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Content 7


The Doctor and the Pharmacist

Radio Show Articles:
October 29, 2011

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Swimming Against the Current: Hormonal Forces Drive Excess Body Weight
Chantix (Varenicline) Might Not Increase Risk for Serious Neuropsychiatric
  Symptoms, FDA Says
Chinese Firms Still Supplying Heparin to U.S.?
Scientists Say Suggested Mercury Ban Could Threaten Vaccines
Researchers: Benefits of Screening Mammography Are an 'Exaggeration'
Yoga and Conventional Stretching Classes Both Improve Low Back Pain
Prenatal Folic Acid Lowers Risk for Language Delay
FDA: Do Not Use Jet Injectors with Flu Vaccines
Annual Screening Chest X-Rays Don't Lead to Increased Survival in Lung Cancer
Elevated Risk for Prostate Cancer Found with Vitamin E Supplementation
Use of Stimulants in Adolescents with Substance Abuse and ADHD
Flu Vaccine–Associated Neurological and Immunologic Sequelae
Screening for Down Syndrome: Why, When, and How
Sperm Washing with Assisted Reproduction — Safe and Effective for
  HIV-Serodiscordant Couples
NSAIDs and Early Pregnancy Failure
Key Obstetric Risk Factors for Cerebral Palsy
Diet, Genes, and Stroke Risk: Another Look at Homocysteine and Folate
Vitamin D Appears to Prevent Falls in Some High-Risk Subgroups
Omega-3 Fatty Acids for Depression? The Jury Is Still Out

MM: A benefit of the HCG weight loss protocol is that it seems to improve the leptin-ghrelin balance in the body. This decreases the amount of hunger both during and after the protocol. This decreased hunger and urge is likely a large part of why people who do this program tend to gain back very little of the weight they have lost. For more information on the HCG weight loss protocol and Metaboluic Syndrome, please visit www.markdrugs.com.
N Engl J Med 2011 Oct 27; 365:1597
Swimming Against the Current: Hormonal Forces Drive Excess Body Weight
Hormones that regulate hunger and energy storage make it hard for overweight people
to lose weight.

     Many of us were taught, and still believe, that being overweight or obese results from lack of discipline about diet and exercise. However, during the past 20 years, a group of hormones produced by adipose tissue and the gut have been shown to affect appetite and energy metabolism.
     An Australian team enrolled 50 overweight or obese participants without diabetes in a severe caloric-restriction program. The program lasted 10 weeks and led to an average weight loss of 14%. Thereafter, participants were given individualized instructions on caloric intake and exercise needed to maintain weight loss. At 62 weeks, participants had regained a mean of about half their lost weight.
     Caloric restriction and weight loss were associated with dramatic increases in hormones (such as ghrelin), which increase appetite and energy storage, and with dramatic decreases in multiple hormones that encourage satiety and promote energy expenditure (such as leptin). Even those participants who remained very overweight after the weight-loss program experienced strong hormonal urges to eat more and to burn less energy.
     Comment: Ubiquitous fast food and lack of exercise profoundly influence obesity. Although limited by its relatively small size and high attrition rate, this study suggests that a biological component also might be present. People who are overweight are constantly in a hormonal environment that makes them hungry and causes them to burn less energy during exercise. Trying to lose weight through diet and exercise feels like swimming against the current.
Anthony L. Komaroff, MD Published in Journal Watch General Medicine October 27, 2011
     Citation(s):Sumithran P et al. Long-term persistence of hormonal adaptations to weight loss. N Engl J Med 2011 Oct 27; 365:1597.
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Chantix (Varenicline) Might Not Increase Risk for Serious Neuropsychiatric Symptoms, FDA Says
     Patients may ask about reports on two FDA-sponsored studies suggesting that the smoking cessation drug varenicline (Chantix) does not increase the risk for hospitalizations for neuropsychiatric symptoms (e.g., depression and suicidal thoughts) when compared with nicotine patches. A review of the studies was released by the FDA yesterday.
     The results are not definitive, however. Both studies "had a number of study design limitations," the agency says, and the boxed warning to alert patients of the risk for neuropsychiatric symptoms will be kept on the drug's label.


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Chinese Firms Still Supplying Heparin to U.S.?
     Two Chinese companies that were implicated in supplying contaminated ingredients three years ago to Baxter International Inc. for manufacturing heparin may still be supplying product to the U.S., according to reports. Heparin is given to about 12 million people in the U.S. each year. A Congressional committee began investigating contaminated heparin in February and expanded its investigation in May to seek information from U.S. Immigration and Customs Enforcement and from industry leaders in June.
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Scientists Say Suggested Mercury Ban Could Threaten Vaccines
     Scientists have warned officials negotiating a global treaty on mercury that banning the deadly chemical completely would be dangerous because of the chemical's use (thiomersal, thimerosal) in vaccines.
     The World Health Organization states that mercury is one of the top 10 chemicals of public health concern and is highly toxic. These worries are primarily centered on mercury emissions from burning coal, gold mining, and people eating mercury-tainted fish.
     "Not being able to use mercury is not a viable option," said David Wood, a WHO vaccines expert." According to Wood, there isn't a viable alternative to thiomersal at the moment. If banned, preservative-free vaccines would be required. (Editor's Note: This would then require single-dose vials/amps and not multiple-dose vials.)

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Researchers: Benefits of Screening Mammography Are an 'Exaggeration'
     The benefits of screening mammography are an "exaggeration," researchers conclude in the Archives of Internal Medicine. Their modeling study found that the majority of women with screen-detected breast cancer have not had their lives saved by mammography.
     Using national survey data, the researchers developed a model to estimate the probability that breast cancer death is avoided because of screening mammography. They found that for a 50-year-old woman with screen-detected cancer, the probability that she avoids breast cancer mortality because of mammography is just 13%. For all age groups, the probability that screening is lifesaving was under 25%.
     Commentators call the findings "convincing" and say that providers should deliver clear and simple messages to patients about screening — for example, "I recommend screening every 2 years for my patients aged 50 to 74 years." They emphasize that for women aged 40 through 49 or over 74, "providers should ensure that the patient does not have an overly inflated perception of the benefits of screening."
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Yoga and Conventional Stretching Classes Both Improve Low Back Pain
     Yoga and stretching classes are equally effective in managing the symptoms of moderate low back pain, according to an Archives of Internal Medicine study.
     Researchers randomized some 230 adults with chronic low back pain to one of three treatments: 12 weekly yoga classes, 12 weekly stretching classes, or self-care with the aid of The Back Pain Helpbook. The primary outcomes were back-related functional status and self-rated symptom "bothersomeness" at 12 weeks.
     After adjustment for baseline values, patients in the yoga and stretching groups had superior outcomes compared with those in the self-care group. There were no differences between the yoga and stretching groups, however.
     A commentator writes that the results are "actionable for practice," and that the study "reinforces the evidence that exercise is safe and moderately beneficial" in these patients.
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JAMA 2011 Oct 12; 306:1566
Prenatal Folic Acid Lowers Risk for Language Delay
The benefits of folic acid supplementation extend to language development during early childhood.
     Knowledge of the protective effect of folic acid against neural tube defects has led to concerted public health campaigns to promote folic acid supplementation. Despite these efforts, periconceptional supplementation rates remain suboptimal in the U.S. To examine whether folic acid has other benefits in neurodevelopment, investigators in Norway — a country that does not fortify foods with folic acid — prospectively evaluated the association between maternal report of folic acid supplementation early in pregnancy and language delay in nearly 39,000 offspring. Severe language delay (defined as limitation to 1-word or unintelligible utterances at age 3 years) was measured by maternal report on a validated language grammar rating scale.
     After adjustment for confounding factors including maternal education, parity, and marital status, children of women who reported supplemental folic acid use from 4 weeks before conception to 8 weeks after conception had significantly lower odds of having severe language delay, compared with children of mothers who reported no supplement use (adjusted odds ratio, 0.82; 95% confidence interval, 0.69–0.97). This association was not seen in women who took supplements containing no folic acid during the same period, reducing the likelihood that the results are merely explained by benefits afforded to health-conscious patients. In addition, folic acid did not affect risk for severe gross motor delay. Both of these findings support the likelihood that folic acid deficiency plays a causal role in language delay.
     Comment: That folic acid supplementation might have advantages beyond protection against neural tube defects is not surprising; what is surprising is that high-quality study results supporting this notion have been so long in coming. Because of the association between periconceptional folic acid and anomalies of the central nervous system, a randomized controlled trial in which this micronutrient is withheld would be unethical. Thus, large prospective observational studies such as this one are as close as we will likely come to proving folic acid's other reproductive benefits. The association between maternal folic acid intake during early gestation and developmental outcomes will be strengthened in future studies that use standardized tests of neurodevelopment. In the meantime, these data provide even more compelling reasons to improve efforts to ensure periconception folic acid repletion among all women, especially very young women and racial and ethnic minorities who historically have had woefully low rates of adequate folic acid intake.
Allison Bryant, MD, MPH Published in Journal Watch Women's Health October 27, 2011
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FDA: Do Not Use Jet Injectors with Flu Vaccines
     Jet injectors should not be used to administer any immunization except the measles, mumps, and rubella vaccine, the FDA reminded healthcare providers on Friday.
     The agency issued the notification in response to queries about using injector devices with flu vaccines, which are approved for administration only via needle injection or intranasal spray. Jet injectors could change the characteristics of a vaccine, the agency said, and there are no data available on their safety or efficacy with vaccines other than MMR.
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Annual Screening Chest X-Rays Don't Lead to Increased Survival in
Lung Cancer

     Lung cancer mortality is not reduced among people who undergo annual screening with chest x-rays, according to a report in JAMA.
     Some 155,000 people aged 55 through 74 were randomized either to annual screening with chest radiographs or to usual care for 4 years. After a median follow-up of 12 years, lung cancer mortality in the two groups was roughly the same: 14.0 per 10,000 person-years in the x-ray group and 14.2 among controls.
     An editorialist says that the results are valuable for putting to rest the question of whether lung cancer screening with chest radiographs is effective.
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MM: I always appreciate feed back and although this article was previously referenced, a comment from a CCN (Certified Clinical Nutritionist) who receives these articles was submitted that I would be remiss in not sharing. “Back in August, we went over the study at the annual IAACN conference (CCN's). The major flaw in that study was that they used d-alpha Vitamin E. You can't use just one fraction of Vitamin E and ever get a positive outcome. It will over-ride the other fractions, gamma, beta, and delta and cause some unusual outcomes, like heart disease and colon cancer. The gamma fraction is important to protect against heart disease, colon cancer, and a number of other important functions. Take a clue from the study and see that foods with high amounts of vitamin E did not cause any problems. Why? The foods contain all the fractions. That should have been a no-brainer. So the answer, use mixed tocopherols.”
JAMA 2011 Oct 12; 306:1549
Elevated Risk for Prostate Cancer Found with Vitamin E Supplementation
Clinicians should counsel older men about vitamin E use.
     Basic science and epidemiologic data have suggested that vitamin E and selenium supplementation lower risk for prostate cancer. However, when early results from a large controlled trial of vitamin E supplementation showed no fewer cases of — and a possible excess risk for — prostate cancer after 3 years, supplementation was halted (JW Gen Med Jan 15 2009). This new report includes data from 3 additional years of follow-up.
     Originally, the 35,533 men were randomized to daily selenium (200 µg) plus vitamin E placebo, vitamin E (400 IU) plus selenium placebo, both selenium and vitamin E, or double placebo. Participants (age, ≥50 for blacks, ≥55 for whites) had prostate-specific antigen levels ≤4 ng/mL and normal digital rectal exams. Nearly 1800 incident cases of prostate cancer were diagnosed initially, and an additional 521 cases were diagnosed during the latest follow-up. The overall risk for prostate cancer was significantly elevated (by 17%) in the vitamin E group, with no significant difference in the other treatment groups. Excess risk was similar for patients with Gleason scores ≥7 and for patients with scores <7, but only the overall results achieved statistical significance.
     Comment: These results confirm what was suspected in the first analysis: Vitamin E raised risk for prostate cancer, and that risk was mitigated by selenium supplementation. Because many older men take vitamin E for a wide range of unsubstantiated benefits, clinicians should ask about and counsel them about vitamin E use.
Thomas L. Schwenk, MD Published in Journal Watch General Medicine October 25, 2011
     Citation(s):Klein EA et al. Vitamin E and the risk of prostate cancer: The Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 2011 Oct 12; 306:1549.
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J Am Acad Child Adolesc Psychiatry 2011 Sep; 50:903.
Use of Stimulants in Adolescents with Substance Abuse and ADHD
Adding stimulant treatment to behavioral therapy did not further reduce ADHD symptoms or substance use.
     Attention-deficit/hyperactivity disorder (ADHD) is associated with a twofold lifetime risk for substance use disorder. Among adolescents referred for substance use treatment, 30% to 50% also have ADHD. Clinicians might be reluctant to prescribe stimulants for treatment of ADHD in adolescents with substance use disorder because of concern about medication efficacy, abuse, and diversion (JW Pediatr Adolesc Med Jul 26 2006). In a 16-week controlled, multisite trial, researchers randomized 303 adolescents (age range, 13–18 years) who met DSM-IV criteria for ADHD and substance use disorder to receive cognitive-behavioral therapy (CBT) for treatment of substance use disorder SUD plus either long-acting methylphenidate or placebo. Outcome measures included parent- and adolescent-reported standardized ADHD rating scales, adolescent-reported substance abuse, and weekly urine drug screening.
     Adolescent reports indicated a clinically and statistically significant decrease in ADHD scores in both treatment groups but no between-group differences. In comparison, parent-reported ADHD scores were significantly lower in the methylphenidate-plus-CBT group than in the placebo-plus-CBT group. Reported days of substance use also decreased significantly in both treatment groups, but between-group differences were not significant (–5.7 and –5.2 days during the last 28 days of the study). However, adolescents treated with methylphenidate plus CBT had a modest but significantly greater number of negative weekly urine drug screening tests than those in the placebo group.
     Comment: Differences in outcome reports between parents and adolescents have been observed in other ADHD treatment studies. In this study, adolescents with ADHD and substance use disorder reported equally reduced core ADHD behaviors with CBT with or without stimulant medication, while parents observed fewer ADHD symptoms in adolescents who received stimulants. Further, adding stimulant treatment to CBT did not reduce substance use. A study that also measures functional impairments (e.g., peer and family relationships and academic achievement) might provide more-useful information. As a pediatrician, I am most comfortable collaborating with a mental health professional in the management of adolescents with a combination of ADHD and substance use disorder.
Martin T. Stein, MD Published in Journal Watch Pediatrics and Adolescent Medicine October 26, 2011
     Citation(s):Riggs PD et al. Randomized controlled trial of osmotic-release methylphenidate with cognitive-behavioral therapy in adolescents with attention-deficit/hyperactive disorder and substance use disorders. J Am Acad Child Adolesc Psychiatry 2011 Sep; 50:903.
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MM: Although this study indicates a low statistical incidence of adverse effects from the H1N1 vaccine, it also notes that many seasonal flu vaccines are now found in combination with the H1N1 vaccine and we do not have a significant amount of data to determine safety of this combination.
BMJ 2011 Oct 12; 343:d5956.
Flu Vaccine–Associated Neurological and Immunologic Sequelae
The H1N1 influenza vaccine used in Sweden was associated with relatively few — and generally mild — neurological and autoimmune complications.
     Concern about possible neurological and immunologic complications is thought to be one of the main factors driving avoidance of influenza vaccination. Now, researchers have examined the incidence of such complications in Sweden, where a population-based vaccination program with the monovalent adjuvanted pandemic influenza A (H1N1) vaccine Pandemrix occurred from October 2009 to March 2010.
     Using data on influenza vaccination and information on healthcare utilization in Stockholm County for October 2009 through August 2010, these researchers compared the incidence of autoimmune disorders (including rheumatoid arthritis, inflammatory bowel disease, and type 1 diabetes) and neurological conditions (including Guillain-Barré syndrome, Bell palsy, multiple sclerosis, polyneuropathy, esthesias, and narcolepsy) between 1,024,019 vaccinees and 921,005 unvaccinated controls.
     Compared with the unvaccinated cohort, the vaccinated cohort had an overall increased risk for Bell palsy (hazard ratio, 1.25; 95% confidence interval, 1.06–1.48; i.e., 8.4 excess cases per 100,000 vaccinated person-years). They also had an overall increased risk for paresthesia (HR, 1.11; 95% CI, 1.00–1.23; 9.2 excess cases per 100,000 vaccinated person-years). Risk for these complications — and for inflammatory bowel disease — was increased only among individuals vaccinated during the early phase of the campaign, when high-risk groups predominated. No increased risk was noted for Guillain-Barré syndrome, multiple sclerosis, type 1 diabetes, or rheumatoid arthritis. Mortality risk was lower in the vaccinated cohort than in the unvaccinated one. Narcolepsy cases were too few to allow valid comparison.
     Comment: It is reassuring that in this large, well-controlled study, there were few neurological and immunologic sequelae — and even fewer serious ones — associated with the H1N1 vaccine. However, the preparation studied is different from the ones used in other areas of the world, so we may not be able to extrapolate to other regions. In addition, H1N1is now generally incorporated into seasonal influenza vaccines.
Stephen G. Baum, MD Published in Journal Watch Infectious Diseases October 26, 2011
     Citation(s):Bardage C et al. Neurological and autoimmune disorders after vaccination against pandemic influenza A (H1N1) with a monovalent adjuvanted vaccine: Population based cohort study in Stockholm, Sweden. BMJ 2011 Oct 12; 343:d5956.
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MM: It’s true that expectant parents have the option to test and determine whether or not to terminate a pregnancy. It’s also true that no matter what the decision, if there is a likely birth defect that decision will cause added stress to a marriage and family relationships. Aside from the ethical aspects of termination, there still remains a very real danger to a marriage and to an expectant mother’s psyche with this decision. I guess the underlying question is, “Just because wwe have the ability to discover these potential problems, should we?”
Screening for Down Syndrome: Why, When, and How
Evaluation during pregnancy can include blood tests, ultrasound examinations, chorionic villus sampling, and amniocentesis.
     Once, expectant parents didn't know of the health or sex of their babies before birth. Now, pregnant women routinely are asked if they want to know the sex of the fetus (developing baby) and are offered antenatal (before birth) screening tests for certain birth defects. Additional screening — as well as genetic counseling — is also offered to some women before or during pregnancy based on personal and family health histories. The American College of Obstetricians and Gynecologists recommends that all pregnant women be informed about screening for the most common detectable birth defect, Down syndrome.
     Birth defects are physical, mental, or biochemical abnormalities that are present at birth. Down syndrome — a genetic disorder that causes mental retardation, developmental delays, and physical disorders — is one example. Many pregnant women opt for screening tests to detect possible problems. Ultrasound imaging can provide clues to some physical defects in the fetus, such as heart problems, neural tube defects (for example, spina bifida, in which the baby's spine does not develop completely), and abdominal wall defects (when the abdominal organs are not in their proper places).
     Antenatal screening has advantages and disadvantages. All screening tests carry the possibility of false positives (which indicate that a condition might be present when it really is not) — and false negatives (which indicate that the condition is not present when it really is). Both false-positive and true-positive results can cause anxiety as you decide whether or not to have a more specific test and, if you choose further testing, while you await the results. However, false-negative results can give mistaken reassurance.
     Why consider screening? Think about how having a baby with a birth defect would affect you and your family. You might choose screening because you would opt to terminate a pregnancy (have an abortion) if you were carrying a fetus with a serious health problem. Or you might choose screening because you would like to know about and prepare for a special-needs child (or for the medical procedures needed to correct certain physical defects). Some women feel that they and their partners would do nothing differently if the baby has birth defects; in that case, they might choose not to be screened.
     No single screening test can tell for sure if your baby has Down syndrome. Clinicians rely on a combination of tests as well as your age (being older is a risk factor) and your health history to determine if Down syndrome is likely.
     First-trimester Down syndrome screening can be done during the 10th to 13th week. The screening includes blood tests to measure levels of two substances that can be altered in women carrying fetuses with Down syndrome and ultrasound imaging to look for fluid around the back of the fetus's neck, called nuchal translucency. Experts use the results of these tests in combination with your age to determine the likelihood of Down syndrome. If the probability is high, further testing of cells from the fetus can provide confirmation. These more accurate tests are chorionic villus sampling (in which a sample of cells is taken from the placenta during the first trimester [the first 3 months of pregnancy]) and amniocentesis (in which a sample of fluid and cells is taken from inside the uterus during the second trimester [the middle 3 months]).
     If you would consider terminating a pregnancy should Down syndrome be confirmed, learning about the condition during the first trimester allows you to have an earlier abortion. Many women find earlier abortions to be less emotionally and physically stressful than later abortions.
     Women who do not get prenatal care until the second trimester can be screened between the 14th and 20th week. This screening combines the results of four blood tests with other factors to determine the likelihood of Down syndrome. If the tests show a high risk, amniocentesis can be performed — with complete results available within 2 weeks.
     Tests performed during the first or second trimester are quite accurate at determining whether a fetus has Down syndrome. However, these tests do miss some cases. A process known as integrated screening is even more accurate: Blood samples are taken from the mother during both the first and the second trimesters and then analyzed together, along with the first-trimester ultrasound, as well as any additional information.
     Other testing strategies also are possible; however, not all approaches are available in all areas. Your clinician should discuss what testing options he or she offers. If you or your partner have a personal or family history of inherited genetic problems or birth defects, or if you have health problems or must take certain medications for your own health, talk with your clinician — in advance of pregnancy if possible — about the recommended antenatal screening procedures. You might also decide to see a genetic counselor.
     Although there is no known way to prevent Down syndrome, some birth defects and health problems can be prevented. Quitting smoking, avoiding harmful medications, getting immunizations, taking a daily prenatal vitamin or folate supplement, and getting medical care as soon as you know you are pregnant all improve your chances of having a healthy baby.
     When you are pregnant, you will be offered screening to detect birth defects such as Down syndrome. You will have the most choices if you obtain prenatal care early. Your clinician will discuss how and when the testing can be done. Ask questions and make sure you understand the meaning of the tests so that you can make informed decisions.
Down Syndrome: http://www.mayoclinic.com/health/down-syndrome/DS00182
Genetic Counseling: http://www.marchofdimes.com/pregnancy/trying_geneticcounseling.html
Antenatal Screening for Birth Defects: http://www.acog.org/publications/faq/faq165.cfm
Chorionic Villus Sampling: http://www.mayoclinic.com/health/chorionic-villus-

Amniocentesis: http://www.marchofdimes.com/prenatalcare_amniocentesis.html
Diane E. Judge, APN/CNP Published in Journal Watch Women's Health October 20, 2011
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Fertil Steril 2011 Apr; 95:1684.
Sperm Washing with Assisted Reproduction — Safe and Effective for HIV-Serodiscordant Couples
In a group of studies that involved more than 1700 HIV-serodiscordant couples undergoing sperm washing with assisted reproduction, none of the women or newborns seroconverted to HIV-positive.
     Many HIV-serodiscordant couples of reproductive age are now electing to have children. For couples in which the infected partner is the man, semen processing (sperm washing) has been used in combination with assisted reproductive technologies — such as intrauterine insemination (IUI), in vitro fertilization (IVF), and intracytoplasmic sperm injection (ICSI) — to reduce the risk of viral transmission to the woman.
     Researchers recently evaluated the safety and effectiveness of this approach via a systematic review of the literature. They identified 17 observational studies on the topic (mostly in Europe) but no randomized trials. Eligibility criteria for the HIV-infected men in these studies typically included stable HIV disease and consistent use of condoms.
     A total of 3900 IUI cycles and 738 IVF/ICSI cycles were studied. No seroconversions were reported in the female partners or in the newborns, either at birth or during 3 to 6 months of follow-up. For each treatment modality, pregnancy rates were comparable to those previously reported for HIV-uninfected couples undergoing assisted reproduction.
      Comment: These findings reinforce previously published data demonstrating the safety and effectiveness of sperm washing in conjunction with assisted reproductive technologies. Indeed, a study by my own group (not included in this analysis) showed similar results: no seroconversions — and no negative effects of sperm washing on reproductive outcomes — among 1036 HIV-serodiscordant couples who underwent 3315 cycles of sperm washing with IUI or IVF/ICSI (AIDS 2007; 21:1908). The collective evidence should reassure physicians and patients alike that semen processing with assisted reproduction is currently the gold standard for preventing viral transmission in couples seeking to reproduce safely.
     Notably, some HIV-serodiscordant couples, in which the men are fully suppressed on antiretroviral therapy, are considering unprotected intercourse using pre-exposure prophylaxis (PrEP) for the women, so that they can conceive without the cost and invasiveness of assisted reproductive technologies. However, the data on this approach are currently too limited to allow for comment on its safety or effectiveness (AIDS 2011; [e-pub ahead of print]). Couples exploring their reproductive options must be fully counseled on the potential risks of natural conception and PrEP as compared to the proven safety and effectiveness of sperm washing and assisted reproductive technologies.
— Carole Gilling-Smith, MD, PhD Dr. Gilling-Smith is Vice President of CREAThE, Medical Director of the Agora Gynaecology and Fertility Centre in Brighton, and Director of Fertility Services for patients with viral illness at the Chelsea and Westminster Hospital in London. She reports no conflicts of interest.
Published in Journal Watch HIV/AIDS Clinical Care October 7, 2011
     Citation(s): Vitorino RL et al. Systematic review of the effectiveness and safety of assisted reproduction techniques in couples serodiscordant for human immunodeficiency virus where the man is positive. Fertil Steril 2011 Apr; 95:1684.
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CMAJ 2011 Sep 6
NSAIDs and Early Pregnancy Failure
Nonsteroidal anti-inflammatory drug use during early pregnancy was associated with excess risk for miscarriage — but the case against NSAIDs as a causal agent remains largely unproven.
     Clinicians generally advise women to avoid nonsteroidal anti-inflammatory drugs (NSAIDs) during pregnancy; however, early exposure is sometimes unintentional or unavoidable, and data conflict on adverse pregnancy events related to NSAIDs. To explore this issue, Canadian investigators conducted a nested case-control study of 67,000 women who were enrolled in a prescription drug plan. Use of NSAIDs (defined as having filled a prescription for a medication in this class during or just before pregnancy) was assessed in women who experienced spontaneous abortions before 20 weeks' gestation and in controls who did not experience early pregnancy loss. NSAIDs are covered by insurance, minimizing the likelihood of over-the-counter use.
     Overall, 4705 participants experienced early pregnancy failures. Women who filled NSAID prescriptions were 2.4 times more likely to suffer miscarriages than were women without NSAID exposure (7.5% vs. 2.6%; P<0.05). This excess risk was not dose-dependent and was only marginally higher when NSAID use occurred during the 2 weeks before miscarriage compared with use at any time during pregnancy.
     Comment: These authors relied on circumstantial evidence of NSAID use and were not able to make firm conclusions about actual use, nor did they control for all indications for NSAID use (e.g., febrile illness, degenerating uterine fibroids, severe comorbidities) that might be associated with miscarriage. Thus, the case against NSAIDs as a causal agent for spontaneous abortion remains largely unproven, and women who have used NSAIDs before they know they are pregnant should not be made unduly fearful about the possibility of early pregnancy loss. Still, these findings provide additional support for the conventional wisdom that "less is more" with respect to medication use during early pregnancy — and that assessment of relative risks and benefits is always necessary.
Allison Bryant, MD, MPH Published in Journal Watch Women's Health October 6, 2011
     Citation(s): Nakhai-Pour HR et al. Use of nonaspirin nonsteroidal anti-inflammatory drugs during pregnancy and the risk of spontaneous abortion. CMAJ 2011 Sep 6; [e-pub ahead of print]. (http://dx.doi.org/10.1503/cmaj.110454)
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Obstet Gynecol 2011 Sep; 118:576
Key Obstetric Risk Factors for Cerebral Palsy
Upper respiratory and gastrointestinal infections were not among the maternal infections associated with CP.
     In an analysis of epidemiologic risk factors for cerebral palsy (CP), Australian researchers used nationwide information from perinatal databases, CP registries, and maternal questionnaires to estimate the relative influences of various risk factors in a cohort of 587 children and adolescents (age range, 5–18) with CP and in 1154 controls.
     Certain maternal infections (particularly those that occurred during gestational weeks 21–40 and that caused fever) were associated with CP (41.4% of cases vs. 31.3% of controls; odds ratio, 1.6; P<0.001). However, common upper respiratory tract and gastrointestinal infections were not associated with CP. Other significant risk factors included birthweight <3rd percentile (OR, 11.8), gestational age <32 weeks (OR, 59.2), and twin birth (OR, 6.6). Factors not associated with CP included forceps- or vacuum-assisted birth, maternal age, diabetes, body-mass index outside the normal range, hypertension, alcohol consumption, anemia, and hypothyroidism.
     Comment: Because all study participants were white and of Australian descent, the ability to generalize these findings to other populations is limited. Nonetheless, because the authors used maternal questionnaires to supplement national data, the results provide additional details about certain cerebral palsy risk factors (possible recall bias notwithstanding). These findings confirm the four primary risk factors for CP (preterm birth, intrauterine growth restriction, perinatal infection, and multiple birth) while reassuring women who contract common upper respiratory and gastrointestinal infections during pregnancy that such infections do not raise risk for CP in their offspring.
Diane J. Angelini, EdD, CNM, FACNM, FAAN, NEA-BC Published in Journal Watch Women's Health September 29, 2011
     Citation(s):O'Callaghan ME et al. Epidemiologic associations with cerebral palsy. Obstet Gynecol 2011 Sep; 118:576.
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Lancet 2011 Aug 13; 378:584.
Diet, Genes, and Stroke Risk: Another Look at Homocysteine and Folate
A genetic analysis and a meta-analysis suggest that lowering homocysteine levels reduces stroke risk more in low-folate regions than in areas with folate fortification, and that folate status modifies the effect of MTHFR alleles on stroke risk.
     The MTHFR 677C->T polymorphism is associated with elevated homocysteine levels and with increased stroke risk. Vitamin therapy with folic acid, vitamin B6, and vitamin B12 lowers homocysteine levels; however, randomized controlled trials (RCTs) of vitamin therapy for elevated homocysteine levels have not shown reductions in stroke risk (Arch Intern Med 2010; 170:1622). Folate consumption affects serum homocysteine levels and varies by geographic region. The RCTs evaluating the effect of homocysteine lowering on stroke risk were predominantly performed in areas with folic acid supplementation, which could explain the lack of benefit.
     To investigate the potential modifying effect of folate status on the association between the MTHFR 677C->T variant and stroke risk, researchers reassessed genetic studies that included data for homocysteine concentration and stroke. The investigators compared their genetic-analysis findings with a meta-analysis of 13 RCTs of homocysteine-lowering treatments to reduce stroke risk and found the following:

     Comment: These findings suggest that homocysteine-lowering therapy would have the greatest effect in geographic areas with low dietary folate consumption. Because RCTs have failed to show benefit of folate therapy (Arch Intern Med 2010; 170:1622) and have suggested that there may even be harm (N Engl J Med 2006; 354:1578), I would not currently recommend folate supplementation. However, folate supplementation may have a role in those with the MTHFR 677C->T variant, particularly in low-folate regions. To date, no trial has been conducted exclusively in a low-folate region to evaluate the effect of homocysteine reduction on stroke risk. The ongoing China Stroke Primary Prevention Trial — which is comparing stroke risk with enalapril alone to enalapril plus folic acid in hypertensive individuals without established cardiovascular disease — may show whether homocysteine lowering can reduce stroke risk in low-folate regions.
— Amytis Towfighi, MD Dr. Towfighi is Assistant Professor, Department of Neurology, University of Southern California, Los Angeles; and Chair, Department of Neurology, Rancho Los Amigos National Rehabilitation Center, Downey, CA.
Published in Journal Watch Neurology October 25, 2011
     Citation(s): Holmes MV et al. Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: A meta-analysis of genetic studies and randomised trials. Lancet 2011 Aug 13; 378:584.
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J Clin Endocrinol Metab 2011 Oct; 96:2997
Vitamin D Appears to Prevent Falls in Some High-Risk Subgroups
The benefit appeared limited to those who received >800 IU of vitamin D daily.
     Some, but not all, studies have shown that vitamin D supplementation reduces risk for falls in elders, presumably through direct effects on muscle function. Researchers performed this meta-analysis of 26 randomized controlled trials of vitamin D supplementation that reported falling as one outcome. The mean age of the 46,000 participants was 76, 78% of participants were women, and median duration of vitamin D administration was 1 year. Baseline risk for falling was high in these trials.
     Vitamin D was associated with a significant reduction in risk for falling (odds ratio for risk of at least one fall, 0.86). In prespecified subgroup analyses, this benefit was seen primarily in patients who also received calcium supplementation and in those with vitamin D deficiency at baseline (but definitions of deficiency varied across studies). Although the benefit appeared limited to those who received >800 IU of vitamin D daily (compared with lower doses), the interaction between dose and falls did not reach statistical significance.
     Comment: This analysis suggests that vitamin D supplementation — administered with calcium — reduces risk for falling, particularly among older vitamin D–deficient women who are at high baseline risk for falling. The findings thus support selective use of vitamin D in such patients. However, the authors believe that the quality of the evidence is low to moderate due to publication bias, heterogeneity across studies, and several other factors.
Allan S. Brett, MD Published in Journal Watch General Medicine October 27, 2011
     Citation(s): Murad MH et al. The effect of vitamin D on falls: A systematic review and meta-analysis. J Clin Endocrinol Metab 2011 Oct; 96:2997.
MM: EPA may be a valuable adjunct to antidepressant thepapy but I would use caution in over-emphasizing the use of JUST EPA. There is a tendency to focus on ONLY the “active component”, whereas it makes much more sense to use the “whole product” whenever possible. None the less, I am certain that we can look forward to someone using this data to bring an EPA only product to market and in my opinion, bringing unforeseen problems to this patient group.
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MM: EPA may be a valuable adjunct to antidepressant thepapy but I would use caution in over-emphasizing the use of JUST EPA. There is a tendency to focus on ONLY the “active component”, whereas it makes much more sense to use the “whole product” whenever possible. None the less, I am certain that we can look forward to someone using this data to bring an EPA only product to market and in my opinion, bringing unforeseen problems to this patient group.
J Clin Psychiatry 2011 Aug; 72:1054
Omega-3 Fatty Acids for Depression? The Jury Is Still Out
A meta-analysis says success depends on a high percentage of EPA, but a large study using this dose finds only small effects in less severely ill patients.
     Associations between depression and low fish consumption or low blood levels of omega-3 polyunsaturated fatty acids (PUFAs) have prompted numerous small studies of PUFAs for treating depression. Two recent reports provide new insights.
     In a meta-analysis of 15 mostly small, placebo-controlled trials in depressed patients (2 studies with >100 patients; total N, 916), Sublette and colleagues dichotomized the studies by the percentage of eicosapentaenoic acid (EPA) content used in the PUFA preparation. The eight studies using at least 60% EPA showed a moderate antidepressant effect; no effect was seen in studies using lower levels of EPA. Age and treatment duration were unrelated to results. Seven studies used EPA as monotherapy, but whether effects varied by approach (monotherapy vs. augmentation) was not reported.
     Lespérance and colleagues conducted a randomized, placebo-controlled trial of PUFAs in 432 depressed patients, the largest trial reported so far. The preparation contained over 80% EPA (1050 mg); the study included patients with comorbid anxiety disorders and was stratified by whether patients were using antidepressants (40% of patients). PUFAs showed no antidepressant effect in the entire group, but in preplanned analyses they had a small effect in a subgroup without comorbid anxiety (47% of patients) and showed a trend toward positive effects when used as monotherapy (60% of patients) compared with augmentation.
     Comment: These two reports suggest some modest antidepressant effects for PUFAs in depressed patients who are less likely to be treatment-resistant (i.e., lacking anxiety and not already taking antidepressants). Both studies support using an EPA dose (1–2 g) constituting at least 60% of the entire preparation. Because almost two thirds of the U.S. population are already taking supplements or alternative treatments, this option may be appealing to many, although it is likely to be effective only as an initial treatment option for less difficult-to-treat depression.
Peter Roy-Byrne, MD Published in Journal Watch Psychiatry October 17, 2011
     Citation(s):Sublette ME et al. Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. J Clin Psychiatry 2011 Sep 6; [e-pub ahead of print]. (http://dx.doi.org/10.4088/JCP.10m06634)
Lespérance F et al. The efficacy of omega-3 supplementation for major depression: A randomized controlled trial. J Clin Psychiatry 2011 Aug; 72:1054.
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