Microbirthing: The " Vaginal Seeding" is growing fad, but thin evidence concerns physicians!

Every 4^th baby in UK is born by Caesarean Section. Parents of the Caesar babies are requesting a procedure called as ‘microbirthing’ or ‘vaginal seeding’.

Vaginal seeding involves taking a swab from mother’s vagina and swabbing it over babies face, eyes, mouth and skin immediately after caesarean birth.

This article is based on recent editorial in BMJ (BMJ 2016; 352:i227) by Cunnington A.J. et al “Vaginal seeding” of infants born by caesarean section. How should health professionals engage with this increasingly popular but unproved practice?

Our body is colonized with millions of microbes, collectively called as microbiota. They outnumber our cells by 10:1. The microbiota varies according to parts of our body and also person to person. As described by microbiology professor Graham Rook at University College London, we are designed to live in nature’s biodiverse ecosystem encountering our old microbial friends as part of our early immune education.

During the process of vaginal birth, specific species of good bacteria are transferred to the baby during and immediately after birth via the birth canal, immediate skin-to-skin contact and breastfeeding. This is the seeding of the baby's microbiome. The process heralds the training of baby’s immune system to recognize between ‘good’ and ‘bad’ bacteria and protect the neonate from diseases now and also in future.  Large epidemiological studies and reviews have concluded that babies delivered by C-section have moderately high risk of obesity, asthma, and autoimmune diseases, these  diseases being associated with alteration in microbiota.

For babies entering this world via a C-section, this microbial transfer from the mother to baby is interfered with or bypassed completely. According to the latest research if the baby is not seeded with mother’s bacteria, it can have significant health consequences. Dr Rodney R Dietert, Professor of Immunotoxicology at Cornell University says “Over the past 20-30 years, we've seen dramatic increases in childhood asthma, type 1 diabetes, coeliac disease, childhood obesity. We've also seen increases in Caesarean delivery. Does Caesarean cause these conditions? No. What Caesarean does is not allow the baby to be seeded with the microbes. The immune system doesn't mature, and the metabolism changes. It's the immune dysfunction and the changes in metabolism that we now know contribute to those diseases and conditions.”

So, many researchers advocate that even if vaginal birth is not possible, immediate skin to skin contact and breast feeding should be initiated.

A new documentary “MICROBIRTH” warns how our children are born could have serious repercussions for their lifelong health. “Microbirth” is a new sixty minute documentary looking at birth in a whole new way: through the lens of a microscope. Investigating the latest scientific research, the film reveals how we give birth could impact the lifelong health of our children. http://microbirth.com

In spite of all the hypotheses, we lack scientific proof at present. The newborn may be at risk of developing infection, being exposed to vaginal commensals that the mother maybe harboring without any symptoms. These include group B streptococcus (the most common cause of neonatal sepsis), herpes simplex virus, Chlamydia trachomatis, and Neisseria gonorrhoeae (the last two, causes of ophthalmia neonatorum). These pathogens may also be transferred on a vaginal swab, potentially voiding the protection offered by elective caesarean section.

Clinically we are aware of only one clinical trial going on, called as Potential Restoration of the Infant Microbiome (PRIME) trial. That study is expected to be completed in February, 2019.It is looking at the neonatal microbiota according to mode of birth, the women being screened beforehand for potential pathogens.

Dr. Cunnington, who is the lead author of the article, affirms the lack of sufficient evidence to put vaginal seeding into routine practice. Studies need to be sufficiently large, randomized and need follow up of many years before a recommendation can be made.  

In a statement Dr Cunnington says: "Demand for this process has increased among women attending hospitals in the UK - but this has outstripped professional awareness and guidance. At the moment we're a long way from having the evidence base to recommend this practice. There is simply no evidence to suggest it has benefits - and it may carry potential risks." He also believes in fully informing the risks and harm of this simple procedure to the patients who are demanding it.

He also emphasizes that there are other ways of   influencing baby’s microbiota at birth and “Encouraging breast feeding and avoiding unnecessary antibiotics may be much more important than worrying about transferring vaginal fluid on a swab.”

References:

http://www.criver.com/about-us/eureka/blog/april-2014/early-immune-education

http://articles.mercola.com/sites/articles/archive/2014/12/27/seeding-baby-microbiome.aspx

http://www.actionbioscience.org/genomics/the_human_microbiome.html

http://www.nytimes.com/2013/08/29/science/human-microbiome-may-be-seeded-before-birth.html?_r=0

http://www.huffingtonpost.co.uk/toni-harman/microbirth-babys-mircobiome_b_4947959.html

https://clinicaltrials.gov/show/NCT02407184?link_type=CLINTRIALGOV&access_num=NCT02407184

                                          

Vaginal Ring: Could it be a potential option for HIV prevention?

Currently 35million persons are living with HIV-1 infection and about half of them are women. The majority of these live in sub Saharan Africa, which has the highest incidence of HIV infection in any given population.

Using antiretroviral (tenofovir ) as pre exposure prophylaxis ( PrEP) in the form of  pills and vaginal gel  is assuring  approach against fight against  HIV, but patient compliance is very poor and protection was not shown.

Vaginal rings containing exogenous hormones for contraception (Nuvaring ) and HRT are licensed and in use since long and provide a sustained and control release of medication.

The results of two studies were presented at Conference on Retroviruses and Opportunistic Infections (CROI) from February 22 to February 25, 2016,   in Boston, Massachusetts.

One of the study (ASPIRE study) was published today in New England Journal of Medicine and the result of other study( Ring study) was presented as an abstract in the conference.

The trials evaluated the safety and efficacy of a monthly vaginal ring (Ring-004), containing 25 mg of Antiretroviral (ARV) dapivirine, which women placed themselves and replaced each month.

Both the dapivirine and placebo rings were manufactured by QPharma under contract with the International Partnership for Microbicides.

Both studies were double blind randomized placebo controlled trials. The ASPIRE study enrolled 2629 healthy, sexually active, nonpregnant, HIV-1–seronegative women between the ages of 18 and 45 years at 15 research sites in Malawi, South Africa, Uganda, and Zimbabwe women: 1313 in the dapivirine group and 1316 in the placebo group.

In the ring study 1959 women (1762 in South Africa and 197 in Uganda) were randomized in a 2:1 ratio to receive either a dapivirine ring or a placebo ring.

In both studies,the primary efficacy end point was HIV-1 infection, identified with the use of a standard seroconversion algorithm and the primary safety endpoint was incidence of adverse events (AEs).

In both trials the ring was found to be effective in reducing the incidence of HIV-1 infection by 27% (ASPIRE study) and 31% ((Ring study). Both study found that in women less than 21 years of age, the risk of acquiring the infection was not much decreased; probably the women were not compliant enough.

Compliance is also a big issue with the Truvada (Tenofovir disoproxil/emtricitabine), the once a day oral PrEP. Studies have found it to be effective in preventing infection in 92% of cases, but adherence to daily regimen is a problem.

The ring adds a new tool in HIV prevention armament, which could be used discreetly by women, without asking her male partner to use protection. It is especially useful in African countries were women are at highest risk. In the study about 1 in 3 infection were prevented.

The ring is also cost effective, costing only $5 as compared to other PrEP which costs thousands of dollars. Although it is not in the market yet, it gives a lot of hope and optimism for HIV prophylaxis.

Reference:

http://www.avac.org/press-release/first-evidence-vaginal-ring-hiv-prevention

http://www.nejm.org/doi/full/10.1056/NEJMoa1506110#t=articleDiscussion

http://www.healthnewsreview.org/review/vaginal-ring-for-hiv-prevention-small-details-would-have-elevated-good-coverage-to-great/

http://www.croiconference.org/sessions/safety-and-efficacy-dapivirine-vaginal-ring-hiv-1-prevention-african-women

Talc powder and ovarian cancer! Does evidence prove causation?

Recently a Missouri jury has awarded $72 million to the family of an Alabama woman who died from ovarian cancer in October 2015, which she said was caused by using Johnson & Johnson's baby powder and other products containing talcum powder.

The jury found Johnson & Johnson guilty of negligence, and conspiring to hide facts by not issuing a warning on the product used.

The general public has spoken in favor of the women but, does evidence linking use of the talcum powder as feminine hygiene product and development of ovarian cancer exist in studies and clinical research?

Talcum powder is made from talc, a mineral made up mainly of the elements magnesium, silicon, and oxygen. As a powder, it absorbs moisture well and helps cut down on friction, making it useful for keeping skin dry and helping to prevent rashes.

Since early 1980s, a few studies have found that women who regularly used talc powder for feminine hygiene had higher than average rates of ovarian cancer. Yet the evidence–which fell short of proving causation–was mostly confined to medical journals, and not known to general public.

According to an article published in Journal of  Toxicology and  Environmental Health 1976 Nov;2(2):255-84, researchers at Mount Sinai Hospital in New York published test results  on 20 talc-based consumer products, including baby and facial powders. All the formulations were before 1973. Of the 20 products 10 contained detectable amounts of tremolite and anthophyllite, principally asbestiform, while some also contained fragmented forms of these minerals They found two types of asbestos, tremolite and  anthophyllite, in 10 of the 20 products.

Before the 1970s, talcum powder was often contaminated with asbestos fibres which are known to cause cancer. But since then, all home products containing talcum powder are legally obliged to be asbestos-free.

J &J claims that all its talcum products are free of talc and are manufactured according to strict US pharmacopoeia standard.

Dr. Daniel Cramer, MD, ScD, an obstetrician/gynecologist at Brigham and Women's Hospital and Harvard Medical School in Boston and a prominent researcher in this field opines that talc does cause ovarian cancer. He was the first to link talc with ovarian cancer in his pilot study published in 1982.

He has recently published a paper in Epidemiology journal December 2015 issue, citing over 20 well executed case-control studies that support this association. In this article he has established a dose –response relationship with the trend increasing as number of years of talc use accrues. According to him “Subtypes of ovarian cancer more likely to be associated with talc included invasive serous and endometrioid tumors and borderline serous and mucinous tumors”.

Many other control studies have documented a 30% increase in risk of ovarian cancer, but the single cohort study done has not documented causation.

Due to this inconclusive research evidence, talcum powder is classified by the InternationalAgency for Research on Cancer (IARC) aspossibly carcinogenic (cancer causing) to humans when applied to the genital area. IARC is a part of the World Health Organisation which convenes international expert working groups to evaluate the evidence of the carcinogenicity of specific exposures.

While the American Cancer Society says “It is not clear if consumer products containing talcum powder increase cancer risk”.

Many research papers and epidemiology studies have specifically evaluated talc and perineal use and these studies have found talc to be safe. For example, the Nurses’ Health Study (2010)2 and the Women’s Health Initiative Observational Cohort (2014)3 are two large-scale prospective studies looking at talc and ovarian cancer. Both found no causal relationship between talc and ovarian cancer.” Both these studies were criticized insufficient exposure to the talc powder.

Meanwhile the J& J spokesperson Carol Goodrich said, "We sympathize with the plaintiff's family but firmly believe the safety of cosmetic talc is supported by decades of scientific evidence." The company is expected to appeal the ruling.

The possible mechanism of cancer causation by the talc is chronic inflammation. Very small particles of talc migrate from vagina to the upper genital tract. In fact, Jackie Fox, whose ovarian cancer prompted the court case in St Louis, had talc found in her surgically removed ovaries, according to news reports.

The American Cancer Society advises the consumers to use corn starch based products, until a definite answer to the role played by talcum powder in ovarian cancer causation is found.

The US National Toxicology Program (NTP) is formed from parts of several different government agencies, including the National Institutes of Health (NIH), the Centers for Disease Control and Prevention (CDC), and the Food and Drug Administration (FDA). The NTP has not fully reviewed talc (with or without asbestos) as a possible carcinogen.

Further research is needed to determine whether and how talcum powder might increase the risk of ovarian cancer.

References:

http://www.cancerresearchuk.org/about-cancer/causes-of-cancer/cancer-controversies/cosmetics-and-toiletries#Cosmetics2

http://www.safetyandcarecommitment.com/ingredient-info/other/talc

http://www.cancercouncil.com.au/86105/cancer-information/general-information-cancer-information/cancer-questions-myths/clothing-cosmetics-tattoos/there-is-inconclusive-evidence-that-using-talcum-powder-can-cause-cancer/

http://journals.lww.com/epidem/pages/articleviewer.aspx?year=9000&issue=00000&article=99086&type=abstract

http://www.cancer.org/cancer/cancercauses/othercarcinogens/athome/talcum-powder-and-cancer

Large randomized trial does not support the use of progesterone in recurrent miscarriage.

Recurrent miscarriage affects about 1% of all women of child bearing age.

50% of all early pregnancy loss are due to chromosomal aberration, most common being aneuploidy.  

Progestogens play an important role in implantation, cytokine balance, natural killer cell activity, arachidonic acid release and myometrial contractility. It is secreted by corpus luteum till 7-8 weeks, when the function is taken over by developing placenta. Lack of progesterone support in the luteal phase increases the chances of early pregnancy loss; hence progesterone is often used specially in women with history of recurrent pregnancy loss!

Results of a recent large RCT published in the November issue of  New England Journal of Medicine concluded that Progesterone Doesn't Improve Outcomes After Recurrent Miscarriages.

This large multicenter, double-blind, placebo-controlled, randomized trial recruited 1568 women aged 18-39 years with a history of three or more consecutive or nonconsecutive first-trimester pregnancy losses. Women with anatomical, medical or hematological causes that explain the reason behind miscarriages were excluded from the study.

The study group (n=404) were assigned to receive 400mg of vaginal micronized progesterone , while the control group ( n=432) received a similar looking placebo as soon as the pregnancy were confirmed till 12 weeks of naturally conceived pregnancy.

The live birth rate in progesterone group was 65.8% vs. 63.3% in placebo group. The rate of ectopic pregnancy, congenital anomalies, miscarriage and still birth rates were also comparable in both the groups.  

A Cochrane review in 2013 based on smaller number of trials and subject reported lower rate of miscarriage with progesterone support. This large RCT lead us to a different conclusion.

Management of women with RPL is a challenge in itself, as these women are very anxious and apprehensive and ask for some form of ‘therapy’ to avert a loss again. Over the years many other modalities like heparin, aspirin and acupuncture have been evaluated with mixed results.

There are many unanswered question in therapy of RPL, including the definition of RPL, the evaluation and the timing of starting treatment. Progesterone is an important part of regimen offered, being having endometrial supportive and immune-modulating effects.

Different studies have come up with different results; the study also differed in patient population, mode and type of progesterone and the initiation of treatment since pregnancy confirmation.

Whatever the results and conclusions of different trials may be, the psychological and placebo effect of the progesterone cannot be overlooked for patients who have a high level of anxiety and are afraid of another loss.

References:

http://www.ncbi.nlm.nih.gov/pubmed/26677905

http://www.medscape.com/medline/abstract/22503277

http://www.nejm.org/doi/full/10.1056/NEJMoa1504927

http://www.ncbi.nlm.nih.gov/pubmed/24173668

ACOG committee opines in favor of using vaginal estrogen in Breast Cancer Survivors.

The American College of Obstetricians and Gynecologists’ (ACOG) Committee on Gynecologic Practice advocated in favor of using vaginal estrogen in  breast cancer survivors in forthcoming march issue of  Obstetrics & Gynecology: (March 2016 - Volume 127 - Issue 3 - p e93–e96) .

In general population, systemic and vaginal estrogen preparations are in wide use for relief of vasomotor symptoms, Lower UTI, vaginal atrophy and dysparunia.

However, some cancers are hormone sensitive creating a safety issue specially in those patients who have breast cancer or are breast cancer survivors.

Healthcare providers are becoming increasingly aware of the need to address female-specific survivorship issues especially the urogenital symptoms arising due to hypoestrogenic state because of cancer surgeries or natural menopause in survivors.

Nonhormonal methods like moisturizers, lubricants, and topical anesthetics, are always the  first-line of treatment   for urogenital symptoms or atrophy-related urinary symptoms experienced by women during or after treatment for breast cancer but in some women these treatment have temporary or limited effect.

Studies have shown that low dose vaginal estrogen are devoid of systemic side effects caused by oral preparations, because of minimum absorption and levels attained in blood comparable to natural menopause.

Options include creams, ring and vaginal tablets. The data regarding 17β-estradiol (commonly referred to as estradiol) cream is more robust than data on creams with conjugated equine estrogen because of heterogeneity of the formulation.

Controversy exists in use of vaginal estrogen in those women with breast cancer using aromatase inhibitor. Such women may benefit from the short-term use of estrogen to improve symptoms, followed by a return to normal aromatase inhibitor therapy for the duration of the treatment course.  On the other hand women on Tamoxifen can safely use vaginal estrogen preparation.

The committee also advocates that treatment should be tailored to each patient depending upon the need, therapy received and hormonal status of the cancer cells.

The treatment should always be initiated in coordination with the woman’s oncologist. It should also be preceded by informed decision making explaining the risk benefit ratio.

When a final decision regarding prescription is made, it should be prescribed in the lowest dose to relieve vaginal symptoms and for minimum amount of time.

References:

http://journals.lww.com/greenjournal/Fulltext/2016/03000/Committee_Opinion_No__659___The_Use_of_Vaginal.43.aspx

Leptin as a biomarker in assisted reproductive cycles!

Leptin is an adipose tissue hormone regulating the food intake and energy production in humans, with a role in female reproductive functions. This hormone also plays a crucial role in animal and human studies conducted to elucidate the mechanism behind infertility in obese individual.

A review published in forthcoming issue of Human Reproduction Update  aims to provide a perspective of physiological role of leptin, the role it plays in human reproduction and its role as a prognostic predictor of IVF outcome. All the articles  published in PubMed till January 2015  with keywords: leptin, reproduction, infertility, IVF and controlled ovarian stimulation were included.

Human and animal studies showed that leptin levels communicate with CNS regarding the nutritional status. It plays a role in reproductive function by its direct action on ovaries and indirectly by its action on CNS.

The review also confirmed the earlier assumption that high leptin serum /or follicular fluid leptin concentrations have correlated negatively with cycle outcome.

It is seen that high follicular fluid leptin (FFL) levels were associated with abdominal obesity, insulin resistance, and a lower live birth rate after IVF-ICSI.  Many studies have associated high leptin levels with poor oocyte and embryo quality, resulting in poor IVF outcome.

Circulating leptin levels are strongly correlated with obesity, which is frequently associated with polycystic ovarian syndrome (PCOS), a major form of dysovulatory infertility in women, characterized by endocrine abnormalities such as hyperandrogenism and inappropriate LH secretion.

Thus it is seen that leptin plays an important role in nutritional status, energy production and reproduction mainly through its action on hypothalamic-pituitary-ovarian function. Further investigations are warranted to define its precise role at cellular and molecular levels in obesity, and insulin resistance on IVF-ICSI outcomes. Its role as biomarker in predicting the IVF outcome also seems promising but needs larger data before it is routinely used!

References: 

https://humupd.oxfordjournals.org/content/early/2015/12/08/humupd.dmv057.abstract 

http://www.ncbi.nlm.nih.gov/pubmed/23919188

http://www.ncbi.nlm.nih.gov/pubmed/26644849

http://www.ncbi.nlm.nih.gov/pubmed/25439803

Abnormal Uterine Bleeding (AUB)

Abnormal Uterine Bleeding (AUB) also called as dysfunctional uterine bleeding is a common problem especially at the beginning and end of the reproductive years affecting 14–25% of women.

An orderly approach using the International Federation of Gynecology and Obstetrics

(FIGO) PALM-COEIN (Polyp, Adenomyosis, Leiomyoma, Malignancy (and hyperplasia), Coagulopathy, Ovulatory disorders, Endometrial, Iatrogenic and Not otherwise classified) classification helps in arriving at accurate diagnosis and well informed management options for the patient.

Fibroids are the most common cause in women presenting with AUB especially by the age of 50, According to a paper by Baird  DD et al the estimated cumulative incidence at this age is almost 70% of white women and >80% of black women will have developed at least one fibroid.

As women postpone motherhood in favor of better career choices, fertility preservation and newer medical options becomes genuine choices as treatment options.

This review by Whitaker L and Critchley H.O.D published in forthcoming issue of Best Practice & Research Clinical Obstetrics & Gynecology considers the FIGO classification of   AUB and addresses the general principles of managing it in premenopausal women.

FIGO in 2009 defined chronic AUB as ‘bleeding from the uterine corpus that is abnormal in volume, regularity and/or timing that has been present for the majority of the last 6 months’.

With regard to volume, however, both the Royal College of Obstetricians and Gynaecologists (RCOG) and American College of Obstetricians and Gynecologists (ACOG) prefer the patient-centered definition of HMB, ‘excessive menstrual blood loss which interferes with a woman's physical, social, emotional and/or material quality of life’ as an indication for investigation and treatment options.

FIGO classification of cause: ‘PALM-COEIN’ is now being increasingly used for categorising causes: Polyp, Adenomyosis, Leiomyoma, Malignancy (and hyperplasia), Coagulopathy, Ovulatory disorders, Endometrial, Iatrogenic and Not otherwise classified The ‘PALM’ are assessed visually (imaging and histopathology) and the ‘COEIN’ are non-structural.

Adapted from Best Practice & Research Clinical Obstetrics & Gynecology March 2016 issue.

Assessment of the patient presenting with AUB and fibroids

Adapted from Best Practice & Research Clinical Obstetrics & Gynecology March 2016 issue.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 Structured history for coagulopathy screen. Adapted from Koudies et al. .

Criteria
1. Heavy bleeding since the menarche
2. One of the following: Postpartum haemorrhage •Surgical-related bleeding •Bleeding associated with dental work
3. Two or more of the following: Bruising 1–2 times/month Epistaxis 1–2 times per/month Frequent gum bleeding Family history of bleeding problems

Endometrial sampling

Endometrial sampling: In the UK, NICE recommend endometrial sampling in women with persistent inter-menstrual bleeding or aged ≥45 years with treatment failure .This has been highlighted in the RCOG guidelines with an exception of reducing the age of sampling in the context of treatment failure to 40 . With the marked increase in endometrial cancer, the authors would encourage all gynaecologists to continue to excise their clinical judgement for those women aged <40 years with HMB who have risk factors for premalignant change such as obesity and PCOS.

Approach to management

In those patients where the cause of AUB is fibroid, the treatment should be tailored based on individual symptoms and requirements.  It should be based upon fertility desire, age of the patient, and associated co morbidities.

Specific treatment options for individual PALM-COEIN causes of AUB.

AUB  Sub-classification	Specific treatment
Polyp	Resection
Adenomyosis	Surgery: hysterectomy; adenomyomectomy (not frequently performed)
Malignancy	Surgery +/− adjuvant treatment High-dose progestogens (if surgery not possible)  Palliation (including radiotherapy)
Coagulopathy	Tranexamic acid  DDVAP
Ovulation	Lifestyle modification Cabergoline (if hyperprolactinaemia)  Levothyroxine (if hypothyroid)
Endometrial	Specific therapies await further delineation of underlying mechanisms
Iatrogenic	Refer to FSRH CEU guidance on problematic bleeding with hormonal contraception
Not otherwise classified	Antibiotics for endometritis  Embolisation of AV malformation

Some salient features in  the management are:

• Fully non hormonal medical options are Tranexamic acid and NSAIDs (e.g. mefenamic acid)
• While the risk for expulsion due to distortion of the cavity does exist, (LNG–IUS) are still efficacious in controlling the bleeding.
• The current Cochrane review only includes mifepristone, and a future review that includes other medical options is awaited. Although  PEARL II study has documented the efficacy of SPRM ulipristal acetate (UPA) particularly in short term use before surgery.
• With regards to interventional radiological procedures like uterine artery embolism and it’s comparison to myomectomy, the authors are awaiting the result of FEMME trial to provide robust evidence.
• Hysterectomy will remain the definitive treatment, especially in context of HMB in patients who have completed the families, until alternative treatment strategies are developed and well documented.

References:

http://www.bestpracticeobgyn.com/article/S1521-6934%2815%2900226-6/fulltext

Fraser, I.S., Langham, S., and Uhl-Hochgraeber, K. Health-related quality of life and economic burden of abnormal uterine bleeding. Expert Rev Obstet Gynecol. 2009; 4: 179–189

Baird, D.D., Dunson, D.B., Hill, M.C. et al. High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence. Am J Obstet Gynecol. 2003; 188: 100–107

NICE. Clinical Guideline 44; Heavy menstrual bleeding 2007. National Institute for Health and Clinical Excellence (NICE); Available at: http://www.nice.org.uk/nicemedia/pdf/CG44FullGuideline.pdf.

Munro, M.G., Critchley, H.O., Fraser, I.S., and for the FIGO Working Group on Menstrual Disorders. The FIGO classification of causes of abnormal uterine bleeding.. Int J Gynaecol Obstet. 2011; 113: 1–2

Kouides, P.A., Conard, J., Peyvandi, F. et al. Hemostasis and menstruation: appropriate investigation for underlying disorders of hemostasis in women with excessive menstrual bleeding. Fertil Steril. 2005; 84: 1345–1351

Serum Biomarkers to predict outcome in women with threatened abortion: A systemic review and diagnostic accuracy meta-analysis.

Threatened abortion approximately affect 20% of pregnancies and 50% of those will end up in miscarriage.  It has also been associated with poor obstetric outcome such as preterm labor, low lying placenta, low birth weight and PROM.

The uncertainty of prognosis makes it a challenging task for healthcare professionals.Various biomarkers have been used, with variable results to predict the prognosis of bleeding in early pregnancy.

This systemic review and meta-analysis was published in the forthcoming issue of Human Reproduction update, it aims to determine the diagnostic accuracy of various biomarkers.

A total of 19 studies were found after electronic searching of databases to determine outcomes for women with threatened abortion at 5–23 weeks gestational age.

15 studies (including 1263 women) were found eligible using QUADAS-2 (Quality Assessment for Diagnostic Accuracy Studies-2: A Revised Tool) to include in the qualitative data assessment.

The biomarkers that were looked into included serum progesterone, hCG, pregnancy associated plasma protein A, estradiol and cancer antigen 125 (CA 125).

Interestingly, serum CA 125 appeared to be the most promising marker (n = 648 women, 7 studies), whereas serum progesterone and hCG are less useful once fetal viability is established.

CA-125 is a glycoprotein and its origin is uncertain during pregnancy. It arises during the first trimester and return to a non-pregnancy range in late pregnancy.

CA 125 showed a sensitivity of 90% (95% confidence interval (CI) 83–94%), specificity of 88% (95% CI 79–93%), positive likelihood ratio of 7.86 (95% CI 4.23–14.60) and negative likelihood ratio of 0.10 (95% CI 0.06–0.20). The inverse of negative likelihood ratio was 9.31 (95% CI 5–17.1) indicating that a negative test is likely to identify those who are likely to continue with the pregnancy.

Nevertheless, when vaginal bleeding had been present for 3 days or more and there was high maternal serum CA125 activity, the abortion risk was found to be 100%.

Since this was a qualitative analysis, no cut-off value for CA125 was determined but in most studies patients who eventually aborted had values of CA-125 more than 125 IU/ml while the control had a value not more than 93 IU/ml.

A rising value of CA 125 combined with gestational sac diameter that does not correspond to the pregnancy dating is highly significant in predicting the prognosis.

Serum estradiol was the next best marker with a sensitivity of 45% (95% CI 6–90%), a specificity of 87% (95% CI 81–92%), a positive likelihood ratio of 3.72 (95% CI 1.01–13.71) and a negative likelihood ratio of 0.62 (95% CI 0.20–1.84).

References:

https://humupd.oxfordjournals.org/content/22/2/228.abstract 

https://www.researchgate.net/publication/21703609_The_prognostic_significance_of_maternal_serum_CA125_measurement_in_threatened_abortion.

https://www.researchgate.net/publication /237514290_Threatened_abortion_A_risk_factor_for_poor_pregnancy_outcome

https://www.glowm.com/pdf/FromPreconceptionToPostpartum-InTech-CC%20BY-Ch05.pdf

http://europepmc.org/abstract/MED/12235698

http://www.reproductivemedicine.com/toc/auto_abstract.php?id=17836

http://www.ncbi.nlm.nih.gov/pubmed/12235698

The ICSI procedure: looking into the past and future

ICSI is the most common ART technique currently in use and accounts for 70-80% of all cycles performed.

It was first started in 1990 to assist those couples with severe male factor infertility, who could not be helped by the conventional IVF.

And since the birth of first ICSI baby in 1992, the procedure is well standardized now, making it possible for substantial number of couples to have there own biological child instead of using a donor’s sperm . More than 95% of males can father their own genetic child due to ICSI.

This review published in the current issue of Journal of Human Reproduction Update provides the most recent knowledge on the technical aspects of many ICSI procedures to improve its competence. It reviews the most recent publications dealing with specific situations that may help embryologist to offer the best laboratory individualized treatment.

More than 1770 articles were found between January 1996 and March 2015, after going through PUBMED. Out of which 90 studies were related to the issues developed for female gametes and 55 for the issues developed for male gametes.

According to these studies:

• the injection of rescue metaphase I oocytes should be discouraged due to poor clinical outcomes and a high aneuploidy rates;
• laser-assisted ICSI represents an efficient method to solve the high oocyte degeneration rate;
• the optimal ICSI timing and the best polar body position during the injection have not been clarified;
• injected zona-free oocytes, if handled carefully, can develop up to blastocyst stage and implant;
• efficient options can be offered to patients who suffered fertilization failure in previous conventional ICSI cycles.
• Most debatable and inconclusive were the data on the method to select viable spermatozoa when only immotile spermatozoa are present in the sample.
• Till date, no data is available on reliable approach to filter out spermatozoa with fragmented DNA from the sample.

The drawback with this review was that most study did not report the final clinical outcome after the ICSI, which can establish the safety of a particular procedure.

Inspite of which the embryologist might benefit from the reviews and improve the outcome of ICSI.

References:

• Rubino P, Viganò P, Luddi A et al The ICSI procedure from past to future: a systematic review of the more controversial aspects Hum. Reprod. Update (March/April 2016) 22 (2): 194-227 first published online November 18, 2015 doi:10.1093/humupd/dmv050

OPPTIMUM Trial: vaginal progesterone does not help in preterm birth prevention !

Preterm birth is a global problem, with a prevalence of 8 to 12% depending on location.

Several large trials and systematic reviews have shown progestogens to be effective in preventing or delaying preterm birth in selected high risk women with a singleton pregnancy (including those with a short cervix or previous preterm birth).

However, the OPPTIMUM study results presented recently at the Society for Maternal and Fetal Medicine (SMFM) 36^th Annual pregnancy meeting at Atlanta Georgia in February, 2016 have shown that vaginal progesterone confers no obstetrical or neonatal benefit, and no long-term benefit with respect to cognitive and neurosensory outcomes in children when used to prevent preterm birth.


The findings from OPPTIMUM – the largest trial to date looking at progesterone for the prevention of preterm birth – have important implications for current practice. Vaginal progesterone is not currently approved for the prevention of preterm birth in the United States, but is commonly used off label for this purpose.

The OPPTIMUM study is a randomized double blind placebo controlled trial recruited over 1,228 women around  UK to test whether giving natural progesterone daily from 22 to 34 weeks of gestation is a cost-effective way to reduce the likelihood of preterm birth.  It also aims to look whether compared to placebo, vaginal progesterone:

• improve obstetric outcome by lengthening pregnancy and thus reducing the incidence of preterm delivery (before 34 weeks gestation)?
• improve neonatal outcome by reducing a composite of death and major morbidity?
• lead to improved childhood cognitive and neurosensory outcomes at two years?
• represent cost effective management for women at high risk of preterm delivery?

Dr. Jane Norman, MD, from the University of Edinburgh in the United Kingdom said “We saw no significant effect of vaginal progesterone on obstetrical, neonatal, or childhood outcomes, this was true even for women with a cervix of 25 mm or less, and "we found no evidence of benefit in any identifiable subgroups."

A Cochrane meta-analysis  in 2013 assessed the role of both the vaginal and intramuscular form of progesterone in preventing PTB (Cochrane Database Syst Rev. 2013;7:CD004947). Progesterone was shown to prevent preterm births, reduce perinatal mortality, reduce the incidence of birthweight below 2500 g, and reduce neonatal deaths. In women with a short cervix, progesterone was shown to reduce preterm births, but did not affect the other parameters. 

But there has been little information about the long-term risk this may have on children Dr Norman explained. "We felt we needed to look at the long-term effects. We cannot assume that things with short-term benefit will not have long-term harm," she added.

The study recruited 1228 women with singleton pregnancies at risk for preterm birth because of a positive fetal fibronectin test, a history of spontaneous preterm birth at 34 weeks of gestation or earlier, or a cervical length 25 mm or less.

About 618 women were randomized to receive 200 mg of natural vaginal progesterone starting at 22-24 weeks and continuing to 34 weeks, compared with 600 women who received placebo.

The primary obstetric outcome was delivery <34 weeks of gestation, the primary neonatal outcome is a composite of death or two markers of neonatal morbidity (brain injury or bronchopulmonary dysplasia); and the primary childhood outcome is developmental status at two years. A formal economic evaluation was also a key part of the study.

It was seen that progesterone had no significant effect on either the obstetric or childhood outcomes. It also had no significant effect on any components of the primary outcome, including fetal death or live-born delivery before 34 weeks.

“A secondary analysis looking at the individual components of the composite neonatal outcomes showed that progesterone reduced the risk of brain injury and neonatal death, but not bronchopulmonary dysplasia.” Dr. Norman said.

“We were really surprised that we didn’t show that progesterone prevented preterm birth, and we became concerned that perhaps our cutoff of 34 weeks was just the wrong time to choose a cutoff,” Dr. Norman said, noting that a post hoc survival curve analysis was performed to look at the trajectory to delivery, and a “very marginal benefit” was seen with progesterone, but the difference was not statistically significant.

On subgroup analysis it was seen that in women with a short cervix, no evidence was seen that progesterone was more or less effective than in women with a longer cervix. Other subgroups studied included fibronectin-positive and fibronectin-negative women and women with a history of preterm birth. Progesterone was no more or less effective in any of these subgroups. 

“OPPTIMUM is the largest trial of progesterone to prevent preterm birth, and after adjusting for multiple comparisons as we planned, we did not disprove the null hypothesis that progesterone doesn’t prevent preterm birth, it doesn’t reduce adverse neonatal outcomes, and it doesn’t have a beneficial effect on childhood outcomes,” Dr. Norman said, concluding that “there is a remaining unmet need for a safe and effective agent to prevent preterm birth.”

Further it was commented at the  Society for Maternal and Fetal Medicine (SMFM) conference by Mary D'Alton, MD, the William C. Rappleye Professor of Obstetrics and Gynecology at the Columbia University Medical Center in New York Citythat that the results should not be extrapolated to 17-hydroxyprogesterone, which was not part of this analysis.

This certainly gives pause around vaginal progesterone," said Mary D'Alton, MD, the William C. Rappleye Professor of Obstetrics and Gynecology at the Columbia University Medical Center in New York City. But she said she would not advise a change in practice before seeing the final published results.

The US Food and Drug Administration has not approved vaginal progesterone for the prevention of preterm birth in women with a short cervix.

History of preeclampsia linked to coronary artery calcification 30 years later.

Preeclampsia (PE) is a hypertensive pregnancy disorder complicating 1-5% of all pregnancies, and is a major cause of maternal and fetal morbidity and mortality.

In-fact it is known as the modulator of the offspring health, as many studies have associated it with increased incidence of metabolic syndrome later in the life of the offspring. 

A substantial number of epidemiological studies in recent year have also documented it to be a risk factor for increased cardiovascular and renal diseases for mother later in life. 

Women who have history of preeclampsia have a 2 fold increase in CVD and 5-12 fold in end stage renal  diseases(ESRD).

A recent study by White WM et al in the forthcoming American journal of obstetrics & gynecology concluded that a history of preeclampsia is associated with an increased risk of coronary artery calcification more than 30 years after affected pregnancies, even after controlling individually for traditional risk factors.

This paper was also presented recently at the  Society for Maternal and fetal Medicine (SMFM) 36^th Annual pregnancy meeting at Atlanta Georgia in February, 2016.

This study by White WM et al is important because it is the first prospective cohort study with confirmation of preeclampsia by medical record review.

They recruited 40 women with history of preeclampsia and 40 women without such history were recruited from a large cohort of population in Olmsted County, MN and who delivered between 1976 and 1982.

They were matched for parity and age at the time of index birth. Cat scan was performed to measure the coronary artery calcification in Agatston Units. The mean age at imaging was 59.5 (± 4.6) years.

It was seen that the frequencies of being diagnosed with hypertension (60% v. 20%, p < 0.001) and higher BMI (29.8 vs. 25.3) were both greater in women with H/O preeclampsia.

The frequency of a CAC score > 50 Agatston units was also greater in the preeclampsia group (23% v. 0%, p=0.001). Compared to women without preeclampsia, the odds of having a higher coronary artery calcification score was 3.54 (1.39 - 9.02) times greater in women with prior preeclampsia without adjustment, and 2.61 (0.95 - 7.14) times greater after adjustment for current hypertension.

The presence of coronary artery calcifications may be able to identify those at a particularly high cardiovascular risk, since CAC is  a strong predictor of  CHD.

According to a recent Multi-Ethnic Study of Atherosclerosis (MESA) by Joshi PM et al in the Journal Atherosclerosis showed that a high burden of coronary artery calcium (CAC) is a strong predictor of coronary heart disease (CHD) among persons at low risk.

Recognition of PE as a risk factor for CVD allows identification of a young population of women at high risk of developing of cardiovascular disease.

Current guidelines recommend cardiovascular screening and treatment for formerly preeclamptic women. However, these recommendations are based on low levels of evidence due to a lack of studies on screening and prevention in formerly preeclamptic women.

The American Heart association guidelines have listed preeclampsia as an independent risk factor for CHD, as strong as a failed stress test— but larger studies are still needed to understand the underlying mechanism. 

The current study strongly advocates the need for research on mechanisms of late disease manifestations, and on effective screening and therapeutic strategies aimed at reducing the late disease burden in formerly preeclamptic women. Identification of women with CAC score > 50 carries significant potential therapeutic implications.

 References:

http://www.ncbi.nlm.nih.gov/pubmed/26841074

http://www.ajog.org/article/S0002-9378%2816%2900287-8/abstract

http://www.ncbi.nlm.nih.gov/pubmed/26792940

Endometrial cancer management guidelines updated: assorting the uncertainties! -----3

The first joint European Society for Medical Oncology (ESMO), European SocieTy for Radiotherapy & Oncology (ESTRO) and European Society of Gynaecological Oncology (ESGO) consensus conference on endometrial cancer was held on 11–13 December 2014 in Milan, Italy.

These guidelines were published in an article by Colombo N et al in January issue of Annals of Oncology. 

These guidelines were developed based on 12 questions identified by the expert panel.

The earlier 2 questions were answered in previous parts.

The third question is: Which (molecular) Markers Can Help Distinguish (pre)Cancerous Lesions from Benign Mimics?

 

Differential diagnosis between benign uterine lesions and endometrial (pre)carcinomas is based mainly on morphological criteria but may be supported by additional immunohistochemical (IHC) markers and molecular alterations in problematic cases.

Currently, AH/EIN is the preferred terminology of the precursor lesion of the most common type of endometrial carcinoma, endometrioid carcinoma, including its variants.

Recommendation 3.1: In case of uncertainty low threshold referral to a specialised gynaecopathologist is recommended.Level of evidence: V,Strength of recommendation:A.


Recommendation 3.2: PTEN and PAX-2 IHC is recommended to distinguish AH/EIN from benign mimics. Other markers that can be used in this context are MLH1 and ARID1a by IHC.Level of evidence: IV,Strength of recommendation: B


Recommendation 3.3: IHC is not recommended to distinguish APA from AH/EIN.Level of evidence: V,Strength of recommendation: B


Recommendation 3.4: p53 by IHC is recommended to distinguish serous endometrial intraepithelial carcinoma (SEIC) from its mimics.Level of evidence: IV,Strength of recommendation: A


Recommendation 3.5: A panel of markers must be used in cases where endocervical cancer is suspected. This panel should include at least ER, vimentin, CEA and p16 by IHC, and needs to be assessed in the histologic and clinical context. In addition, HPV analysis can be considered.Level of evidence: IV,Strength of recommendation: B


Recommendation 3.6: WT-1 by IHC is the recommended marker to determine the origin of serous cancer.Level of evidence: IV,Strength of recommendation: A



Recommendation 3.7: Morphology (and not IHC) should be used to distinguish AH/EIN from EEC.Level of evidence: IV,Strength of recommendation: A


To be continued…..

References:

Colombo N,Creutzberg CL, Amant F et al. ESMO-ESGO-ESTRO consensus conference on endometrial cancer: diagnosis, treatment and follow-up. Ann Oncol 2016; 27: 16–41.