December 6, 2013. Marta Wegorzewska, PhD candidate.

We learned that fetal DNA can be found in the mother’s blood. Companies are using this finding to create new prenatal screening tests. This finding also raises some interesting questions we will examine in a two part series.

How does fetal DNA get into the mother’s blood?

I spent a lot of time during my PhD thinking about how this could happen! Let’s tap into the mind of a scientist….

Maybe the answer lies in the placenta.

The placenta is a unique organ. Like the stomach, it is a sac. It doesn’t hold food, however, but blood. Unlike the stomach, only women can have a placenta, but they are not born with one. A placenta is made with each new pregnancy and is discarded after nine months. The placenta supports the growing fetus’ nutritional needs. It provides the fetus with oxygen and disposes of waste.

Maternal and fetal blood fills up sePages from Finding fetal DNA in Mom’s Blood – A Needle in a Haystackparate compartments of the placenta. These compartments come into close contact at the maternal-fetal interface (Figure 1).1

Three layers (back, blue, green arrows) separate the maternal blood from the fetal blood at the interface (Figure 1). Nutrients (iron), gases (O2 and CO2) and waste can freely pass between the mother and the fetus through the three layers (Figure 1).

Scientists thought the placenta was a perfect physical barrier preventing blood from the mother and the fetus from mixing. The discovery that fetal DNA floats in the mother’s blood raises the question: can fetal cells cross the three layers of the placenta?

Or maybe fetal cells fall off the placenta and into the mother’s blood. The three layers are fetal in origin. They come into direct contact with the mother’s blood. If cells shed from layer one, they will fall directly into the mother’s blood.2

And there are more possibilities! Only time will tell as scientists work to figure out the answer.

This work is funded in part by the Graduate Student Internships for Career Exploration (GSICE) program at UCSF

This post is checked by the following science articles:

1. Maltepe, E., Bakardjiev, A.I., and Fisher, S.J. 2010. The placenta: transcriptional, epigenetic, and physiological integration during development. J Clin Invest 120: 1016-25.

2. Bianchi DW. 2004. Circulating fetal DNA: its origin and diagnostic potential-a review. Placenta Suppl A:S93-S101.

Fetal Cells Cross Enemy Lines Wearing a Cloak of Invisibility

December 5, 2013. Marta Wegorzewska, PhD candidate.

In the last blog post, we learned fetal DNA swims in the mother’s blood!1

Now, in a two series blog post, we are going to talk about two questions scientists are thinking about since we learned fetal DNA is found in the mother’s blood.

How does it get there?

Does the mother’s immune system know the fetal DNA is there?

The answers to these questions are important because scientists are beginning to think too much fetal DNA in the mother’s blood may cause problems during pregnancy. DNA from the mother can also be found in fetal blood, and evidence is building that increased levels of the mother’s DNA in fetal cord blood may be associated with preterm labor. If we know how it is getting there, we can stop it!

This work is funded in part by the Graduate Student Internships for Career Exploration (GSICE) program at UCSF

This post is checked by the following science articles:

1. Lo YM, Corbetta N, Chamberlain PF, Rai V, Sargent IL, Redman CW, Wainscoat JS. 1997. Presence of fetal DNA in maternal plasma and serum. Lancet 350: 485-7.

The Fine Print Behind the Next Generation of Non-Invasive Prenatal Tests

November 25, 2013. Marta Wegorzewska, PhD candidate, in collaboration with Dr. Seth Bokser, MD. Edited by Tracey McLean, MD.

Every parent dreams about having a healthy baby. Some parents want to know before birth if their child will have a genetic disorder.

Genetic disorders are caused by chromosomal abnormalities. Chromosomes carry DNA that determines characteristics such as height, hair color, and nose shape. Having too much, too little, or mixed up DNA causes problems.

Prenatal genetic testing helps parents who want to know if their baby will be born with a chromosomal abnormality. Today, there are numerous tests available that fall into two categories. Screening tests estimate a potential risk of a genetic disorder. Diagnostic tests confirm the existence and type of genetic disorder.

Traditionally, doctors recommend prenatal genetic screening tests at 10-13 or 16-18 (or both) weeks of gestation.1 Maternal blood is screened for markers associated with chromosomal abnormalities.2 An ultrasound reveals abnormal physical characteristics on the growing fetus.3

When these traditional screening tools indicate a high likelihood of a genetic problem, women are referred for diagnostic tests that give definitive information about chromosomal mishaps on fetal DNA.

Where does the fetal DNA come from? Fetal DNA is found in the fluid the fetus swims in (amniotic fluid) or in the placenta (chorionic villus). Getting a sample of fetal DNA involves invasive procedures (amnioscentesis, chorionic villus sampling) that carry a small risk of miscarriage but are very good at diagnosing chromosomal problems.4,5

Recently, finding fetal DNA has gotten easier. Scientists discovered fetal DNA in the mother’s blood!6 Some chromosomal abnormalities can now be detected from a maternal blood sample.7-10

Four companies (Verinata, Sequenom, Ariosa, and Natera) have packaged this idea into new non-invasive prenatal tests (NIPT: Verifi, MaterniT21, Harmony, Panorama, respectively) available to most women. The tests are done early in pregnancy and the results come back in about a week.

The best part is only a small sample of blood is needed. What is the catch?

The Fine Print

Because this exciting technology is brand-new, it is not surprising NIPT have some limitations.

1. They are available to most women, BUT we do not always know how to interpret the result. The original validation studies used blood from women whose fetuses were known to have chromosomal abnormalities.7-11 We don’t know what the results mean for the general population or for women carrying multiple pregnancies (twins, triplets etc).

2. They are sensitive and specific,7-10 BUT we do not know if they are clinically useful. The companies have shown that the the tests perform well technically. They are sensitive, meaning if a patient has a disease, the test is likely to find it. We also know the tests are specific, meaning if a patient does not have the disease, the tests will most likely come back with a negative result. Both sensitivity and specify affect how well the tests perform, but it is does not help physicians answer an important question. “If a test gives a positive result, what is the chance the fetus will have a genetic condition?” This is called predictive value and describes how clinically useful the tests are. How well a result translates to a clinical outcome is crucial information because for some women the result may mean making a very difficult decision about the pregnancy.

3. It is easy and non-invasive BUT limited. The new test detects fewer genetic abnormalities than the traditional screening tests. A negative result on the new test does not rule out rare chromosomal abnormalities.

What does this mean for you?

The medical community has recognized the value and limitation of this test. The following recommendations have been made:12

1. The test is not recommend for low-risk women. It is also not recommended for women carrying multiple pregnancies. The results in these populations are difficult to interpret and are based on what is known in the high-risk population. Insurance will not cover the cost of the test for these women.

2. High-risk women can choose between the new, non-invasive test and the traditional invasive test. Insurance will cover the new test in this scenario only. Because no information is available at this time about how clinically useful the test is, it is difficult to predict the odds a positive result will translate to a genetic condition. Even if the new test is performed, the invasive tests are recommended to confirm the result.

3. High-risk women  with a family history of a genetic condition not detected on the new test are advised to get the traditional screening test and the invasive tests.

The new test entered the market very rapidly. Its fast, easy and non-invasive properties are emphasized to entice buyers. The new non-invasive test may represent a big leap forward, but the science needs time to catch up! If you choose to proceed with the test, know:

1. It’s only recommended as a screening and not a diagnostic tool. If you want a diagnosis, you will need to decide if you want the more invasive tests performed.

2. Its screening abilities are more limited than the traditional screening tests.

How does this information change what you thought about the new non-invasive prenatal test?

This post is checked by the following science articles:

1. Borrell A, Casals E, Fortuny A, Farre MT, Gonce A, Sanchez A, Soler A, Cararach V, Vanrell JA. First-trimester screening for trisomy 21 combining biochemistry and ultrasound at individually optimal gestational ages. An interventional study. Prenat Diagn. 2004 Jul;24(7):541-5.

2. Brambati B, Macintosh MC, Teisner B, Maguiness S, Shrimanker K, Lanzani A, Bonacchi I, Tului L, Chard T, Grudzinskas JG. Low maternal serum levels of pregnancy associated plasma protein A (PAPP-A) in the first trimester in association with abnormal fetal karyotype. Br J Obstet Gynaecol. 1993 Apr;100(4):324-6.

3.Taipale P, Hiilesmaa V, Salonen, Ylöstalo P. Increased Nuchal Translucency as a Marker for Fetal Chromosomal Defects. N Engl J Med 1997; 337:1654-1658.

4. Wilson RD, Langlois S, Johnson JA; Society of Obstetricians and Gynaecologists of Canada. Mid-trimester amniocentesis fetal loss rate. J Obstet Gynaecol Can. 2007 Jul;29(7):586-95.

5. Alfirevic Z, Sundberg K, Brigham S. Amniocentesis and chorionic villus sampling for prenatal diagnosis. Cochrane Database Syst Rev. 2003;(3):CD003252

6. Lo YM, Corbetta N, Chamberlain PF, Rai V, Sargent IL, Redman CW, Wainscoat JS. Presence of fetal DNA in maternal plasma and serum. Lancet. 1997 Aug 16;350(9076):485-7.

7. Fan HC, Blumenfeld YJ, Chitkara U, Hudgins L, Quake SR. Noninvasive diagnosis of fetal aneuploidy by shotgun sequencing DNA from maternal blood. Proc Natl Acad Sci U S A 2008;105:16266–71.

8. Chiu RW, Akolekar R, Zheng YW, Leung TY, Sun H, Chan KC, et al. Non-invasive prenatal assessment of trisomy 21 by multiplexed maternal plasma DNA sequencing: large scale validity study. BMJ 2011;342:c7401.

9. Ehrich M, Deciu C, Zwiefelhofer T, Tynan JA, Cagasan L, Tim R, et al. Noninvasive detection of fetal trisomy 21 by sequencing of DNA in maternal blood: a study in a clinical setting. Am J Obstet Gynecol 2011;204:205.e1–11.

10. Sparks AB, Wang ET, Struble CA, Barrett W, Stokowski R, McBride C, et al. Selective analysis of cell-free DNA in maternal blood for evaluation of fetal trisomy. Prenat Diagn 2012;32:3–9.

11. Palomaki GE, Kloza EM, Lambert-Messerlian GM, Haddow JE, Neveux LM, Ehrich M, et al. DNA sequencing of maternal plasma to detect Down syndrome: an international clinical validation study. Genet Med 2011;13:913–20.

12. American College of Obstetricians and Gynecologists Committee on Genetics. Committee Opinion No. 545: Noninvasive prenatal testing for fetal aneuploidy. Obstet Gynecol. 2012 Dec;120(6):1532-4.

All Scientific Studies are NOT Created Equal

suggestion box
Hash Milhan
November 6, 2013. Marta Wegorzewska, PhD candidate, in collaboration with Dr. Seth Bokser, MD. Edited by Dr. Darya Rose, PhD.

All Scientific Studies Are NOT Created Equal

If a scientific study claims eating garlic daily during pregnancy shortens labor, should pregnant women start eating garlic every day?

It depends on the type of scientific study. All studies are not created equal. Some studies prove, and others suggest.

Studies that suggest may be right, but they may also be wrong. For example, Facebook suggests people we may know. Some of them we do know and request their friendship. Some of the suggestions are wrong, and we ignore them.

Which studies prove and which suggest?

Studies that Prove

The best study would ask, “Does garlic shorten labor?”

To answer this question, women would be asked to volunteer for the study. They would have just found out they are pregnant so they could eat garlic throughout nine months of pregnancy (prospective).

Hundreds to thousands of women would be involved in the study to ensure any observations are not due to chance. The women would be randomly split into two groups (randomized). The due dates for the two groups would be similar. One group would eat garlic throughout pregnancy and the other would not (control).

The number of hours the women are in labor would be recorded. To prevent unintentional bias, the individual recording the time would not know whether the woman ate garlic or not. He would be “blinded” to that information.

Women who require a drug to speed labor would be excluded from the study.  Excluding these cases ensures the effect on labor is from the garlic and not from the drug (confounding factor).

This type of study is called a prospective randomized control study.

The strength of this type of study is that it proves if one factor (garlic) causes another (shorter labor). If the number of hours of labor is shorter for women who ate garlic during pregnancy compared to those that didn’t, the study proved garlic shortens labor!

Why aren’t all studies designed as a prospective randomized control study?

Imagine if scientists wondered if women who are obese during pregnancy give birth to sick babies.

A prospective randomized control study would ask women to voluntarily become obese during pregnancy to see if their babies would be born sick. No woman would volunteer for this study! It would be unethical to conduct a study that would potentially harm mom and baby.

Studies that Suggest

Other studies would provide clues.

A case control study would look at already sick babies. This study would compare the weight of pregnant women delivering sick babies to women delivering healthy babies.

A cohort study would look at already obese pregnant women. The health of their babies would be compared to the health of babies of non-obese women.

These studies would not prove that obesity causes sick babies. They would suggest that being obese during pregnancy may be associated with (linked to) sick babies.

Case control and cohort studies suggest instead of prove because they have limitations. They cannot eliminate other factors that may contribute to sick babies. For example, maybe obese pregnant women eat more fast food because they are struggling financially, working longer hours and are more stressed. Stress may be another factor that could impact a baby’s health. A prospective randomized control study would avoid this problem by randomly splitting women into groups. Stress would affect both groups equally and cancel out. Any differences seen between the groups would be due to obesity.

That being said, are you going to start eating garlic every day?

If a prospective randomized control study proved garlic causes shorter labor, I would try to eat garlic even if I hated it.

If a case control or cohort study suggested garlic is linked to shorter labor, I might eat garlic if I didn’t mind it, but I wouldn’t view garlic as a guarantee my labor would be shorter. If I hated garlic, I would ignore this suggestion.

This work is funded in part by the Graduate Student Internships for Career Exploration (GSICE) program at UCSF