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Fruit of the Womb
Fruit of the Womb

Low Pregnancy-Associated Plasma Protein A (PAPP-A) and Pregnancy Outcome

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On August 27, 2007, K left the following comment on my previous post entitled
"Abnormal First Trimester Screening Results" published earlier this year:

I had a 1st trimester screen and while most of the results came back normal, my PAPP-A level was 0.25 MoM (which the counselor told us was very low). My hCG was .78 MoM. She said that there is an increased risk for low birth weight but nothing else. I have done some online research though and seen that a low PAPP-A can also mean an increased risk for stillborn and delayed fetal development. Is that true? Can you shed any light on the PAPP-A result on its own. (Like I said, all other test results were within a normal range). Thanks, K

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. For example, a widened nuchal translucency (NT) has also been correlated with risk for having a baby with a cardiovascular malformation, even when that fetus is confirmed to be chromosomally normal. In a similar vein (no pun intended), an abnormal Doppler waveform in the first trimester, showing reverse end-diastolic velocity in the fetal ductus venosus, presumably secondary to tricuspid regurgitation, has also been correlated with both cardiovascular malformations and aneuploidy.

Our reader was counseled regarding another observation that has been made of first trimester screening - the association between ‘abnormal’ levels of the maternal serum markers, PAPP-A and hCG, used in the screening assessment, and pregnancy outcome. She 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 0.25 MoM (multiples of the median). The first thing I want to remind her about is that first trimester screening does not help to detect ALL chromosomal abnormalities – it is most reliable for trisomies 21 (Down syndrome), 18, and 13. Secondly, whether the baby is chromosomally normal or not, a ‘reassuring’ screen does not rule out the possibility of other fetal abnormalities – physical or developmental or abnormalities of placentation. In other words, a ‘normal’ screen does not ensure a normal baby or pregnancy outcome, although it does increase the probability of both!

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. As we have mentioned in previous posts, 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.

Recent studies would support this association between low PAPP-A levels in first trimester and risk for poor pregnancy outcome. 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 low 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 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).

Anyway, not to belabor the point, but to make a long story short, the simple answer to our reader’s question is that low PAPP-A levels are not only associated with certain fetal chromosomal abnormalities, but also with an increased risk for a poor pregnancy outcome. BUT, despite this association, the positive predictive value of a low PAPP-A for one of these outcomes is still relatively low. That means the chance of one of these events is higher with a low PAPP-A, but you shouldn’t panic at the outset that something bad is going to happen.

Several things our reader's providers could do that might help elucidate her actual risk for problems throughout her pregnancy include the following: 1) A screen for MSAFP at 16 weeks (ask your doctor to explain this); 2) a ‘targeted’ ultrasound to carefully evaluate the baby’s anatomy and growth; 3) Doppler flow velocimetry of the uterine arteries at the time of the ‘targeted’ ultrasound to look for increased resistance to maternal-placental perfusion (indicative of an abnormality of placentation); 4) Serial assessment of fetal growth, and; 5) Doppler flow studies on the fetal umbilical cord and middle cerebral arteries to look for evidence of increased resistance to fetal-placental perfusion (again, indicative of abnormal placental vascularization) and fetal blood flow redistribution (suggestive of preservation of the brain at the expense of perfusion of less ‘essential’ organs), respectively. 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.

Hope that helped K. Best regards, thanks for reading, and best of luck to you!
Dr T
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