Composite Results are the Strength of First Trimester Screening for Aneuploidy

The reader below faces what appears to be a growing dilemma for patients (and their providers) in the laboratory reporting of results from first trimester screening for aneuploidy. The data that supports this screening modality has always emphasized that the power of the screening test is in the COMPOSITE test results and NOT the individual ‘analytes’ which include the actual nuchal translucency measurement along with the hCG, PAPP-A, and other factors.

As can be seen from the ‘results’, she is being given risk results for trisomy 21 (Down syndrome) that range between 1 in 47 ( based on the biochemical screening alone) to 1 in 612 (based on the ultrasound evaluation of the baby). The COMPOSITE (and in my mind the KEY information) is the 1 in 292 “adjusted risk” but as a patient (and even as a doctor), how are you going to sit with reconciling the great disparity in risks in a way that will help you make the most unbiased decisions possible regarding further evaluation of the baby and, particularly, the invasive diagnostic studies which carry their own inherent risks…?

Singapore Mother has left a new comment on your post "Understanding Interpretation of First Trimester Sc...":

Dear Dr. T,

I am 39 years old. The results of my test are as follow:

@ 12 weeks + 0 days

Crown-rump length (CRL) 56.1mm
Nuchal translucency (NT) 1.4mm

Maternal Serum Biochemistry
Free B-hcg 129.4 IU/I = 1.993 MoM
PAPP-A 0.557 IU/I = 0.578 MoM

Trisomy 21
1:122 (Background risk)
1:612 Adjusted risk (US)
1:47 Adjusted risk (BC)
1:292 (Adjusted risk)

Kindly please shed some light... Thank you so much!


To Singapore Mother July 7: Personally, I think it is VERY confusing and unfair to present the data to patients in this way. The strength of the first trimester screening is in the COMPOSITE results and NOT the individual tests - and yet you were given the risk assessment based on those individual tests. All that can do is make you worry about the greates ‘risk’ estimate and any laboratory that does this should be banned from first trimester screening because they are presenting 'data' out of both sides of their mouths without providing adequate counseling to the patients or realistic expectations as to what balanced information most providers can offer! Albeit, this is just my opinion.

The long and short of your results are that you have a 1 in 292 risk of Down syndrome which is less than half your age alone risk. Some laboratories will still report this as "screen positive" because it falls below there cut off, but that also means your baby has a 291 out of 292 chance of being chromosomally normal. If the odds still worry you, then you can have either a genetic amniocentesis done or simply have an expert sonogram done at 18-20 weeks. If the latter is 'normal' your a priori risk is reduced by at least another 50%. Best wishes and let us know how things turn out.
Dr T

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Low hCG and PAPP-A in a Patient with an Autoimmune Disorder

The following comment was left on an old post "Affect of Smoking on PAPP-A Levels in First Trimester." The case is interesting because it reminds us that abnormal maternal serum markers in first trimester might be the result of factors unrelated to fetal chromosomal abnormalities....

Hi! I just got my 1st trimester screening test results today, and would love you thoughts.

I will be 40 years old when I deliver. I was 12 weeks when I did the testing.

NT: 1.5
Nasal Bone present
Free b - HCG: 0.29 MoM
Papp A - 0.34 MoM

Down syndrome risk: 1:1600
Trisomy 18 & 13: 1:50 (normal for my age 1:150)

I have an autoimmune condition, polymyositis that is under control. I am taking 12.5mg prednisone 1xday. I am ANA and Jo-1 positive.

Can you please help me understand these results? I am trying to look at the fact that it is only a 2% chance of the trisomy abnormalities, but it is difficult.

Are there any other reasons that my blood levels would be so low for both? Is there anything I should be precautionary about through the rest of my pregnancy because of this?

Thanks,
WJD

The combination of the low hCG and the low PAPP-A is typically a pattern seen in pregnancies complicated by trisomies 18 and 13 (in contrast to an elevated hCG coupled with a low PAPP-A in Down syndrome – trisomy 21). Both hCG and PAPP-A are produced by the trophoblasts of the placenta and low values could be the result of either a small placental mass or decreased production because of metabolic dysfunction. Both of these factors might be at work in trisomies 18 and 13.

However, in your case, there is also the possibility that your baby is chromosomally normal but has an abnormality of placentation that resulted from your autoimmune disorder. The immune system probably plays a very important role in normal placentation and the presence of certain autoantibodies (e.g., antiphospholipid antibodies, lupus anticoagulants, and anti-beta-2-glycoprotein-1) are thought to be associated with increased risk for abnormalities of placentation resulting from abnormal trophoblast migration and invasion of the maternal spiral arterioles. Indeed, if you have not been screened for these specific autoantibodies, I would recommend that you have that done. Such pregnancies are at increased risk for poor fetal growth (intrauterine growth restriction), fetal loss, pregnancy-induced hypertensive disorders, and early delivery. If you have any of these other autoantibodies, you might also be at increased risk for thromboembolic complications as well.

Whenever we find a pregnancy that has low hCG and PAPP-A levels and a chromosomally normal baby, it is recommended that fetal growth be followed at serial intervals, Doppler flow studies (e.g., umbilical, uterine , and fetal middle cerebral arteries) be done to evaluate impaired placental perfusion from either the fetal or maternal side and evidence of fetal blood flow redistribution (preservation of the brain at the expense of perfusion of ‘nonessential’ organs because of reduced placental transfer), and both mother and baby be monitored carefully for evidence of compromise. Your doctors can give you specific details of what should be done with regard to the latter.

Best of luck to you and please let us know how things turn out.
Dr T

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Celiac Disease and Pregnancy

In our last post, we responded to several questions from a reader named Kate concerning the implications of low PAPP-A levels detected during the course of first trimester screening for aneuploidy. Not addressed in our last post were her two other comments: Is there a correlation with celiac disease and placental health or low PAPP-A levels? I have read reports of celiac disease causing many of same risk factors associated with low PAPP-A.

To begin to address these issues, it is important to discuss first what celiac disease is to better understand how it might have an impact on pregnancy. Celiac disease (CD) is the result of intolerance of the gastrointestinal tract to gluten. Gluten is a protein contained in wheat, barley, and rye and is therefore present in many cereals, pasta, flour, breads and as an additive in many processed foods, medicines, vitamins, and even lip balm. As the consequence of an abnormal immune response (with production of antibodies such as antigliadin type IgA and IgG and IgA antitransglutaminase), individuals with CD damage their own intestinal villi that are necessary for the absorption of nutrients into the blood stream. Thus celiac disease can result in not only gastrointestinal symptoms, but malabsorption and nutritional deficiencies that can have significant consequences on the long-term health of an individual if CD is not recognized and treated. However, the complications related to CD can be dramatically reduced by strict adherence to a “gluten-free” dietary regimen.

The tendency to develop CD appears to be genetically inherited but there is a great variability in age of onset, severity of symptoms, and consequences of the condition even within families. Fasano and colleagues (Arch Int Med 2003;163:268-92) estimated that in the U.S., about 1 in 133 people have CD. Rodrigo reported (World J Gastroenterol 2006;12:6585–6593) that 4 to 12 percent of an affected person’s first-degree relatives will also have the disease. Gastrointestinal symptoms of CD include abdominal pain and bloating, chronic diarrhea, pale, foul-smelling and fatty stool, occasionally vomiting and constipation, and weight loss. Even in the absence of significant gastrointestinal complaints, individuals with CD may develop conditions such as iron deficiency anemia, osteoporosis and bone pain or arthritis, chronic fatigue, depression, anxiety, numbness and tingling in the hands and feet, oral ulcers, and even seizures. Dermatitis herpetiformis, an itchy, blistering skin rash, affects 15 to 25 percent of individuals with celiac disease. CD has even been implicated in menstrual irregularity, infertility, and recurrent early pregnancy loss. There is also an association of CD with chronic liver disease and intestinal cancer.

With all that said and done, let’s begin to look at the consequences of celiac disease for pregnancy. Nørgård and colleagues (Am J Gastroenterol 1999;94:2435-40) reviewed birth outcomes in Danish women with CD between 1977 and 1992. They found that before women were first treated for CD there was an increased risk of low birthweight (odds ratio [OR] = 2.6, 95% CI = 1.3-5.5) and intrauterine growth retardation (OR = 3.4, 95% CI = 1.6-7.2). Pregnant women who were given dietary counseling before delivery had no increased risk of low birthweight and no babies with intrauterine growth retardation. Therefore, treatment of women with CD is important in the prevention of fetal growth retardation. Similarly, Ludvigsson and colleagues (Gastroenterology 2005;129:454-63) compared pregnancy outcomes in 1149 offspring of women diagnosed and treated for CD prior to birth and 929 offspring to women diagnosed after delivery. They found that “undiagnosed CD was associated with an increased risk of intrauterine growth retardation (OR = 1.62; 95% CI: 1.22-2.15), low birth weight (OR = 2.13; 95% CI: 1.66-2.75), very low birth weight (OR = 2.45; 95% CI: 1.35-4.43), preterm birth (OR = 1.71; 95% CI: 1.35-2.17), and caesarean section (OR = 1.82; 95% CI: 1.27-2.60). In contrast, a diagnosis of CD made before the birth was not associated with these adverse fetal outcomes.” Again, the risks of CD, at least with regard to fetal growth, can often be dramatically reduced by identification and treatment of women with CD.

However, because CD is the result of an aberration of the immune response, reminiscent of that seen in autoimmune conditions, the questions remain, could this abnormal immune response also contribute to poor pregnancy outcome in ways other than impairing fetal growth and what are the mechanisms of the impairment in growth and perhaps other suboptimal pregnancy outcomes in women with CD? It is well-known that people with CD are at greater risk for having or developing other autoimmune conditions such as type 1 diabetes, autoimmune thyroid, liver and adrenal disease, and other autoimmune conditions such as rheumatoid arthritis and Sjogren’s syndrome. Conceivably, autoantibodies causing these conditions could cross the placenta to the baby and cause complications. Indeed, in the case of Sjogren’s syndrome, this is often associated with the production of antibodies (anti-Ro (SS-A) and anti-La (SS-B)) that can cause congenital heart block and cardiac malformations.

Although an association of CD with systemic lupus erythematosus and antiphospholipid antibody syndrome has not been widely recognized, there have been very recent case reports of the same (Gupta, et al., Rheumatol Int. 2008;28:1179-80; Jorge, et al., Rev Esp Enferm Dig 2008;100:102-3). Furthermore, the presence of anticardiolipin antibodies have been demonstrated in some patients with CD (Karoui, et al., Dig Dis Sci. 2007;52:1096-100) and CD antibodies have been demonstrated in some patients with antiphospholipid syndrome (Shamir, et al., Lupus 2004;13:214)! If this holds true, there is a subpopulation of pregnant women with CD who will be at increased risk for thromboembolic complications and, perhaps, abnormalities of placentation that could lead to intrauterine growth restriction, pregnancy-induced hyperetensive disorders, premature delivery, and even ‘unexplained’ fetal death. And, to answer Kate’s question, when this is associated with an abnormality of placentation, there is a very good chance that first trimester PAPP-A levels will be on the low side – indeed, perhaps we should be screening for CD in women with low PAPP-A and also we should consider screening of women with known CD for PAPP-A to possibly help identify that subpopulation of women at risk for the pregnancy complications we have noted above.

Diagnosis of CD is usually made by the detection of anti-tissue transglutaminase (tTGA) and anti-endomysial (EMA) antibodies in the blood (and confirmed by duodenal biopsy). Anti-gliadin antibodies can also be demonstrated in many individuals with CD. The question then arises, could these CD-associated antibodies cause damage to the placenta and/or the fetus and compromise pregnancy outcome? Robinson and colleagues (Placenta 2006;27:148-57) have demonstrated that tissue transglutaminase (tTG) protein and mRNA are expressed in stromal cells and trophoblasts in first trimester and at term, with higher levels later in pregnancy and suggested that this could be a target for CD-associated antibodies. To support this hypothesis, Bustos and colleagues (Am J Reprod Immunol 2006;55:201-7) have shown that the prevalence of positive antibodies for antigliadin type IgA and IgG and IgA antitransglutaminase in women with recurrent pregnancy loss RPL was significantly higher than controls (P < 0.04).

In a very interesting article, Hadziselimovic and colleagues (Fetal Pediatr Pathol 2007;26:125-34) looked at the amount of gliadin that was present in term placentas of compliant (women who maintained a gluten-free diet) and noncompliant CD patients and correlated that with placental damage to the extravillous trophoblasts and fetal birth weight. They described the extravillous trophoblasts in the noncompliant women as being “overloaded with gliadin” whereas there was moderate to no gliadin present in the controls. “The weight of newborns was lower if extravillous trophoblasts were loaded with gliadin (-2.24SD) (p = 0.004)” and there was increased apoptosis (cell death) of the trophoblasts in the placentas of the noncompliant women.

In conclusion, there appear to be various mechanisms by which CD might deleteriously affect pregnancy outcome, and perhaps others we have not yet explored, such as specific nutrient deficiencies that might lead to certain fetal anomalies. The ‘autoimmune’ component of CD seems to play a major role in terms of fetal growth impairment as pregnancy progresses and perhaps by increasing the risk for early abnormalites of placentation that could contribute to both early pregnancy loss and later pregnancy complications. The reassuring point we can glean from the literature regarding CD and pregnancy is that strict adherence to a gluten-free diet appears to overcome many of the risk factors that have been correlated with CD. I wish that could be true for some of the other major pregnancy complications we face on a regular basis!

Labels: celiac disease, PAPP-A

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Low PAPP-A and Celiac Disease in Pregnancy

One of the reasons I love the comments we get from our readers is that they often make me look at pregnancy-related conditions and complications from a different perspective. I stated from the outset of this blog that I was looking forward to participating in the learning experience with our readers. Such is the opportunity afforded to us by Kate’s concerns below…

Kate said...

Dear Dr.T,
I have been following your site and articles ever since my NT (nuchal translucency - combined first trimester screening) and your information, insight and attentive responses to your readers have been exemplary. Thank you SO much for writing and responding to all of us! I am 36 years old with my first baby and currently 16w3d. No history of smoking or drinking. At my NT everything looked good: my Down’s risk was 1:800 and trisomy 18/13 1:7000. I did not need to do an amnio. However my PAPP-A was .44MOM (10th percentile). I also have "suspected" Celiac disease which I will be retested for later.

I have been concerned with this low PAPP-A and when I asked my OB she was not very helpful. So in reading you articles I have gained insight but have further questions:
1) The report said my .44MOM was at 10th percentile...yet I saw many other readers with .4 etc. and were considered 5th percentile (which is a percentile cited as of concern)...am I marginally at 10th percentile and is there a big difference? Should I be concerned?
2) Is there correlation with celiac disease and placental health or low PAPP-A levels? I have read reports of celiac disease causing many of same risk factors associated with low PAPP-A.
3) The other day, I felt a gush of fluid and went to the OB where she tested me for amniotic fluid. She only did a Nitrazine and "thought" all was fine. I revisited PAPP-A levels and their correlation with PROM (premature rupture of membranes)...do you have any insight or advice on this? As a first time mom, I don't even know what a gush of amniotic at 16 weeks might feel like. But moreover...I am concerned about PAPP-A, celiac disease , and PROM.
Many thanks Dr. T!

To Kate:

Let me briefly answer the first and third questions before spending more time with the second in another post. Multiples of the median (MoM) are a measure of how far an individual test result deviates from the median. The ‘median’ is the middle of a distribution: half the scores are above the median and half are below the median. It is less sensitive to extreme values than the mean and this makes it a better measure than the mean for highly skewed distributions. The median is found by arranging all the observations from lowest value to highest value and picking the middle one. MoM is commonly used to report the results of medical screening tests, as is done with the concentrations of the maternal serum markers in both first and second trimester screening tests during pregnancy, where the median is highly variable and dependent on the gestational age. This allows comparison between laboratories and helps to ‘standardize’ interpretation of tests for sake of comparison that may be performed differently in different laboratories. In your case, the MoM for your PAPP-A value at 16 3/7 weeks is 0.44. This is less than half the median for that gestational age and places you between the 5th and the 10th percentiles, but this is not what we consider to be extremely low as would be the case at the 1st percentile. In your case, I would not see that as cause for panic!

All that said and done, as we have discussed in previous posts, the further the PAPP-A is below the median, the greater the risk is for certain pregnancy-related complications such as intrauterine growth restriction, premature labor, unexplained fetal demise, pregnancy-induced hypertensive disorders, and cesarean delivery. However, on an individual basis, the absolute risk is difficult to predict and some women with extremely low PAPP-A values have none of these complications. In the case of preterm delivery, a recent article by Spencer and colleagues (Ultrasound Obstet Gynecol 2008;31:147-52) concluded that women with PAPP-A levels in the range of yours had about twice the risk of delivery before 37 and 34 weeks.

You do raise an interesting question though and that is related to the risk of premature rupture of membranes (PROM) and low PAPP-A. I had not heard, or even thought, about that association before you raised the question. Certainly, premature labor and delivery in general is often preceded by PROM, but in the case premature delivery in association with a low PAPP-A, we tend to think more in terms of this being necessitated by fetal and/or maternal complications. Interestingly, I did find and article by She and colleagues (Taiwan J Obstet Gynecol. 2007:46:242-7) that reported that low maternal serum levels of pregnancy-associated plasma protein-A during the first trimester are associated with subsequent preterm delivery with preterm premature rupture of membranes and the authors concluded that this may be the result of “a trophoblast invasion defect in the maternal-fetal interface” which sets up the series of events leading to both PROM and preterm labor.

So Kate, thanks for the great questions and we will continue with your concerns related to celiac disease and pregnancy in our next post. And, to all our readers, have a very HAPPY THANKSGIVING!

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Ethnic Differences in Components of First Trimester Screening for Aneupolidy

In our last post, we briefly discussed the use of fetal nasal bone (NB) assessment in first trimester screening for aneuploidy and mentioned in passing that ethnic differences have been described. The reader below was curious to find out if ethnicity plays a role in the interpretation of the various components of the screening...

• At Wed Jul 02, 11:35:00 PM 2008, Anonymous said…

Out of curiosity, when you mention race being one of the factors taken into consideration, how does that play out? Are you (when combined with the other factors) at a higher risk for an abnormality if you are African American or Asian than you are if you're Caucasian, etc? Thanks.

• At Thu Jul 03, 02:46:00 PM 2008, Kenneth F. Trofatter, Jr., MD, PhD said…

To anonymous July 2: Ethnicity alone does not necessarily increase risk for certain fetal abnormalities or chromosomal abnormalities, but it does factor in to what is considered 'normal' ranges for the maternal serum markers (β-hCG and PAPP-A) in first trimester. Below is an abstract from an article that makes this point. Furthermore, there are differences in the rate of visualization of fetal nasal bones in first trimester in mothers of different ethnic origins. Yeung Leung and colleagues (Am J Obstet Gynecol 2008;epub ahead of print) found a higher incidence of absent nasal bones in women of Asian origin than in Caucasians and, similarly, Prefumo and colleagues (BJOG 2004;111:109-112) found a lower rate of visualization in women of African origin. Thus, when nasal bone detection is included in first trimester risk assessment, its absence may result in greater false positive screening rates in women of these ethnic backgrounds unless that factor is corrected for statistically or by a sufficient ethnic-specific population database.

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Maternal weight and ethnic adjustment within a first-trimester Down syndrome and trisomy 18 screening program. Krantz, et al., Prenat Diagn 2005;25:635-40.


OBJECTIVE(S): To estimate weight and ethnic group correction factors for first-trimester screening markers. METHODS: Ethnic-specific median MoM free beta hCG and pregnancy associated plasma protein A (PAPP-A) and delta nuchal translucency values were calculated for cohorts of maternal weight (20 lb each) using data from 51,206 patients undergoing first-trimester screening. False-positive rates for Down syndrome and trisomy 18 were evaluated both prior to and after weight and ethnicity adjustment. RESULTS: Free beta hCG and PAPP-A significantly decreased with increasing maternal weight while nuchal translucency increased by a clinically insignificant amount. For free beta hCG the regression formula indicated that after accounting for maternal weight MoM values were 16% higher for African Americans, 6% higher for Asians and 9% lower for Hispanics compared to Caucasians (p < 0.001, p = 0.001, p < 0.001, respectively) but there was no significant difference for Asian Indians. For PAPP-A, MoM values were 35% higher for African Americans (p < 0.001) but were not significantly different for the other ethnic groups compared to Caucasians. Down syndrome false-positive rates did not vary with maternal weight prior to (p = 0.291) or after weight adjustment of biochemistry (p = 0.054). Trisomy 18 false-positive rates varied significantly with weight both before (OR = 1.455 per 20-pound increase, p < 0.001) and after (OR = 1.066 per 20-pound increase, p = 0.01) weight adjustment of biochemistry; however, the odds ratio was greatly reduced after weight adjustment. CONCLUSION(S): The first-trimester screening markers, free beta hCG, PAPP-A and nuchal translucency vary with maternal weight and ethnicity. Adjustment of free beta hCG and PAPP-A is indicated but adjustment of nuchal translucency results may not be necessary. Copyright 2005 John Wiley & Sons, Ltd.

Labels: first trimester screening, hCG, nasal bone assessment, PAPP-A

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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:

CRL:57.9mm
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,
Jackie

• 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.
Jackie

• 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

COMMENT:
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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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 3.50 - Parallel Universes

Many thanks to Dr. Emer at Parallel Universes for including my post regarding the association of "Low Pregnancy-Associated Plasma Protein A (PAPP-A) and Pregnancy Outcome" in this week's stellar Grand Rounds 3.50! This post was written in response to a reader's queries regarding her own pregnancy and it is a format I would like to continue over time - so keep the good comments and questions coming and, who knows, you could be the next 'featured guest' at Fruit of the Womb! And while you're at it, be sure to check out this week's Grand Rounds.

Labels: PAPP-A, pregnancy-associated plasma protein-A

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

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

Labels: fetal growth restriction, PAPP-A, preeclampsia; low birth weight, preterm delivery

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