO free copies (one EXTRA from Mom and one from Dad) of chr 13 + one free copy (from Dad) chr 15 = TRISOMY 13
• 4) Two free copies chr 13 (one from Mom and one from Dad) + ONE free copy of chr 15 (NONE from Mom and one from Dad) = MONOSOMY 15
• 5) Chr 13:15 + one free copy of chr 13 (from Dad) + TWO free copies (one EXTRA from Mom and one from Dad) chr 15 = TRISOMY 15
• 6) ONE free copy chr 13 (NONE from Mom and one from Dad) + two free copies of chr 15 (one from Mom and one from Dad) = MONOSOMY 13.

Therefore, to answer one of our reader’s questions, mathematically, she has only a 2 in 6 (33.3%) chance of having a baby that has the correct TOTAL amount of genetic material; one of these will be entirely chromosomally normal and the other will be a translocation ‘carrier’ just like herself. Two-thirds of her babies are at risk for being chromosomally ABNORMAL.

But, her actual risk for delivering a baby with a chromosomal abnormality is much lower than this. The monosomy 13 and 15 embryos will not be successful at all and the trisomy 15 embryos also have very little chance of surviving much of the first trimester. Most trisomy 13 embryos will also be lost early in first trimester as well and the few that survive will have only a small chance of surviving the pregnancy and even a smaller chance of living more than a few hours or days after birth. Indeed, the ‘selective forces’ are so strong against these chromosomally abnormal babies that at least two-thirds of her pregnancies in which a pregnancy is actually confirmed will be chromosomally normal and the chances of actually DELIVERING a chromosomally abnormal baby are probably only about 1%! The overall risk of miscarriage is about 25%.

Now, I should mention this because it has also been a source of confusion (and some anguish) for some readers in the past. All that I have said to this point only pertains to balanced Robertsonian translocations in which the two chromsomes that are joined together are DIFFERENT. If the balanced translocation involves two of the same chromosomes, such as 21;21 or 14;14 or 13;13, etc, then no normal babies are possible. They will all have either three copies or only one copy of that particular chromosome.

My second question is: Is my “apparent low level mosaicism for Turner syndrome (2 out of 50 cells)” a great cause for concern?

This is a harder question to answer. I do not think it is a “great cause of concern” but it may or may not slightly increase your risk for having a baby who survives with a chromosomal abnormality. The reason I am hedging is that in circumstances with low levels of mosaicism (two populations of cells with different chromosomal complements in a single individual) not all bodily tissues may be affected equally by the mosaicism. In other words, your ovaries (and eggs) may contain an equal, a higher, or even a lower percentage of cells that contain the Turner syndrome (single female X chromosome) genetic make up.

My third question is: Given my (13:15) translocation and mosaicism for Turner syndrome, what are the specific tests that I should opt for if I undertake 1) amniocentesis or 2) CVS? And if CVS is done very early, is there a chance the baby will develop an abnormality in the growth of the baby’s limbs?

This is your choice and depends on how urgently you need to know early in the pregnancy and your level of risk tolerance. Remember, even in experienced hands, the risk of losing a baby as the result of chorionic villus sampling (CVS) is probably about 1%, whereas the risk of an amniocentesis at 16 weeks is only about 0.1% (1 in 1000). The risk of limb reduction abnormalities following CVS has been minized by performing the procedure later in first trimester.

Some women with balanced translocations will simply let nature take its course in first trimester rather than risk losing a normal baby as the result of a CVS. In other words, if the baby is lost, it was probably chromosomally unbalanced. The tougher decision occurs when the baby appears ‘normal’ and has survived first trimester – should you proceed with an amniocentesis or not because the baby has at that point a higher likelihood of having a balanced chromosomal complement (either completely normal or as a balanced translocation carrier). Again, that’s a personal decision. Most geneticist will tell you that because of the chromosomal rearrangements, the baby is at a slightly higher risk for having a subtle chromosomal abnormality as well, and would recommend the amniocentesis at that point. You also might consider that more seriously because of your Turner’s mosaicism.

My fourth question is: Will amniocentesis be able to diagnosis if my baby has is a translocation carrier or it is only possible to know after she/he is born and a chromosomal test is carried out?

Yes, the amniocentesis should be able to tell you that before the baby is born. It may not be able to tell you, however, if the baby has a mosaicism or, even if a mosaicism is detected, how extensive that may be.

My last question is: My hubby and I really love to form a complete family and is determination (keep trying) the best solution? I understand that IVF with PGD does increase my chance of having a healthy embryo but it also subjects me to the risks of failure under IVF although I have no problem with my progesterone levels. Thank you very much. Best Regards Fanny

Quoting myself from my previous post, with regard to the question of IVF (in vitro fertilization) and PGD (prenatal genetic diagnosis), I have a significant amount of ambivalence. If you have the money to burn, these are certainly options, but they are very expensive procedures. And, if you have no difficulty conceiving and are willing to trust nature to do the right thing, as pointed out above, the risk for actually delivering a baby with an unbalanced amount of chromosomal material is so small, that it is often simply waiting until the dice roll correctly to have a normal baby. I know that can be difficult psychologically and at times physically. However, because there is nothing that can be done to correct a translocation, if one can accept the fact there is an increased risk for miscarriages, and that when these occur, it is probably the result of a chromsomally unbalanced fetus, dealing with the pain of pregnancy loss may be a little bit easier.

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Is 17-Hydroxyprogesterone Caproate (17P) Safe for the Baby During Use in Preterm Birth Prevention?

Recently, I received the following two comments from readers regarding their concerns about the use of 17-hydroxyprogesterone caproate or 17P (formerly known as Delalutin) in the management of preterm labor. Their specific concerns are related to the possibility of congenital birth defects. My greater concern is that despite the fact both of them previously had preterm births, I am not sure either one of them has a really good reason to be placed on 17P, but we will save that discussion for another day!

•At Wed Jan 02, 10:11:00 AM 2008, Anonymous said…

Hello- I'm currently 15 weeks pregnant with my 3rd child. I have six year old twins that were born at 34 weeks (I originally went into PTL at 29 weeks). With a few rounds of Mag Sulfate and bedrest and drugs at home I was able to hold off until 34 weeks for delivery. My OB is suggesting Delalutin at 16 weeks in an effort to avoid the possibility of preterm labor with the pregnancy. I'm concerned because there are so many horror stories on the web about limb deformitites and stillborn babies from delalutin. Most seem to be from the 70's - has the product changed much since then? Wouldn't it make sense to assume my previous pre-term issues were related to a twin pregnancy?

Thanks

•At Wed Jan 09, 10:38:00 AM 2008, Anonymous said…
I too am in a similar situation. I gave birth to my son at 29 weeks due to a severe infection. My doctor also wants to put me on Delalutin injections starting at 17 weeks with my current pregnancy. I have researched this injection and found similar results to yours in terms of limb and genital defects as well as still births. I am extremely concerned and wondered in this medication has improved at all from the 70's as well. Any information would be greatly appreciated!

The use of 17P to help prevent early miscarriage and preterm birth dates back to the time before I started my residency in OB/GYN. In fact my first three children were 17P babies after my wife had had three consecutive miscarriages. Although there were no good controlled clinical trials, the teaching was that “It worked,” the side-effects for the mother were minimal (mostly injection site discomfort), and there did not appear to be the same level of risk for birth defects that was seen with DES. We went for a long period of time, however, when 17P was dropped from our regular armamentarium as we tried certain other drugs to help interrupt and delay preterm labor and birth. Unfortunately, none of these drugs have been very effective, almost all have unsatisfactory side-effects (and, in some situations, may be dangerous), and despite all efforts, the preterm birth rate has only continued to increase in the U.S. as we have addressed in this forum on previous occasions.

Although it is very difficult to predict who will have preterm labor and delivery, certain risk factors are associated with it and one of the most reliable is a prior history of preterm birth. Indeed, the earlier in gestation a prior preterm birth occurred, the greater the likelihood a woman will deliver prematurely again. And, if she has two or more preterm births, her risk can approach 50% that the next baby will be delivered early.

It was with cautious optimism then that we welcomed, a large, multicenter, randomized, double-blinded, placebo-controlled trial that showed weekly injections with 17P reduced by about one-third the risk of preterm delivery in women who had previously had a preterm birth (Meis, et al., N Engl J Med 2003;348:2379-85). That optimism grew when secondary analysis of the data revealed that 17P had its most beneficial effects on reduction of deliveries less than 34 weeks which incur the greatest risks for short- and long-term morbidity and mortality and excessive cost of medical care (Spong, et al., Am J Obstet Gynecol 2005;193:1127-31). In this later analysis, however, some concerns were also raised that there appeared to be a slightly higher fetal loss rate in the women who had received the 17P, but at this time, it cannot be concluded that this was the result of the drug itself or of other factors related to this high risk population of women. Early miscarriage rates and birth defects could not be commented upon in this study because the 17P was not begun until the patients were at least 16 weeks pregnant – well past the time of organogenesis and the usual time of miscarriage.

Anyway, returning to our readers’ comments, my first answer is no, the medication has not changed at all from the time it was introduced years ago. In fact, if anything, since the drug is now ‘formulated’ at compounding pharmacies across the nation, and is not under the scrutiny of BIG PHARMA (the product is no longer made by a pharmaceutical company – just wasn’t worth holding onto over the years), it’s composition is even less rigorously controlled, although the formulation is probably too simple to mess up in any way that would deleteriously affect either its safety or efficacy.

With regard to the issue of birth defects, especially the concerns related to limb and genital defects, let me first state that should probably not be a major worry at this point. As stated above, the currently recommended use of the drug involves starting it well beyond the development of the baby’s arms, legs, heart, genitalia, etc. All of that is basically completed by 12 weeks, and most even earlier. It is true that continued growth of all organs proceeds throughout the pregnancy and neurologic development, in particular, well beyond first trimester is especially important to the baby’s outcome, but to date, no data would suggest a major problem related to this. Of course, it will take many years to sort out whether or not subtle effects on the brain and neurologic or behavioral abnormalities are associated with the use of 17P.

To support these points, let me cite a few references. In 1982, Varma and Morsman evaluated the use of hydroxyprogesterone hexanoate (very similar to 17P) in early pregnancy for its adverse effects on fetal development (Int J Gynaecol Obstet 1982;20:13-17). One hundred and fifty women were begun on this drug by intramuscular injection at 6-8 weeks gestation and continued on therapy until 16-18 weeks. The control group consisted of 150 women with similar problems, primarily, recurrent miscarriages, who received no hormonal therapy. No significant differences related to adverse fetal/neonatal outcome or development were noted between the two groups.

The teratogenic effects of 17P have been evaluated in several animal studies. Seegmiller and colleagues (Teratology 1983;28:201-8) treated mice with doses of 17P ranging between 10 and 200 times the human therapeutic dose. At the highest doses (100 and 200 times the human doses), they found higher risks of maternal deaths (8% and 13%, respectively); and, all doses resulted in a slight increase in embryonic resorption (4-12% above controls). However, in surviving animals and their offspring, there were no significant affects on intrauterine growth, sex ratio, or malformation rates and it was specifically noted that the drug did not increase rate of masculinization, nor did it alter the development of nonreproductive organs.

In a later study, also done in mice, doses of 17P equivalent to 0.7, 7.0, and 70.0 times the dose in humans were administered between gestational days 7 through 19 – roughly equivalent to the period of most significant embryologic development in humans (Carbone and Brent, Am J Obstet Gynecol 1993;169:1292-8). In this study, no differences in fetal weight, resorptions, fetal deaths, number of male fetuses, or malformations were noted between the treated and untreated animals. Again, because of anecdotal concerns raised many years earlier, they specifically noted that there were no no increases in genital or nongenital birth defects, and no increase in limb deformities or bone calcification in the group treated with the 17P.

Hendrickx and colleagues (Teratology 1987;35:129-36) studied the effects of 17P given alone or with an estrogen (estradiol valerate) in rhesus and cynomolgous monkeys at weekly intervals between 20 and 140 days gestation. Although a higher rate of embryologic deaths were noted in the Rhesus monkeys (but not in the cynomolgous monkeys) at doses equivalent to (1X) and 10 times the human dose, no significant malformations or developmental abnormalities were identified. Not to belabor the work done to date in animal models, I would simply refer you to a recent review article on the subject by Christian and colleagues (J Matern Fetal Neonatal Med 2007;20:89-112). In this comprehensive review, the authors conclude that 3 studies point to a higher risk of embryo-fetal toxicity, including the ones cited above, but no consistent or significant teratogenic effect has been confirmed with the use of 17P.

Bringing this home, perhaps more reassuring is another recent study (Northen, et al., Obstet Gynecol 2007;110:865-72) that did follow-up evaluations of the babies born in the original 2003 17P trial of Meis and colleagues. At a mean age of follow-up in 194 children exposed to 17P and 84 placebo controls, “no significant differences were seen in health status or physical examination , including genital anomalies” between the 17P and the placebo children. Testing scores for “gender-specific roles” were also normal and comparable between the two groups. Since this is the only randomized, controlled study of substance published to date, it must be considered the most reliable information available as well and it would appear that 17P, as used in this trial, beginning at 16-18 weeks gestation, has a minimal risk for the fetus and newborn, at least from the standpoints of birth defects and development.

So, the final question...would I use 17P on my own kids again? Yeah, they all did turn out a little on the strange side, but look at who's their Daddy!

Labels: 17-hydroxyprogesterone caproate, 17P, delalutin., preterm delivery

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Readers' Questions About Rh-negative Blood Types and Complications

Hello again. I apologize to all of you for my recent 'down-time' but the Chairman of our department decided to retire on very short notice and I have been put in the position of 'interim Chair' until we can get someone to replace him. I sincerely hope that will not be a long process. Been there, done that, don't want to do it again! Over the past week or so, I have accumulated MANY questions/comments from readers and my responses to several may be used as posts over the next few days to play catch up! Hope you don't mind. The three comments below pertain to Rh-negative status and complications related to Rh-sensitization. This seems to be an area of ongoing confusion among many of you, and for those of you who understand it completely already, I apologize again!

Anonymous Mon Jan 07, 07:47:00 PM 2008 said…

I am 33 years old and my husband and I are actively trying to conceive. Both my husband and I have been cleared of any complications by our fertility doctor. My concern is that I am B-negative and I was recently informed that in the event of a pregnancy, that I would need to get an antibody (Rh-immune globulin) given to me. This does not concern me, but what does is that when I was 15, I had an abortion at 16 weeks and was not given the antibody and I do not know if the father was Rh-negative or -positiive. Neither do I know if the baby was Rh-negative or -positive. I am now worried that my future pregnancies could be affected. How do I find out if I am sensitized?

Kenneth F. Trofatter, Jr., MD, PhD said...

To anonymous Jan 7: To find out if you were 'sensitized' to Rh-D or any other blood antigen, simply ask your doctor to perform a blood type and antibody screen. If the antibody screen is negative at this time you are probably in good shape, but you will be rescreened early in a pregnancy as part of the routine new OB labs. Odds are you are just fine. Incidentally, the Rh-immune globulin you will receive in pregnancy will help protect you from becoming sensitized in the event the baby is Rh-positive. Good luck to you and thanks for reading. Dr T
Fri Jan 11, 05:33:00 PM 2008


Ditchdoc Tue Jan 08, 01:44:00 AM 2008 said…

I have A+ blood and my husband has B+ blood but our 9 year old daughter has AB-. How is this? My grandfather was B-. Could the negative allele have come from him by succession?

Kenneth F. Trofatter, Jr., MD, PhD said...

To ditchdoc26 Jan 8: If your husband is indeed the baby's father, that simply means that both of you are heterozygous for the D allele - in other words, you each have one D gene and one gene without D and are then D/-. This happened because you each inherited one chromosome from each of your parents. On one chromosome you inherited the Rh-D gene and on the other you did not. That means when you have children, 1/4 will be D/D (Rh-positive; homozygous), 2/4 will be D/-; also Rh-positive but heterozygous like you and your husband - remember the D gene is expressed dominantly, two doses are not required to be Rh-positive), and 1/4 will be -/- (Rh-negative; you must have BOTH negatives to be Rh-negative). Hope that helps. Thanks for reading! Dr T
Fri Jan 11, 05:40:00 PM 2008


Amy & Damon Thu Jan 10, 06:55:00 PM 2008 said...

I am a 26 year old and I developed antibodies in my first pregnancy. The baby had to be induced but was full term. She had phototherapy for 5 days before being discharged.

My second child was monitored using the Doppler flow every 2 weeks. Then had his first fetal transfusion at 23 weeks and had to have one every 3 weeks. He was induced at 36 weeks weighing 3.35kg so in total he had 4 fetal transfusions. After he was born he had phototherapy for 5 days. Then needed another transfusion, at 2 weeks of age. Now he is 7 and a half months old and very healthy, normal and happy boy.

Now I am pregnant with my 3rd child (not planned but we are both happy) and scared what's going to happen? As I understand with each pregnancy it gets worse! I do have an appointment with a specialist in Maternal-Fetal Medicine in a few days but would love to know your opinion.

Yours sincerely
Amy

P.S I have no complaints about the Doppler method. Their was a very close call at 23 weeks as the doctors didn’t think the levels would rise so fast, but it all worked out I am just very greatful, we have such great technology and doctors!
I am very sad to hear about your baby passing away. It’s heart breaking and my biggest fear.

Kenneth F. Trofatter, Jr., MD, PhD said...

To Amy and Damon: Thank you for sharing your story. I am sure many readers will appreciate what you have been through because of your Rh-sensitization. Actually (hopefully!), it usually doesn't get much worse than it did the last time. The MFM doctor will probably recommend at the least starting the Doppler studies (peak systolic velocities in the middle cerebral artery) even earlier and they may recommend serial cord blood sampling, prepared to move directly to transfusion each time, because outcomes are a little less predictable in women who are sensitized and have had severely affected babies previously. As you know by now, there are risks each time that you have the cord blood sampling and a transfusion done, but in your case, all of that will probably be necessary again. Good luck to you and please let us know how things turn out. Regards. Dr T
Fri Jan 11, 05:44:00 PM 2008

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

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Diabetes in Pregnancy - 7 - Self-Monitoring of Blood Glucose Levels

After discussing the basics and importance of diet, the next step in counseling for the newly diagnosed woman with gestational diabetes mellitus (GDM) revolves around the means of assessing her ‘diabetic control’. The mainstay of management is frequent self-monitoring of blood glucose levels. The equipment (“glucometers”) currently available to perform self-testing is highly reliable, relatively inexpensive, and simple to use. Furthermore, the better units available on the market have built in memory from which can be downloaded the dates, times and values of blood sugar determinations (not that we don’t ever trust our patients with what they tell us!). It is the rare patient over the years that I have found who cannot learn, or is unwilling, to do this testing herself and in those few circumstances, there is usually a close family member (sometimes even children) who step up to help out. Self-testing actively involves the patient in her own care and allows a great deal of flexibility in diet and medical management that could (in the days of my training) only be accomplished in a hospital setting at great expense.

The patient is informed that the test is done on whole (capillary) blood obtained by fingerstick and that the glucose values we want to achieve are < 95 mg/dL on fasting values and < 120 mg/dL on values obtained two hours after meals. These correspond to venous plasma values of < 105 mg/dL and 130 mg/dL respectively. Initially, we ask the patient to obtain at least 4 blood sugar determinations each day, a fasting value and two hours after every major meal, breakfast, lunch, and supper. An example to show how this is worked into the diet routine of 3 meals and 3 snacks is as follows:

_Check fasting blood sugar within 30 minutes before breakfast; eat breakfast

_Check blood sugar two hours after breakfast; then eat snack

_Eat lunch

_Check blood sugar two hours after lunch; then eat snack

_Eat supper

_Check blood sugar two hours after supper; then eat snack before bedtime

If it possible, the patient is asked to establish a ‘routine’, trying to eat her meals and snacks and check her blood sugars on a regular time schedule each day. She is asked to record all her blood sugars on a weekly log sheet with which we provide her, recording the date, time, and blood sugar levels. This log sheet is then faxed to our office (or called to our staff) and reviewed by a physician on a weekly basis and more often if necessary. I generally will give our patients with GDM (who have never had it before) a week of diet and blood sugar determinations before deciding if medical therapy is necessary unless the levels are so high that it is clear that treatment is needed sooner. If a woman had GDM with a previous pregnancy and required medical therapy (oral agent or insulin) I will usually offer her the opportunity to resume that therapy at the time of the initial consultation since there is a very high likelihood it will be necessary again.

I think it is valuable to have the patient return to the office a week after her initial visit to review the blood sugars face-to-face, answer questions regarding her concerns and course to that point, and discuss thresholds and options for therapy, even if therapy is not yet necessary, as well as indications and methods of fetal surveillance for the rest of her pregnancy. If the blood sugar control is not adequate, we have a very low threshold for starting medical therapy and approaches to that will be the subject of our next post…

Labels: blood glucose self-monitoring, gestational diabetes

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Thanks to Dr. Bongi for a New Year's Grand Rounds

Many thanks to Dr. Bongi at Other Things Amanzi for a most extraordinary and colorful Grand Rounds. All I can say is what a great way to start the new Year! Between the photographs of Africa and the selection of submissions, this is one Grand Rounds you will not want to miss. Also, thanks for the kind words and for including my recent post on the significance of "Low Pregnancy Hormone Levels: hCG and Progesterone" and their relevance with regard to pregnancy outcome.

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