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Fruit of the Womb

Low PAPP-A in Presence of Low Risk for Fetal Aneuploidy

Below are comments from a woman aged 44 who is carrying a pregnancy conceived by in vitro fertilization (IVF) using a ‘donor egg’ from a 21 year old woman. She had combined first trimester screening done with composite results that were very reassuring with regard to risks for having a baby with trisomy 21 or trisomies 18 or 13, however she is concerned that the PAPP-A level in the screen was only 0.269 MoM (at about the 2.5 percentile). She is 44 years old, and that alone increases her risk for pregnancy complications related to abnormalities of placental growth and complications related to that during pregnancy and, indeed, low PAPP-A levels may reflect those abnormalities. However, I want to remind our readers at the outset that the ‘positive predictive value’ for low PAPP-A is not very good and means the chance of one of these events is higher with a low PAPP-A but does not mean that she will inevitably develop complications during her pregnancy…

• At Mon Apr 28, 02:45:00 AM 2008, Anonymous said…

Hi Dr T,
I am having trouble getting anyone to take my numbers seriously. The NT scan showed up a low PAPP-A result and the sonographer told me to ask my GP to watch this and to make sure my OB consultant knew about it. My GP wrote to the OB consultant and she has just told me this morning that "Don't worry - they are not concerned as the PAPP-A result is low which is good!" Even I know that this does not make sense. Can you please help me by giving your opinion as most info I have read on this amazing site seems to point towards a possible problem:

NT: 1.6mm
Placenta:posterior high
Free B-hcg: 0.956 MoM
PAPP-A: 0.269 MoM
Egg was IVF donor egg -maternal age 21 yrs.
I was 11weeks and 6 days when the scan was done.

I look forward to hearing from you.
Many thanks,

• At Wed Apr 30, 05:05:00 PM 2008, Kenneth F. Trofatter, Jr., MD, PhD said…

To Jackie Apr 28: I wish I knew how old you are, what sort of medical problems you have, what was the cause of your infertility, and have you ever had any pregnancies (successful or not)? Barring that, it would be helpful to know what the calculated risk assessment result was for Down syndrome and trisomies 18/13 based on your test results.

Regardless, the low PAPP-A may not be good, but it may not be bad either! If you have read the posts I have written on this subject, and some of the comments from our readers and my responses, you will better appreciate why I seem to be talking out of both sides of my mouth. The reassuring components of your screen are the normal NT (nuchal translucency) and hCG measurements. With a "21 year old egg", I doubt your calculated risk for aneuploidy was very high. You are probably at modest risk for a small baby and the things that might go along with that, such as preterm labor, early delivery, preeclampsia, and cesarean section, but there might be other factors you have not told me about (or are not aware of) that might also put you at risk for these. My bet right now is that you will do fairly well with the pregnancy and nothing is wrong with your baby! Let us know how things turn out.
Dr T

• At Thu May 01, 03:16:00 AM 2008, Anonymous said…

Hi again Dr T,
I am so grateful for your reply and apologies for omitting some of the info. I am 44 years old with no medical problems except a fibroid which has appeared with this pregnancy. The infertility was unexplained, save for mild endometriosis. I had one pregnancy last year (natural) which ended after just 6 weeks with no explanation. I have had 2 previous rounds of IVF - the first produced 4 follicles and 2 embryos were implanted but did not take. The second produced no follicles.

The adjusted risk for Downs was 1:1804 and for Trisomy 18+13 was 1:18628. I was advised that no amniocentesis or CVS (chorionic villus sampling) would be necessary. My main concern is the IUGR/stillbirth scenario which seems to go hand in hand with a low PAPP-A result. Do you imagine that my doctors would keep a closer eye on me - in your opinion what should I be pushing for at my 20 week scan? Will the AFP result throw anything in to the mix as I am yet to receive that?
Thank you again.

• At Thu May 01, 10:49:00 AM 2008, Kenneth F. Trofatter, Jr., MD, PhD said…

Hello again Jackie. When the PAPP-A is low, the women at greatest risk for complications are those that also have a placenta that is smaller than normal and/or did not have normal growth into the lining of the uterus (specifically into the uterine spiral arterioles). The MSAFP (maternal serum alphafetoprotein test at 16 weeks can sometimes provide an insight to that as a possibility. If the AFP is abnormally high, and there are no apparent abnormalities (such as a neural tube or abdominal wall defect) of the baby to be seen, then that "false positive" result may actually reflect an underlying placental problem (that may not manifest itself as a problem such as fetal growth restriction or maternal preeclampsia until later in the pregnancy).

The other procedure we use that can also anticipate risks down the line is Doppler flow velocimetry. This is an ultrasound technique that can help us to detect degrees of 'resistance' to blood flow. If you and/or the baby are found to have trouble pushing blood through the placenta by virtue of increased resistance in the uterine or umbilical arteries, respectively, this can be another reason to keep a closer eye on the baby's growth, development and overall well-being. None of these will accurately predict outcome, but if they are abnormal, can justify more intensive antepartum fetal surveillance so that chances of delivering a healthy baby, regardless of the gestational age, are improved. So, do not panic at this point! Again, thanks for your questions and let us know how things turn out!
Dr T

As we have pointed out before, first trimester screening for aneuploidy can have some benefits for detecting potential complications of pregnancy other than certain chromosomal abnormalities. Our reader reports that her ‘composite’ first trimester screening result was reassuring with regard to risk for a chromosomally abnormal baby, but one of the maternal serum markers, PAPP-A (pregnancy-associated plasma protein-A), was “low” at 0.269 MoM (multiples of the median).

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). 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 formation of the placenta 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. It has been postulated that low levels of PAPP-A, resulting in less release of IGF, could be a pathway by which placentation abnormalities occur that culminate in these poor pregnancy outcomes.

Several studies confirm the association of ‘pregnancy complications’ with low levels of PAPP-A. 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 less than or equal to 24 weeks, 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). Spencer and colleagues (Ultrasound Obstet Gynecol 2006;28:637-43) evaluated first trimester markers in 54,722 chromosomally normal singleton pregnancies. They found that the odds for fetal loss at anytime in pregnancy was about three-fold that of ‘normals when the PAPP-A levels were at or below the 5th percentile (0.415 MoM).
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