Elevated hCG Detected at the Time of First Trimester Screening for Aneuploidy

Below are comments and questions from a reader who underwent combined first trimester screening for aneuploidy. Although the composite screening results did not place her at increased risk for having a baby with trisomy 21 (Down syndrome) or trisomies 18 and 13, she expressed some concern about the significance of the high free-β-hCG result. High free-β-hCG accompanied by low PAPP-A levels (which she did not have) are major determinants of risk for Down syndrome, regardless of the nuchal translucency result. Since I have gotten several queries about this, I thought it might be a good idea to post my thoughts, both in general and with specific attention to our reader’s medical history detailed as follows:

Fri Mar 28, 12:01:00 PM 2008, Anonymous said…

Hi Dr. Trofatter,
This is a great blog, thank you! I've been searching for clues as to what else causes elevated free-β-hCG levels (besides trisomy 21) and have gotten only research papers and your blog. I would really appreciate it if you had a moment to look at my case.

My combined screenings came out as follows:
singleton
CRL 63.6mm, GA 12w6d
Overall risk assessment:
Trisomy 21 risk - 1 in 743
Trisomy 13/18 risk - 1 in 14,901
_______________________________

Free-β-hCG % 97.5/2.88 MOM
PAPP-A % 40/MOM 0.84
_______________________________

NT 1.2mm (Trisomy 21 risk 1 in 4764 on this basis alone)
_______________________________
My stats are that I am a 33 year old (at term), Caucasian, 115 lbs maternal weight.

I know one poster already presented with a free-β-hCG of 2.59 MOM, but she also had a high level of PAPP-A, where as I do not. You also mention in the main article that hCG levels tend to diverge and PAPP-A levels converge... A midwife at my hospital called me back and assured me you're not allowed to pick one marker out of the screening to be alarmed, but she also couldn't tell me what else could cause such an elevated level of the hCG.

Since you mentioned these markers are produced by placental cells, perhaps it's of some interest that the ultrasound results also indicate a low anterior placenta, and they weren't sure if the umbilical cord had 2 or 3 blood vessels. Perhaps it is also of interest that I miscarried and had a D&C a couple months before this pregnancy? (I also had an elective abortion at age 19.) I was 9.5 weeks pregnant when I got into a car accident on 11 Nov. 2007. The next day the loss of the baby was confirmed (CRL correlated with fetal death at 9.5 weeks) and dilation commenced that day with the curettage the next morning. They told me to wait one cycle before trying again, and bingo presto, my LMP was 17-December-2007. This perhaps explains my weird implantation site (low anterior), but I have no idea if it explains anything else :(

Thanks *so* much for reading and have a good weekend!

Sun Mar 30, 04:38:00 PM 2008, Kenneth F. Trofatter, Jr., MD, PhD said...

To Anonymous Mar 28: In addition to high hCG levels in Down syndrome (and some other chromosomal abnormalities), sometimes folks just have bigger placentas that make more hCG! This is commonly seen in some diabetics and in multiple gestations. Elevated levels of hCG are also found with molar (or partial molar as would be the case with a baby present) pregnancies and choriocarcinoma. These latter conditions are called ‘gestational trophoblastic diseases’ and they are accompanied by uncontrolled proliferation of the placental trophoblasts and excretion of very high levels of hCG (much higher than yours). Also, in your situation, the hCG may be somewhat ‘artificially elevated’ because of your slight build (although the results are generally ‘corrected’ for maternal weight, there are some difficulties in interpretation at the high and low extremes). However, let me postulate another possible cause in your case (and bear in mind this is JUST a hypothesis)…

There is a possibility that because of the short interval between the previous pregnancy loss with the D&C and the conception of your current pregnancy that this baby implanted on a denuded (still healing) portion of the endometrium and had growth of the trophoblasts (placental cells) into the myometrium ( muscle of the uterus) rather than just the endometrium alone. Under normal circumstances, there is a balance between proliferation and invasion of the trophoblasts and your body's immune system which limits that growth and invasion. The myometrium is not able to control the growth of the trophoblasts as well as can be done in the endometrium. (We see this, routinely, with ectopic pregnancies that grow into and sometimes through the muscular wall of the fallopian tube).

My concern is that if this has occurred, it may increase your risk for a placenta accreta wherein the portion of the placenta that has invaded the myometrium does not detach normally following delivery. I don't know for sure in your case, but this is certainly a possibility and one of the reasons I recommend to women that they wait at least 2-3 months after a D&C to get pregnant again. Sometimes we can actually visualize a placenta accreta by ultrasound later in the pregnancy and you might ask your doctors to consider this option.

Anyway, despite my positing, the overwhelming odds are that both you and the baby are going to do just fine this pregnancy. So, good luck to you, thanks for reading, and let us know how things turn out.
Dr T

Labels: first trimester screening, hCG, PAPP-A

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Reader's Questions Related to Low PAPP-A in First Trimester Screening for Aneuploidy

The following comments and questions were left on my previous post regarding Low Pregnancy-Associated Plasma Protein-A (PAPP-A) and Pregnancy Outcome. The questions are excellent and summarize the concerns of many of our readers who have a low PAPP-A value detected at the time of first trimester screening for aneuploidy, so I thought it worthy of a full post. My responses are in italics after each of her questions.

• At Sun Mar 23, 02:20:00 PM 2008, Anonymous said…

First of all I want to thank you for this wonderful website. This is the best PAPP-A site on the internet, and believe me I have seen all of them.

These are my first trimester screening results:

Nuchal (translucency) scan was normal
Free beta hCG: 0.7677 MoM
PAPP-A: 0.1358 MoM

This PAPP-A put me in high risk of a chromosomal abnormality. I did CVS (chorionic villus sampling) and results were normal. Now I am worried about nonchromosomal issues like placental dysfunction and restricted fetal growth. I have a number of questions:

1) For the blood test they dated my pregnancy based on the scan as 13 weeks. I am sure that I was 12wk 3d or 12wk 4d only. I read that PAPP-A doubles each 3 or 4 days during first trimester. I wonder if the result would not be so low if they would have dated my pregnancy as 12wk 3d or 12wk 4d. Would it be 0.2716 MoM instead of 0.1358 MoM?

Dr T: 3-4 days should not make any significant difference in the interpretation of the test and the MoM does not change at the same rate as the PAPP-A.

2) The fact that hCG is also low, does it mean anything?

Dr T: The hCG is NOT especially low.

3) What is the risk of placental dysfunction with PAPP-A levels as low as mine?

Dr T: The lower the PAPP-A, the greater the risk for intrauterine growth restriction and other complications (I answer this point more specifically in my post on “The Affect of Smoking on PAPP-A levels Detected in First Trimester Screening” on March 25, 2008)

4) I am a non-smoker but I am a passive smoker, could this influence the PAPP-A levels?

Dr T: Passive exposure to cigarette smoke could potentially reduce the PAPP-A levels (again, see the March 25, 2008 post) although I have never seen that addressed in the scientific literature! Maybe you should make the smokers in the family “take it outside” for your baby’s sake!

5) During the nuchal translucency scan, the baby’s size was found to be normal or even big for the age. Is this a good sign or it is irrelevant?

Dr T: I would rather see a larger baby than a smaller one at this point although it's probably irrelevant! Abnormalities of placentation usually are not reflected in effects on fetal growth until after 20 weeks’ gestation.

6) I have been advised to have a scan at 28-30 weeks to assess fetal growth. Should my doctors start monitoring this earlier? If there is placenta dysfunction, does it only start in 3rd trimester or could it start earlier? If the latter, wouldn't it be better to start monitoring earlier? You recommend serial assessment of fetal growth, what is the frequency and when to start? Same question for the Doppler.

Dr T: Placental dysfunction can lead to intrauterine growth restriction (IUGR) much earlier than 28-30 weeks. Although low PAPP-A levels are not invariably associated with IUGR, yours is low enough that I would consider assessment of growth at 24-26 weeks. If there is a significant abnormality of placental vascularization (not just a small placenta), Doppler flow studies can often detect those that early, even before the baby starts to fall off the growth curve. If growth and Dopplers are normal at that time, I would probably repeat both studies about 4 weeks later (28-30 weeks). Based on that later study, I would then decide if further fetal evaluation is necessary.

7) Is it worth buying my own blood pressure monitor to control the preeclampsia risk? My doctor will only test me every 3 weeks.

Dr T: Just go to a local pharmacy. Most of those have blood pressure devices that you can use for free and they are more accurate than if you did it yourself (P.S., Remember to relax and uncross your legs while you are having your BP checked!).

8)Is the low PAPP-A level and placental dysfunction related to the age (I am 36) and do I have more chance of having the same issue in a future pregnancy?

Dr T: It is conceivable that your age is contributing to a suboptimal site for placentation if you have had, for example, many previous pregnancies or D&Cs, or have a uterine septum or adhesions, or uterine fibroids. Chance of recurrence is going to depend on why it happened this time! One of the old adages in obstetrics, however, is that "history tends to repeat itself" even if we aren't smart enough to figure out why!

9) Is there a link between restricted fetal growth and cerebral palsy?

Dr T: There is a greater risk for both cerebral palsy and developmental problems in growth restricted babies that is dependent on the actual reason for the IUGR. Examples of causes for IUGR include congenital infections such as cytomegalovirus (CMV), chromosomal abnormalities, genetic problems or syndromes, placental insufficiency, premature delivery, and maternal preeclampsia are the most common.

Anyway, I hope this helps. Any more and I would have to send you a bill for my time! (JUST KIDDING). Great questions and good luck for the rest of the pregnancy. Let us know how things turn out, MJ!

Dr T

Labels: aneuploidy screening in first trimester, first trimester screening, PAPP-A

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Affect of Smoking on PAPP-A Levels in First Trimester Screening for Aneuploidy

The reader below underwent combined first trimester screening for aneuploidy. The composite result was very reassuring with regard to her risks for Down syndrome and trisomies 18/13, however, she also observed that both her PAPP-A (Pregnancy-Associated Plasma Protein-A) and hCG levels were “low,” a combination that often accompanies an ‘increased risk’ for trisomy 18. She then also noted that she had been misclassified on the report form as a “smoker” and wondered if this had given her a result that was falsely reassuring. This is an excellent question and worthy of a full response so that other readers might appreciate another source of relatively low maternal serum markers in first trimester and the importance of honesty in their responses to questions related to smoking during pregnancy!

• At Wed Mar 19, 09:32:00 PM 2008, Anonymous said…
Hi everyone. I am Jean, 33 years old, a Singaporean Chinese, now 15-week pregnant. I am a non-smoker.

I had my 1st trimester screening at 11 week 6 days. The screening test has however misclassified me as a smoker. I wonder how this would have affected the risk estimation outcome.

The test results are as follows:-
NT scan : 1mm
hCG: 0.62 MoM
PAPP-A: 0.58 MoM

Risk for Trisomy 21 is 1/8000
Risk for Trisomy 13+18 is 1/14000

The risk is low despite the lower than normal PAPP-A & hCG. Also, would wrongly being classified as a smoker reduce my PAPP-A and hCG MoM ratio ?

Anyone have any ideas? I intend to bring this up to my Obs at the 16th week appointment too.

Regards,
Jean•

At Thu Mar 20, 06:43:00 PM 2008, Kenneth F. Trofatter, Jr., MD, PhD said…

To Jean Mar 19: Your question is excellent. I will elaborate on my comments below, but to give you a brief answer to your question, smoking significantly reduces PAPP-A and, to a lesser degree, hCG in first trimester screening. Most laboratories do perform a 'correction factor’ for smokers but I do not know what that factor actually is. In your case that means, you are probably at greater risk than indicated by your final results, but even if that risk was doubled (and I cannot believe the correction factor is more than 10-20%), you would still be at very low risk for trisomy 21 and trisomies 18/13. For peace of mind, you could ask your doctors to call the lab and get a corrected result based on the fact you are not a smoker and that was reported in error. Thanks again for the great question and let us know how your pregnancy turns out!
Dr T

*************************************************************************************
As we have discussed in a previous post, PAPP-A is produced by the placental trophoblasts, especially, by the extravillous cytotrophoblasts (Handschuh, et al., Placenta 2006;27 suppl A:S127-34). It is a ‘protease’ for insulin-like growth factor (IGF) binding proteins 4 and 5 (Boldt and Conover. Growth Horm IGF Res. 207;17:10-18). This means it has the ability to help release IGF from these binding proteins so that it is free to interact with its cell receptor (Laursen, et al., Mol Endocrinol 2007;21:1246-57). IGF is thought to play an important role in trophoblast invasion and hence the early development and vascularization of the placenta and the placental bed. These early events in placental development are critical to pregnancy outcome and, when abnormal, are associated with miscarriage, intrauterine growth restriction (IUGR) of the baby, pregnancy-induced hypertensive disorders, fetal death in utero, premature delivery, and even cesarean section for indications of fetal or maternal compromise.

Data suggest that low levels of PAPP-A, resulting in less release of IGF, could be a pathway by which early abnormalities of placentation culminate in these poor pregnancy outcomes. Spencer and colleagues (Ultrasound Obstet Gynecol 2006;28:637-43) evaluated first trimester markers in 54,722 chromosomally normal singleton pregnancies. At the 5th percentile of PAPP-A (0.415 MoM), the odds ratios for fetal loss before 24 weeks, at or above 24 weeks, and at any gestational age were 3.3, 1.9, and 2.8. In other words, there was about a three-fold risk of losing a baby with low PAPP-A levels. Cowans and Spencer (Prenat Diagn 2007;27:264-71) recently confirmed the association between low PAPP-A and small for gestational age birth weight babies as well. Indeed, they found a linear relationship between the severity of growth restriction and the decrease in PAPP-A levels – in other words, the lower the PAPP-A, the smaller the babies at any gestational age. Several other studies confirm the association of the other ‘pregnancy complications’ noted above with low levels of PAPP-A. For example, as a spin-off of the results in the First and Second Trimester Evaluation of Risk (FASTER) trial, it was found that women with PAPP-A at or below the 5th percentile “were significantly more likely to experience fetal loss at < or = 24 weeks gestation, low birth weight, preeclampsia, gestational hypertension, preterm birth (P < .001) and stillbirth, preterm premature rupture of membranes, and placental abruption (P < .02)” (Dugoff, et al., Am J Obstet Gynecol 2004; 191:1446-61).

I am not sure if smoking was factored into the analysis of pregnancy outcome risk in the FASTER trial when the group of low PAPP-A women were evaluated, because in recent years, smoking, as an independent risk factor, while it may be associated overall with smaller babies, is also correlated with a decreased risk for preeclampsia! However, over the past decade, smoking by itself, has also been found to be correlated with lower PAPP-A levels. In 1999, Spencer reported an analysis of 3111 singleton pregnancies in which first trimester screening was performed and found a 15% reduction in PAPP-A in smokers compared to nonsmokers (Prenat Diagn 1999;19:1065-6). Subsequent studies confirmed this 15-20% reduction of PAPP-A during first trimester maternal serum marker evaluation in smoking pregnant women around the world (deGraaf, et. Al., Prenat Diagn 2000;20:186-9; Spencer, et al., Prenat Diagn 2003;224:169-73; Ardawi, et. al., Prenat Diagn 2007;27:303-11). In a recent study of 92,287 nonsmokers and 13,976 smokers, Kagan and colleagues (Prenat Diagn 2007;27:849-53) were able to confirm a ‘dose-dependent’ effect of cigarette smoking on first trimester PAPP-A levels.

In another very recent article, Miron and colleagues (Prenat Diagn 2008;28:180-5) reported that smoking was associated with decreases in both PAPP-A and free β-hCG in dried blood specimens in first trimester, but also appeared to be correlated with an increase in detection of trisomy 18! This raises the interesting possibility that smoking, just as it inexplicably decreases the occurrence of preeclampsia later in gestation, might also increase survival of babies with trisomy 18 in early pregnancy – most of which are typically miscarried before the end of first trimester!
Dr T

Labels: aneuploidy screening in first trimester, first trimester screening, PAPP-A

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Grand Rounds 4.27 at Monash Medical Student

Many thanks to Jeffrey Leow at Monash Medical Student for the hard work in putting together a great collection of Grand Rounds offerings. Thanks also for including a link to my recent post that reviewed Chromosomal Mosaicism Detected at the Time of Chorionic Villus Sampling.

Not only is the decision to have invasive diagnostic testing done during early pregnancy a difficult one, but sometimes the results aren't as straightforward as we would like them to be. Such is the case with chromosomal mosaicism. When counseling prior to performing the procedure is done, these subtleties are often left out of the discussion because "the patient can only digest so much at one time." Admittedly, it is a complex subject, but it does occur in 1-2% of cases, so it is a 'risk' that sooner or later will have to be confronted by any provider who performs CVS. The finding of mosaicism creates incredible uncertainty and anxiety and may lead a pregnant woman to harder decisions, more invasive procedures, and lingering doubt about the baby's outcome, even when follow-up results are reassuring, that can haunt her until after the baby is born...

Labels: chromosomal mosaicism, CVS

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Chromosomal Mosaicism Detected at the Time of Chorionic Villus Sampling

Since the widespread acceptance of first trimester screening for fetal chromosomal abnormalities (aneuploidy), and following the recommendations that this should be offered to all pregnant women, not just those considered to be ‘at risk’ for indications such as ‘advanced maternal age’, early invasive testing by chorionic villus sampling (CVS) has become more widely employed as a means of diagnosing aneuploidy. Any diagnostic procedure has its risk and limitations. The comment from the reader below is related to one of the major ‘risks’ of CVS, that is the risk associated with the interpretation of the significance of the test results themselves when the diagnosis of ‘mosaicism’ returns from the laboratory…

Thu Mar 20, 08:27:00 PM 2008, Anonymous has left a new comment on your post "Invasive Diagnostic Testing after Reassuring First...":

Dear Dr. Trofatter:
I am a 35 yr old who is 13 weeks pregnant. This is my first pregnancy and I am seeing a high risk specialist since I had bleeding from week 4-6. Two weeks ago, I had CVS and the preliminary results (I assume FISH) results showed a healthy baby girl without any chromosomal abnormalities. A week later the genetic specialist called me and told me the final results showed mosaic Turner's syndrome and that I need to have an early amniocentesis to determine if this finding is limited to the placenta only. Why did the preliminary results show a false negative? Should I rely on the FISH results from amniocentesis in order to make my decision regarding termination or wait for the final amniocentesis results? Thank you!

Sat Mar 22, 03:23:00 PM 2008, Kenneth F. Trofatter, Jr., MD, PhD said...

Chromosomal mosaicism is defined as the presence of two or more populations of cells having different chromosomal complements in the same individual. Usually, this involves one population of cells that is chromosomally “normal” and another that is not, often with either one extra (trisomy) or one too few (monosomy) chromosomes. Mosaicism can involve both the fetus (true fetal mosaicism) and the placental tissues or the placental tissues alone. The latter is termed “confined placental mosaicism” and was first described by Kalousek and Dill in 1983 (Science 1983;221:665-667).

Placental mosaicism has been found at the time (9-12 weeks’ gestation) of chorionic villus sampling (CVS) to occur in approximately 1-2% of all pregnancies (Hahnemann and Vejerslev, Prenat Diagn 1997;17:801-20; Grati, et al., Eur J Human Genetics 2006;14:282–288). Under most circumstances, mosaicism is though to result from either a chromosomal nondisjunction event in the early stages (zygote/blastocyst) after conception, generating a trisomic cell line (single extra chromosome) in an initially normal baby, or as the result of the loss of one chromosome in an initially trisomic baby (“trisomy rescue”). When the latter occurs, the resulting fetal and/or placental tissues can end up with two identical chromosomes from one parent (rather than two slightly different ones from each). This is termed “uniparental disomy (UPD)” and is a condition that itself has associated risks which will not be included in today’s discussion.

When placental mosaicism is found at the time of CVS, there is a 10-12% chance the baby (not just the placental tissues) will share the mosaicism. However, even if the baby is affected, it is highly variable as to what percentage of fetal cells and even which organs will be involved in the mosaicism. Generally, the earlier the nondisjunction event occurs, the greater the likelihood that a higher percentage of placental and fetal cells will be involved in the chromosomal abnormality.

In the case of confined placental mosaicism (CPM), when the baby is not affected directly by the aneuploid cell line, the outcome of the pregnancy is somewhat influenced by which (and how many) placental cells are affected by the mosaicism. Three types of CPM have been described and are based on which placental cells are affected (Kalousek, et al., Hum Genet 1992;88:642–646; Simoni and Sirchia, Prenat Diagn 1994;14:1185–1189). In type I, the abnormal cell line is confined to the cytotrophoblast; in type II, it affects only the mesenchymal cells of the stromal villous core; and in type III, it involves both tissues. Although the distribution of these types differs somewhat by the study reported, as an aexample of the same, Grati and colleagues (Eur J Human Genetics 2006;14:282–288) found mosaicism confined to the placenta in 177 cases (87.2%): 39.9% type I, 40.4% type II and 6.9% type III.

When CVS is done, usually samples of both cells lines (cytotrophoblasts and mesenchymal cells) are obtained. Chromosomal analysis of these cell lines can be performed by means of direct preparations (such as fluorescent in situ hybridization, or FISH), short-term cultures (cytotrophoblasts), or long-term cultures (mesenchymal cells) of the chorionic villi. With reference to the mechanisms of mosaicism we have discussed above, type I and II CPMs are usually the consequence of postconceptional nondisjunction events, and type III is the result of “trisomy rescue” (from a meiotic error of maternal or paternal gamete formation prior to conception). The latter is associated with an increased risk of pregnancy complications and of UPD in the 'rescued' diploid fetus (Robinson, et al., Am J Hum Genet 1997;60:917–927). In the case of type I and II CPM, the risk of UPD is very low (Kalousek, Am J Med Genet 2000;91:39–45).

For the purposes of counseling our reader, the type of CPM is very important and to some degree, the risk to the baby of sharing in the mosaicism, or of having UPD, is often reflected in the laboratory test results. Mosaicism not detected in the cultures, but only in the direct preparation is more likely to represent CPM. Furthermore, certain mosaicisms , such as those involving sex chromosomes (such as Turner syndrome, 45,XO) or trisomies 8, 9, 12, 13, 15, 18, 20, and 21 often involve the baby and are therefore considered high-risk for true fetal mosaicism and the consequences of the same (Association of Clinical Cytogeneticists Working Party on chorionic villi in prenatal diagnosis Prenat Diagn 1994;14:363-379; Hahneann and Verjeslev, Am J Med Genet 1997;70:79-187). Grati and colleagues (Eur J Human Genetics 2006;14:282–288) found that type I CPM was associated with a 2.4% risk of fetal mosaicism, type II with 12.8%, and type III with 46.1%.

As is in the case of our reader, when mosaicism is found after CVS, either in the direct preparation (cytotrophoblasts) and/or in the cultures (mesenchymal cells), amniocentesis is usually recommended to determine if the abnormal cell line is confined to the placenta. Ninety percent of the time, the amniotic fluid results are “normal” and truly reflect a chromosomally normal baby. However, even when the amniotic fluid chromosome results return normal, there is a small chance of pregnancy complications as the result of a low level of fetal mosaicism (cryptic fetal mosaicism), UPD, and placental dysfunction as a consequence of the aneuploid cell line.

Although most pregnancies with CPM continue to term with no complications and are accompanied by normal fetal development, if a significant percentage of placental cells are aneuploid, this could result in impaired growth or even the loss of a chromosomally normal baby, and is more likely to be seen with type III CPM. Furthermore, if the baby has UPD, and this results in metabolic dysfunction, even though the total number of chromosomes is normal, a poor outcome might also result.

Returning to our reader’s questions, I would offer the following responses: First, the fact that the direct preparation (FISH) demonstrated a normal fetal karyotype and the cultured preparation suggested a Turner’s mosaicism (45,XO) speaks to the inherent weakness of rapid preparations in accurately establishing a diagnosis. Their positive predictive values are good if an abnormality is found, but due to the small number of cells obtained, resulting in 'sampling error', their false negative rate is relatively high. For the same reason, I do not think you should necessarily rely on the FISH results alone from amniocentesis when you have that done, particularly, if your plans are to terminate the pregnancy if a Turner’s mosaicism is found. I would strongly suggest you get some good genetic counseling prior to making any final decision in that regard as well.

Thank you for reading, for sharing your story, for your excellent questions and for giving me the opportunity to expound on a very important subject that may affect many of our readers.
Dr T

Labels: aneuploidy, chorionic villus sampling, chromosomal mosaicism, first trimester screening

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Folate Receptor Antibodies and Congenital Birth Defects

We have such great readers! The comment and questions below were shared with us by a physician who had a twin pregnancy in which both of her babies were lost early in third trimester with different major congenital birth defects - one involving the neural tube and one with a complex congenital heart abnormality. Both of these types of abnormalities have been found to be associated with folic acid deficiency and abnormalities of the folic acid-dependent metabolic pathways. She, herself, was found to have high titers of autoantibodies against the folic acid receptor which, perhaps, led to a relative deficiency in folic acid, resulting in her identical twin babies' disparate birth defects...

• At Mon Mar 10, 07:41:00 PM 2008, Anonymous said…
Hi Dr. T:

Six months ago I lost a monozygotic dichorionic twin pregnancy in which one twin had a neural tube defect and the other had hypoplastic left heart syndrome. Since then, I learned that I have a high titer of folate receptor autoantibodies (Rothenberg, et al. NEJM, Jan 2004;350:134-142)
I had a few questions for you:

1. What, if any, experience do you have with folate receptor autoantibodies in pregnancy?

2. What is the safety and/or utility of low dose steroids (prednisone 5 mg) pre-conception and throughout pregnancy as treatment for such autoantibodies?

Thank you!

Dr. S


• At Fri Mar 14, 02:33:00 PM 2008, Kenneth F. Trofatter, Jr., MD, PhD said…

To Dr S Mar 10: As you correctly surmised, both the neural tube defect and the complex congenital heart defect in your twins might well have been the result of relative folate deficiency as a consequence of your folate receptor autoantibodies. Orofacial clefting in both animal models and humans has also been correlated with folate deficiency states. In 2003, da Costa and colleagues (Birth Defects Res A Clin Mol Teratol. 2003;67:837-47) demonstrated that serum containing folate receptor antibodies given to pregnant rats early in gestation had a dose-related effect on embryo viability and organogenesis. Folinic acid prevented teratogenicity resulting from smaller doses of antiserum, but not that caused by larger doses. Resorption of embryos with the larger doses of the antiserum was prevented by dexamethasone which appeared to reduce embryo damage by preventing immune-mediated cell lysis. In the article you cite by Rothenberg and colleagues (N Engl J Med. 2004;350:134-42) autoantibodies to folate receptors were found in 9 of 12 women who had had, or were carrying, babies with neural tube defects. Interestingly, these antibodies were also found in 2 of the 20 ‘control subjects’ who had babies that did not have neural tube defects.

Although I do not have a lot of experience with the management of individuals known to have antifolate receptor antibodies, my experience with autoimmune conditions associated with autoantibodies in general would lead me to suspect that low-dose prednisone alone is NOT the answer. My gut (and clinical experience) and the animal studies tell me that high dose folic acid and B-complex vitamin supplementation is the way to go and, if more is needed, either higher dose prednisone and/or high-dose intravenous immunoglobulin (IV Ig) should be considered. I have used prednisone for various reasons during pregnancy over the years and generally found it to be quite safe. There is a slightly increased risk for having a baby with facial clefting, but the primary complications I have seen are increased risk for gestational diabetes, premature rupture of membranes, and early delivery. Hypertensive disorders also occur frequently in women who require prednisone, but that may be more an effect of the underlying medical conditions being treated than the drug itself.

It is interesting that folate receptor antibodies can be found in ‘normal’ women. Digging into the literature, one finds that folate receptors are expressed in many body tissues, especially tissues of the central nervous system and the immune system, and in various malignancies. In fact, antifolate receptor therapy as an adjunct to treatment of conditions such as ovarian cancer have been considered. In a mouse model for systemic lupus erythematosus, it was found that depletion of folate-receptor positive macrophages decreased expression of the disease and prolonged the life of the animals (Varghese, et al., Mol Pharm. 2007;4:679-85). My point for telling you this is simple. Folate receptor antibodies may be a natural modulator of the immune response (and perhaps mediator of tumor suppression?!?) that in some individuals is out of whack, producing too much of these antibodies, resulting in the complications that our reader (and others) experienced in her pregnancy by causing a ‘relative folate deficiency’ during the critical stages of her babies’ development.

So, to our reader, thanks for reading and for the great questions and if you find out anything else, let me know! I am here to learn too!
Dr T

Labels: congenital heart defects, folate metabolism, folate receptor antibodies, folic acid, neural tube defects

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Grand Rounds 4.25 at Canadian Medicine

Many thanks to the good folks at Canadian Medicine for including a link back to us at Fruit of the Womb in this week's Grand Rounds 4.25. So what did Jane Austen really die of?!? I suggested acute intermittent porphyria and will defend that possibility in a post sometime in the future. Do any of you have any ideas? Would love to hear from you myself!
Dr T

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Congenital Sebaceous Cysts and Familial Adenomatous Polyposis?

The comments and questions below recently left by one of our readers are interesting because they raise the possibility (again) that the congenital conditions with which all three of her children (and perhaps even the one she is currently carrying) were born could be related to a single genetic defect. It may be a bit of a ‘stretch’ on my part, but if my readers didn’t challenge me to think, then you all would not have to put up with my vivid imagination!

• At Thu Mar 06, 10:34:00 PM 2008, Anonymous said…

Dear Dr. T:

I am 40 years old and am 16 weeks pregnant with my 4th child. I am scheduled for a level 2 ultrasound and consult with a perinatologist tomorrow. A couple of weeks ago, I thought I was 12 weeks based on my last cycle. However, I was measuring larger so I had an ultrasound to determine dates. The ultrasound showed I was 14 weeks and they also found a large cystic hygroma with edema (hydrops) of the skin. I don't think they told me the exact measurement of the cystic hygroma.

My first pregnancy was uncomplicated. My first son developed Fifth’s disease (parvovirus B19) when I was pregnant with my second son which, I was told caused encephalitis of the brain. They also found a cyst on his brain which later disappeared. I was given a 50% change of his survival. My son is now 13 years old. He was born with a sebaceous cyst on the side of his nose and has been diagnosed with ADHD. I also have a 2 1/2 yr old daughter who was born with a sebaceous cyst on the back of her head. I am pretty sure she has ADHD as well. Both are very smart. I had gestational diabetes with all three pregnancies. I am also Rh-negative. My questions are:

1) Do you think that there could be any association between the sebaceous cysts of my other children and the cystic hygroma of the baby I am now carrying?

2) I think my daughter had Fifth's disease during this pregnancy. Is it possible to get parvovirus B19 more than once? I'm wondering if the possible exposure to parvovirus B19 caused the cystic hygroma and hydrops?

3) Is it possible that my RH negative condiditon caused the hydrops?

4) Finally, I have been doing a great deal of reading about this condition and researched natural vitamin and herbal supplements that reduce edema. I have found that they have been successful doing clinical studies on pregnant women in Europe with no ill effects on the babies using some of the same vitamin/herbal supplements to reduce hemorrhoids. The products I am considering taking are supposed to reduce or eliminate edema and strengthen veins. They are Diosmin & Hesperidin (Citris bioflavanoid), Horse Chestnut extract, and Butcher's Broom Extract. I found documentation from the FDA that deemed the bioflavanoids safe during pregnancy in the U.S. However the studies on the herbals were done in Europe and the Netherlands.
I would greatly appreciate your comments and/or advice on all of my questions. I have also been taking dandelion leaf extract to try to reduce the hydrops. I was told it was perfectly safe during pregnancy. I am so surprised that no one is trying to do anything to reduce edema (hydrops) since that seems to be the biggest concern and is associated with increased risk of fetal of demise. Thank you so much!!

• At Sat Mar 08, 04:33:00 PM 2008, Kenneth F. Trofatter, Jr., MD, PhD said…

To Anonymous Mar 6: Let me answer the questions as best I can in the order you asked them:

1) The cystic hygroma is probably not related to the sebaceous cysts of your other children. It is much more likely at your age that the baby with the cystic hygroma has a chromosomal abnormality. As you point out, the hydrops is not good and often is associated with loss of the baby in utero. If the baby turns out to be chromosomally normal, then it could be related to the genetic condition I will discuss below.

In that regard, the issue of the "sebaceous cysts" in two of your children and, perhaps, even the intracranial “cyst” in your first child is interesting in its own right. Could these all be related? Congenital sebaceous cysts are unusual. In my review of the literature, I did find an association between congenital sebaceous cysts and a condition called 'familial adenomatous polyposis (FAP)' (Bisgaard, et al., Am J Genet A 2006;140:200-4 and Cross, et al., J Med Genet 1992;29:175-9) and Gardner’s syndrome, which is a phenotypic variant of FAP. These conditions are caused by mutations of the APC (adenomatous polyposis coli) gene found on the short arm of chromosome 5 (5q21). The normal APC gene encodes a tumor suppressor gene product.

Gardner’s syndrome is an autosomal dominant condition (i.e., it only takes one bad gene mutation rather than two to cause disease) that causes familial (hereditary) polyposis of the colon and rectum, osteomas (bone tumors), and cutaneous epidermoid (sebaceous) cysts. Colon cancer will develop in virtually 100% of individuals with this condition during their lifetimes (usually in the third and fourth decades of life) unless the colon is removed prophylactically. Individuals with FAP can also develop polyps of the upper gastrointestinal tract, dermoid cysts, desmoid tumors, congenital hypertrophy of the retinal pigment epithelium, maxillary (jaw bone) disorders and dental abnormalities (Chimenos-Kustner, et al., Med Oral Patol Oral Cir Bucal 2005;10:402-9). One article even describes a case of a cortisol-producing tumor (causing Cushing’s syndrome) in an adrenal gland of a 36 year old woman with Gardner’s syndrome (Beuschlein, et al., Endocr Res 200;26:783-90). What I found most fascinating is that individual’s with Gardner’s syndrome are also at risk for a variety of intracranial solid and cystic tumors (Goodin, et al., Pediatr Blood Cancer 2008;50:409-12).

You might want to discuss this possibility with a good genetic counselor to review your family history and to see if there are any genetic or other diagnostic studies necessary that should be done to determine if the children have this condition.

2) I doubt you would be at risk with this pregnancy if your daughter had Fifth's disease. You should be immune to it now and it is unusual to get that twice.

3) I very much doubt the current baby's problems are at all related to your Rh-negative status. Even if you are ‘isoimmunized’ (had antibodies against Rh), which your doctors could tell you by now, that usually does not cause problems with babies until later in midtrimester at the earliest.

4) The edema is not just there as a disease entity in and of itself. Most of the time it is the result of fetal heart failure and there can be lots of reasons for that (.e.g., structural malformations of the heart, fetal arrhythmias, and chromosomal abnormalities or metabolic abnormalities resulting in dysfunction of the heart). Hydrops in the setting of cystic hygromas has a fetal loss rate that approaches 100%. I would be very cautious of any herbal preparations to try to treat this yourself. One of the problems with over-the-counter herbal preparations is that they are not standardized, may vary from batch to batch and from company to company, and may contain products and impurities other than those listed on the bottle. Most of the ones you have mentioned should not have a deleterious effect on the pregnancy, but again, you may not really be sure what it is you are taking into your body.

Best wishes to you and thank you for some excellent questions! Let us know how things turn out and what you learn about the other children who were born with the sebaceous cysts!
Dr T

Labels: congenital sebaceous cysts, cystic hygroma, epidermoid cysts, familial adenomatous polyposis, Gardner's syndrome

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Symptoms Accompanying Methotrexate Therapy for Ectopic Pregnancy

Below is a comment with questions from a reader who is undergoing methotrexate therapy for a tubal ectopic pregnancy. Ectopic pregnancy has been on the rise over the past 30-40 years and current rates are in the range of 1-2 per 1000 pregnancies. Fortunately, with early diagnosis, facilitated by rapid quantitative assays for hCG (human chorionic gonadotropin, the ‘pregnancy hormone’ measured in most pregnancy tests) and ultrasound, the death rate accompanying ectopic pregnancy has dropped dramatically during the same time period. A pregnancy should be visible within the uterus by transvaginal ultrasound by the time the hCG level reaches 2000 mIU/ml (5-6 weeks, or 1-2 weeks after the first missed menstrual period). The advantage of early diagnosis has been the option to consider ‘medical therapy’ with methotrexate prior to rupture of the ectopic that usually necessitates a surgical procedure. This option for therapy has gained well-deserved popularity in recent years, so there are many readers who may benefit from the comments below…

• At Wed Mar 05, 07:30:00 AM 2008, Anonymous said…

Hi, I had an ectopic pregnancy and I had gone through the methotrexate treatment just this past Sunday. How long roughly should my cramping and bleeding last? I also just started to have today pressure in my very lower abdomen region and also my bum region is this normal, its not extremely painful but is quite annoying? Also today I had a almost like a blood clot come out when I went to the washroom but it was more mucousy-like. Is this something that will happen? This is my first pregnancy ever and well this whole thing is scary because I have gotten no definitive answers on anything. Basically what should I be going through while this drug does its thing? What is considered normal and how long does it last?

• At Wed Mar 05, 10:32:00 AM 2008, Kenneth F. Trofatter, Jr., MD, PhD said…

Many women who receive one or more doses of methotrexate for medical treatment of an ectopic pregnancy report cramping abdominal pain during the first 2 to 3 days (sometimes longer) of treatment. This is one of the most common side-effects of therapy. However, more severe and diffuse pain should be reported to your doctor because this can be a sign that the ectopic pregnancy has ruptured.

Vaginal bleeding and passage of mucous, such as you describe is also quite common. Progesterone produced by the corpus luteum (site of production of the egg that became the pregnancy) and the pregnancy hormones that are produced, even with an ectopic pregnancy, cause changes (decidualization) of the lining of the uterus in excess of that which occurs during a menstrual cycle. When the pregnancy is interrupted by the methotrexate, there is usually a heavy ‘withdrawal bleed’. In addition to the bleeding and ‘cramping’ (or “pressure” sensation associated with the distention of the fallopian tube or accompanying blood in the abdomen), occasionally, women will develop nausea, vomiting, indigestion, and feel tired, lightheaded and dizzy.

However, if you were selected by the recommended standard criteria for receiving medical therapy with methotrexate, there is a 70-95% chance that you will not require surgery. Selection criteria for methotrexate therapy include a patient who is hemodynamically stable, has no evidence of tubal rupture or significant amount of blood in the abdomen, has a tubal diameter of no more than 4 cm, understands the risks of the therapy, and is willing to return for follow-up. Resolution of the ectopic pregnancy using methotrexate results in tubal patency rates in the range of 80%, comparable to, if not higher than, those seen with surgery.

Remember that for whatever reason you had an ectopic pregnancy this time, you are at increased risk for another one with a future pregnancy, so always seek out early prenatal care when you think you might be pregnant and inform your provider that you had an ectopic pregnancy in the past. Recurrence rates overall are in the range of 20%. Conditions that increase the risk for recurrence include history of or evidence of previous pelvic inflammatory disease (PID), history of ruptured appendicitis, particularly if this was accompanied by rupture of the appendix, pregnancy after reconstructive tubal surgery or tubal ligation, pregnancy despite the presence of an intrauterine device, pregnancy with progestin-only oral contraceptives, and a history of infertility requiring ovulation induction. Interestingly, women who undergo in vitro fertilization have a risk for ectopic pregnancy in the range of 2-5% and this risk is even greater if they have had known ‘tubal factors’ and undergone reparative surgery for the same.

Incidentally, do not take any vitamin supplements that contain folic acid (like prenatal vitamins!) while you are undergoing treatment because the methotrexate works as a potent folic acid antagonist and you do not want to decrease its effectiveness. Report any unusual side-effects to your doctor and return for appropriate follow-up. The greatest risk of an ectopic pregnancy is not being aware that you might have one and ignoring the typical signs and symptoms that usually accompany it. Best of luck to you. You will probably feel much better within the next 7-10 days.

Dr T

Labels: Ectopic pregnancy, methotrexate therapy

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Thanks to ChronicBabe for Grand Rounds 4.24!

Many thanks to Jenni Prokopy at the award-winning site ChronicBabe for including a link to my post entitled "Heterozygosity for Homocystinuria and Heterotaxia Syndromes." in this week's Grand Rounds 4.24.

I did laugh out loud when Jenni notified me that "even though I had no clue what your post means, I included it...because I think it's interesting that you created a new post from a new reader comment, and my theme is about new beginnings." Although the post may not generate widespread interest, this is another one of those occasions where a curious reader may have stumbled on a previously unsuspected association as the result of having two children affected by what appears to be separate genetic problems. Of course, the two might not be at all related, but it is always exciting to me to explore those sorts of possibilities when there is at least a common thread!

Labels: heterotaxia syndromes, homocystinuria

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Hereditary Hemorrhagic Telangiectasia (HHT) and Pregnancy

Below is a recent comment from a reader in which she asks several interesting questions, but the most important answer was to a question she did not ask...!

• At Sun Feb 17, 08:23:00 PM 2008, Seri said…

I read your answers to the patient who had a Du-positive blood type . I was 18 and gave blood and was informed I am O-positive (Du-positive). I was not sexually active and of course never pregnant and I am white. My Dad was O-positive and Mom was A-positive. How can that be? I have never had a blood transfusion, but my husband and daughter have HHT and both have required blood. Should I or we be concerned about transfusions?

• At Fri Feb 29, 06:49:00 PM 2008, Kenneth F. Trofatter, Jr., MD, PhD said…

To Seri Feb 17: Given your parents' blood types, there is no reason you couldn't have the blood type you were born with. One (at least) of your Rh-positive parents is Du-positive, the other is likely to be heterozygous (a carrier of only one dose) for the Rh-D antigen, and you simply inherited the Du-variant of Rh and the chromosome from the other parent that was Rh-D-negative. The Du-variant is sometimes referred to as the 'weak' Rh-D antigen, but technically this still makes you Rh-positive. You only need only one dose of any Rh-D or -Du gene to have that expressed on your blood cells. Du-positive women cannot become sensitized to the D-antigen. Therefore, Du-positive women do NOT need Rh-immune globulin (Rhogam) during their pregnancies. If you get it inadvertantly, it would probably not cause any harm to the baby, but you just don't need it. Du is very common, but not exclusively found, in Black women.

As far as the HHT (hereditary hemorrhagic telangiectasia) in your daughter and husband is concerned, that does not put you or a baby you are carrying at any risk for needing blood transfusions. Your daughter got that only from your husband and not from you. It is inherited in an autosomal dominant pattern, i.e., it too requires only one dose of the bad gene to be expressed. However, your daughter needs to be concerned if and when she ever gets pregnant (but maybe we can cross that bridge when she comes to it!).

HHT is a condition that is actually caused by at least two different gene mutations and affects about 1 in 5000 individuals. A defect in the ‘endoglin’ gene is found in HHT type 1 (HHT1) and a defect in ALK-1 (activin receptor-like kinase-1), a type I receptor of the transforming growth factor (TGF)-β superfamily, causes HHT type 2 (HHT2). You will sometimes find HHT referred to in the medical literature as Osler-Weber-Rendu (OWR) after the doctors who first described it and suspected the hereditary nature of the disease. Clinical findings in individuals with HHT result from abnormalities in the development of some of their blood vessels.

Arteries carry the well oxygenated blood from the heart under high pressure through smaller and smaller vessels until the tiniest vessels (the capillaries) are reached and where most oxygen and nutrient is exchanged between the blood and the body tissues. The deoxygenated and nutrient-depleted blood then exits the capillaries into the veins that return the blood under much lower pressure to the heart. Individuals with HHT have a tendency to develop blood vessels that lack the capillaries (very small blood vessels) between their arteries and veins. This means that in HHT, arteries (with their thick muscular walls which are able to withstand the high pressures) are connected to veins that are only designed to tolerate relatively low pressures.

The site at which the artery and the vein are connected tends to weaken with time, eventually ‘balloons’ out (and remember, once a balloon gets past a certain point, it is easier and easier to distend), and can eventually rupture, resulting in bleeding. When these vascular abnormalities involve the small blood vessels in the skin or mucous membranes, we call these abnormalities ‘telangiectasias’ and if larger vessels are involved, we call these arteriovenous malformations (AVMs). Obviously, the abnormalities only involve a small percentage of an individual’s blood vessels, but the expression of the condition is highly variable between individuals, even within the same family.

The vascular malformations in individuals with HHT tend to occur more frequently in certain tissue areas although the reasons for this are unknown: the skin (especially face and hands), mucous membranes of the nose and mouth, lining of the stomach and intestines (GI tract), as well as the lungs, liver and brain. The larger (AVM) tend to occur more frequently in the internal organs and may be relatively asymptomatic for years before they expand and/or rupture. The diagnosis of HHT is considered definite if three or more of the following four criteria are present, or suspected if two of the following four criteria are present:

• Nosebleeds: spontaneous and recurrent
• Telangiectasias: multiple, at characteristic sites, including lips, oral cavity, fingers and nose
• Internal telangiectasias or AVM: lung, brain, GI, liver or spinal
• Family history: parent, sibling or child with HHT

As I mentioned above, I am more worried about our reader’s daughter when it comes time for her to consider pregnancy. I am not particularly worried about any children she might have with regard to pregnancy outcome (unless of course she had a complication related to her HHT). Because the mutations for HHT are inherited in an autosomal (non-sex chromosome) dominant fashion, they can equally affect both male and female offspring. However, while in the womb, it is quite unusual for babies with HHT to develop complications related to it. Arteriovenous malformations in fetuses have been detected, are quite rare, and can be quite devastating, but I do not believe these have been clearly correlated with HHT. Studies have shown expression of the genetic abnormality in fetal tissues (Abdalla, et al., Hum Mol Genet 2000;9:1227-37), but this is not associated with adverse pregnancy outcome for the baby as far as I am aware.

In contrast, the mother with HHT can be another story altogether. During pregnancy, the plasma volume normally expands 30-50% and to accommodate this, the cardiac output increases and the blood vessels must also relax, reducing peripheral vascular resistance. This involves some degree of ‘softening’ of the connective tissues in the blood vessel walls. One could easily see that this combination of events might lead to complications in the pregnant woman with HHT. Indeed, catastrophic events in pregnant women with HHT related to enlargement or rupture of AVMs in the lungs (e.g., intrapulmonary shunt deterioration and fatal pulmonary hemorrhage), brain (cerebrovascular accidents), and liver have all been described (Shovlin, et al., QJM 1995;88:879-87). However, if care is taken in the evaluation and management of young women with HHT, prior to and during pregnancy, risk for the mothers can be reduced (Schwebel, et al., Gynecol Obste Invest 2007;65:142-44).

There is one last concern I wish to mention regarding the woman with HHT who is considering pregnancy. If she has had bleeding problems that required transfusion, she is at risk for ‘isoimmunization’ to red blood cell antigens for which she was not crossed-matched prior to transfusion (this might involve Rh-antigens other than D and also non-Rh antigens). Depending on which antigens these are, her baby may be more or less at risk for hemolytic anemia and/or hyperbilirubinemia.

If a woman has HHT and is considering pregnancy, or is already pregnant, the HHT International Foundation can refer her to a clinic or center that specializes in the diagnosis, management and treatment of HHT, both here in the U.S. and around the world.

Thanks for writing. Bet you didn’t realize your questions were so GREAT!
Dr T

Labels: Du antigen, hereditary hemorrhagic telangiectasia, HHT, isoimmunization

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Midtrimester Loss: Preterm Labor vs. Cervical Incompetence

Below is a sequence of comments between a reader and me related to the unending difficulties we encounter sorting out the cause of midtrimester pregnancy losses: Is it preterm labor, cervical incompetence, uterine infection, fetal chromosomal abnormality (or some other problem) or a combination of more than one factor? When I trained, I was taught that “if the patient is having contractions, it is preterm labor and not cervical incompetence and a cervical cerclage (stitch around the cervix) was NOT indicated” and many physicians still believe that. But over the years, I have learned that things are not always that simple!

Thanks to the many desperate patients I have had with advanced cervical change in midtrimester (generally, at 24 weeks or less), no evidence of overt infection, but some uterine contractions, who begged me to “do something because we have nothing to lose by trying at this point”, I quickly learned that many of these patients could have their pregnancies salvaged by using broad-spectrum antibiotics, a ‘rescue’ cervical cerclage, and suppressing the uterine contractions. In many (actually, most in my experience) of the cases, the pregnancies carried until there was a good outcome for both baby and mother. The only thing I asked these patients to agree with me on up front was that I would have to end the pregnancy, regardless of gestational age, if there was evidence of intrauterine infection. At that point, the mother’s life is at risk and there is no further benefit to the baby to remain in the uterus.

The series of comments below help you to understand the physician’s thought processes and, to some extent, the patient’s misconceptions, that occur around the always traumatic experience of losing babies in midtrimester. (I apologize to the reader because I have edited some of her comments).

• At Wed Feb 06, 06:57:00 AM 2008, Anonymous said…

Dear Dr T,
After my last miscarriage, my doctor evaluated me for the possibility of a thrombophilia problem but found nothing. Me and my partner have also had our chromosomes examined and both of us were normal. The upshot was that no causes for the miscarriages were found. This leaves me with a lot of questions. Why did I have twice very late miscarriages? Currently I am pregnant again, but I am very afraid that it will happen again. I fear that there is something wrong with me which have caused the miscarriages. How likely is this if I already have had a full term delivery? Could my second miscarriage have been caused by the progesterone injections I was given because of my first loss? Would you advise me to take progesterone injections in this pregnancy (my doctor does). Does progesterone have any adverse effects on pregnancies? I would be very grateful if you would like to answer these questions or advise me further on this.
Kind regards

• At Sun Feb 10, 07:02:00 PM 2008, Kenneth F. Trofatter, Jr., MD, PhD said…

To Anonymous Feb 6: Answer several questions for me and then I will be in a better position to respond to yours:

1) Did you have the full-term pregnancy and then have the miscarriages?
2) Did you have any complications with the full-term pregnancy or with the delivery?
3) Did you have a vaginal delivery or a cesarean?
4) Have you had any cervical operations such as LEEP or cervical conization done?
5) How "late" were the miscarriages you had?
6) What were the circumstances surrounding those miscarriages, i.e., did the babies die in utero; did you have premature labor; did you break your bag of waters prematurely; did you have any evidence of 'infection'; did you labor or did your doctors put you into labor; did you receive progesterone with either of those losses; and, do you have any medical problems?

There are reasons for ALL of these questions and the answers will help me get a better idea as to what happened with your previous losses. Dr T

• At Wed Feb 13, 05:17:00 AM 2008, Anonymous said…

Here are my answers:

1) Yes, I had a full-term pregnancy first and had the two miscarriages thereafter.

2) The full-term delivery took very, very long (almost 40 hours from the first signs) and eventually I was given medicine to deliver my daughter. I could not have done it by myself probably. I had heavy bleeding afterwards (post-partum hemorrhage) and was very weak for more than two weeks following the delivery.

3) It was a vaginal delivery.

4) I don’t know what these (LEEP and cervical conization) are, but before having my daughter and the miscarriage, I had two abortions (I was too young then). And after the first late miscarriage the doctor cleaned up my uterus (did a D&C) as the pregnancy product did not leave my uterus completely (retained placenta).

5) The first time the baby was 20 weeks and a couple days old, he was born alive and I had premature labor. After this miscarriage the doctor thought (although I didn't have any infections) that the miscarriage might have been caused by a bacteria (slight increase of granulocytes in my blood) or cervical incompetence. However, he was not sure. I also then had a severe allergic reaction to the antibiotic I was given in the hospital in order to prevent any infections. My blood pressure was 80/40 and I was in very bad condition. So maybe this might also have caused the increase of the granulocytes or even the eventual delivery as I did not have a lot of dilation at first, but the situation got worse after I got the antibiotics.

The second time I delivered at 19 weeks; the baby probably had died at 15/16 weeks. I had no labor at all and was given medicine to deliver. Only in this pregnancy I was given progesterone (starting at week 16 because of the first miscarriage and in order to prevent any cervical incompetence. Again this time there were no signs of infections, and to my knowledge I am healthy and do not have medical problems. My age is 35.

In both cases I did not have break of bags/water.

So this leaves me with questions: Why does this happen so late and do I have to live with the knowledge that this kind of thing happens without reasons? And, could the second miscarriage have been caused by the progesterone as the period the baby died was more or less the period I started with the injections? Would you advise me to take these injections also in this pregnancy?

Would you advise me to take extra vitamins, other than folic acid (as I have been pregnant many times in a relatively short period)? Could this circumstance have played a role (short period in between pregnancies) in my losses? I would be grateful for your answers.

• At Fri Feb 22, 07:06:00 PM 2008, Kenneth F. Trofatter, Jr., MD, PhD said…
To Anonymous Feb 13: I do not think the abortions you had when you were younger contributed in any way to your more recent losses. However, I am worried that the first full-term delivery might have. You could have had damage to your cervix from the difficult labor and delivery or from the D&C procedure that had to be done to stop your hemorrhage.

I believe your first loss at 20 weeks, was the result of cervical incompetence and probably a secondary ascending infection. Once the cervix started to change, the contents (baby, membranes, and placenta) are more readily exposed to the bacteria within the vagina. I am not sure you really had an 'allergic reaction’ to the antibiotics. The low blood pressure and being in “very bad condition” is more consistent with 'septic shock’ resulting from a bacterial infection that had gotten into your blood stream from your uterus. I also do not think either the antibiotics or your 'bad reaction' caused you to lose that baby, it may well have just seemed that way because everything was getting worse after the antibiotics were given, but it was probably too late for them to be of any benefit. Significant infections in the womb will usually cause delivery within 48-72 hours regardless of any antibiotics that could be given to you.

Your loss at 15-16 weeks might also be the result of infection, or perhaps the baby had a chromosomal abnormality and that’s why he/she died. It is VERY unlikely the progesterone alone caused you to lose that baby. Indeed, the baby could have died even before you got the first shot based on the timing you have given to us. However, some people believe that progesterone can possibly reduce your body's ability to fight off some infections (although that has NOT yet been proven), so I will not rule out that possibility completely.

Before you get pregnant again, I would recommend that you have a sonohysterogram and perhaps a hysteroscopy done to evaluate the uterine cavity for any abnormalities that could be present (e.g., fibroids, polyps, scar tissue, and endometriosis). Your doctor might also consider treating both you and your husband with a 10-14 day course of an antibiotic such as doxycycline. I would suggest starting a prenatal vitamin and extra folic acid a month or two before you decide to try again and then, when you do get pregnant, personally, I would recommend placement of a cerclage at 13-14 weeks. I also recommend that before that is done (at 11-12 weeks), you have first trimester screening for aneuploidy (fetal chromosomal abnormality) performed. This involves only a simple ultrasound of the baby and some blood work on you. Your doctors can explain all of these procedures and the reasons for having them done. Incidentally, I would probably also offer you the progesterone injections again, serially follow your cervix by ultrasound starting at 15-16 weeks,and periodically evaluate you for evidence of asymptomatic urinary tract and vaginal infections until you got past 28 weeks.

Best of luck to you and please let us know what is found, what you do, and how things turn out!
Dr T

Labels: 17-hydroxyprogesterone caproate, cerclage, cervical incompetence, midtrimester pregnancy loss, preterm labor

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