Few decisive articles in obstetrics from 2015

Role of progesterone in preventing recurrent preterm births (PTB)

It is widely accepted that progesterone supplementation in pregnancy reduces the risk of recurrent preterm birth. But, according to a secondary analysis of data  from Maternal-Fetal Medicine Units Network Trial of hydroxyprogesterone caproate for prevention of recurrent preterm birth before 37wks concluded that the drug may not be effective in women with a BMI>30 kg/m^2. The cut off weight is 168 pounds or 75 kg. This finding may be due to subtherapeutic serum levels in women with increased BMI or weight. Further larger and planned studies in women with BMI >30 kg/m² are warranted and also the universal use of progesterone in women independent of BMI also deserves reassessment.

Heyborne KD et al - Does 17-alpha hydroxyprogesterone caproate prevent recurrent preterm birth in obese women?

Am J Obstet Gynecol. 2015 Aug;

Maternal Hypertension in Pregnancy predisposes the offspring for higher risks of Congenital Heart Disease

According to a systemic review and metaanalysis published in the journal of pediatric cardiology robust associations were observed between maternal hypertension and overall CHDs, irrespective of being treated or untreated. The authors identified 16 studies that met the study criteria. The effect was also uniform across all the subtypes of CHDs. The results were also similar for various type of antihypertensive medications used.

The authors propose to understand the mechanisms to design strategies to reduce the risks..

Ramakrishnan A et al- Maternal Hypertension During Pregnancy and the Risk of Congenital Heart Defects in Offspring: A Systematic Review and Meta-analysis.

Pediatr Cardiol. 2015 Oct;36(7):1442-51. Epub 2015 May 8.

The downside of improved control of malaria.

We are recently seeing improved malaria control in many endemic areas worldwide, leading to a decrease in immunity in the population. A large observational study carried out in Mozambique assessed the prevalence of Plasmodium falciparum infection among 1819 Mozambican women who delivered infants between 2003 and 2012.

A major decline in maternal level of antimalarial IgG antibodies were seen in pregnant women both for pregnancy specific parasitic lines as well as general parasitic lines.

It was also seen that those women who developed malaria antenatally had a larger reduction in hemoglobin levels as well as the neonatal birthweight as the immunity declined.

Mayor A et al- Changing Trends in P. falciparum Burden, Immunity, and Disease in Pregnancy. N Engl J Med. 2015 Oct 22;373(17):1607-17.

Uterine exteriorization at cesarean delivery

Uterine exteriorization vs in situ repair has always been a topic of debate among obstetricians.  In A large meta-analysis of 16 studies amounting to a total of 19,439 subjects 9,736 underwent exteriorization, 9,703 had in situ uterine repair. It was seen that the estimated blood loss was not statistically significant between the two groups as well as other perioperative outcomes. Individual preferences and individual intraoperative circumstances should guide the decision.

Zaphiratos V et al- Uterine exteriorization compared with in situ repair for Cesarean delivery: a systematic review and meta-analysis.

Can J Anaesth. 2015 Nov;62(11):1209-1220.

The best time to perform External Cephalic Version (ECV)

The optimum age to perform ECV has always been a debatable issue.

External cephalic version (ECV) of the breech fetus at term (after 37 weeks) has been shown to be effective in reducing the number of breech presentations and caesarean sections, but the rates of success are relatively low. This systemic review of Cochrane Data base examines studies initiating ECV prior to term (before 37 weeks' gestation).

Pooled results suggested that early ECV reduced the risk of non-cephalic presentation at birth, failure to achieve vaginal cephalic birth, and vaginal breech delivery. However there was no statistical significant difference in Caesarean Section rate between the two groups. There was evidence that risk of preterm labour was increased with early ECV compared with ECV after 37 weeks. Future research reporting infant morbidity outcomes in these late preterm births is warranted.

Hutton E.K et al- External cephalic version for breech presentation before term.

Cochrane Database Syst Rev. 2015 Jul 29;7:CD000084.

Limited value of fetal ST-segment analysis

STAN S31 is a one-of-a-kind fetal monitor which exclusively combines standard CTG technology with ST-Analysis of the fetal ECG (FECG) during labour. The combined analysis of the CTG and fetal ECG helps to detect a fetus that is exposed to hypoxia and which needs remedial action, and also provides reassurance when no intervention is required.

However, It is not clear whether use of STAN 31 as an adjunct to other conventional fetal heart rate monitor improves the intrapartum and neonatal outcome.

This Multicenter RCT of about 11,108 subjects included women with a single fetus undergoing vaginal delivery at more than 36 weeks of gestation with cervical dilation of 2 to 7 cm. They were randomly assigned to "open" or "masked" monitoring with fetal ST-segment analysis. The masked system functioned as a normal fetal heart-rate monitor (FHR). The open system functioned as both FHR as well as fetal ECG monitor.

The primary outcome was a composite of intrapartum fetal death, neonatal death, an Apgar score of 3 or less at 5 minutes, neonatal seizure, an umbilical-artery blood pH of 7.05 or less with a base deficit of 12 mmol per liter or more, intubation for ventilation at delivery, or neonatal encephalopathy.

It was observed that fetal ECG monitoring along with FHR  did not improve perinatal outcome or decreased the rate of caesarean delivery. The primary outcome occurred in 52 fetuses or neonates of women in the Fetal ECG group  and 40 fetuses or neonates of women in the FHR  group.

Belfort M.A- A Randomized Trial of Intrapartum Fetal ECG ST-Segment Analysis.

N Engl J Med. 2015 Aug 13;373(7):632-41.

Expectant management of mild preeclampsia near term is feasible.

There is little guidelines for the management of women with mild preeclampsia with stable maternal and fetal conditions at 34 to 36 weeks of gestation. The study by Broekhuijsen K et al in Lancet 2015, investigated the effect of immediate delivery versus expectant monitoring on maternal and neonatal outcomes in such women. This open-label, randomised controlled trial, in seven academic hospitals and 44 non-academic hospitals in the Netherlands confirmed that most patients will reach term without progressing into severe disease and the expectant management buys us valuable time for optimum neonatal maturity without any harm to the mother.

References:

• Relation of body mass index to frequency of recurrent preterm birth in women treated with 17-alpha hydroxyprogesterone caproate.Co AL, Walker HC, Hade EM, Iams JD. Am J Obstet Gynecol. 2015 Aug; 213(2):233.e1-5
• Ramakrihnan A et al- Maternal Hypertension During Pregnancy and the Risk of Congenital Heart Defects in Offspring: A Systematic Review and Meta-analysis.Pediatr Cardiol. 2015 Oct;36(7):1442-51
• Mayor A et al- Changing Trends in P. falciparum Burden, Immunity, and Disease in Pregnancy. N Engl J Med. 2015 Oct 22;373(17):1607-17.
• Zaphiratos V et al- Uterine exteriorization compared with in situ repair for Cesarean delivery: a systematic review and meta-analysis.Can J Anaesth. 2015 Nov;62(11):1209-1220.
• http://www.news-medical.net/Stan-S31-Fetal-Monitor-from-Neovent
  
  

Progestins in Endometrial Cancer ------ It’s all about the targeted mode of drug delivery!

Endometrial cancer is the sixth most common cancer in women worldwide (fourteenth most common cancer overall), with 320,000 new cases diagnosed in 2012.

In the United States, as with other developed countries, uterine cancer was the most common gynecologic malignancy, with over 50,000 new cases and almost 8600 deaths from the disease in each year.

The 5-year prevalence of women globally living with endometrial cancer is 46.8 per 100,000 (estimated from incidence and observed survival by cancer and age group).

 It is estimated that half million cases of endometrial cancer would be diagnosed worldwide by 2035.

Adenocarcinoma of the endometrium (lining of the uterus) is the most common histologic site and type of uterine cancer.

Endometrial hyperplasia is the precancerous condition that eventually will progress into endometrial cancer.
It is classified into four categories on the basis of histological appearance; the simple hyperplasia has only 1% chance of developing into cancer while complex hyperplasia with atypia has 25% chance of ending into malignancy.

The main risk factor for endometrial carcinoma is an excess of endogenous or exogenous estrogen without adequate opposition by a progestin (eg, postmenopausal estrogen therapy without a progestin). Other risk factors include tamoxifen therapy, obesity, and nulliparity.

The main symptom of endometrial cancer is irregular bleeding, and every patient with this symptom should be thoroughly investigated!

Once the diagnosis is made, the treatment could be medical or surgical depending on the histologic type, the patient age future desire for fertility and other risk factors!

In this systemic review and metaanalysis by Hashim  H.A et al published in October issue of  AJOG evaluated the therapeutic efficacy of levonorgestrel-releasing intrauterine system (LNG-IUS) with oral progestins for treatment of non-atypical endometrial hyperplasia (EH).

Seven RCTs were included amounting to a sample size of 766 women, (329 in the LNG-IUS group and 437 on oral progestin group).

All the women included in the study had simple or complex hyperplasia without atypia.

The oral progestin preparations used included medroxyprogesterone acetate (MPA), norethisterone acetate, and dydrogesterone.

Histological response was evaluated as the main outcome measure at follow-up pathologic examination at 3, 6, 12, and 24 months of treatment. The type of endometrium looked at was proliferative, secretory, atrophic, or inactive endometrial pattern.

A need for hysterectomy and the frequency of irregular bleeding were also analyzed as secondary outcome measure.

It was seen that LNG-IUS fared quite well as compared to oral progestin, the odds ratio at increased from 2.30 at 3 months to 7.46 at 24 months, with fewer patients being ended up in hysterectomy in the LNG-IUS group.

In fact another meta-analysis by Beining R.M et al showed a preventive effect of LNG-IUS on the rate of development of endometrial cancer.

There was no significant difference in rate of irregular bleeding between the two groups.
It was concluded that LNG-IUS could be safely offered to those women, who have atypical hyperplasia and who wish to retain the uterus.

LNG-IUS also has other advantage over oral progestins. Significantly higher dose of the drug could be delivered at the site of pathology without any systemic side effects.

A pooled analysis of data collected in the Epidemiology of Endometrial Cancer Consortium has shown that LNG-IUS induces a number of immunological and biochemical changes in the uterine environment that could affect endometrial cancer (EC) risk and progression.

The limitations of review were most studies included had a short follow up of 1 year and didn’t include women with atypia. Studies doing longer follow up are needed before the full potential of LNG-IUS is exploited.

References:

1. http://www.ajog.org/article/S0002-9378%2815%2900267-7/abstract
2. http://www.cancer.gov/research/progress/snapshots/endometrial
3. http://www.uptodate.com/contents/endometrial-carcinoma-epidemiology-and-risk-factors
4. http://www.wcrf.org/int/cancer-facts-figures/data-specific-cancers/endometrial-cancer-cancer-lining-womb-statistics
5. http://onlinelibrary.wiley.com/doi/10.1002/ijc.29229/abstract
6. http://www.sciencedirect.com/science/article/pii/S1047279707004905
7. Meta-Analysis of Intrauterine Device Use and Risk of Endometrial Cancer Beining, Robin M. et al. Annals of Epidemiology, Volume 18, Issue 6, 492 - 499

Is there a link between NSAID and Infertility?

Diclofenac Tablets

NSAIDs are the most commonly prescribed class of drugs worldwide and frequently consumed by patients of all age groups including women of child bearing age.

In USA most of them are freely available over the counter! According to the American College of Preventive Medicine (ACPM) report they are the second most commonly sold medications second to cough/cold and allergy remedies.

ACPM reported that over 430 million pack units of these medications were sold in the US during 2009.

The Medical world is well aware of the gastrointestinal, cardiovascular and nephrotoxicity of these class of drugs. It is also known that the potential cause of prolongation of labor, premature closure of the fetal ductus arteriosus, and increased risk for postpartum hemorrhage is due to near term use of NSAIDs.

It is the potential of these drugs to effect ovulation, conception and hormone levels in women of reproductive age that is catching attention recently.

Sporadic case series of reversible ovulatory failure associated with the development of luteinized unruptured follicles in women with inflammatory arthritis taking non-steroidal anti-inflammatory drugs appeared in medical literature as back as 1996.

Small prospective RCTs have demonstrated that NSAIDs and COX-2 inhibitors produce a reversible delay in follicular rupture. Unruptured follicles were more often observed in a significantly higher proportion of women using these agents, and this effect is reversible upon drug discontinuation.

The most recent study was presented as a poster in this year’s European League Against Rheumatism (EULAR) Annual Congress by Salman S et al. In this small trial of 39 randomly selected women who visited the Rheumatology consultation clinic, the investigators divided them into 3 groups. 

• Diclofenac, 100 mg once daily;
• Naproxen, 500 mg twice daily;
• Etoricoxib (a COX-2 inhibitor not available in the United States), 90 mg once daily.

A fourth group served as controls, who received no treatment (control volunteers).

The treatment was started on Day 10^th  of the menstrual cycle and it was given for 10 days A baseline blood sample was taken from each patients for hormonal analysis (progesterone level) together with an ultra sonsography to assess the mean diameter of the dominant follicle.

The tests were repeated after 10 days of treatment.

It was seen that out of the women receiving NSAIDs, 6.3% ovulated in the diclofenac group, 25% ovulated in the naproxen group, and 27.3% ovulated in the etoricoxib group, compared with 100% of the control group.

All three treatment groups experienced decreases in progesterone level, and about one third of women developed functional cysts due to unruptured follicles, which disappeared by the next cycle.
Ovulation returned to normal once the women discontinued NSAID or COX-2 inhibitor use.

The investigators advocated the use of NSAID or COX-2 inhibitor with caution in those women who wants to conceive.

To summarize, these small  studies and case reports  have demonstrated an association between NSAIDs, COX-2 inhibitors and  LUFS, delayed ovulation, or ovulation failure, although no causation is demonstrated between infertility and use of these drugs.

This findings calls for more large scale and robust studies in the future to establish a link as  NSAIDs and COX-2 inhibitors are commonly prescribed and  also abused by women of childbearing age as they are freely available OTC.

Physicians should be aware of these potential adverse effects, particularly in women being treated for infertility.

For now it seems wise to proceed with caution when using them in women with fertility concerns and substitute them with acetaminophen. 

References:

1. http://ard.bmj.com/content/74/Suppl_2/117.3
2. Matyas RA, Mumford SL, Schliep KC, et al. Effects of over-the-counter analgesic use on reproductive hormones and ovulation in healthy, premenopausal women. Hum Reprod. 2015;30:1714-1723.
3. Akil M, Amos RS, Stewart P. Infertility may sometimes be associated with NSAID consumption. Br J Rheumatol. 1996;35:76-78.
4. http://www.medscape.com/viewarticle/856186
5. Salman S, Sherif B, Al-Zohyri A. Effects of some non steroidal anti-inflammatory drugs on ovulation in women with mild musculoskeletal pain. Ann Rheum Dis. 2015;74(Suppl 2):117-118.

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Is Pravastatin the magic Bullet to quench Preeclampsia!

Preeclampsia complicates approximately 3-5% of pregnancies and remains one of the major causes of maternal and neonatal morbidity. In fact it is linked to one in 20 stillbirths.

The human placenta is central to the development of preeclampsia. The incidence of preeclampsia increases as pregnancy proceeds from singleton to twin, triplets and quadruplets as the mass of placenta increases.

It shares pathogenic similarities with adult cardiovascular disease as well as many risk factors. According to American Heart Association Preeclampsia doubles the risk for stroke and quadruples the risk for high blood pressure later in life.

Worldwide attempts to prevent preeclampsia using various supplements or other class of drugs have met with limited success, so a policy regarding there use could not be adopted.

In contrast the reduction of Cardiovascular Morbidity and Mortality using 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors, or statins, is widely accepted.

Pravastatin and other statins have shown to reverse various pathophysiologic pathways associated with preeclampsia, such as angiogenic imbalance, endothelial injury, inflammation, and oxidative stress.

Therefore, According to a forthcoming article is the ACOG Journal, Eunice Kennedy Shriver National Institute of Child Health and Human Development Obstetric--Fetal Pharmacology Research Units Network undertook a pilot trial to collect maternal--fetal safety data and to evaluate pravastatin pharmacokinetics when used as a prophylactic daily treatment in high-risk pregnant women.

So, we now have encouraging data from 3 small  pilot clinical trials across the globe.

A small observational pilot study by Dr. Fiona C. Brownfoot carried out at the University of Melbourne in Heidelberg, Victoria, Australia, showed promising results in stabilizing the disease process, resolving the symptoms.

The second trial is known as StAmP trial. StAmP stands for ‘Statins to Ameliorate early-onset Pre-eclampsia’ initiated by Vascular Research team at Aston Medical School, Birmingham, U.K. It is the world’s first randomized controlled clinical trial on the use of statins in pregnancy, and has the potential to completely transform the way we treat preeclampsia. The trial has recruited 64 patients and the final results are awaited.

Professor Asif Ahmed of Aston University, who led the UK trial, said: ‘Although we don’t know the full results, I believe there were no ill effects among the 64 women involved. What we have discovered here is a way of putting the brakes on pre-eclampsia.’

Meanwhile, the results of the small pilot RCT by Eunice Kennedy Shriver National Institute of Child Health and Human Development Obstetric--Fetal Pharmacology Research Units have shown promising results.

It is a pilot, multicenter, double-blind, placebo-controlled, randomized trial of women with singleton, non-anomalous pregnancies at high risk for preeclampsia

The 10 women in this study received 10 mg of oral Pravastatin daily, started between 12-16 weeks, while the 10 controls received placebos.

Primary outcomes were maternal-fetal safety and pharmacokinetic parameters of pravastatin during pregnancy.

Secondary outcomes included rates of preeclampsia and preterm delivery, gestational age at delivery, birth weight, and maternal and cord blood lipid profile.

Four subjects in the placebo group developed preeclampsia compared to none in the pravastatin group.

This study provides preliminary safety and pharmacokinetic data regarding the use of pravastatin for preventing preeclampsia in high-risk pregnant women. Although the data are preliminary, no identifiable safety risks were associated with pravastatin use in this cohort.

 This favorable risk-benefit analysis justifies using pravastatin in a larger clinical trial with dose escalation.

References :

• https://www.researchgate.net/publication/235366972_Pravastatin_for_the_Prevention_of_Preeclampsia_in_High-Risk_Pregnant_Women [accessed Dec 23, 2015]

• Effects of Pravastatin on Human Placenta, Endothelium, and Women With Severe Preeclampsia.Hypertension. 2015;66:687-697, published online before print July 27 2015

• http://www.ncbi.nlm.nih.gov/pubmed/?term=Asif+Ahmed+%2C+pravastatin

• Costantine  M.M et al.Safety and Pharmacokinetics of Pravastatin Used for the Prevention of Preeclampsia in High-Risk Pregnant Women: A Pilot Randomized Controlled Trial.American Journal of Obstetrics and Gynecology, Volume null, Issue null, Page null

• http://hyper.ahajournals.org/content/early/2015/07/27/HYPERTENSIONAHA.115.05445.abstract

• Costantine MM et al. Pravastatin for the prevention of preeclampsia in high-risk pregnant women. Obstet Gynecol 2013 Feb; 121:349. (http://viajwat.ch/XVjnWQ)

• Ahmed A and Ramma W. Unravelling the theories of pre-eclampsia: are the protective pathways the new paradigm?British Journal of Pharmacology , Vol 172 Issue 6

• http://www.isshp.org/hunting-for-a-treatment-for-pre-eclampsia/

Forever Young--------- Secret to fountain of youth using ovarian tissue transplant to stall menopause

The dramatic increase in average life expectancy during the 20th century ranks as one of society’s greatest achievements. Most babies born in 1900 did not live past 50! But currently worldwide, the average life expectancy at birth is 71.0 years (68.5 years for males and 73.5 years for females) over the period 2010–2013 according to United Nations World Population Prospects.

Japanese women took the top spot in average life expectancy worldwide for the third consecutive year by living up to average age of 86.83 years. Women, who tend to outlive men, will comprise the bulk of the older adult population and it is predicted that women will live up to 100 by the year 2055.

According to National Institute on Aging, the “oldest old” (people aged 85 or older) constitute 8 percent of the world’s 65-and-over population: 12 percent in more developed countries and 6 percent in less developed countries.

Assuming the median age for the onset of menopause is 51; women will spend about 40 years in menopause deprived of naturally produced oestradiol and progesterone, leading to an increasing incidence of menopause-related disorders such as osteoporosis, dementia, neuromuscular degenerations, cardiovascular diseases and lack of general well-being.

Currently, exogenous oestradiol is being used in its various forms as a preventive as well as curative modality.

This article by Andersen  C.Y and Kristensen S.G in August issue of Reproductive Bio-Medicine Online  discusses a radical new method to postpone menopause. It is based on the hypothesis that ovarian cortical tissue freezing in order to permit future transplantation can become a possible option for a great number of women for postponing menopause and thus alleviating its sequelae.

The surplus ovarian follicles in youth could be cryopreserved, to be used after natural menopause

Currently the main use of ovarian tissue preservation is to preserve the fertility in patients with malignancy  but the endocrine potential of the preserved cryo tissue can be exploited for a more physiological solution to menopause related medical problems.

This appealing technology is already available, but it is to be seen whether it works to postpone menopause, possible in those patients who already have done ovarian preservation.

The ovaries of a newborn female contain a million eggs in the form of resting follicles. An average women will ovulate on an average 450 times from puberty to menopause, the rest 99.9% of eggs will undergo degeneration.

Many of the follicles constituting this enormous loss possess the ability for growth and development and hence sex-steroid secretion, but may not contain oocytes best suited for reproduction.

It is also known that a woman with one ovary is as fertile as women with both the ovaries, according to a large study by Lass et al, 1997 in Journal of Human Reproduction.

Two large studies by  (Bjelland et al, 2014, Yasui et al, 2012) also proved that the age of menopause is only one year earlier for women with one ovary as compared to her normal counterpart.

All the information about safety and efficacy of the re-transplanted ovaries comes from patients affected by cancer who cryopreserved ovarian tissue prior to gonadotoxic insults (chemotherapy or radiotherapy).

It is seen that menstruation cycle is reestablished in most patients with a clinical pregnancy rate of 30% is achieved.

Current experience from the author’s center shows that the re-transplanted ovaries functioned normally for 6-11 years. .

It is noticeable that tissue in these patients has been transplanted with the intention of providing fertility, which requires a larger pool of follicles (i.e. more tissue) to be transplanted than for providing menstrual cycles alone. Therefore the longevity of this tissue if the aim was to postpone menopause would probably be longer.

In addition, ovarian tissue will start to work in most places in the body and may be transplanted subcutaneously during local anaesthesia. In this way natural fertility will be avoided and will prevent senior women from becoming pregnant.

The risks associated with extending the menstrual cycle past the age of natural menstrual cycles may augment the risk for cancers like breast cancer? In recent years much of the risk of breast cancer due to MHT has been alleviated. What about the uterus and the cervix? Should hysterectomy and mastectomy be a part of ovarian transplantation to treat menopause in order to reduce the late-onset risks of cancer?

Careful consideration, individually tailored advice and close monitoring are needed for women who may want to use their ovarian tissue for postponing menopause.

Thousands of women worldwide have already had ovarian tissue frozen for fertility preservation due to different malignancies. For various reasons, a large number of these women will not have used their tissue by the time they reach menopause, either prematurely or at the expected time of menopause and will have tissue available for continued ovarian function. Some of them might want to use it for postponing menopause. They will indeed have this opportunity available without experiencing additional risks and may represent a group of patients in which initial results can be obtained.

Furthermore cryopreservation of isolated human pre-antral follicles is now also available which implies that a predetermined number of follicles may be transplanted in small alginate beads just a few microlitres in size.

Currently, the only use of ovarian cryopreservation is for fertility preservation, but in near future transplantation of frozen-thawed ovarian tissue may serve as a physiological solution to prevent the massive medical legacy of osteoporosis and other menopause-related disorders in the ageing population.

The unanswered questions at present are i) Does the grafted tissue carries a higher risk of malignancy? (ii)The functional integrity of the tissue in women who are menopausal? and (iii) How many women will be attracted to postponed menopause, with continued menstruation?

It is also thoughtful to think of other aspects of this procedure such as these patients sometimes have other co- morbidities that must be taken into account. Access to healthcare will be another challenge as well as whether it will be covered by insurance or not?

If proven successful, will it save billions of dollars in healthcare spending due to morbidities of menopause like CVD and osteoporosis?

The aim of this article was to open up a discussion about the new endeavor of technical opportunity to postpone menopause further? In the future, will it be possible to utilize the enormous loss of human follicles that naturally occur to avoid menopause for prolonged periods of time?

In principle the authors see no reasons why ovarian transplants to treat menopause ought not be pursued. But before going forward a large number of issues need to be addressed and the foremost is to show this form of transplantation is really a useful tool in alleviating the debilities associated with menopause without causing or exacerbating other health risks.

Only then it could be offered as therapy!

References:

• http://www.telegraph.co.uk/news/politics/11348561/Average-life-expectancy-heading-for-100.htm
• https://www.nia.nih.gov/research/publication/global-health-and-aging/living-longer
• http://www.japantimes.co.jp/news/2015/07/31/national/social-issues/japanese-women-top-life-expectancy-third-year/
• http://www.nhs.uk/news/2015/09September/Pages/UK-womens-life-expectancy-second-worst-in-Western-Europe.aspx
• https://www.google.com/?gws_rd=ssl#q=average+life+expectancy+in+world
• http://www.rbmojournal.com/article/S1472-6483%2815%2900249-7/fulltext
• Lass et al, 1997Lass, A., Paul, M., Margara, R., and Winston, R.M. Women with one ovary have decreased response to GnRHa/HMG ovulation protocol in IVF but the same pregnancy rate as women with two ovaries. Hum. Reprod. 1997; 12: 298–300
• Bjelland, E.K., Wilkosz, P., Tanbo, T.G., and Eskild, A. Is unilateral oophorectomy associated with age at menopause? A population study (the HUNT2 Survey). Hum. Reprod. 2014; 29: 835–841
• Yasui, T., Hayashi, K., Mizunuma, H., Kubota, T., Aso, T., Matsumura, Y., Lee, J.S., and Suzuki, S. Factors associated with premature ovarian failure, early menopause and earlier onset of menopause in Japanese women. Maturitas. 2012; 72: 249–255
• Donnez, J., Dolmans, M.M., Pellicer, A., Diaz-Garcia, C., Ernst, E., Macklon, K.T., and Andersen, C.Y. Fertility preservation for age-related fertility decline. Lancet. 2015; 385: 506–507
• Stoop, D., Cobo, A., and Silber, S. Fertility preservation for age-related fertility decline. Lancet. 2014; 384: 1311–1319
• Camboni, A., Van Langendonckt, A., Donnez, J., Vanacker, J., Dolmans, M.M., and Amorim, C.A. Alginate beads as a tool to handle, cryopreserve and culture isolated human primordial/primary follicles. Cryobiology. 2013; 67: 64–6

Effectiveness of semen washing to prevent human immunodeficiency virus (HIV) transmission and assist pregnancy in HIV-discordant couples: a systematic review and meta-analysis.

A systemic review and meta-analysis by Zafar M et al in a forthcoming edition of journal ‘Fertility and Sterility’ evaluated the effectiveness of semen washing in human immunodeficiency virus (HIV)–discordant couples in which the male partner is infected.

Primary outcome: HIV transmission to HIV-uninfected women.

Secondary outcomes: HIV transmission to newborns and proportion of couples achieving a clinical pregnancy.

Conclusion:

•  It was seen that No HIV transmission occurred in cycles of assisted reproduction with the use of washed semen.
• Among the subset of HIV-infected men without plasma viral suppression at the time of semenwashing, no HIV seroconversions occurred among after cycles of assisted reproduction with the use of washed semen.
•  Studies that measured HIV transmission to infants reported no cases of vertical transmission.
• Overall, 56.3% of couples achieved a clinical pregnancy with the use of washed semen.
• The study results are especially useful in low-income countries, especially those with a large burden of HIV. Integration of semen washing into HIV prevention interventions could help to further reduce the spread of HIV

A hope that Ovarian Cancer screening may save lives!

A hope that Ovarian Cancer screening may save lives!

Each year, about 20,000 women in the United States get ovarian cancer.

Ovarian cancer accounts for approximately three percent of cancers in women. Ovarian cancer ranks fifth in cancer deaths among women, accounting for more deaths than any other cancer of the female reproductive system.

A woman’s lifetime risk of developing invasive ovarian cancer is 1 in 75. A woman’s lifetime risk of dying from invasive ovarian cancer is 1 in 100.

Ovarian cancer rates are highest in women aged 55-64 years. The median age at which women are diagnosed is 63, meaning that half of women are younger than 63 when diagnosed with ovarian cancer and half are older.

Ovarian cancer has a poor prognosis, with just 40% of patients surviving 5 years.

image courtesy: seers data

The American Cancer Society estimates for ovarian cancer in the United States for 2015 are:

•     About 21,290 women will receive a new diagnosis of ovarian cancer. 
•   About 14,180 women will die from ovarian cancer.

 A paper published on-line in Lancet on December 17, 2015, gives us the first evidence that screening can save lives from ovarian cancer as a paradigm shift in our approach to the disease.

UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) is a Randomized control trial which recruited more than  200,000  postmenopausal women aged 50–74  from June 2001 to October 2005

The women were assigned to one of the following three groups in the ratio of 1:1:2

• 50,624 underwent annual multimodality screening, which consisted of a serum cancer antigen 125 (CA125) test interpreted with the risk of ovarian cancer algorithm (ROCA) plus ultrasound;
• 50,623 underwent annual transvaginal ultrasound screening alone;
• 101,299 underwent no screening.

The women in 13 centers in UK followed for nearly 14 years with a median of 11.1 year.  

Annual screening in the MMS group used serum CA125 concentration testing, with the pattern over time interpreted with use of the risk of ovarian cancer calculation ( ROCA), which identifies significant rises in CA125 concentration above baseline.

Next, ROCA triaged women to normal (annual screening), intermediate (repeat CA125 concentration testing in 3 months), and elevated (repeat CA125 concentration testing and

transvaginal USS as a second-line test in 6 weeks) risk

Annual screening in the USS group used transvaginal USS as the primary test, which was classified as normal (annual screening), unsatisfactory (repeat in 3 months), or abnormal (scan with a senior ultrasonographer within 6 weeks).

In both groups, women with persistent abnormalities had clinical assessment and additional

investigations within the NHS by a trial clinician.

The primary outcome was ovarian cancer death by Dec 31, 2014, secondary outcome was death due to ovarian and primary peritoneal cancer. 

At a median follow-up of 11.1 years (interquartile range, 10.0 - 12.0), ovarian cancer had been diagnosed in 1282 (0.6%) women — 338 (0.7%) in the multimodality group, 314 (0.6%) in the ultrasound group, and 630 (0.6%) in the no-screening group.

When the researchers analyzed the 14-year data, they found a reduction in the rate of death from ovarian cancer of 15% (95% confidence interval [CI], –3 to 30; P = .10) in the multimodality group and of 11% (95% CI, –7 to 27; P = .21) in the ultrasound group.

The screening test involves a simple blood test, which can be done anywhere and sent to a lab," he said. This could have an effect on the more than 100,000 deaths from ovarian cancer each year around the world.
Overall, there was an average reduction in mortality of 20% in favor of multimodality screening. The reduction in mortality was 8% in the first 7 years and 28% in the subsequent 7 years.

Cancer was detected at an early stage in more patients in the multimodality group than in the no-screening group (39% vs 26%; P < .0001).

Experts opinions on the trial 

This is the first-ever evidence to suggest that screening for early detection of ovarian cancer may save lives," said Ian Jacobs, MD, president and vice-chancellor of the University of New South Wales in Sydney, Australia , in a news bulletin.

"More follow-up is needed, but the results are encouraging and exciting and open up the possibility that many lives could be saved," said Dr Jacobs, who led the trial with Usha Menon, MD, from the Institute for Women's Health, University College London, United Kingdom.

"Research now needs to accelerate to refine screening and confirm the benefit, so that, in due course, widespread national screening programs can be put in place," Dr Jacobs said.

"We have the first evidence that ovarian cancer screening can save lives, but we need further follow-up to confirm the findings," added Dr Menon.

"However, screening is not without harms, which include some women undergoing surgery to find they only have benign ovarian lesions or normal ovaries," she told Medscape Medical News.

Experts agree that longer follow-up is needed to determine how effective annual screening will turn out to be.
"Although still at an early stage, the initial results from the UKCTOCS trial into screening for ovarian cancer are promising," Clare Mckenzie, MD, consultant gynecological oncologist and vice president of the Royal College of Obstetricians and Gynaecologists, said in a statement.

Gary S. Leiserowitz, MD, professor and chair of the Department of Obstetrics and Gynecology, and chief of the division of gynecologic oncology at the University of California Davis Health System in Irvine commented that  "Two other studies — one from Japan and the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial from the United States — were smaller, and neither showed statistically significant benefits to large-scale ovarian cancer screening. The UK trial showed some evidence of early detection with both multimodality and ultrasound, plus moderate reduction of mortality using post hoc statistical analyses. The effects were greater with longer follow-up."

So far, results suggest that approximately 15 deaths could be prevented with CA125 screening for every 10,000 women screened, Dr Mckenzie noted. "However, for every woman with a positive screen who underwent surgery and was found to have ovarian cancer, two did not," she added.

Karen H. Lu, MD, chair of gynecologic oncology and reproductive medicine at the University of Texas M.D. Anderson Cancer Center in Houston said that “I believe that while the results from UKCTOCS are not practice-changing right now, they have a very real potential of being practice-changing in the near future."

Conclusion.

Key strengths of this trial include scale, with more than 202000 participants, more than 670000 annual screening episodes, and more than 2·19 million women-years of  follow-up; the multicentre setting within the UK NHS.

The main limitation of this trial was failure to anticipate the late eff ct of screening in the statistical design.

Implications of all the available evidence --Our findings suggest that a multimodal approach to screening might detect ovarian cancer sufficiently early to reduce mortality. To establish the magnitude of this reduction in deaths, a longer duration of follow-up is needed. Meanwhile, efforts to refine ovarian cancer screening strategies should continue.

References:
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2815%2901224-6/abstract
http://www.cdc.gov/cancer/ovarian/statistics/
http://www.ovariancancer.org/about/statistics/
http://www.cancer.org/cancer/ovariancancer/detailedguide/ovarian-cancer-key-statistics
http://www.medscape.com/viewarticle/856099#vp_1

Guidelines advocate a more tailored approach in management of Menopause!

Guidelines advocate a more tailored approach in management of Menopause!

photo courtesy -dreams time

The evaluation and treatment of menopause has undergone a sea change in last two decades, but this was not always backed up by evidence.

The Endocrine Society has updated the latest guidelines, and the recommendations are all backed by solid clinical research. The guidelines were published online October 7 and appeared in the November issue of the Journal of Clinical Endocrinology & Metabolism.

The article is primarily derived from the journal article “Treatment of Symptoms of the Menopause: An Endocrine Society Clinical Practice Guideline.” In the November issue of The Journal of Clinical Endocrinology & Metabolism 2015 100:11, 3975-4011

In 2002, a large government study called the Women’s Health Initiative study generated intense scrutiny on the practice of menopausal hormone therapy due to concerns about increased risk for blood clots, stroke, breast cancer and heart attacks. Since then, physicians all over the world are very cautious in prescribing hormones as a therapy for management of menopausal symptoms.

The guidelines advocates that the individual risk is lower in younger women who have recently gone through menopause, and varies based on a woman’s health history, age and other factors. Developed by Endocrine Society menopause experts, the guideline provides recommendations on how to tailor treatments to suit a woman’s individual symptoms, health history and preferences and how to assess which women could consider menopausal hormone therapy.

The guidelines were developed by a panel of six experts on the subjects and were chaired by Cynthia Stuenkel, MD. She is a founding member of The North American Menopause Society (NAMS) and also a clinical professor of medicine at the University of California, San Diego School of Medicine and an attending physician for the university’s Endocrinology and Metabolism Service.

“There is no need for a woman to suffer from years of debilitating menopausal symptoms, as a number of therapies, both hormonal and non-hormonal are now available,” said Cynthia A. Stuenkel, MD, in a press release .She also said that “Every woman should be full partners with her health care providers in choosing whether treatment is right for her and what treatment option best suits her needs. The decision should be based on available evidence regarding the treatment’s safety and effectiveness, as well as her individual risk profile and personal preferences.”

Women are eligible for HRT if they are younger than 60 years old and are no more than 10 years into menopause, Dr Stuenkel emphasized.

Before putting a patient on Menopausal Hormone Therapy (MHT), clinicians need to assess a patient's baseline risk for cardiovascular disease or breast cancer -- a high risk for either condition can constitute a contraindication to use of HRT.
Standard cardiovascular disease risk-assessment scores from organizations such as the American Heart Association has Standard cardiovascular disease risk-assessment scores for women who are at moderate or low risk for cardiovascular events; women falling into both of these categories can be considered for HRT.
 National Cancer Institute Breast Cancer Risk Assessment Tool is utilized by clinicians to calculate a woman's 5-year risk for invasive breast cancer, whereas the International Breast Intervention Study calculator predicts a woman's 10-year and lifetime risk.
The Updated guidelines specifically targets vasomotor symptoms (hot flushes/flashes/night sweats) and genitourinary tract symptoms (vaginal dryness or discharge, pain, burning or itching, urinary frequency, recurrent urinary tract infections).
Menopausal symptoms typically start a year before the last period and can be very bothersome for unpredictable time period; it could be as little as few months or 10-14 years after the last period.
"The most effective therapy [for both sets of symptoms] is HRT," Dr Stuenkel said.
"But we have listed many other nonhormonal and over-the-counter [OTC] options that physicians can use as well, and each of these options can be discussed with patients."
Current evidence does not justify the use of MHT to prevent coronary heart disease, breast cancer, or dementia.
These guidelines emphasize safety in identifying which late perimenopausal and recently postmenopausal women are candidates for various therapeutic agents.
Dr Stuenke advocates that women for HRT can receive estrogen replacement alone if they are without a uterus; if women have a uterus, they require the combination of estrogen plus progestogen to prevent endometrial hyperplasia and cancer.
Additional hormonal options for women with a uterus include estrogen combined with bazedoxifene and tibolone where available.
Women in the United States and some other countries have a broader range of therapeutic choices than ever before, including: MHT dose, type, and route of administration; new selective estrogen receptor modulators (SERMs) as solo or combination therapies; and expanded choices of nonhormonal prescription medications.
Other medical options recommended by the Endocrine Society include

• Transdermal estrogen therapy by patch, gel or spray is recommended for women who request menopausal hormone therapy and have an increased risk of venous thromboembolism – a disease that includes deep vein thrombosis.
• Progestogen treatment prevents uterine cancer in women taking estrogen for hot flash relief. For women who have undergone a hysterectomy, it is not necessary.
• If a woman on menopausal hormone therapy experiences persistent unscheduled vaginal bleeding, she should be evaluated to rule out endometrial cancer or hyperplasia.
• Medications called selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), gabapentin or pregabalin are recommended for women who want medication to manage moderate to severe hot flashes, but either prefer not to take hormone therapy or have significant risk factors that make hormone therapy inadvisable.
• Low-dose vaginal estrogen therapy is recommended to treat women for genitourinary symptoms of menopause, such as burning and irritation of the genitalia, dryness, discomfort or pain with intercourse; and urinary urgency or recurrent infections. This treatment should only be used in women without a history of estrogen-dependent cancers.

Impact on quality of Life

The impact of severe menopausal symptoms on quality of life may be substantial," Dr Stuenkel noted.
In light of this, there are circumstances under which a woman with a history of coronary artery disease or even breast cancer might choose to accept a degree of risk that initially might outweigh the benefits of HRT.
Nevertheless, patients should be fully informed about the risks and benefits associated with HRT to enable them to make a decision that best balances these risk and benefits, Dr Stuenkel emphasized.
"We in the Endocrine Society were dismayed by the incredible drop-off in the use of HRT [following the Women's Health Initiative study]," she noted.
A 2012 Endocrine Society survey found that 72% of women currently experiencing menopausal symptoms had not received any treatment for them.
"And while we don't blame the average clinician for being confused or frustrated by all the contradictory data that have emerged over the past decade, we wanted to take a strong stance to simplify these data and to say that in carefully selected women, HRT will be the most effective therapy we have for menopausal symptoms," Dr Stuenkel added.
"So...the data we present in our guidelines help substantiate why HRT is a reasonable approach for carefully selected women, and physicians should be revisiting this question annually with their patients to discuss their decision regarding HRT and perhaps modify it if other health concerns have arisen in the preceding year."

Stopping the MHT

The guidelines also state that the approach to discontinuation of HRT is an individual choice, too.
Menopausal symptoms and joint pain can recur when HRT is discontinued, and depending on the severity of the symptoms, women may elect to restart HRT, perhaps at a lower dose, or seek relief with nonhormonal therapies.
"Anecdotally, some women find that a very low dose...maintains adequate symptom relief and well-being and prefer that to complete discontinuation," state the recommendations.
Resources for patients are available at www.menopausemap.org. The Hormone Health Network also offers a digital toolkit for healthcare providers.

Summary of Recommendations

·        The clinical symptoms, menstrual history, history of surgery (Hysterectomy with Bilateral oophorectomy) are sufficient to make the diagnosis of menopause for the majority of women. Laboratory studies are not a prerequisite for the diagnosis but may be used when necessary.

·        Menopausal Transition is also a good time for addressing other health issues   such as bone health, smoking cessation, alcohol use, cardiovascular risk assessment and management, and cancer screening and prevention.

·        For menopausal women < 60 years of age or < 10 years past menopause with bothersome VMS (with or without additional climacteric symptoms) who do not have contraindications or excess cardiovascular or breast cancer risks and are willing to take menopausal hormone therapy (MHT), the study suggest initiating estrogen therapy (ET) for those without a uterus and estrogen plus progestogen therapy (EPT) for those with a uterus.

·        Women at high risk for CVD, should receive nonhormonal therapies to alleviate bothersome VMS (with or without climacteric symptoms) over MHT.

·        Women at moderate risk  for CVD should  be started on transdermal estradiol as first-line treatment, alone for women without a uterus or combined with micronized progesterone(or another progestogen that does not adversely modify metabolic parameters) for women with a uterus, because these preparations have less untoward effect on blood pressure, triglycerides, and carbohydrate metabolism.

·        Non-oral estrogen is also preferred in the treatment of menopausal women with an elevated risk for venous thromboembolic disease. These patients should also receive a progestogen, such as progesterone or dydrogestone, which is more neutral in its effects on coagulation.

·        Women at high or intermediate risk of breast cancer considering MHT for menopausal symptom relief, the guideline suggest nonhormonal therapies over MHT to alleviate bothersome VMS.

·        The treatment plan should be reviewed annually, estimating the risk and benefits.

·        The taskforce also called on physicians to advise women about the uncertainty of over the counter medicines for menopause.

·        The study also  recommend informing women about the possible increased risk of breast cancer during and after discontinuing EPT and emphasizing the importance of adhering to age-appropriate breast cancer screening.

·        For young women with primary ovarian insufficiency (POI), premature or early menopause, without contraindications, we suggest taking MHT until the time of anticipated natural menopause, when the advisability of continuing MHT can be reassessed.

·        Stopping the MHT should be a shared decision-making approach to elicit individual preference about adopting a gradual taper vs abrupt discontinuation.

·        For women seeking pharmacological management for moderate to severe VMS for whom MHT is contraindicated, or who choose not to take MHT, we recommend selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) or gabapentin or pregabalin (if there are no contraindications).In  women not responding to these drugs  a trial of clonidine is suggested.

·        This new term “genitourinary syndrome of menopause” (GSM) combines the conditions of VVA and urinary tract dysfunction.

• Women with symptoms of vulvovaginal atrophy may be treated initially with a trial of vaginal moisturizers at least twice weekly. Low-dose vaginal estrogen therapy can be introduced if initial treatment is insufficient.
• Women with a history of endometrial or breast cancer may initiate treatment with vaginal estrogen therapy, but this decision-making process should involve the treating oncologist.
• Low-dose vaginal estrogen therapy does not require co-treatment with a progestogen.

·        Women with moderate to severe dyspareunia and vaginal atrophy may be offered a trial of ospemifene, which has been demonstrated to reduce dyspareunia and improve sexual satisfaction in randomized controlled trials.

·        Diabetes is considered by the AHA to be a CHD risk equivalent , which would suggest that women with diabetes should not take MHT. The evidence at this time is inadequate to make firm recommendations. An individualized approach to treating menopausal symptoms could be considered, with a low threshold to recommend nonhormonal therapies, particularly in women with concurrent CVD.

The Hormone Health Network, the Endocrine Society’s public education arm, developed an interactive digital resource called the Menopause Map^TM for women to explore the stages of menopause and learn about symptoms they may experience. The Menopause Map^TM related resources are available at
http://www.hormone.org/menopausemap/postmenopause.html

The Hormone Health Network also offers a digital toolkit for health care providers.

References :
http://press.endocrine.org/doi/citedby/10.1210/jc.2015-2236
http://www.medscape.org/viewarticle/853793
https://www.endocrine.org/membership/email-newsletters/endocrine-insider/2015/october-16-2015#/9
http://menopausehealthmatters.com/hormone-replacement-therapy/
http://answers.webmd.com/expert/39928/cynthia-stuenkel-north-american-menopause-society
https://www.endocrine.org/news-room/current-press-releases/experts-recommend-assessing-individual-benefits-risks-of-menopausal-therapies