Metformin or Oral Contraceptives for treatment of Polycystic Ovarian Syndrome in Adolescents: A Meta-analysis

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorder in adolescent and adult women affecting 1 in 15 women worldwide and have important metabolic and reproductive implication.  

The diagnosis of PCOS is challenging specially in adolescent as normal pubertal changes can mimic the signs of PCOS. The Rotterdam criteria are widely in use for diagnosis. These criteria require that patients have at least two of the following conditions: ovulatory dysfunction, androgen excess, and polycystic ovaries. It is also necessary to rule out other causes of androgen excess and ovulatory dysfunction before a diagnosis of PCOS is made. 

The treatment approach varies according to the age of the patient, desire for pregnancy and the presenting symptoms.  

The Endocrine Society guidelines for the treatment of adults with PCOS recommends using oral contraceptive pills (OCPs) to control symptoms of androgen excess, while reserving metformin for cases with impaired glucose tolerance or features of metabolic syndrome.

However, evidence is sparse to support the best first-line medication in adolescents with PCOS.

Investigators Dr. Reem A. Al Khalifah and colleagues of King Saud University in Saudi Arabia published a metaanalysis and systemic review of randomized, controlled trials (RCTs) to evaluate the use of metformin versus OCPs for the treatment of PCOS in adolescents ages 11 to 19 years in the Pediatrics, online April 28.

The team searched the literature through Ovid Medline, Ovid Embase, Cochrane Central Register of Controlled Trials, and gray literature resources, up to January 29, 2015. Only four RCTs met the inclusion and exclusion criteria’s amounting to 170 patients in total. 

It was seen that OCP treatment resulted in improvement in menstrual irregularities with a modest improvement in the acne scores.  On the other hand, metformin improved the BMI, decreased dysglycemia prevalence and improved total cholesterol and low-density lipoprotein levels. Both treatment modalities have a similar effect on hirsutism. 

However, the evidence quality was very low, so "treatment choice should be guided by patient values and preferences, while balancing potential side effects" said Dr. Al Khalifah

But, as PCOS is a spectrum with many girls presenting with obesity and hairiness while others have normal body weight and just have menstrual irregularities. So, depending upon the symptoms, the treatment is tailored according to the patient need, with either OCP or metformin being the first line of treatment. 

Concurrently, the importance of life style modification and statin is also stressed to provide long term cardiac protection in these patients.

References:
http://womenshealth.gov/publications/our-publications/fact-sheet/polycystic-ovary-syndrome.html#b
http://www.ncbi.nlm.nih.gov/pubmed/26280343
http://press.endocrine.org/doi/abs/10.1210/jc.2013-2350

Elective oophorectomy or ovarian conservation at the time of benign hysterectomy?

Hysterectomy is the second most common surgery performed in US after cesarean section.  According to CDC data approximately 600,000 hysterectomies are performed each year. A nationwide study further reported that unilateral or bilateral oophorectomy was performed in 68 percent of women at the time of abdominal hysterectomy, 60 percent at laparoscopic hysterectomy, and 26 percent at vaginal hysterectomy.

Women have an option of undergoing elective oophorectomy (EO) along with benign hysterectomy to reduce the risk of ovarian cancer, thereby reducing a chance of second surgery coupled with decreased perceived   anxiety of breast and ovarian cancer subsequently.But there are negative side effects of this surgical induced menopause such as death, total cancer mortality, osteoporosis, cognitive decline, decreased sexual drive and increased cardiac mishap support conservation of ovarian function.

There is considerable debated going on between EO and ovarian conservation, with strong statements are put forward in favor of each. Currently ACOG recommends “strong consideration should be made for retaining normal ovaries in premenopausal women who are not at increased genetic risk of ovarian cancer. [However,] given the risk of ovarian cancer in postmenopausal women, ovarian removal at the time of hysterectomy should be considered for these women.”

Arguments in favor of ovarian conservation:

• EO is detrimental for the overall health of women and decreases the life expectancy due to coronary artery disease. In a landmark study by Parker et al using Surveillance, Epidemiology, and End Results (SEER) database, the National center for Health Statistics, the Women’s Health Initiative, and the National Inpatient Sample it was seen that there is no clear cut benefit of EO at any age and women died early due to associate morbidity.
• The neuroprotective benefits of estrogen were seen in multiple studies and was further supported by declining cognitive functions specially in women undergoing EO under 50 yrs.
• EO leads to increase in hip fracture due to decrease in BMD as estrogen levels plummet. This was specifically seen in the light of mass discontinuation of hormone replacement therapy among postmenopausal women when results of Women’s Health Initiation trial published.
• A decrease in sexual desire and function, resulting in quality of life issues and conflict in interpersonal relationship, depression was seen after oophorectomy.

Arguments in favor of EO:

• Ovarian cancer is the fifth leading cause of death among women in US with estimated 22,280 new cases and  14,240 deaths in 2016. A woman’s lifetime risk of ovarian cancer is 1 in 70 or 1.4% with no known effective screening method that could diagnose it at very early stage. Researchers have estimated   that 1000 new cases of ovarian cancer could be avoided if EO is performed in women undergoing hysterectomy in women 40 years and older.
• In women at high risk for ovarian cancer (especially with familial history or genetic predisposition, BRCA1 or BRCA2 mutations) risk-reducing oophorectomy (RRO) reduced cancer specific mortality.
• In general population RRO is an ideal treatment for the prevention of ovarian cancer in women who have known risk factors like being white, never having been pregnant, late age of menopause, and a long estimate number of years of ovulation in absence of effective screening strategies.
• EO leads to avoiding the risk of second surgery after hysterectomy due to adnexal disease or masses.
• Effective replacement therapy available to prevent osteoporosis, cardiac and sexual dysfunctions is being put as a valid argument in support of EO, specifically after the beneficial results of hormone therapy from Women’s Health Initiative studies.
• A recent study by Trabuco et al published in the May issue of Obstetrics and Gynecology has concluded that even if ovaries are spared at the time of hysterectomy, it affects the ovarian reserve as evident by declining levels of Antimüllerian hormone. The study also reported that women undergoing hysterectomy became menopausal 1.9 years earlier than referent patient who has not undergone any surgery.

Despite all these arguments studies have recently documented that of all the hysterectomies performed for benign reason 36%-38% were deemed unnecessary and histologically normal.

So, the decision for EO should be made according to each woman’s individual genetic test results and her risk for developing ovarian malignancy. Age at the time of benign hysterectomy is an important decisive factor. In 2010, recommendations from the Society of Gynecologic Oncologists state “Ovarian conservation before menopause may be especially important in patients with a personal or strong family history of cardiovascular or neurological disease. Conversely, women at high risk of ovarian cancer should undergo risk-reducing bilateral salpingo-oophorectomy.”

A women’s risk of cardiovascular disease, dementia, osteoporosis, and family history must be taken into account before decisions for EO or ovarian conservation are made in woman considering hysterectomy.

References:

http://www.cdc.gov/reproductivehealth/data_stats/

http://journals.lww.com/greenjournal/Fulltext/2009/11000/Nationwide_Use_of_Laparoscopic_Hysterectomy.13.aspx

http://seer.cancer.gov/statfacts/html/ovary.html

http://www.ncbi.nlm.nih.gov/pubmed/1923173

http://journals.lww.com/greenjournal/Fulltext/2016/05000/Association_of_Ovary_Sparing_Hysterectomy_With.3.aspx

http://www.oncologypractice.com/home/article/high-rates-of-oophorectomy-documented-in-premenopausal-women/36d1b8f86358a40f14c648990ea87471.html?trendmd-shared=0

http://www.obgynnews.com/specialty-focus/gynecology/single-article-page/study-finds-inappropriate-oophorectomy-at-time-of-hysterectomy/afc916acf84845b47cce45ad136610e5.html

FDA evaluating the safety of oral fluconazole in pregnancy.

In the light of new evidence linking oral fluconazole to miscarriages the FDA is currently reviewing the safety of oral fluconazole as a vaginal yeast infection treatment in pregnancy. This review comes in the wake of Danish study published in JAMA which reports abnormalities at birth when  oral fluconazole is taken in higher dose of 400-800 mg/day.

It was a Nationwide register-based cohort study in Denmark from 1997-2013. From a cohort of 1,405, 663 pregnancies, 3315 women were exposed to oral fluconazole from 7 through 22 weeks’ gestation. About 147 experienced a spontaneous abortion compared with 563 among 13,246 unexposed matched women (HR 1.48).

The current FDA drug label states that data available from studies in people do not suggest an increased risk of problems during pregnancy or abnormalities in developing babies when women are exposed to a single 150 mg dose of oral fluconazole to treat vaginal yeast infections.

FDA cautions the healthcare professionals about the use of this drug until the review is complete. The agency has previously classified it as  pregnancy class D, meaning that there is evidence of risk to the fetus, but it may be used if the mother's condition is serious or life-threatening.

CDC guidelines also recommend only using topical antifungal products to treat pregnant women with vulvovaginal yeast infections, including for longer periods than usual if these infections persist or recur.

FDA is also urging people and researchers to report any untoward effects of the drug. It is also reviewing additional data related to the drug use in pregnancy.

In addition to its use as antifungal for vaginal yeast infection, it is also used to treat infection of mouth, and esophagus. fungal infection of the brain and spinal cord called cryptococcal meningitis.

References:

Mølgaard-Nielsen D, Svanström H, Melbye M, Hviid A, Pasternak B. Association Between Use of Oral Fluconazole During Pregnancy and Risk of Spontaneous Abortion and Stillbirth. JAMA. 2016;315(1):58-67. doi:10.1001/jama.2015.17844.

http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm497656.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery

Breast cancer risk prediction improved by adding Multiple Biological Risk Markers.

Risk prediction models always have very important public health implications by identifying high risk population for that disease and targeting them  for increased screening , chemoprevention or other risk reducing life style management regimens.

Various models have been in use to calculate the risk score of developing breast cancer in women. Two most frequently  used  and well validated  models are Gail and Rosner-Colditz.  

The Gail score includes: age at menarche, number of previous breast biopsies, presence of atypical hyperplasia at biopsy, age at first birth, number of first-degree relatives with a history of breast cancer, and age.

In clinical studies the Rosner-Colditz model slightly outperforms Gail model and additionally includes: premenopausal duration (age at menopause minus age at menarche), postmenopausal duration (current age minus age at menopause), type of menopause, age at first birth minus age at menarche, birth index, history of benign breast disease, duration of PMH use by type (estrogen, estrogen plus progesterone, or other) and timing (current v past), body-mass index (BMI; trajectory from age 18 years to current), height, alcohol intake (from age 18 years to current).

Even combined, these models include only what are called the traditional risk factors and does not include genetic risk score (GRS), mammographic density (MD), and postmenopausal endogenous hormone levels collectively called as biological risk factors.

Addition of the biological risk factors to the existing models improve the risk prediction especially in postmenopausal women not using hormone therapy (HT), according to research paper presented here at the AACR Annual Meeting 2016, April 16-20. Subsequently this improves the tailoring of chemoprevention and screening strategies in women opined Xuehong Zhang, MD, ScD, lead author of the study  and  assistant professor of medicine at Harvard Medical School and associate epidemiologist at Brigham and Women's Hospital in Boston.

“We conducted the first comprehensive evaluation of the independent and joint contribution of several biological markers of risk in the two validated breast cancer risk prediction models [Gail and Rosner-Colditz models] using data from up to 10,052 breast cancer cases and 12,575 controls of European ancestry from the Nurses’ Health Study (NHS) and NHS II,” he added.

“A genetic risk score can summarize in a single number an individual’s genetic predisposition to a certain disease outcome [e.g., breast cancer in this study] based on multiple risk alleles,” Zhang explained. He and colleagues calculated a breast cancer genetic risk score based on 67 single-nucleotide polymorphisms (SNPs) identified from a recently published meta-analysis of nine genome-wide association (GWAS) studies.

The data was stratified according to menopausal status and age and area under the curve (AUC) was calculated for the 5-year risk of invasive breast cancer and estrogen receptor (ER) and progesterone receptor (PR) positive disease (ER+PR+) after adding the biological risk factors to the prevailing models.

In both models, about 45% of women were premenopausal, 25% were postmenopausal and not using hormone therapy, and 30% were postmenopausal and using hormone therapy.

"The improvement in risk prediction was greatest in postmenopausal women not taking hormone therapy, the group where all three hormones could be measured and hence contribute to the model," Dr Zhang said in news release.

The AUC improved by 11.7 units and 9.4 units for Gail and Rosner-Colditz models, respectively in risk prediction for ER+PR+ breast cancer development in post-menopausal women adding the biological markers. 

These results have tremendous significance because recent data from the US National Health and Nutrition Examination Survey shows that 90% of postmenopausal women are not on hormone therapy, thus the improvements seen for this subgroup would apply to the majority of postmenopausal women in the U.S.," Zhang said in a statement released by AACR. "An important next step in this research will be to validate these initial findings in other study populations." 

References:

Zang X, Rice M, Tworoger SS, et al. Zhang, Xuehong, Breast Cancer Risk Prediction Models Improved by Adding Multiple Biological Markers of Risk. Presented at: AACR 2016 Annual Meeting; New Orleans, Louisiana, April 16-20, 2016. Abstract 2600

http://www.cancernewsincontext.org/2013/10/rosner-colditz-model-predicting-breast.html

http://onlinelibrary.wiley.com/doi/10.1002/cncr.25386/full

http://www.aacr.org/Newsroom/Pages/News-Release-Detail.aspx?ItemID=860#.Vx6UXDArLIU

http://www.onclive.com/conference-coverage/AACR-2016/using-multiple-biomarkers-improves-risk-prediction-for-breast-cancer

Every 1 in 3 babies in US is delivered by C-section.

Cesarean section is the number one surgery performed in US today, even surpassing all the orthopedic and heart surgeries. About 1.3 million babies are delivered by Cesarean every year, which roughly equals to every 1 in every 3 children born in US.  This is in stark contrast to a world cesarean section rate of 19%, according to data published in the Journal of the American Medical Association in December, 2015. 

United states have seen a steep rise in the C-section rate from 5 percent in 1970 to nearly 33% in 2016.

Consumer report finds a wide variation across US and also among different hospitals in the same region. The rate for low risk deliveries varies from 11% to 53% state wise to 17% to 30% in the same community. In fact Hialeah Hospital, outside of Miami, had the highest C-section rate of 66% of all hospitals in US. In fact, there were 221 hospitals in the U.S. with C-section rates above 33.3 percent for low-risk deliveries.

The National Target is 23.9% for nulliparous, low risk women, with only 40% of the hospitals meeting the target. Researchers estimate that almost half of all the C-sections could be avoided and babies delivered safely by vaginal route.

The American Congress of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) were so concerned by the rising rate that they jointly issued a recommendations  to prevent the first C-section.

Dr. Thomas Weiser, an assistant professor of surgery at Stanford School of Medicine says “As countries increase the number of C-sections they provide, mortality goes down— but only to a point, when the C-section rate tops 19 percent, benefits for maternal and infant health plateau.”

Aaron B. Caughey, M.D., chair of the Department of Obstetrics and Gynecology at Oregon Health & Science University School of Medicine in Portland and a lead author of the new ACOG/SMFM recommendations says “Once cesarean rates get well above the 20s and into the 30s, there are probably a lot of non-medically indicated cesareans being done, that’s not good medicine.”

But, the rise in Cesarean rates have not helped in bringing down the mortality and infant mortality rates in US, which sadly stands at 14 deaths per 100,000 live births and 5.6 per  1000 babies respectively, far worse than other developed countries, according to CDC statistics.

So, what are the causes for such high C section rates in  US? 

• Repeat cesarean section was the most common indication with low rate of VBAC constituting about one third of all cesarean deliveries.
• Experts blame a part of it on technology advances like continuous fetal monitoring.  Continuous FHR monitoring is not backed by extensive research when it comes to interpreting the results. Different obstetricians have different policies and when they see ups and down in the FHR tracing, it may trigger a Cesarean Section, even if it is not clear whether the baby is actually in distress.
•  In approximately 44% of patients, the labor was induced instead of allowing them to go into spontaneous labor. These patients had C-section rate twice that of patients who opted for a natural onset of labor.
• Obstetricians in USA are sued a lot, so the idea of practicing ‘defensive medicine’ prevails in the labor room also. It is always justified to explain a mishap in labor when cesarean section was performed than being delivered vaginally.
• Women is US can choose to be delivered by cesarean section like most western countries.  According to a study Zhang et al in American Journal of Obstetrics and Gynecology elective cesarean section accounts for less than 10% of all scheduled procedures.
• And the current focus in obstetrics is to manage postpartum hemorrhage, prevention of thromboembolism and ecclampsia which have all shown an increasing trend.

So, to bring down the cesarean section rate in US, preventing unnecessary primary cesarean deliveries is the key, because they contribute to one third of total cesarean deliveries.

If first Cesarean is prevented than we are preventing the subsequent ones down the lane. According to Dr. Shah from Harvard Medical school Right now in the U.S., if you get a C-section the first time, you have a 90 percent chance of getting another one the second time. 

If the fetus status is reassuring than awaiting for vaginal births in patients with dystocia could also bring down the rate. A further small reduction can be achieved by external cephalic version (2-3%) and attempting VBAC.

References:

http://www.cdc.gov/reproductivehealth/maternalinfanthealth/infantmortality.htm

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2947574/

http://www.consumerreports.org/doctors-hospitals/your-biggest-c-section-risk-may-be-your-hospital/

http://www.acog.org/Resources-And-Publications/Obstetric-Care-Consensus-Series/Safe-Prevention-of-the-Primary-Cesarean-Delivery

https://www.statnews.com/2015/12/01/cesarean-section-childbirth/

Is Time Lapse Morphokinetics the future for embryo selection in IVF?

When we look at other industries, a rapid progress and evolution has resulted in remarkable products, specifically computers and software. Incidentally, the birth of apple computer and the birth of first IVF baby Louis Brown were achieved in the same year 1978. Looking back the technology advances in IVF are also at par with that in computer industry.

IVF Techniques have also evolved over years, with embryo cryopreservation, gamete cryopreservation, embryo biopsy, Intracytoplasmic sperm injection, assisted hatching and genetic testing introduced into day to day practice.

Various types of incubators were introduced in markets, starting from Australia introduced mini-incubator, called the MINC in 1990. Embryos are routinely cultured till the blastocyst stage, before they are transferred. However, the pregnancy and live birthrate did not go parallel with the technology innovations. It could be explained in many ways, namely aging mothers with poor egg quality and ability to treat couples with complex infertility causes.

But, embryo selection does play a part and till now they were selected based on morphology at pre-defined interval alone. The introduction of TL technology allows us to continuous monitoring of embryos without compromising the culture environment. Several different time lapse incubators with automated image capture are in use by ART specialists.

But, are TL systems for efficient in selecting good embryos than simple morphology? Few randomized studies have been conducted till now. One such study by Goodman and colleagues was published in the February, 2016 issue of Fertility and Sterility. 

This was a randomized controlled trial with about 300 patients, in which all embryos were cultured in TL, but in control group they were only assessed once a day and in experimental group precise timing of various kinetic events (time to pronuclear fading, two-cell, three-cell, four-cell, five-cell, eight-cell stage, start of compaction, time to morula/ blastocyst, expanded blastocyst formation) as well as cleavage anomalies were used to identify the embryo to be transferred.

Embryos were scored using these markers. It was seen that pregnancy and implantation rates were higher in TL group, but the difference was not statistically significant.

Multinucleation and uneven cleavage was seen much more clearly in TL group. So, some researchers opine that TL is a good for deselecting the embryos, which otherwise would have been transferred but would not have implanted.

One other RCT by Rubio et al., 2014 reported   a clear cut advantage of TL systems over traditional incubators, with increased implantation rates and ongoing pregnancy rate. But, it did have many limitations due to methodology and protocols in embryo transfer, using separate incubators in control and study group. Thereby limiting benefit of the undisturbed culture conditions or the selection based on morphokinetic parameters.

In the present study both control and experimental embryos were cultured in TL incubators under similar conditions, and only the selection for transfer differed. However, there may be other factors like morphokinetic parameters, chromosomal compositions and implantation potential responsible for successful live births than just selecting some competent embryos.

But, TL embryo monitoring does offer several benefits like undisturbed embryo culture, recording of embryo development for quality control, and standardization of morphologic assessment and when combined with other advance technique like array CGH does results in improved pregnancy rates.

As time goes by, the high cost of these technologies significantly decreases and their efficacy will also increase with standardized guidelines, and combining it with other techniques, the world of morphokinetics of TL systems is here to stay!

References:

http://www.sciencedirect.com/science/article/pii/S0015028215020208?np=y

http://www.ncbi.nlm.nih.gov/pubmed/21828117

http://www.ncbi.nlm.nih.gov/pubmed/24951056

http://humrep.oxfordjournals.org/content/early/2014/10/24/humrep.deu278.full

http://www.fertstert.org/article/S0015-0282(15)02020-8/references

Migraine linked to increase in pregnancy, labor and neonatal complications!

The occurrence and frequency of migraine attacks in women is influenced by hormonal changes throughout the lifecycle. More than 50% of women report an improvement in attacks, especially during the second and third trimester irrespective of the type of migraine.

If migraines do occur, they do so most often during the first three months of pregnancy due to the rise in estrogen level. The other triggers for attacks in pregnancy are possibly from lack of sleep, additional stresses, or other headache causes.

Women who have migraine during pregnancy end up having higher rates of preeclampsia, preterm delivery, and low-birthweight babies that far exceed national statistics, a new study suggests.  In Women older than 35years of age, it is an independent risk factor for adverse pregnancy outcome.

The study was presented on April 17, 2016 at the American Academy of Neurology (AAN) 68th Annual Meeting in Vancouver, Canada.

"Over half the patients experienced some type of adverse birth outcome, which suggests that pregnancies in such patients should be considered high risk, especially in older women," said lead author Matthew S. Robbins, MD, associate professor, clinical neurology, Albert Einstein College of Medicine, chief of neurology, Jack D. Weiler Hospital, Montefiore Medical Center, and director of inpatient services, Montefiore Headache Center, Bronx, New York.

Researchers at Montefiore Medical Center reviewed 5 years of data between July 1, 2009, to June 30, 2014 and identified 90 women, who had severe attack during pregnancy.

The findings included:

• About 38.8% of women were African American, 76.7% were obese with body mass index of 30 kg/m² or more and a third of the group (30%) was nulliparous.
• More than half of these women (54 percent) had at least one complication.  
• About 30 percent of the women had a preterm delivery, as compared to nearly 10 percent in general population.
• About 20 percent of the women with migraine had preeclampsia, compared to between 5 and 8 percent in the general population.
• 19 percent of the women with migraine delivered babies with low birthweight, compared to 8 percent in the general population.
• Researchers do not know the cause for these increased incidences of co-morbidities, but is possibly linked to increased cardiovascular complications in these women, or changes in   the endothelium leading to preecclampsia.

Dr. Robbins caution against generalizing these findings to other population, as the study involved a small inner city population but does suggest a close follow up of women with migraine and treating them as high risk.

The study had many limitations, notable lack of control group of women who had migraine but did not report to physician for care. Also, Sixty-two percent of the women in the study received treatment for their migraine, which also could have played a part in the pregnancy and birth complications.

David J. Dickoff, MD, a general community neurologist in Yonkers, New York summed it well saying "The importance of the migraine study is to alert all doctors, especially obstetricians, that history of migraine headaches is a risk factor for pre-eclampsia," Dr Dickoff said. "These patients may need to be considered high risk and followed more closely for BP [blood pressure] elevations and proteinuria."

References :

http://www.prnewswire.com/news-releases/pregnant-women-with-severe-migraine-may-be-at-increased-risk-for-labor-and-delivery-complications-300230520.html

http://www.ncbi.nlm.nih.gov/pubmed/9825951

Olanzapine: A significant breakthrough in reducing chemotherapy induced nausea and vomiting.

The worst fear patients have when they are diagnosed with metastatic cancer is chemotherapy-induced nausea and vomiting, and Olanzapine (OLN) is ‘A Milestone in Antiemetics’, for treating and alleviating the symptoms of these patients. 

This article is mainly based on talk by Mark Kris from Memorial Sloan Kettering Cancer Center and work by Rudolph M. Navari, MD, PhD. He is currently based in Geneva, Switzerland, serving as Director of the World Health Organization Cancer Care Program in Eastern Europe.

The most emetogenic drugs used in cancer chemotherapy are anthracycline and doxorubicin combinations and cisplatin.

A randomized, double-blind, phase III trial was performed in patients who have not received chemotherapy earlier with 192 patients in the olanzapine arm and 188 in the placebo arm. The two groups were well matched for gender, age and diagnosis.

All the patients received cisplatin (≥ 70 mg/m²), or cyclophosphamide (600 mg/m²) plus an anthracycline (60 mg/m²)   and standard combination of   aprepitant, a 5-hydroxytryptamine 3 (5-HT3) receptor antagonist (ie, palonosetron, ondansetron, or granisetron), and dexamethasone pre and post therapy.

Only the study group received 10 mg of oral olanzapine on day 1 before the chemotherapy and day 2 and 4 post chemotherapy while the control group received a matching placebo.

The primary end point was no nausea and a secondary endpoint was complete response (no emesis, no rescue).

It was seen that the drug was able to improve nausea significantly in all the three phases namely   acute (0–24 hours post chemotherapy), delayed (24–120 hours post chemotherapy), and overall (120 hours post chemotherapy) phases. Patients on olanzapine also had a significantly better complete response than the placebo group.

The only side effect observed with the drug was mild sedation on second day, which resolved on further dosing on day 3 and 4.

Dr Mark Kris calls this trial as landmark one as there was no treatment for chemotherapy induced nausea in decades, even the addition of 5-HT3 antagonist along with newer antiemetics failed to improve the nausea.

Olanzapine is approved by the U.S. Food and Drug Administration (FDA) as an antipsychotic but does not have approval as an antiemetic.

The investigators noted that the study results were consistent with current guidelines from the National Comprehensive Cancer Network, which recommends the use of olanzapine with standard antiemetics as an option for preventing chemotherapy-induced nausea and vomiting in patients receiving emetogenic chemotherapy.

References

http://meetinglibrary.asco.org/content/155048-165

Navari R, Qin R, Ruddy J, et al: Olanzapine for the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients receiving highly emetogenic chemotherapy (HEC): Alliance A221301, a randomized, double-blind, placebo-controlled trial. 2015 Palliative Care in Oncology Symposium. Abstract 176. Presented October 9, 2015.

National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Antiemesis, Version 2.2015. Available at nccn.org. Accessed April 15, 2016

CDC Confirms the link between Zika infection and microcephaly.

Zika has been linked to microcephaly since Brazil reported a sudden increase in number of infants born with microcephaly in September 2015, but causation was not established. CDC today made an important announcement after careful review of all the possible evidence that Zika virus is a cause of microcephaly and other severe fetal brain defects.

The study is published online in the New England Journal of  Medicine today.

“This study marks a turning point in the Zika outbreak.  It is now clear that the virus causes microcephaly.  We are also launching further studies to determine whether children who have microcephaly born to mothers infected by the Zika virus is the tip of the iceberg of what we could see in damaging effects on the brain and other developmental problems,” said Tom Frieden, M.D., M.P.H., director of the CDC. “We’ve now confirmed what mounting evidence has suggested, affirming our early guidance to pregnant women and their partners to take steps to avoid Zika infection and to health care professionals who are talking to patients every day. We are working to do everything possible to protect the American public.”

The investigators examined the causality evidence in light of Shepard’s criterias, which is set of rules that must be satisfied before labeling  an agent being ‘ teratogenic’  and causing  congenital malformations. According to the Shepard’s criterias, causality is established when either criteria 1, 3, and 4 (rare exposure–rare defect approach) or criteria 1, 2, and 3 (epidemiologic approach) are fulfilled.

So, the relationship between Zika infection and microcephaly was termed casual under the rare exposure–rare defect approach as criteria 1, 3 and 4 were fulfilled:

1. Proven exposure must occur at a critical time during prenatal exposure: The microcephaly and other anomalies occur when the exposure occurs during first trimester or early second trimester. 
2. Careful delineation of clinical cases with the finding of a specific defect or syndrome: Infants with Zika infection do have a typical pattern which includes severe microcephaly, intracranial calcifications, and other brain anomalies, sometimes accompanied by eye findings, redundant scalp skin, arthrogryposis, and clubfoot which led the scientist to coin a term “Congenital Zika Syndrome.”
3. Rare exposure and a rare defect: This criterion was met because microcephaly is a rare defect with an incidence of 6 infants per 10,000 liveborn infants in the United States and infection in travelers who spent a limited amount of time in Brazil with active infection, constitute rare exposure for the patients.

Also supportive of causation is lack of alternative explanation for sudden increase in microcephaly cases in Brazil, French Polynesia and Colombia.

But, proving the causation is not enough in the fight against Zika infection. Many key questions are yet to be answered that have important implications.

CDC's director, Tom Frieden, MD said “We are launching further studies to determine whether children who have microcephaly born to mothers infected by the Zika virus is the tip of the iceberg of what we could see in damaging effects on the brain and other developmental problems," in a statement.

In addition to this researchers are also interested in knowing relative and absolute risk of infection and malformation. At present 1% to 29% of babies are born with microcephaly of all the mothers infected with the virus. They are also looking at other factors that modify the risk and severity of infections, such as gestational week at infection, additional morbidities and co-viral infection like Dengue fever.

CDC has not changed the travel warning or guidelines related to Zika infection after this publication.

Mark S. DeFrancesco, MD, MBA, President of the American College of Obstetricians and Gynecologists (ACOG), released the following statement regarding the U.S. Centers for Disease and Control and Prevention (CDC) paper addressing Zika virus “The message of the CDC paper underscores the importance of ongoing research into this outbreak. We once again encourage Congress to act swiftly to pass emergency funding to enhance our public health preparedness and enable America’s researchers to lead the charge in the development of a vaccine or treatment for this virus. Ongoing support for Zika virus research will protect American families and, indeed, families around the world."

References:

http://www.nejm.org/doi/full/10.1056/NEJMsr1604338?query=featured_home&

http://www.acog.org/About-ACOG/News-Room/Statements/2016/ACOG-Statement-on-the-CDC-Update-on-Zika-Virus

http://www.cdc.gov/media/releases/2016/s0413-zika-microcephaly.html

Our food choices and sustainability

Courtesy: gentleworld.org

Yesterday, I had an opportunity to listen to Dr. Richard Oppenlander at a lecture arranged by Vegetarian Society of Hawaii. Dr. Richard Oppenlander is  a sustainability consultant, researcher, and author whose  award winning first book Comfortably Unaware,is endorsed as a must read by Ellen DeGeneres and Dr. Jane Goodall, among others. Dr. Oppenlander's most recent book titled Food Choice and Sustainability has won numerous awards including the 2014 International Book Award and the 2014 Green Book Festival

Award and is being used by think tanks and strategists for developing initiatives to advance global change. Dr. Op-penlander is a much sought after international lecturer on the topic of food choice and how it relates to sustainability, speaking most recently to the European Parliament, and served as the lead consultant for two full -length environ-mental documentary films.

Dr Oppenlander recent book

Since 1976, he has extensively studied the effect our food choices have on our health and the immense impact those choices have on our environment. Sustainability of food is a term which is confusing to many people; a truly sustainable food system is one which nurtures the people, the animals, the land, the community and the environment.  The food choices we make have an immense influence on our health and also the planet we live in.

While carbon emission due to automobile and aviation industry has been blamed as a major cause of Global warning, Oppenlander reveals that “Our current food choices detrimentally affect climate change and global warming more so than do all the cars, planes, trucks, buses, and trains used worldwide.”

He further opines that we should not be only worried about “Global warming “but we should be more worried about “Global depletion”, but “Global Depletion” is much less known. As vast as Global Warming may seem, it is only a small piece in the growing puzzle of Global Depletion, which refers to the loss of all of Earth’s renewable and non-renewable resources.

It is not our lights being left on or our fans running (although they contribute) that are destroying our planet; it is our eating habits. And it is not turning off the lights or air conditioning that will save the Earth; it is the shift to a plant based diet.

The animal industry is simultaneously depleting our natural resources of land, water, air, diversity, soil and our health. According  to him “Of the four leading causes of death and disease in the U.S. today, animal products and animal protein are implicated in all four—coronary heart disease, cancer, cerebrovascular disease, and diabetes, as well as their precursors, hypertension and obesity.

from the book" Food choice and Sustainability".

 Eating only plant-based foods prevents and reverses these diseases, as well as lowering one’s risk of contracting numerous other conditions, such as kidney stones and gallstones, kidney disease, osteoporosis, Crohn’s disease, Parkinson’s, multiple sclerosis, Alzheimer’s disease, osteoarthritis, and many other degenerative diseases, gastrointestinal conditions, and asthma. Of the five most common cancers—lung, colon, breast, pancreatic, and prostate—consuming animal products has been linked as a significant risk factor in all five, as well as many more. I need to emphasize that this is about animal products and the type of protein, which does not change if the animal is grass fed."

More than $3 trillion dollars were spent on health care in 2012 ($2.83 trillion in 2009, growing at 6 percent per year) in the U.S.

Of that, minimally $130 billion dollars spent were due to dietary choices related to livestock. I believe this figure is quite conservative and could be as high as $350 billion due to eating animals, because this is how some of the $3 trillion was spent:

$300 billion—heart disease
$200 billion—diabetes
$190 billion—obesity
$124 billion—cancer
$88 billion—food-borne illness

These figures are truly staggering and are for just one single year. They also do not reflect loss of productivity. For obesity alone, it is estimated that the annual cost of the workdays missed is $30 billion, with employers losing, on average, $3,800 per year for a single obese person.

“Fifty-five percent of our fresh water is being given to livestock… Over 70 percent of the grain in the United States is fed to livestock… It takes 10 to 20 gallons of water to produce one pound of vegetables, fruit, soybeans, or grain… over 5000 gallons of water to produce one pound of meat… over 30 percent of all usable total land mass on the earth is used by livestock.”

Dr. Oppenlander first book.

Here are some horrifying facts on fresh water usage from Comfortably Unaware’s Dr. Richard Oppenlander:

—>50% of all the water used in the U.S. is given to the animals people eat.
—>70 billion animals are raised and killed each year for food. A few billion of these animals need up to 40 or more gallons of water per day…which is over 100 times what we, individually, consume daily.
—>The average water footprint per calorie of beef is TWENTY times larger than for grains.
—>Legumes (or “pulses”: lentils, beans, peas) require FORTY-FIVE times less water to produce versus beef and they are excellent sources of protein.
—>To produce 1 pound of meat, it takes:

1,800-2,500 gallons of water per pound of beef

731 gallons per pound of sheep

127 gallons per pound of goat

468 gallons per pound of chicken

880 gallons per gallon of milk

60-120 gallons to produce 1 egg

11.6 gallons to slaughter and process 1 chicken

The image below is from Farmscape and the data is from 2010,  but the ratios of comparison say it all.

http://farmscapegardens.com/blog/food-production-and-water-use/

It is estimated that eating purely plant-based foods provides the following protective benefits, as compared to individuals eating the average amount of meat:

• 50 percent less risk of coronary heart disease (CHD)
• 40 percent less risk of cancer (breast, colon, prostate, ovarian, 
pancreatic, lung)
• 70 percent less likelihood of adult onset diabetes
• 50 percent less likelihood of developing hypertension

As an example of what effect a purely plant-based diet would have on health care costs, let’s look for a moment at hypertension. Worldwide, $500 billion was spent on hypertension in 2011—twice that amount if indirect costs are included. A 50 percent less risk factor in developing hypertension, simply by a change in food choice (elimination of all animal products from the diet), would save billions of dollars as well as improving the lives of millions.

Dr. Oppenlander’s goal with this book is to increase awareness in order to effect positive change—before it is too late. This is a groundbreaking book, and given the urgency and magnitude of the problem, it's a book that anyone who cares about our future and that of other species should read —individuals, academic institutions, businesses, organizations, and policy makers.

This book also unveils a new model of multidimensional sustainability for developing countries to eradicate world hunger and poverty as it compels us all to become aware of the enormous effect of our food choices, make necessary changes, and then, inspire others to do the same.

These are things that every person should be aware of, and has the right to be aware of.

References:

http://gentleworld.org/comfortably-unaware-why-every-environementalist-should-be-vegan/

http://plantbaseddietitian.com/tag/dr-richard-oppenlander/

http://comfortablyunaware.com/books/food-choice-and-sustainability/

https://happyherbivore.com/2014/04/food-choice-sustainability-dr-oppenlander-giveaway/

Assisted Reproductive Technology is associated with higher risk of Birth Defects!

Since 1981, ART has been used in the United States. Today approximately 1.6% of all infants born in the United States every year are conceived using ART.  According to 2014 data by CDC, 208,786 ART cycles were performed, resulting in 57,332 live births (deliveries of one or more living infants) and 70,352 live born infants.

As the number of infants conceived by ART continues to increase, it was observed that those conceived after Assisted Reproductive Technology (ART) was born with several Birth defects, especially nonchromosomal birth defects as compared to those conceived the natural way! In fact according to CDC, the risk of certain birth defects was 2 to 4 fold as compared to those conceived naturally.

The largest study of its kind was published in April issue of JAMA pediatrics. The researchers linked ART surveillance, birth certificates, and birth defects registry data for 3 states (Florida, Massachusetts, and Michigan) during a period of 10 years from 2000-2010. The exposure studied was ART and certain techniques among ART births. The main outcome measures were prevalence of selected chromosomal and nonchromosomal birth defects that are usually diagnosed at or immediately after birth.

Of the total 4,618,076 live births, 64,861 or (1.4%) were conceived using ART. According to the lead investigator Sheree L. Boulet, DrPH, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia higher prevalence of  nonchromosomal birth defects (59.57 per 10,000) in ART infants compared with non-ART infants (48.40 per 10,000, P<0.001) was reported. Even after adjustment of all the confounders (maternal age), there was 28% higher risk of non chromosomal anomolies with ART.

Infants born after ART were also more likely to be born prematurely, have lower birth weights and mothers who underwent ART were higher educated, nulliparous, career oriented, elderly (>30 Years) and non-Hispanic white. They were also more likely to have Diabetes and Hypertension.

The birth defects most commonly observed were reduction deformity of the lower limbs (P=0.007), rectal and large intestinal atresia/stenosis (P<0.001), and tracheoesophageal fistula/esophageal atresia (P=0.001) compared with those conceived spontaneously. No statistically significant difference in birth defects was seen among fresh vs frozen embryos.

Other systemic reviews, metaanalysis and registry based studies have also concluded that birth defects are more common in infants conceived after ART, and stress upon need of further research according to various sub-groups of ART.

It was also seen that maternal age is inversely related to risk for chromosomal defects in ART, including trisomy 13, trisomy 21 (Down syndrome), and trisomy 18, probably because older mother undergo Preimplantation Genetic Diagnosis (PGD) as compared to younger woman, primarily for aneuploidy.

"It is possible that younger women with an ART-conceived pregnancy were less willing to undergo chorionic villue sampling or amniocentesis because of heightened concerns about risks to the fetus," wrote Boulet and colleagues. "Another potential explanation is that young women undergoing ART have more serious underlying health issues than older women and thus have poorer-quality embryos."

Other studies have found increased incidence of cancer, heart defects, genitourinary malformations and malformations of the eye later in life.

The current study has several limitations; it lacked data on pregnancies that did not end up in live births, so the prevalence of birth defects may be underestimated. Also infants born with ART are closely followed than those born naturally, so the detection of birth defects may be higher!

The study implies that patients should have a good discussion with their physicians about the ART procedure, including detail information on all the birth defects resulting due to the ART. They should also understand that the actual risk for individual family is very small, but the odds are increased. A careful evaluation of long term effects and defects later in life is also necessary by designing studies for long term follow up of such infants.

References:

http://www.cdc.gov/media/pressrel/2008/r081117.htm

http://www.medpagetoday.com/OBGYN/Pregnancy/57161

http://www.ncbi.nlm.nih.gov/pubmed/23449641

http://archpedi.jamanetwork.com/article.aspx?articleid=2506140

http://www.newsmax.com/Health/Health-News/IVF-reproductive-technology-birth/2016/02/04/id/712683/

http://www.reuters.com/article/us-health-ivf-birth-defects-idUSKCN0X122D

http://www.medscape.com/viewarticle/861447

Kelley-Quon L, et al "Congenital malformations associated with assisted reproductive technology: a California statewide analysis" AAP 2012.