Last fall, biotech company Sequenom began marketing MaterniT21, a prenatal screening test for trisomy 21, or Down syndrome. Professor Jacob Canick, PhD, and Associate Professor (Research) Glenn Palomaki, PhD, in the Division of Medical Screening and Special Testing in the Department of Pathology and Laboratory Medicine at Women & Infants Hospital, published their study of the test in the journal Genetics in Medicine. In 1988, Canick and Palomaki were involved in the development of prenatal triple marker screening, which is now used throughout the world.

How does the new DNA-based screening test for Down syndrome work and who might take advantage of it?

The test extracts the small fragments of maternal and fetal DNA that circulate in the mother’s blood. The DNA is analyzed, looking for a slight increase in the proportion of DNA fragments derived from chromosome 21, which signals Down syndrome. In our study, the test identified 98.6 percent (209/212) of the Down syndrome pregnancies, while only 0.2 percent of the normal pregnancies were mistakenly called positive. The mothers included in the study sample were all at high risk for having a child with Down syndrome—they were older than 38 years of age, had had abnormal ultrasound findings, or abnormal results for one of the maternal serum screening tests that are currently used.

The problem with current prenatal tests for Down syndrome is the false positive rate of 2 to 5 percent needed to identify about 90 percent of cases. After a positive screening result, pregnant women are offered either amniocentesis or chorionic villus sampling. These are diagnostic tests that will reliably identify any genetic anomalies in the fetus, but both are invasive procedures that carry about a 1 in 200 risk for fetal loss. With the new DNA-based test the number of these procedures is dramatically reduced because it would be unusual to have a woman originally at high risk who also has a positive DNA test have a normal pregnancy.

Right now, the DNA test is complex, resource intensive, and has not been validated as a primary screening test for every pregnant woman. But for women at high risk, it’s an effective tool that will prevent unnecessary procedures while maintaining high detection.

Last January, the Journal of the American Medical Association (JAMA) published a study that concluded that for mild to moderate depression, most antidepressants are not more effective than placebos. Dr. Peter Kramer, clinical professor of psychiatry and human behavior and the author of Listening to Prozac and Against Depression, offers his perspective. What would you advise doctors whose patients have been taking antidepressants for mild to moderate depression? Should they discontinue the treatment on the assumption that the drugs are acting only as placebos?

The JAMA report is a meta-analysis, a statistical integration of individual research trials – in this instance, studies of antidepressant efficacy.

The mainstream press broadcasted the report’s conclusions—that medications’ utility “may be minimal or nonexistent, on average, in patients with mild or moderate symptoms”—as if they were decisive. But it is important to remember that meta-analyses are themselves experiments, limited by the choices researchers make as they prepare to combine data from existing studies.

Here, the authors began with 2164 research reports that they might have analyzed. The criteria that the researchers adopted caused them to discard all but six studies. Three involved imipramine, an older antidepressant, and three, paroxetine (Paxil). The winnowing was idiosyncratic. Because antidepressants have repeatedly been shown to work for chronic minor depression, the researchers chose to ignore studies targeting that condition. Also, many outcome trials begin with a washout period in which subjects who recover in a week or two are dropped, on the grounds that they do not really have the condition under study or they respond too readily to placebo. Washouts are especially important because of a problem called “rater inflation”; in their eagerness to enroll subjects and full up a study quickly, researchers may exaggerate subjects’ symptoms at intake; as a result, rapid apparent recoveries are common among the subjects with few initial symptoms. Since their interest was in placebo responses, the JAMA authors excluded studies with a washout phase. It is thus not surprising that in the handful of remaining studies, the scientists found strong placebo responses (along with strong medication responses) in less ill subjects. Among more severely ill patients, it was harder to find placebo effects, but the medication effects continued to be apparent. This pattern is the one that was summarized in the finding that medications had been shown to outperform placebos only in severely ill patients.

The conclusion that antidepressants work for severe acute depression and mild chronic depression but uniquely not for mild acute depression is one that would require further explanation. The JAMA study should serve as a stimulus to additional meta-analyses and, ideally, to clinical trials designed specifically to look how well or poorly antidepressants work in people with different levels of acute depression. In themselves, the JAMA findings should not transform clinical practice—although it is important to add that the broader literature and clinical consensus suggest that doctors should consider psychotherapy, alone or in combination with medications, in the treatment of minor depression.

What are you advising your patients in light of the government advisory panel guidelines?

Acknowledging the limitations of mammography, we continue to recommend screening beginning at age 40 because this remains our best tool for early detection and successful treatment of breast cancer. In fact, screening mammography is a principal reason the U.S. breast cancer mortality rate has steadily declined since 1990. Annual mammographic screening realizes maximum effect in women aged 50 to 74, but most research indicates at least a 15 percent reduction in mortality in women aged 40 to 49. Women with personal risk factors or family history should begin screening at least at 40. If women delay mammography to age 50, there will definitely be delays in diagnosis which will impact survival. Mammography’s risk in younger women is “false positive” results that lead to additional imaging, needle biopsy, and more frequent follow up. This may add to some women’s anxiety, but may reassure others. We hope the recommendations continue to increase dialogue on the benefits and limitations of screening and acknowledge a great need for more effective screening approaches.

I am a health care provider. How can I reduce my risk of illness from swine-origin H1N1 influenza (S-O H1N1) virus?

Although many Americans have been affected by S-O H1N1, there’s not enough herd immunity to circumvent resurgence in the fall. To date, there does not appear to be any evidence of increasing virulence in the Southern Hemisphere where the virus is now spreading nor is there evidence of widespread oseltamivir (Tamiflu) resistance as of this time.
• All those with direct patient care responsibilities should, in my opinion, be required to receive both the seasonal flu vaccine and S-O H1N1 vaccine.
• Patients calling your office should be encouraged to stay home if their influenza-like illness (ILI) symptoms are mild. A voice mail message as such may be helpful.
• Patients coming to your office with ILI should be encouraged to put on a procedure or surgical mask and clean their hands upon entering the waiting room. This can be done using a cough etiquette station with appropriate signage in the waiting room (see CDC web site for educational information to put on/near the cough etiquette station). Masking of patients with ILI will reduce transmission risk. If you’re able to separate your waiting room with those with and without ILI that would be ideal. Also, spacing chairs at least 3 feet apart in the waiting room would help mitigate risk of transmission.
• Anyone within 6 feet of patients with ILI should adhere to Droplet Precautions: wear a procedure or surgical mask and scrupulous attention to hand hygiene. Eye protection should either be worn whenever within 6 feet of patients with ILI or if mucous membrane exposure to their respiratory secretions is anticipated. Your wearing a mask is particularly important if your patient with ILI (e.g., a 2-year-old or a confused/combative adult) is unable to keep a mask on during their visit.
• Minimizing potential aerosol-generating/cough-inducing procedures (e.g., jet nebulizer use; high-flow oxygen mask use; open airway suctioning; sputum induction; bronchoscopy) will also reduce risk of transmission. If such procedures must be done, they should be done with respiratory protection consisting of wearing an N95 respirator and eye protection or use of a PAPR and appropriate room ventilation. Crash carts in the office should also be stocked with such respiratory protection.
• A large number of U.S. health care workers who have so far been infected by S-O H1N1 acquired their illness from an ill colleague. Thus, if you have ILI symptoms stay home and don’t go to work.
It will be important to stay up to date with S-O H1N1 recommendations by checking the RI Department of Health web site on a regular basis http://www.health.ri.gov/news/flu/index.php. A pragmatic approach as noted above will reduce the risk of illness.

What are the risks involved in assisted reproductive technology, and how can they be avoided?

A possible outcome of assisted reproductive technology (ART) is high-order multiple births. But this problem can and should be avoided.

To overcome fertility problems with IVF, the ovary is stimulated to make multiple eggs, which are then fertilized in the laboratory. To make sure that a pregnancy occurs, there is a temptation to put in as many eggs as possible, but this is a delicate balance. We want to make sure couples have the best chance at pregnancy but also decrease the risk for multiples, which come with significant increased risks to the health of the mother and the outcome of the pregnancy.

Advances in laboratory methods and clinical protocols enable us to freeze better quality embryos and place fewer embryos. National standards about the number of embryos transferred – based on a patient’s age and her medical condition – have been set by the American Society for Reproductive Medicine and the Society of Assisted Reproductive Technology. Standards have also been set for careful monitoring of ovarian stimulation with drugs to prevent both complications and multiple pregnancy.

A new technique called in vitro maturation (IVM) enables specialists to recover and mature eggs without fertility drugs. This makes it possible to treat infertile women whose ovaries over-respond to fertility drugs and who have serious problems achieving pregnancy with standard IVF.