PCOS and Infertility: Pretreatment Weight loss hikes the live birth and ovulation rate in overweight and obese patients.

Couples are often puzzled when they face infertility as well as modifiable morbidity (overweight and obesity) limiting the chances of successful conception and healthy pregnancy thereof.   It’s   a tough choice to opt between starting the infertility treatment or correcting the underlying morbidity.

Obesity is associated with delayed conception, increased pregnancy loss, higher rates of preeclampsia and preterm labor and metabolic syndrome leading to perinatal and neonatal morbidity and mortality.

Expert opinion have always advocated that obese women with PCOS delay infertility therapy and pursue lifestyle modification, but has lacked high quality evidence in support of the claim. There are no data on the optimum weight loss as well as duration of preconception treatment.

Dr. Richard S. Legro, MD, from Penn State College of Medicine, Hershey, Pennsylvania, and colleagues recently  published their study findings in online edition of the Journal of Clinical Endocrinology and Metabolism.

“We found that pretreatment lifestyle modification for weight loss, with or without concurrent OC therapy, was associated with a significant improvement in the rate of ovulation and an even greater increase in live birth rate than immediate fertility treatment with clomiphene. Further, ovulation and live birth rates were nearly identical between pretreatment with oral contraceptives vs immediate treatment with clomiphene, suggesting that there is little fertility benefit to pretreatment with hormonal suppression, alone or in combination with lifestyle modification” opined the researchers.

Two very good trials recently were concurrently conducted to demonstrate significant benefits of lifestyle modification on ovulation and live births rate in obese women with PCOS.  The trials are The Treatment of Hyperandrogenism vs. Insulin Resistance in Infertile PCOS Women or OWL PCOS study and The Pregnancy in Polycystic Ovary Syndrome II or PPCOS II study.

Both the trials were multicentric conducted concurrently by the researchers.

The OWL PCOS was a randomized open labeled two site study constituting 149 women, diagnosed with PCOS by Modified Rotterdam criteria. The women were assigned to 3 groups to receive either 16-week Preconception treatment with continuous oral contraception, lifestyle modification or combination of both before going to receive 4 cycles of clomiphene and timed intercourse.

The PPCOS II study was double blind, with 750 women receiving   either 5 cycles of ovulation induction with letrozole or clomiphene citrate and timed intercourse. No study participants received any life style modification earlier.

A secondary post hoc analysis was done by combining data from both the studies. An intentional similar design, with same inclusion/exclusion criteria’s and use of clomiphene for ovulation induction made it feasible to combine the data from the two trials.

The researchers extracted the data for all women in the PPCOS II study in the clomiphene arm who met the BMI criteria of the OWL PCOS study. So, they had data on 187 women from the PPCOS II study and 142 women from the OWL PCOS study.

The primary outcome was live birth, while predetermined secondary outcomes were conception, ovulation and pregnancy loss rates.

It was seen that earlier lifestyle modification leading to weight loss, irrespective of hormonal treatment with OCP resulted in significant improvement in ovulation rate and greater increase in live birth rates as compared to starting immediate clomiphene treatment.

In those patients who only received clomiphene the ovulation rate was 44.7% (277/619), and the live birth rate was 10.2% (19/187) while patients who underwent weight loss before fertility treatment the ovulation rate was 62.0% (80/129), and the live birth rate was 25.0% (12/48).

Patients who underwent lifestyle modification (In the OWL PCOS study, as well as patients in the Combined group of the OWL PCOS study) had 2.5-fold increase in live births. Patients in the Lifestyle modification and Combined groups also had a 1.4-fold increase in cumulative ovulation rate (P .003 and P .001, respectively) compared to treatment with only clomiphene in PPCOS II.

Use of OCP before starting clomiphene did not have any significant effect on ovulation or live birth rates.

Comparing the results at the end of first cycle, only patients who lost weight in OWL PCOS had a significantly improved chance of pregnancy and live birth in the first ovulation induction cycle compared to the first ovulation induction cycle in direct clomiphene group. The study also demonstrated that improving the quality of ovulation is as important as improving the rate of ovulation to achieve a higher live birth rate.  

"Our research holds significant implications for current practice, and supports the concept of delaying fertility treatment to pursue lifestyle modification in overweight/obese women with PCOS. It provides momentum to test this concept more completely and prospectively in properly designed and adequately powered multicenter studies to generate Level I evidence for the practice," the authors explain.

"Future studies may also want to utilize other ovulation induction agents in the infertility treatment phase such as low dose gonadotropin or letrozole, which tend to have greater success rates combined with comparable rates of multiple pregnancy and congenital anomalies as clomiphene," the authors conclude. 

Disclosure Statement: Dr. Legro reports consulting fees from Euro screen, Astra Zeneca, Clarus Therapeutics, Takeda, Kindex and research funding from Ferring and Astra Zeneca. Dr. Estes and Dr. Schlaff reports research funding from AbbVie. Dr. Dokras reports consulting fees from JDS Therapeutics. Mr. Kunselman reports ownership of Merck stock. Dr. Sarwer reports consulting fees from BAROnova, EnteroMedics, and Ethicon. The other investigators report no disclosures. 

References:

http://press.endocrine.org/doi/pdf/10.1210/jc.2016-1659

FDA warns to limit systemic use of fluoroquinolones antibacterial drugs.

The U.S Food and Drug Administration (FDA) has warned against the routine use of fluoroquinolones antibacterial drugs in clinical practice for uncomplicated urinary tract infections and other respiratory infections. These group of drugs outweigh the benefits to patients due to potential serious side effects. FDA advises the use of these drugs only if other options are not available.

A recent FDA safety review has shown that fluoroquinolones when used systemically (i.e. tablets, capsules, and injectable) are associated with disabling and potentially permanent serious side effects involving the tendons, muscles, joints, nerves, and central nervous system. These can occur together or can affect isolated system.The common side effects of the fluoroquinolones are gastrointestinal disturbances, headaches, skin rash and allergic reactions.  Less common but more severe side effects include QT prolongation, seizures, hallucinations, tendon rupture, angioedema and photosensitivity.

FDA is requiring labelling change with updated boxed warning stating that they should only be used if no other treatment option is available for uncomplicated urinary tract infections, acute sinusitis and bronchitis.

The fluoroquinolones currently approved by FDA for systemic use are Moxifloxacin, Ciprofloxacin, Ciprofloxacin extended-release, Gemifloxacin, Levofloxacin, Ofloxacin and moxifloxacin injection.

FDA has asked patients to contact health care providers immediately if any of these symptoms occur while taking the drugs. Some signs and symptoms of serious side effects include tendon, joint and muscle pain, a “pins and needles” tingling or pricking sensation, confusion, and hallucinations.

Physicians and other health care providers should stop using systemic fluoroquinolones if patient reports any of the side effects and should immediately switch to other group of drugs to complete the treatment.

References:

http://www.fda.gov/downloads/Drugs/DrugSafety/UCM500591.pdf

http://www.fda.gov/Drugs/DrugSafety/ucm500143.htm

http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm500325.htm

Quick tests to confirm rupture of membranes and miscarriage in markets shortly!

The definitive and quick diagnosis of rupture of membranes and miscarriage will be commercially available very shortly if data on two important and groundbreaking diagnostic tests falls in place.

The capacity to differentiate high levels of alpha fetoprotein in amniotic fluid or vaginal blood from levels in other body fluids forms the basis of both the tests. Both rely on lateral-flow immunoassay or strip test to detect and the presence of alpha-fetoprotein indicating leakage of amniotic fluid and the second test quantify the alpha-fetoprotein in vaginal blood.

Both the tests were developed by Amir Mor, MD, PhD, a third-year resident in obstetrics and gynecology at the Maimonides Medical Center in Brooklyn, New York. The pilot study was a prospective cohort study involving 52 pregnant women admitted in labor in whom urine and amniotic fluid specimens were collected. Semen specimens were collected from 17 men undergoing infertility evaluation. The study was published in February 2015 issue of Obstetrics and Gynecology.

Pads with the strip incorporated were instilled with the specimens collected to measure the levels of alpha-fetoprotein.  In other 27 pregnant women, normal vaginal discharge was collected and tested by absorbing it in the pads. It was seen that amniotic fluid has significantly higher levels of alpha-fetoprotein than semen, urine or normal vaginal discharge. Receiver operator characteristic curve analysis demonstrated 96.2% sensitivity and 100% specificity for distinguishing the presence of amniotic fluid from normal vaginal discharge on sanitary pads (cutoff 3.88 ng/mL, area under the curve 0.99).

The test can be conducted bedside or at home by the patient herself, but Dr Mor and his colleagues have the patents that prohibit anyone else from developing and marketing the technology. Dr. Mor is in negotiations with several manufactures to bring the detecting pads in the market, which he believes to be under a year.

Both the tests were presented as a poster presentation at the American Congress of Obstetricians and Gynecologists (ACOG) 2016 Annual Clinical Meeting.

In the current study 200 women with confirmed membrane rupture and 70 women with intact membranes used the pads.  All pads worn by women with confirmed rupture of membrane tested positive for alpha-fetoprotein.  While only half of the women with intact membrane activated the test and tested negative. This was expected because, they did not have enough wetness/fluid to activate the strip.

Additional pads were instilled with urine specimens obtained from the 270 women, and 40 pads were instilled with semen collected from an infertility clinic. All these tests were also negative.

Dr Mor said “Although there are several other tests designed to determine whether amniotic fluid has leaked, none are as sensitive, specific, or as fast and easy as this alpha-fetoprotein diagnostic.

Dr. Nathaniel DeNicola, MD, MSC, an obstetrician–gynecologist at the University of Pennsylvania in Philadelphia quoted “Despite the need for more study of the technology, "the excitement is real," If a diagnostic could establish rupture of membranes or a failed pregnancy at the point of care, "doctors and patients would both welcome it, but a single study will not be enough to change practice. It will have to be "verified with repeat studies with more patients."

Test for Miscarriage.

Study data dealing with detection of miscarriage was also presented by Dr. Mor at the conference, winning him the Blue Ribbon from ACOG reviewers.

Dr. Mor said “the test can identify whether the pregnancy is inside the uterus or if it's a failing pregnancy." Dr Mor explained.

At present it is difficult to determine whether the pregnancy will continue or end up in miscarriage, without sending the specimen to laboratory for presence of fetal tissue in the vaginal blood.  But with this test, the differential diagnosis can be clinched bedside.

Earlier studies have shown that levels of alpha-fetoprotein levels are 1000 times higher in fetal blood than in maternal blood in first trimester.

In a small study of 17 women who were postulated to end up in missed or incomplete abortion, Mean alpha-fetoprotein concentration in blood sampled from the vagina was 17,043 ng/mL, and from maternal serum was 116 ng/mL (P < .001).

In other nine women with threatened abortion, mean alpha-fetoprotein concentration in blood sampled from the vagina was 71 ng/mL and from maternal serum was 112 ng/mL (P = .1).

Dr Mor and his colleagues further explained that if alpha-fetoprotein levels in vaginal blood were at least 8000 times higher than the normal range seen in maternal serum, it confirmed an intrauterine pregnancy that had failed. On the other hand, women with confirmed nonheterotopic ectopic pregnancy concentrations of alpha-fetoprotein in vaginal blood were similar to maternal serum.

The concept is new and exciting, but evidence points out that it is possible to distinguish between miscarriage and viable pregnancy by this test.

References:

http://www.cytodiagnostics.com/store/pc/Lateral-Flow-Immunoassays-d6.htm

http://journals.lww.com/greenjournal/pages/articleviewer.aspx?year=2015&issue=02000&article=00025&type=abstract

http://www.medscape.com/viewarticle/863833#vp_1

Two blood tests to rule out pre-eclampsia approved by The National Institute for Health and Care Excellence (NICE), UK.

According to an estimate by NHS mild pre-eclampsia affects up to 6% of pregnancies, while 1-2% of patients develop severe preeclampsia.  Data Centre for Maternal and Child Enquiries Mission statement shows pre-eclampsia, and associated eclampsia, are the second leading cause of direct maternal deaths in the UK.

NICE have approved and recommended two blood tests Triage PlGF test (Alere) and the Elecsys immunoassay sFlt-1/PlGF ratio (Roche Diagnostics) to help rule-out pre-eclampsia between 20^th and 35^th week of pregnancy.

The tests detect changes in the blood indicating that the placenta is not developing properly.

The tests however are not meant for diagnosing preeclampsia.

The tests were approved by NICE after the groundbreaking PROGNOSIS study results were published in New England Journal of Medicine in January,2016. 

The PROGNOSIS study has demonstrated that low ratios of the proteins sFlt-1 and PlGF in the blood of women at high risk of developing of preeclampsia can predict the absence of the condition within a period of one week (the rule-out claim). The data published today show that an sFlt-1/PlGF ratio of 38 and below can rule out the development of preeclampsia within the next week with a very high confidence level of 99.3%.

PROGNOSIS was a multi-center, prospective, double-blind, non-interventional trial evaluating the short-term prediction of preeclampsia, eclampsia and HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome in pregnant women with suspected preeclampsia. Sponsored by Roche, the PROGNOSIS study aimed to address the limitations of the traditional clinical parameters used to predict preeclampsia, and to demonstrate the utility of the Elecsys® preeclampsia ratio test in this context.

Identifying women who are unlikely to develop preeclampsia in the short term will save them from the stress of monitoring and the disruption to their home life caused by a stay in hospital.

The test is available in all countries accepting the CE mark in Europe, Latin America, Middle East, Africa and Asia. The test is currently not available in the United States and Japan.

PROGNOSIS also demonstrated that an sFlt-1/PlGF ratio greater than 38 may help predict whether women with suspected preeclampsia will develop the condition within four weeks (the rule-in claim), allowing doctors to identify at-risk patients who need close monitoring.

Dr Jenny Myers, who is also Senior Lecturer and Consultant Obstetrician, Maternal and Fetal Health Research Centre, Central Manchester Foundation Trust said “At the moment women with suspected pre-eclampsia often have to come into hospital for 24 to 36 hours so we can make a diagnosis, but now, for women between 20^th and 35^th week of their pregnancy, these new tests may avoid the need for admission to hospital.”

“The tests will be extremely valuable to help rule out pre-eclampsia before the 35^th week of pregnancy, when approximately 1/3 of women with pre-eclampsia are diagnosed.

“Doctors will need to be clear with patients, depending on which test is used, the result is only valid for 7 to 14 days and neither test definitively rules out pre-eclampsia for the rest of the pregnancy.

“However these tests represent a great stride forward in the management and treatment of pre-eclampsia.”

The cause of preeclampsia is not fully understood; many factors have been implicated in the development of this life threatening disease. Recent research provides evidence that angiogenic factors such as placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) play a major role in the development of the disease.

It is postulated that preeclampsia is caused by an imbalance of angiogenic factors of sFlt-1 (anti-angiogenic protein) and PlGF (pro-angiogenic protein). During normal pregnancy both these proteins are involved in placental vascular remodeling.

In normal pregnancy, PlGF levels rise and peak at 26 to 30 weeks, so when PlGF levels do not rise during pregnancy this may be an indicator that the placenta is not developing properly, predict subsequent development of preeclampsia.

The Elecsys immunoassay sFlt-1/PlGF ratio also measures a protein called soluble FMS-like tyrosine kinase-1 (sFlt-1). The protein sFlt-1 stops other proteins that help to form blood vessels, like PlGF, from working. In pre-eclampsia if sFlt-1levels are higher than those seen in normal pregnancy it could be an indicator the placenta is not developing properly.

The sFlt-1/PlGF ratio measurement in combination with proteinuria, blood pressure and Doppler ultrasound gives better prediction of preeclampsia.

Professor Carole Longson, director of Centre for Health Technology at NICE added “Until now there have been no tests which doctors can use to confidently rule-out pre-eclampsia. This has meant women with suspected pre-eclampsia often need increased monitoring or have to stay in hospital. Apart from being inconvenient, this can increase anxiety at what might already be a stressful time.

“In recommending these tests the committee highlighted the importance of making sure laboratories explain to clinicians if a test result doesn’t rule-out pre-eclampsia they should not automatically diagnose women with pre-eclampsia.

Instead doctors should follow existing NICE guidelines to make such a diagnosis. This is so that babies aren’t delivered unnecessarily early as a result of these tests.”

Two other tests were also considered initially but later not included in the guidelines.

NICE recommends further research and trials to be carried out using these tests in women with suspected preeclampsia.

References:

http://www.cobas.com/content/dam/cobas_com/pdf/product/Elecsys%20Preeclampsia%20assays%20sFlt-1%20PlGF/Preeclampsia%20Abstract%20Booklet.pdf

http://www.1000livesplus.wales.nhs.uk/sitesplus/documents/1011/CMACE%20Saving%20mothers%20Lives%202011.pdf

http://www.nhs.uk/conditions/pre-eclampsia/pages/introduction.aspx

https://www.nice.org.uk/news/press-and-media/nice-guidance-recommends-new-tests-to-help-rule-out-pregnancy-complication-and-avoid-unnecessary-hospital-admissions

http://www.nejm.org/doi/full/10.1056/NEJMoa1414838

ASCO issues evidence based, global guidelines for managing invasive cervical cancer.

The American Society of Clinical Oncology (ASCO) has issued recommendation on managing invasive cervical cancer.  There exist wide disparities in screening, diagnosing and treatment of patient diagnosed with invasive cervical cancer across the globe. Economic disparity and lack of resources make it impossible to adopt the same guidelines universally. 

ASCO has first time published ‘resource stratified’ guidelines that are tailored according to the resources available in a specific region.

The guidelines were published online before print on May 25, 2016, in Journal of Global Oncology.

According to WHO statistics, an estimated one million-plus women worldwide are currently living with cervical cancer of which about 84 per cent occur in less developed countries.

Dr. Linus Chuang, MD, MS, professor of obstetrics, gynecology, and reproductive science at the Icahn School of Medicine at Mount Sinai in New York City, who is cochair of the ASCO expert panel that developed the guideline said "In those regions, access to pathology services, skilled surgeons, radiation machines, brachytherapy, chemotherapy, and palliative care may all be constrained." 

Dr. Jonathan S. Berek, MD, MMS, professor and chair of obstetrics, gynecology, and gynecologic oncology at the Stanford University School of Medicine in California, and who is also cochair of the ASCO expert panel opined that At least two-thirds of the women who die from cervical cancer have not had regular screening, "If we improved screening and HPV vaccination around the world, we might be able to substantially decrease the mortality from cervical cancer." 

ASCO called upon a multidisciplinary, multinational panel of cancer specialist, medical and radiation oncology, health economic, obstetric and gynecologic, and palliative care experts to develop   guidelines that encompasses resource tiered settings.  A systemic review of literature from the year 1966 to 2015 could not yield sufficiently strong evidence to develop tailored guidelines across the different region globally, so a formal strategy of developing consensus based guidelines was adopted.

Five sets of guidelines from different bodies and societies were reviewed in current context and recommendations were formed into 4 tier that is basic, limited, enhanced, and maximal. For surgery, chemotherapy and radiotherapy treatment combinations and modalities available were formed according to the 4 tier.

1. Surgery: In basic tier Simple (extrafascial) hysterectomy or more extensive hysterectomy can be performed while in maximal  tier facilities Radical hysterectomy, radical trachelectomy, pelvic and paraaortic LN sampling, sentinel node biopsy, and pelvic exenteration; radiation therapy, chemotherapy, interventional radiology, palliative care service, and bevacizumab are all available.
2. Chemotherapy:  In basic tier availability of chemotherapy drugs were unpredictable, while in maximal capacity Chemotherapy available; bevacizumab is also available.
3. Radiotherapy: In basic tier no radiation therapy available while RT including external beam and brachytherapy and interventional radiology available in maximal capacity.

The societies were the National Comprehensive Cancer Network (NCCN) in the United States, and the World Health Organization (WHO), Cancer Care Ontario (CCO) in Canada, the European Society of Medical Oncology (ESMO), the Japan Society of Gynecologic Oncology (JSGO).

Workup, Optimal therapy, follow up and post treatment surveillance and palliative care were earmarked for each of these tiers and stage of cancer.

ASCO emphasized that health care providers and health care administrators should be guided by the recommendations from the highest stratum of resource available to provide women with the best evidence based treatment modality and palliative care.

Some of the key recommendations in treatment for invasive cervical cancer are:

• In Basic setting where radio therapy is not available, extrafascial hysterectomy, either alone or after chemotherapy, can be an option for women with stage IA1 to IVA cervical cancer.
•  In Enhanced and Maximal settings, concurrent radiotherapy and chemotherapy is the standard of care for women with stage IB to IVA disease.
• Adding  Low dose chemotherapy to Radiotherapy is  ideal, but if chemotherapy is not available the radiotherapy should not be delayed for it.
• In limited resource settings where brachytherapy is not available, extrafascial hysterectomy or its modification in patients who still have residual tumor of 2-3 months after concurrent radio and chemotherapy.
• Those patients with stage IV or recurrent cervical cancer in basic settings can be treated with single agent chemotherapy using carboplatin or cisplatin.
• In patients who have disseminated disease and cannot be cured should be given palliative radiotherapy to relieve pain and bleeding.
• In areas with very poor resources, multiple short courses of radiotherapy can be used for retreatment of recurrent or residual diseases.
• In settings where good follow up care can be provided, cone biopsy in basic resources settings and cone biopsy and lymphadenectomy in limited resource setting is the treatment of choice for 1A2 disease. 
• For patients in enhanced and maximal settings, to preserve the fertility in reproductive age group of women radical trachelectomy is recommended for those with stage IB1 disease with tumor size up to 2 cm.
• ASCO also noted that the current guidelines are intended to complement the existing guidelines and not necessary replace it.
• ASCO also provided future directions and stressed the need for prospective comparative research. Radical versus simple hysterectomy (the feasibility and safety of performing cone biopsy or simple hysterectomy) is an active area of investigation in limited resource settings, with stage IA2 versus 1B1 disease.

References:

http://www.wcrf.org/int/cancer-facts-figures/data-specific-cancers/cervical-cancer-statistics

http://www.who.int/reproductivehealth/topics/cancers/en/

http://www.asco.org/sites/new-www.asco.org/files/content-files/practice-and-guidelines/documents/2016-RS-Cervical-Cancer-Treatment-Summary-Table.pdf

http://jgo.ascopubs.org/content/early/2016/05/21/JGO.2016.003954.full

Excess Folate and Vitamin B12 levels in pregnancy linked to Autism.

 Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by social impairment, abnormal communication and repetitive or unusual behavior.

It is one of the rapidly growing developmental disorder in USA, now affecting 1 in 68 children and 1 in 42 boys. Boys are nearly 5 times more likely to develop Autism than girls and there is no medical detection , screening or cure for Autism. 

Some of the known risk factors for Autism spectrum disorder (ASD) are older age of parents, prematurity, LBW, previous sibling being diagnosed with ASD, certain genetic or chromosomal conditions like  Down syndrome, fragile X syndrome,tuberous sclerosis. It also co-occurs with other developmental, psychiatric, neurologic, chromosomal, and genetic diagnoses.

It is well established fact that adequate levels of folic acid are necessary for preventing neural tube defects (NTDs) and pregnant women are advised to start folic acid supplementation as soon as they start planning their pregnancy and through first trimester. In US breads, cereals and other breakfast items are fortified with folic acid.

But, as the saying goes ‘excess of everything is bad’, so is the case with excess of folic acid in blood during the antenatal period. A recent study presented at the 2016 International Meeting for Autism Research in Baltimore have linked excess folic acid and B12 to Autism. The study is also published in April issue of The FASEB Journal.

The researchers analyzed data from nearly 1,391 mother-child pairs in the Boston Birth Cohort, which is an ongoing longitudinal prospective birth cohort study consisting of low-income urban, primarily minority mother-offspring pairs. The children were followed from birth through childhood between 1998–2013. Maternal Blood samples were collected 48-72 hours post delivery and analyzed for plasma folate, Vit B12 and homocysteine  levels. 

A total of 107 infants were diagnosed with autism, Asperger syndrome, and/or pervasive developmental disorder not otherwise specified and were categorized as having ASD.

According to the World Health Organization folate levels between 13.5 and 45.3 nanomoles per liter represent adequate amount of folate for a woman in her first trimester of pregnancy. But, well established threshold for Vit B12 is yet to be researched at.

The researchers found that one in 10 of the study subject had an excess amount of folate (more than 59 nanomoles per liter) and six percent had an excess amount of vitamin B12 (more than 600 picomoles per liter).

It is not known that why some women have such high levels of folate and Vit B12. The researchers link it with diet, genetic makeup for metabolizing folates and supplementation or a combination of all these.  

The findings from this study are still very premature and not been peer-reviewed. The data has to be looked at closely and multiple studies are required before a recommendation can be made.

Principal investigator Daniele Fallin, PhD, director, Wendy Klag Center for Autism and Developmental Disabilities, John Hopkins Bloomberg School of Public Health, said during a press briefing. "When we looked at the vitamin supplementation evidence, we saw what our colleagues see ― that indeed, women who took vitamin supplementation during pregnancy had a lower risk of autism in their children and that is very consistent with the literature." 

"But when we looked at women who had excessively high levels of folate, we saw that very high levels of folate in the mother were responsible for about a twofold increased risk for autism in their child [P = .007], and when we looked at B12, women who had excessively high levels of B12 had a threefold increased risk for their child to have autism [P = .001], while women who had extreme levels of both folate and vitamin B12 had a 17.6 times greater risk of having their child diagnosed with an ASD [autism spectrum disorder] later on [P < .001]," she added.

 "We have long known that a folate deficiency in pregnant mothers is detrimental to her child's development. But what this tells us is that excessive amounts may also cause harm. We must aim for optimal levels of this important nutrient," said Fallin.

This study gives us some important future research topics about how much folic acid supplementation is enough and what constitutes the excess and part played by genetics and diet.

"So for now, the public health message is, supplementation is good, but there may be a subset of women whose levels are extremely high, and these extreme levels may be harmful."

Women should be cautioned about randomly popping vitamin supplements in pregnancy until further larger study data is available.

References:

https://www.autismspeaks.org/what-autism/facts-about-autism

http://www.cdc.gov/ncbddd/autism/data.html

http://www.fasebj.org/content/30/1_Supplement/151.6.short?related-urls=yes&legid=fasebj;30/1_Supplement/151.6

Evidence link habitual physical exercise to proven health benefits in postmenopausal women.

Habitual physical exercise incorporated into daily life have proven benefits in improving many health parameters and quality of life in post-menopausal women. Multiple studies have beneficial impact on many organs and systems.

Members of the Spanish Menopause Society, Spanish Cardiology Society and Spanish Federation of Sports Medicine convened to formulate the recommendations on physical activity for older women and they also reviewed the quality of evidence for the various possible health benefits of exercise.

The new position statement was published in the forthcoming issue of Maturitas.

The panel concluded that resistance and weight training improves the bone health and also improves osteoporosis, benefits not seen by walking alone. But, walking is preferred by many postmenopausal women. In addition, it helps maintain the muscle mass, improves movements and flexibility.

Specific form of exercises like Pilates improves balance and thereby reduces the risk of fall and fractures, a major cause of morbidities in elderly.

Regular and intense exercise has been said to improve sleep quality, reduces anxiety and depression and decrease pain due to fibromyalgia and other chronic conditions. But it needs to be performed regularly and over extended period of time.

Dr. Wolfgang Kemmler of the University of Erlangen-Nuremberg in Germany told Reuters health via email “A plethora of randomized controlled studies determined the positive effect of 'exercise' on risk factors, diseases or complaints related to menopause or increased age. "However, 'exercise' is a rather comprehensive term: there are numerous variations of exercise regimen that may emphasize speed, strength, power, endurance, or coordination."

A British study found that women who are active 3-6 times a week, reaped cardiovascular and cerebrovascular benefits, including protection against blood clots.  Menopause is a good time of life to introduce exercise as a part of daily routine.  

He also opined that most postmenopausal women and elderly people in Germany and US do not do the recommended amount of exercise.

"Thus, the critical issue is much more, whether a single multi-purpose (weekly) exercise program conducted with reasonable exercise frequency (2-3 sessions) and duration (45-60 min) is effective in reducing the most important postmenopausal risk factors and complaints," he said.

The study author  Antonio Cano Sánchez quoted that "Thus, the critical issue is much more, whether a single multi-purpose (weekly) exercise program conducted with reasonable exercise frequency (2-3 sessions) and duration (45-60 min) is effective in reducing the most important postmenopausal risk factors and complaints." 

He also said that to guard against osteoporotic bone loss, a lot of muscle training and high endurance exercise needs to be put in, but some light physical exercise may protect against risk of falling which is as good as good bone density in the event of fragility fracture.

A group exercise class is very good for boosting mood, socializing and motivation to come to the gym daily.

So, mixing endurance, general coordination and resistance exercise is the best choice for postmenopausal women including a balancing aspect for older or less functional women.

 The study highlights by de Guevara, Nicolás Mendoza Ladrón et al are:

1. Physical exercise is a principal strategy for preventing and treating sarcopenia and its effects by increasing muscle mass and function.
2. Physical exercise improves flexibility, balance, and physical function, and corrects disability.
3. Physical exercise reduces the risk of cardiovascular disease in postmenopausal women.
4. Both aerobic exercise and strength exercises can partially or totally counteract the changes associated with metabolic syndrome in sedentary postmenopausal women.
5. Physical exercise is inversely related to the risk of dementia and improves the cognitive function of middle-aged women.
6. Physical exercise improves osteoarticular pain in postmenopausal women with fibromyalgia or breast cancer

References:

http://www.maturitas.org/article/S0378-5122(16)30096-2/fulltext

http://www.ncbi.nlm.nih.gov/pubmed/27137981

http://webcache.googleusercontent.com/search?q=cache:http://uk.reuters.com/article/us-health-fitness-post-menopause-idUKKCN0YB1Q0

Important Policy Updates from American Society of Clinical Oncology (ASCO) supporting HPV Vaccination.

American Society of Clinical Oncology is  the leading professional body committed to decrease the burden of cancer and hence promote any underutilized intervention that have potential to save millions of lives by preventing cancer incidences.

An extremely important policy statement from the American Society of Clinical Oncology (ASCO), published ahead of print on April 11, 2016 regarding the HPV Vaccination

ASCO states that more than 10% of cancers worldwide (more than million cases per year) are caused by viruses with HPV contributing about 600,000 to the pool.

In addition to cervical cancer, HPV is also responsible for causing anal cancer, vaginal cancer, and vulvar cancers, and increasingly of oropharyngeal cancer. It is estimated that HPV is responsible for 60% of all oropharyngeal cancer, 90% of which are caused by HPV 16.

HPV is the cause of nearly all cervical cancers with 70% cases caused by genotype 16 and 18.

HPV additionally causes of 91% of anal cancers, 75% of vaginal cancers, 69% of vulvar cancers, and 63% of penile cancers, with HPV 16 being the predominant oncogenic genotype.

Thus HPV causes cancers in both sexes and oropharyngeal cancer is 3-5 times more common in men.

“With safe and effective vaccines readily available, no young person today should have to face the devastating diagnosis of a preventable cancer like cervical cancer. But unless we rapidly increase vaccination rates for boys and girls, many of them will,” said ASCO President Julie M. Vose, MD, MBA, FASCO.

Vaccination against the HPV virus is incredible preventive strategy, because once the HPV virus becomes incorporated into cells lining the cervix, anus or oropharynx it is impossible to eradicate it and it will remain there for life.

A 2011 National immunization survey reported that only 36% of girls 14% of boys have received the full schedule of immunization needed to protect against the virus.  A study in the same year also showed that some of the states with highest rates of HPV related cancers have the lowest rate of immunization.

Therefore, The ASCO recommendations for increasing vaccination awareness and use are summarized here.

1. Education and raising the awareness among health care providers, public health professionals, policy makers and patients about HPV vaccine and the cancers it causes.
2. Increasing the vaccination rates in society by combining it with other vaccines like eg, Tdap and meningococcal virus) for young adolescents. Distribution of educational pamplets, reminders by e-messaging or mailing should also be considered to bring on increase contacts among Drs and patients.
3. ASCO strongly urges the policy makers and insurance company to increase the vaccination coverage, thereby decreasing out of pocket expenses because vaccination rates are strongly related to these factors.  
4. Addressing critical knowledge gaps through research and development, making vaccinations safe and effective.
5. ASCO strongly believed that oncologists can play a very important role in increasing patients compliance for vaccination. They should keep abreast the recent advances by CDC and WHO regarding vaccination and interact with internists, gynecologists and primary care physicians to raise their awareness and interaction. Play a role in policy making in the society so that leaders can understand the critical role played by vaccines in avoiding cancers.

Bivalent (Cervarix), quadrivalent (Gardasil), and, more recently, nonavalent (nine-valent) vaccines against HPV genotypes (targeting those most commonly causing cancer globally) are approved in the United States and other countries for primary prevention of HPV infections 

The current Advisory Committee for Immunization Practices (ACIP)  Vaccine Recommendations are: 

 Usual Adult Dose for Human Papillomavirus Prophylaxis

Gardasil - women and men:
Cervical, vulvar, vaginal, and anal cancer caused by HPV and genital warts (condyloma acuminata) caused by HPV:
9 years through 26 years: one dose (0.5 mL) intramuscularly once. Repeat dose in 2 months and 6 months for a total of 3 doses.
Cervarix - women:
9 years through 25 years: one dose (0.5 mL) intramuscularly at 0, 1, and 6 months.

Usual Pediatric Dose for Human Papillomavirus Prophylaxis

Gardasil - girls and boys:
9 years or older: one dose (0.5 mL) intramuscularly once. Repeat dose in 2 months and 6 months for a total of 3 doses.
Cervarix - girls:
9 years or older: one dose (0.5 mL) intramuscularly at 0, 1, and 6 months.

Vaccine is usually initiated at 11 to 12 years old; optimally, vaccination should be completed prior to onset of sexual activity.

References.

Bailey HH, Chang LT, DuPont NC, et al: American Society of Clinical Oncology statement: Human papillomavirus vaccination for cancer prevention. J Clin Oncol. April 11, 2016 (early release online).

http://jco.ascopubs.org/content/early/2016/04/07/JCO.2016.67.2014.full#sec-11

http://www.ascopost.com/News/39503

http://www.ascopost.com/issues/april-25-2016/asco-urges-aggressive-efforts-to-increase-hpv-vaccination-and-prevent-cancer/?platform=hootsuite

Kish JK, Rolin AI, Zou Z, et al: Prioritizing US cervical cancer prevention with results from a geospatial model. J Global Oncol. April 11, 2016 (early release online).

Elective Induction of labor (IOL) at 39 weeks is in the best interest for mother and baby-- News from ACOG Annual Clinical and Scientific Meeting 2016.

The ideal time for delivery in low risk pregnancies has been debated since very long. ACOG efforts to stop elective induction before 39 weeks in well dated pregnancies have decreased neonatal morbidity and mortality.  So, this year’s debaters for The Edith Louise Potter Memorial Lecture at the ACOG annual conference tried to answer a difficult question by offbeat approach: If recommendation say no elective induction before 39 weeks, why not induce every well dated patient at 39 weeks?

The debaters were Dr. Errol Norwitz, MD, PhD, chairman of the Department of Obstetrics and Gynecology, and professor at Tufts University School of Medicine and Dr. Charles Lockwood, MD, senior vice president, USF Health, dean of the Morsani College of Medicine, University of South Florida, professor of obstetrics and gynecology at Morsani College of Medicine, and professor of health policy and management at the College of Public Health, University of South Florida.

Interestingly both the debaters agreed that continuing pregnancy beyond 39 weeks is risky for the fetus.

Several studies from USA and UK were cited to support the argument. Dr Norwitz said “Continuing the pregnancy beyond 39 weeks is riskier than previously believed for the fetus. In addition, risks to the mother associated with routine induction "are lower than appreciated." 

Dr. Lockwood also seconded the opinion saying "I was absolutely opposed" to the elective induction of labor at 39 weeks but after much reading it's overwhelmingly evident that elective induction of labor is the logical strategy."

Dr Norwitz stressed that higher rates of stillbirths after 39 weeks have been known since 1980’s but the research was always overlooked. According to a study published in BMC Pregnancy Childbirth. 2015; 15(Suppl 1): A11 late stillbirths (pregnancies 28 weeks or later) occur twice a common as deaths due to congenital anomalies; twice as common as deaths due to preterm complications, and ten times more common that Sudden Infant Deaths.

Another retrospective study of 171,527 notified births published in BJOG, evaluated gestation-specific risks of stillbirth, neonatal and post-neonatal mortality. The study concluded that with each passing week the risk of still births and neonatal mortality increases by nearly 11 fold to that at 37weeks.  Multiple factors like the effects of parity, multiple pregnancy, congenital abnormality, meconium aspiration and uteroplacental insufficiency may be responsible for it but, requires further detailed analysis.

Several other studies and meta-analysis have reiterated these findings.

The major risk factor for induction at 39 weeks is failed induction leading to an operative intervention, but surprisingly both Dr. Norwitz and Dr. Lockwood did not see any increased rate of cesarean delivery, albeit they found a decrease.  Because of paucity of data on routine induction at 39 weeks, Dr Norwitz extrapolated data from IOL vs. expectant management (EM) at 41 weeks and it showed a decrease in cesarean section rate.

He and his colleagues performed a comparative-effectiveness analysis and the model consisted of 60 probable outcomes. The team then also created a Monte Carlo microsimulation to map out head-to-head effectiveness.

It was seen that expectant management were associated with higher operative intervention and clear increase in perinatal mortality.  Maternal rates were the same for the two groups, but complications rates were more for mother and infant in the expectant management group.

To conclude Dr Lockwood said “elective IOL at 39 weeks was always the superior decision strategy to expectant EM with IOL at 41 weeks.”

Both the debaters agreed that to induce the patient successfully at 39 weeks requires accurate gestational dating otherwise it may not be beneficial as planned.

In a nutshell Dr. Lockwood concludes “Elective induction of labor at 39 weeks reduces the number of cesarean deliveries, reduces the occurrence of stillbirth, reduces severe complication rates for infants and reduces severe complication rates for mothers in a very highly statistically significant fashion.

References:

http://www.acogdailynews.com/support-for-elective-iol-at-39-weeks-growing/

http://www.acogdailynews.com/support-for-elective-iol-at-39-weeks-growing/

http://www.acogdailynews.com/potter-memorial-lecture-elective-induction-of-labor-at-39-weeks/

http://www.medscape.com/viewarticle/863383

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4413558/

http://onlinelibrary.wiley.com/doi/10.1111/j.1471-0528.1998.tb10047.x/full

Is HPV testing ready to replace Pap testing as the first-line test for cervical cancer screening--News from ACOG Annual Clinical and Scientific Meeting 2016.

On Day 3 of the  Annual Clinical and Scientific meeting, ACOG  2016 the question at this year’s John and Marney Mathers Lecture was Is HPV testing ready to replace Pap testing as the first-line test for cervical cancer screening for women 25 and older?

Warner K. Huh, MD, professor and division director of gynecologic oncology, senior scientist in the University of Alabama-Birmingham (UAB) Comprehensive Cancer Center, and Margaret Cameron Spain endowed chair in Obstetrics and Gynecology at the UAB School of Medicine are positive about it while George F. Sawaya, MD, professor of Obstetrics, Gynecology and Reproductive Sciences and Epidemiology & Biostatistics at the University of California, San Francisco, argued for a more cautious approach during the morning session debate on May 16, 2016.

Dr. Huh believes that HPV testing has the most sensitivity and negative predictive value out of all the screening technologies. A negative result gives a long time assurance about absence of cervical malignancy. In support of his argument he cited the Canadian cervical cancer screening trial (CCCaST) of 10,171 women ages 30-69 randomized to HPV testing or pap test.  The results showed that verification-bias adjusted sensitivity of Pap cytology was 55.4% while that of HPV testing was 94.7%. Pap test also suffers from variation in collection, storage and lab performance.

He also said “Keep in mind that cytology has never been subject to a randomized control trial, and if you actually submitted the test to the FDA today, what’s interesting is that it would probably be resoundingly rejected by the FDA because of its low sensitivity.”

An aggregate of 4 studies published in the Lancet in 2011 found that when all the women who had a normal Pap test were analyzed there was rate of 7.5 instances of cancer per 100,000 women in a year while the same rate for HPV negative patients was 3.8 cervical cancers per 100,000. Women who were both HPV-negative and had a normal Pap test had 3.2 cervical cancers per 100,000.

Dr. Huh opined that when actually calculated it is 60% risk reduction in cervical cancer over the years. HPV screening further missed less cases when it comes to diagnosis of adenocarcinomas.

The Other Debater Dr. Sawaya said that major groups and association continues to discourage HPV testing in women younger than 30 independent of the COBAS HPV strategy of following up a positive test with HPV 16/18 type-specific testing followed by colposcopy, cytology or future follow-up.

He is also of the opinion that HPV testing will lead to more surveillance, uncertainty and confusion specially in the younger and the older age groups. A screening test must simplify life by maximizing benefits and avoiding life style disruptions, unnecessary surveillance, treatment and interventions.

He also talked about the ATHENA Trial, a US-based, 3 years’ multicenter study, comparing COBAS HPV vs. cytology (ASC-US+). According to him both techniques are at par when diagnosing CIN 2+ citing that in the ATHENA   trial a cohort of 1000 women, 25+ and older after the first round of screening, the HPV screening group found CIN2+ in eight women, while cytology found CIN 2+ in six.

The cytology group after the screening has had 10 percent abnormal cytology, 7 percent colposcopy and 5 percent in surveillance while those following COBAS algorithm had 21 percent HPV positive, 10 percent colposcopy and 19 percent in surveillance. The increased percentage of patients in surveillance does have increased psychological issues.

He suggests screening with cytology alone every three years, with HPV triage for ASC-US.

He further added “The loveliness of this strategy is that after a single screening round, they go to colposcopy or go back to routine screening. There’s not this middle ground of coming back in a year. There’s not this uncertainty.” 

But, ACOG does updated its guidelines on December 22, 2015 and the practice bulletin is cited here “The Practice Bulletin provides interim guidance on the use of the FDA-approved HPV test for primary cervical cancer screening, which it states can be considered as an alternative to current cytology-based cancer screening methods (the Pap test) in women 25 years and older. Women younger than 25 years should continue to be screened with cytology alone. Additional guidance is included that addresses a number of important clinical issues not specified in the FDA product labeling for the test, including when to rescreen after a negative test result, how to manage positive test results, and when to stop screening in women with negative screening histories.”

In addition, The Society of Gynecologic Oncology (SGO), the American Society for Colposcopy and Cervical Pathology (ASCCP), with input from representatives of five other US national medical organizations (ACOG, ACS, ASCP, ASC, CAP) issued an Interim Guidance Report after the U.S. Food and Drug Administration (FDA) approved the cobas® HPV Test as a primary, or first, test performed for cervical cancer screening.  This new guidance is in addition to the existing 2012 guidelines and specifically addresses the implementation of HPV testing in primary screening.

The guidance recommends:

• Primary HPV testing can be considered for women starting at age 25.
• Women with a negative primary HPV test result should not be retested again for at least three years. This is the same screening interval recommended under current guidelines for a normal cytology test result.
• An HPV test positive for HPV 16 or 18, two types associated with a higher risk of future disease, should be followed with colposcopy.
• A test that is positive for HPV types other than 16 or 18 should be followed with cytology testing.

References:

https://www.mcgill.ca/cccast/cccast-canadian-cervical-cancer-screening-trial

http://www.hpv16and18.com/hcp/cervical-cancer-screening-guidelines/new-us-primary-screening-guidance.html#sthash.Y5OzbJ7q.dpuf

http://www.acog.org/About-ACOG/News-Room/News-Releases/2015/ObGyns-Update-Cervical-Cancer-Screening-and-Prevention-Guidelines