Saturday, January 30, 2016

Prior First Trimester Uterine evacuation augments the risk for preterm birth in subsequent pregnancies!

Many studies have shown that a history of evacuation in women is associated with increased risk of preterm birth in subsequent pregnancy as compared to women with  no such history. But, many studies have failed to prove a direct cause and effect relationship. Other studies have linked D&C as a cause of subsequent pre term birth (PTB), but no distinction was made between surgical and medical modality of evacuation.

2 systemic reviews and meta-analysis were recently published in 2 separate journals. The first was in January, 2016 issue of Human Reproduction published on behalf of The European Society of Human Reproduction and Embryology  and the second is still in press in the forthcoming issue of  American Journal of Obstetric and Gynecology.

The Primary source of this article is the systemic review and meta-analysis in the journal of Human Reproduction, although both the analysis has concluded that Prior surgical uterine evacuation is a risk factor for subsequent pre term birth (PTB).

This is the first systematic review and meta-analysis addressing the association between D&C and preterm birth.

Since no Randomized Control Trials (RCT) were available, only cohort and case–control studies were included. A total of 21 studies reporting on 1,853,017 women were included out of that 71,231 had a history of at least one D&C in the first trimester of pregnancy. In 66,003 women, D&C had been performed for termination of pregnancy.

The control group consisted of 1,781,786 women, out of which 24. 977 women had received a medical treatment for either miscarriage or termination of pregnancy, while 1189 had had a spontaneous miscarriage and the rest were without a history of miscarriage or termination of pregnancy.

The primary outcome was a preterm delivery subsequent to an H/O curettage. The outcome of PTB was divided into 3 categories <37 weeks, <32 weeks and <28 weeks. The study also investigated a dose –response relationship by comparing women with a history of multiple D&Cs to women without a history of D&C. Many other sub-group analysis comparing   women with a D&C for miscarriage or termination of pregnancy to women with medical treatment for miscarriage or termination of pregnancy on the risk of subsequent preterm birth <37 weeks were also performed. 

The important findings of the study were:
  • It was seen that that women with a previous D&C, for miscarriage or termination of pregnancy in the first trimester, are at increased risk for preterm and especially very preterm birth, in comparison to women without a previous D&C procedure.
  • The increase in risk was statistically significant when it was only run against women who had medical management of pregnancy.
  • The risk of preterm birth increases with number of D&C performed, indicating a dose response relationship.
  • Reasonably, these findings suggest that it is the surgical management, rather than the actual miscarriage or termination, is the deciding factor about the time of delivery in the following pregnancy.

The studies included had many limitations and bias, but the strict inclusion and exclusion criteria, sensitivity and robust analysis, multiple control groups, sub-group  analysis and including prospective cohort studies  helped to limit it to certain extent. 

The mechanism by which the surgical procedure increases the risk for preterm birth remains speculative. Multiple hypotheses have been put forward such as cervical incompetence. Another theory propose a damage to  the endometrial lining which might cause abnormal placentation in a later pregnancy, thus increasing the risk of placental abruption, pre-eclampsia, placenta praevia and intrauterine growth restriction.
It is also postulated that cervical damage might impair the anti-microbial defence mechanism thereby facilitating ascending microbial colonization, a known cause of preterm births.

The clinical implications of this study are:

Frequent follow up and increase obstetrical care for women with h/o D&C, including monitoring of early signs and symptoms of threatened preterm birth.
Avoiding unneeded D&C and going more for non-invasive management options when possible i.e. expectant management or medical management in case of miscarriage, and medical management in case of termination of pregnancy.

No data is yet available on the effect of cervical priming before the D&C and subsequent risk of preterm labor. 

Wieringa-de Waard M, Vos J, Bonsel GJ, Bindels PJ, Ankum WM. Management of miscarriage: a randomized controlled trial of expectant management versus surgical evacuation. Hum Reprod 2002;17:2445–2450
M. Lemmers M, Verschoor MAC, Hooker AB, Opmeer BC, Limpens J., Huirne JAF, Ankum WM, Mol BWM. Dilatation and curettage increases the risk of subsequent preterm birth: a systematic review and meta-analysis. Hum. Reprod. (2016) 31 (1): 34-
History of induced abortion as a risk factor for preterm birth in European countries: results of the EUROPOP survey Hum. Reprod. (2004) 19 (3): 734-740 first published online January 29, 200
You JH, Chung TK. Expectant, medical or surgical treatment for spontaneous abortion in first trimester of pregnancy: a cost analysis. Hum Reprod 2005;20:2873–2878
Pregnancy loss managed by cervical dilatation and curettage increases the risk of spontaneous preterm birth Hum. Reprod. (2013) 28 (12): 3197-3206 first published online September 19, 2013 doi:10.1093/humrep/det332
Shah PS, Zao J. Induced termination of pregnancy and low birthweight and preterm birth: a systematic review and meta-analyses. BJOG 2009;116:1425–1442.

Thursday, January 28, 2016

Umbilical Cord Blood Transplant ---- The past, present and the future!


The first successful cord blood transplant in the world was  performed, by Dr. Eliane Gluckman of St. Louis Hospital, Paris, France on a five-year-old boy named Matthew Farrow, suffering from Fanconi’s Anemia (a blood disorder) in 1988. The cord blood donor was Matthew’s sister at birth and it was stored by Dr. Broxmeyer. Matthew’s U.S. physician was Dr. Joanne Kurtzberg.

Since than the field of UCB banking and transplantation has grown exponentially with over 600000 UCB units been stored for transplantation worldwide, and >30000 UCBTs have been performed.

UCB serves as an alternative stem cell source; because in a multiethnic society   only 30% of patients who require an allograft will have a human leukocyte antigen (HLA)-matched sibling donor.

The successful first transplant opened a new field in allogeneic hematopoietic stem cell (HSC) transplant. Now UCBT is done for correction of inborn errors of metabolism, hematopoietic malignancies, and genetic disorders of the blood and immune system

The main practical advantages of using UCB is the relative ease with which it can be obtained, no ethical issues,  the absence of risk for mothers and donors, the reduced likelihood of transmitting infections, and the ability to store fully tested and HLA-typed UCB in the frozen state for atleast 20 years, available for immediate use. It also seems to be less likely than bone marrow to cause immune rejection or complications such as Graft versus Host Disease. 

Following this first successful transplant, UCB banks were established in order to collect and cryopreserve UCB for related and unrelated use.

UCB can be stored cryopreserved for >20 years with efficient recovery of HSCs and HPCs

Initially, umbilical cord blood transplantation was only limited to children, given the low cell dose infused and was only used for blood disorders and malignancies.  Both related and unrelated cord blood transplants have been performed with high rates of success for a variety of hematologic disorders and metabolic storage diseases in the pediatric setting.

After promising results in children, the initial UCBT experience with adults was poor, with 40% of patients dying before day 100.With time, more studies and improved technique it was realized that higher infused cell dose was associated with superior survival and the common indications were myelodysplasia and early-stage hematologic malignancies.

Given the current estimation of more than 130 million annual births, UCB is considered the most plentiful reservoir of regenerative cells for a large number of clinical applications.

Public versus Private Umbilical Cord Blood Banking


courtesy: Life cell  


Two types of banks work for the collection and storage of umbilical cord blood:

1) Public banks
2) Private banks.

Public banks promote allogeneic (related or unrelated) donation, just like the current collection of whole blood units and storing it in blood bank in the United States. Local network of obstetric hospitals send their unit of collected UCB to this central processing facility. To ensure that there will be enough cells for transplantation, at least 40 mL of cord blood must be collected.
According to ACOG  “Collection can be performed before or after removing the placenta. In either case, thorough cleansing of a section of umbilical cord is performed, and blood is obtained from the umbilical vein by venipuncture and allowed to drain by gravity into a bag supplied by the bank. Blood should be collected as soon as feasible after birth to minimize coagulation and maximize volume .If the specimen is not sterile or is not of sufficient quantity, it will be discarded by the bank”.
Umbilical cord blood collection is not part of routine obstetric care and is not medically indicated. Initial human leukocyte antigen typing of these units allows them to be entered into computerized registries so that when the need arises, a specific unit can be rapidly located for a patient.

Private for-profit banks were initially developed to store stem cells from umbilical cord blood for autologous use (taken from an individual for subsequent use by the same individual) if the child develops disease later in life or for use by other family members. Private banks advertise directly to consumers often encouraging parents to bank their infants’ cord blood as a form of “biological insurance.” The routine storage of umbilical cord blood as biological insurance against future disease is not recommended by the American Academy of Pediatrics.

Currently,  Although UCB is used mainly for hematopoietic progenitor cells (HPC) transplantation to treat blood disorders, the spectrum of diseases for which it is effective has been expanded to non-hematopoietic conditions, and UCBT is also employed as a form of regenerative cell therapy or immune modulation. Multiple Clinical Trial are underway to test the non-hematopoietic use of UCB namely Alzheimer disease, Autism, Bronchopulmonary dysplasi, Diabetes mellitus type 1, Orthopedic cartilage repair, Spinal cord injury, Inborn error of metabolism.   

The limitations of UCB transplants is slow engraftment, delayed immune reconstitution, and increased opportunistic infections, which may be a consequences of  lower cell dose. Scientists all over are working on strategies to improve on these limitations.

As embryo-destructive transplantation medicine continues to evoke prejudices and criticism, UCB will probably continue to grow in future with abundant UCB supply, digitalized UCB selection, multiple new indications, and significantly improved clinical outcomes.


Tuesday, January 26, 2016

ROCA Test for early detection of ovarian cancer rolled out in U.K and 5 US states, sparks concern!

credit: CC BY-NC-ND 2.0

The results of  UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)  was published in  the online edition of  The Lancet on  December 17, 2015.
The trial was conducted by Professor Ian Jacobs, who’s now based at the University of New South Wales Australia, and Professor Usha Menon from University College London, both of whom are gynecologists and have been working on early diagnosis of ovarian cancer since very long.

The trial data does show that annual screening by CA125 does detect cancer at an early stage and the risk of death due to ovarian cancer was reduced by 20% in women screened. Based on this the researcher estimated  that  for every 10,000 women screened every year with a blood test, about 15 lives could be saved, assuming the  women were screened for 7 to 11 years.

The researcher themselves say that “Further follow up to assess mortality reduction is required before firm conclusions can be reached”.

On the basis of the preliminary findings Cancer biomarker pioneer Abcodia Ltd, based in the Cambridge science & technology corridor has already launched the Risk of Ovarian Cancer Algorithm (ROCA®) test which is currently being used by physicians in UK and USA.

In UK it is being used by private clinics and in USA it is available in 5 states namely Arizona, Illinois, Massachusetts, New Jersey and Texas on a self pay basis.

ROCA was co-invented by Professor Ian Jacobs and Dr Steve Skates, and was developed by analyzing the serum CA125 profiles of over 27,000 women, some of whom developed ovarian cancer, in a series of clinical trials in the UK and Sweden. 

The ROCA Test is a quantitative algorithm that takes into account women’s age, menopausal status, and CA125 levels over time to produce a score that indicates her likelihood of having ovarian cancer. The women serve as their own control when they are serially tested for CA 125.

The ROCA Test is the first step in a multi-modal assessment for ovarian cancer and is to be used to help physicians assess whether a woman should undergo additional testing, including transvaginal ultrasound scan of the ovaries.

The ROCA test is intended for:
  • Post-menopausal women aged between 50 and 85, with no known ovarian cancer risk factors, 
  • Women between 35 and 85, who are considered to be at high risk of ovarian cancer due to a family history of ovarian or breast cancer, 
  • Women with mutation in specific genes such as the BRCA1 or BRCA2 or Lynch Syndrome genes.
The standard cut-off for healthy baseline levels of CA125  is 35 unit-per-millilitre (U/ml), but the levels show a considerable variation , including many cases where their baseline level are well above the standard. Moreover, some women with ovarian cancer have changing levels of CA125 that are well below this cut-off and therefore can be missed.

The ROCA Test reports a numerical score for the risk for ovarian cancer e.g. 1 in 5,000. In the clinical trials that validated ROCA, this risk score was then categorized as ‘Normal’, ‘Intermediate’ or ‘Elevated’ as a guide for clinical decision making on further follow up, such as transvaginal ultrasound scan.

Based on these levels, their risk of ovarian cancer (ROC) was interpreted on the algorithm as:
  • normal – return to annual screening
  • intermediate – repeat CA125 in 12 weeks (repeat level I screen)
  • elevated – repeat CA125 and transvaginal ultrasound in six weeks (level II screen) with earlier screens arranged where clinically suspicious
The test detected 86 percent of ovarian cancers with specificity of 99.8 percent. By comparison, conventional fixed CA125 cutoffs of 35 U/ml or 30 U/ml identified 41 percent and 48 percent, respectively.

A separate randomized, prospective trial - the United Kingdom Familial Ovarian Cancer Screening Study (UKFOCSS) - evaluated ROCA in over 4,000 women who had a family history of ovarian/breast cancer, and/or a genetic predisposition to ovarian/breast cancer. Out of BRIP1, BARD1, PALB2 and NBN, it was estimated that the risk of ovarian cancer for women with the BRIP1 mutation was 3.4 times greater than that of the UK general population.

In a similar study led by MD Anderson Cancer Center researcher Karen Lu and published in the journal Cancer in 2013, the ROCA test was able to identify cases of ovarian cancer with 99.9 percent specificity and a positive predictive value of 40 percent in a cohort of 4,051 women followed over 11 years.

Lu and her colleagues at MD Anderson are also continuing their evaluation of the test separate from Abcodia's efforts, and the trial first detailed in the 2013 Cancer study is ongoing. Lu is also co-leading with Skates a study evaluating the test in a high-risk population.

"It's a public health standard for cancer screening that there has to be a decrease in mortality before a cancer screening test is recommended for the general public," she said. "So while the UK study and the US study have shown promise, it is really important to wait for the definitive [mortality and survival] data before using it outside a research setting."

Meanwhile, the Ovarian cancer national Alliance stresses the importance of more long term follow up of the UKCTOCS trial, more long term  mortality data and  a discussion with the scientific community to understand how the test will fit into the preventive strategies for the ovarian cancer.

Abcodia is going to be pursuing FDA approval for the test.

Limitations of the ROCA®test:
  • The ROCA® Test is not intended to be used as the only test to determine whether the patient has a ovarian malignancy and the patient should proceed to surgery. The ROCA® Test is only intended to provide you with a risk score that can help you to determine your patient's need for a transvaginal ultrasound screen, further imaging tests and other clinical assessment.
  • The ROCA® Test fails to detect all ovarian cancers. Up to 15 out of every 100 ovarian cancers in women having screening with the ROCA® Test may be missed. Therefore, it is still very important that the patients and physician should  remain aware of the symptoms of ovarian cancer based on the history, demographic and physical findings.
Financial disclosure:
Two study authors of  UKCTOCS are co-inventors of the risk of ovarian cancer algorithm (ROCA), which is patented and licensed to Abcodia Ltd.
Two other study authors also declare financial interests through Abcodia Ltd.
One of the authors declared a consultancy arrangement with Becton Dickinson in the field of tumour markers. The remaining authors declare no conflicts of interest.

Menon U, Ryan A, Kalsi J, et al. Risk algorithm using serial biomarker measurements doubles the number of screen-detected cancers compared with a single-threshold rule in the United Kingdom Collaborative Trial of Ovarian Cancer Screening [published online May 11, 2015]. J Clin Oncol. doi:10.1200/JCO.2014.59.4945.
 Bonislawski A. Abcodia to launch ROCA ovarian cancer test in UK and US this year. Genomeweb. 2015.
Menon, U, et al. (2014). Ovarian cancer screening-current status, future directions. Gynaecological Oncology, 132(2), pp. 490-495.
Skates, S (2012). Ovarian Cancer Screening: Development of the Risk of Ovarian Cancer Algorithm (ROCA) and ROCA Screening Trials. International Journal of Gynaecological Cancer, 22, S24-S26.

Sunday, January 24, 2016

Study validates an association between thyroid and breast cancer

A single center retrospective case-controlled study performed by Jee Hyun An and colleagues of Seoul National University College of Medicine, South Korea and published in December 2015 issue of Thyroid.

The study group consists of 4243 patients with differentiated Thyroid Carcinoma (TC) and 6833 patients with Breast Cancer (BC) while the control group consisted of age matched patients without second malignancies.

In the study group with TC , 55 patients subsequently developed BC in the 5 year follow up, while among  those patients with BC  81 patients developed subsequent TC during a 6.2-year follow-up.

The expression of estrogen and progesterone receptors was significantly higher in the tissues of BC patients with coexisting TC compared with those with BC alone suggesting  a molecular association between both the cancers.

A slight increase in incidence of BC in TC patients may be due to increased screening procedure due to a primary malignancy.

Clinically, the findings suggest that regular breast examination and screening guidelines to be followed in patients with TC.

However, because there were no clinical predictors of TC development among the BC patients compared with those with TC alone and no evidence of improved prognosis for early TC diagnosis, "screening for TC in BC patients cannot be recommended, irrespective of the patient's age at BC diagnosis."

Many earlier studies have demonstrated an increase prevalence of thyroid disease like nontoxic goiter, Hashimoto's thyroiditis, Graves' disease, thyroid carcinoma, and subacute thyroiditis in patients treated for Breast Cancer as compared to age matched controls.

Clinically this means that women with primary breast cancer, screening for thyroid disease particularly hypothyroidism and autoimmune thyroiditis should be carried out for extended period of time even after the patient is cure of the primary cancer.


Friday, January 22, 2016

Is it possible to protect the gonads during chemotherapy?

 It is estimated that in  USA about 843,820 new cases of cancer all site would be diagnosed in women in the year 2016 out of which 89,140 will be younger than 45 years of age.

As a result of improved knowledge and increased health awareness combined with increased availability of screening tests and healthcare resources many cancers are now diagnosed at a younger age than before.

According to WHO the 5 most common sites of cancer in women are breast, colorectal, lung, cervix, and stomach cancer.

The treatment for cancers diagnosed at early stage is more specific, less destructive and results in more Disease-free survival (DFS) and progression-free survival (PFS) resulting in improved quality of life.

When the rapidly dividing cancer cells are targeted with chemotherapy/ radiotherapy, the germ cells in gonads are also affected and are destroyed.

As a result older women with decreased ovarian reserve may end up in ovarian failure, losing the capacity to reproduce while younger women become hypoestrogenic.

According to the International guidelines on fertility preservation it is recommended that the physicians address the issue of fertility preservation with all patients of reproductive age as early as possible before initiating the treatment and keeping them informed about all the options.

As recommended by the American Society of Clinical Oncology and the European Society for Medical Oncology, sperm cryopreservation and embryo/oocyte cryopreservation are standard strategies for fertility preservations in male and female patients, respectively.

Other strategies (e.g. pharmacological protection of the gonads and gonadal tissue cryopreservation) are still at experimental stage due to lack of large data and guidelines..

This Systematic Review and Meta-analysis by Elgindy E et al published in the December issue of Journal of Obstetrics and Gynecology aims to estimate whether gonadotropin-releasing hormone (GnRH) analog administration during chemotherapy can protect against development of ovarian toxicity.

Many studies have earlier evaluated the use of GnRH to preserve the endocrinological and biological function of the gonads in cancer chemotherapy/Radiotherapy with conflicting results.

Meta-analysis by Shen YW et al published in Journal of Oncotargets and Therapy (2015 Nov 13;8:3349-59) did show that  GnRH agonists cotreatment with chemotherapy in premenopausal women with breast cancer plays a beneficial role in resumption of ovarian function, with a higher rate of resumption of menses. However, treatment with GnRH agonists does not appear to exhibit its protective effects in fertility.

Another Meta-analysis Wang C et al in PloS One(2013 Jun 21;8(6):e66360. Print 2013) also concluded a potential benefit of GnRH cotreatment with chemotherapy in premenopausal women, producing higher rates of spontaneous resumption of menses.

Both the trials reported an increased pregnancy rate, however both these meta-analysis included trials with patients having breast cancer only.

A total of 10 RCTs with 907 women were included in the analysis comparing resumption of ovarian function between use of GnRH analogs plus chemotherapy with chemotherapy without GnRH the analogs.

The primary outcomes were resumed ovarian function at the longest follow-up after the end of chemotherapy. Secondary outcomes were evaluating ovarian reserve parameters and pregnancy.

Resumption of menstrual cycles was observed in 320 of 468 in in GnRH analog arm and 263 of 439 in the chemotherapy alone arm, which did not reach statistical significance.

No significant difference was observed when the data was analyzed according to different type of cancer, age below 40 vs above 40 years.

Other parameters of   ovarian capacity (baseline follicle-stimulating hormone level, anti-Müllerian hormone level, or antral follicle count) and pregnancy rates upon completion of chemotherapy also did not show a significantly difference between the two arms.

On the basis of this meta-analysis, it was seen that GnRHa co-treatment had no significant impact on rates of resumption of ovarian function among reproductive-age women undergoing chemotherapy.

National Comprehensive Cancer Network (NCCN) guidelines have been updated to acknowledge the use of LHRHa in preventing chemotherapy-induced ovarian failure of hormone receptor negative breast cancer patients.

However, ovarian suppression with GnRH during chemotherapy is still considered an experimental strategy to preserve fertility by some international guidelines due to both the uncertainty regarding the efficacy of this strategy and the absence of data on pregnancies and long-term ovarian function.


Wednesday, January 20, 2016

Magnesium Sulfate Use in Obstetrics

The source of this  article is : Magnesium sulfate use in obstetrics. Committee Opinion No. 652. American College of Obstetricians and Gynecologists. Obstet Gynecol 2016;127:e52–3.

The U.S. Food and Drug Administration advises against the use of magnesium sulfate injections for more than 5–7 days to stop preterm labor in pregnant women.

Based on this, the category of the drug was changed from ‘A’ to ‘D’ recently, when it was used for more than 5-7 days to prevent preterm labor in pregnant women.

Concerns for fetal and neonatal bone demineralization and fractures associated with long-term in utero exposure to magnesium sulfate prompted this change.

These concerns were based on reports to the FDA’s Adverse Event Reporting System and results from a number of epidemiologic analyses, although these studies have important limitations in designs.

In these population based studies the  average use of  prenatal Magnesium Sulphate was for 9.6 weeks and the dose was  3,700 g, a much longer duration and much higher dose than is currently recommended. The sample size in these studies were also small leading to bias and confounding in the conclusion drawn.

A total 18 cases were reported of fetal and neonatal long bone demineralization and fractures.

So this change of category addresses an unindicated and nonstandard use of magnesium sulfate in obstetric care.

 So, the use of Magnesium Sulphate that is appropriate in clinical practice is:

  1. Prevention and treatment of seizures in women with preeclampsia or eclampsia and fetal neuroprotection before anticipated early preterm (less than 32 weeks of gestation) delivery.
  2. Short-term prolongation of pregnancy (up to 48 hours) to allow for the administration of antenatal corticosteroids in pregnant women who are at risk of preterm delivery within 7 days.
  3. Tocolysis is not recommended beyond 34 weeks of gestation, and is generally not recommended before 24 weeks of gestation but may be considered based on individual circumstances.


Tuesday, January 19, 2016

Society for Maternal-Fetal Medicine (SMFM) recommendations for screening, treatment, and prevention of vertical transmission of Hepatitis B in pregnancy

The Primary source of this article is the recommendation published by Society for Maternal-Fetal Medicine (SMFM) for screening, treatment and prevention of vertical transmission of Hepatitis B in the January issue of American Journal of Obstetrics and Gynecology by Dionne-Odom J. et al.

Nearly 240 million people worldwide are infected with hepatitis B virus (HBV).

Specific to pregnancy, an estimated prevalence of 0.7-0.9% for chronic hepatitis B infection among pregnant women in the United States has been reported, with >25,000 infants at risk for chronic infection born annually to these women.

While transmission through sexual intercourse and intravenous drug abuse are the major risk factors for acquisition of hepatitis B among adults in the United States, perinatal transmission is responsible for up to 50% of HBV infection worldwide

Vertical transmission of HBV from infected mothers to their fetuses or newborns, either in utero or peripartum, remains a major source of perpetuating the reservoir of chronically infected individuals globally.

From a global public health perspective, chronic HBV infection is the major source of hepatocellular carcinoma, leading to 50% of cases worldwide and 80% in high-endemic areas for HBV.

In contrast to HBV acquisition in adulthood, which more commonly leads to acute resolved infection and immunity, perinatal/neonatal HBV is more likely to lead to chronic infection and its long-term disease risks. Chronic hepatitis B infection will develop in up to 90% of exposed neonates who do not receive appropriate immunoprophylaxis, in contrast to 10-25% of infected children and only 5-10% of exposed immunocompetent adults.

Identification of pregnant women with chronic HBV infection through universal screening has had a major impact in decreasing the risk of neonatal infection. Recent data demonstrate that 95% of pregnant women are currently screened prior to delivery for evidence of chronic HBV infection, with rates of perinatal transmission decreasing significantly over the past 2 decades.

The recommendation of Society for Maternal-Fetal Medicine (SMFM) for screening, treatment and prevention of vertical transmission are:

(1) Perform routine screening during pregnancy for HBV infection with maternal HBsAg testing (grade 1A).

(2) Administer hepatitis B vaccine and HBV immunoglobulin within 12 hours of birth to all newborns of HBsAg-positive mothers or those with unknown or undocumented HBsAg status, regardless of whether maternal antiviral therapy has been given during the pregnancy (grade 1A).

(3) In pregnant women with HBV infection, suggest HBV viral load testing in the third trimester (grade 2B).

(4) In pregnant women with HBV infection and viral load >6-8 log 10 copies/mL, HBV-targeted maternal antiviral therapy should be considered for the purpose of decreasing the risk of intrauterine fetal infection (grade 2B).

(5) In pregnant women with HBV infection who are candidates for maternal antiviral therapy, tenofovir should be used as a first-line agent (grade 2B).

 (6) It is  recommend that women with HBV infection be encouraged to breast-feed as long as the infant receives immunoprophylaxis at birth (HBV vaccination and hepatitis B immunoglobulin) (grade 1C).

 (7) HBV infected women who have an indication for genetic testing, invasive testing (eg amniocentesis or chorionic villus sampling) may be offered–counseling should include the fact that the risk for maternal-fetal transmission may increase with HBV viral load >7 log 10 IU/mL (grade 2C).

(8) Cesarean delivery should not be performed for the sole indication for reduction of vertical HBV transmission (grade 2C).

Issues to be considered in a pregnant woman diagnosed as a chronic HBV carrier?

The majority of pregnant women diagnosed with chronic HBV infection will be asymptomatic and identified through routine screening with initial prenatal laboratory tests.

Identification of a pregnant woman as chronically HBV infected also presents an important opportunity to counsel her regarding risks to other family and household members. HBV is most easily transmitted via sexual exposure or blood exposure but can also be transmitted through casual shared use of household items such as eating utensils and toothbrushes, as well as through personal contact such as kissing or routine childcare. Therefore, family and household members should be evaluated for HBV status and referred for vaccination if found to be uninfected and nonimmune.

The pregnant woman herself should also be assessed for immunity status for hepatitis A and offered vaccination if not immune, since coinfection with another viral hepatitis results in compounded morbidity.

To aid in counseling regarding risks and potential management options as outlined above, baseline LFTs should also be drawn when a positive HBsAg test result is obtained, along with a baseline quantitative HBV-DNA level.

The woman should also be counseled regarding exposures to potentially hepatotoxic medications, even those available over the counter, such as acetaminophen, and to avoid the use of alcohol even when not pregnant.

Even if the maternal viral load is low and antiviral therapy during pregnancy is not recommended, the newborn should still receive standard prophylaxis with HBIG and HBV vaccine within 12 hours of birth, and ongoing surveillance of the woman’s hepatic function after pregnancy is indicated.


Hepatitis B in pregnancy screening, treatment, and prevention of vertical transmission.Dionne-Odom, Jodie et al. American Journal of Obstetrics & Gynecology, Volume 214, Issue 1, 6 - 14

Sunday, January 17, 2016

Microcephaly in Brazil potentially linked to the Zika virus epidemic says European Center for Disease Control (ECDC).

photo by CDC PHIL, Aedes Mosquito

New European Center for Disease Control ( ECDC) risk assessment is currently evaluating a possible link between the observed increase of congenital microcephaly in Brazil and Zika virus (ZIKV) infection.

Until recent months Zika virus was not widely associated with microcephaly.

According to CDC, in the past four months, microcephaly cases in Brazil rocketed to 3,500 from 147, the average for the same time last year (2014).  About 46 babies have died due to birth defects.

The link was first detected when Brazilian health authorities found traces of the Zika virus in a deceased infant born with microcephaly or in amniotic fluid of mothers delivering microcephalic infants.

The first confirmed cases of ZIKV infection in Brazil were reported in May 2015.

Transmission of the virus in Brazil is likely to have started several months before because the disease is new and mild, and could have been unrecognised or misdiagnosed, as dengue and chikungunya epidemics were ongoing.

Microcephaly caused due to any infection is usually caused by transplacental infections occurring early in pregnancy and is only detected during the second half of pregnancy or after birth.

The observed six months delay between the recognition of the transmission of ZIKV in May 2015, and the detection of an increase in microcephaly in November 2015, is therefore compatible with a temporal association between the two events.

Currently there is only ecological evidence of an association between the two events, due to sudden epidemic of microcephalic babies born and clustered around a specific time period.

A possible causative association cannot be ruled out but further investigations and studies are needed to understand the association and the possible role of other factors, states the ECDC risk assessment.

In November the Brazilian Ministry of Health declared a public health emergency in relation to an unusual increase in the number of children born with microcephaly in 2015.

In addition to Brazil's findings, French Polynesian health authorities have also reported an unusual increase in autoimmune and central nervous system malformations in babies born during a Zika virus outbreak on the islands from 2014 to 2015. (73 cases, 42 of them being Guillain-Barré Syndrome, in a population of about 270 000). 

CDC map illustrates areas affected or possibly affected by the spread of Zika virus

Zika virus disease is a mosquito-borne viral disease caused by Zika virus (ZIKV), a flavivirus from the Flaviviridae family and is primarily transmitted through the bite of infected Aedes mosquitoes.

The virus was first identified in 1947 in the Zika forest in Uganda in the rhesus Macaque population and have two main lineages, the African lineage and the Asian lineage.

Prenatal or perinatal complications of ZIKV infections have not been described in the literature. There is some evidence that perinatal transmission can occur, most probably transplacental or during the delivery of a viraemic mother. However, materno-foetal transmission has been demonstrated for several other Flaviviruses (dengue, West Nile fever).

Some other Flavivirus infections are known to have the potential to cause premature birth, congenital defects and microcephaly.

The most common symptoms of Zika virus disease are fever, rash, joint pain, and conjunctivitis (red eyes). The illness is usually mild with symptoms lasting from several days to a week.

Meanwhile, Brazilian officials are also reporting neurologic complications in other Zika virus patients, primarily Guillain-Barre syndrome, which has also been seen in French Polynesian patients who had suspected infections. "Although neither even establishes a causal relation with Zika virus, the hypothesis cannot be ruled out," says a health official in Brazil.

In conclusion, a causative association between microcephaly in newborns and ZIKV infection during pregnancy is plausible, but not enough evidence is available yet to confirm or refute it. Many studies are needed before a definite conclusion can be reached.

There is no vaccine to prevent infection or medicine to treat Zika virus.

Meanwhile, CDC issues a travel advisory to pregnant women  to consider postponing travel to areas where Zika virus transmission is ongoing.


Thursday, January 14, 2016

Intravaginal dehydroepiandrosterone (DHEA) relieves women of postmenopausal pain, dryness and atrophy.

The most bothersome symptoms of menopause is moderate to severe pain due to vulvovaginal atrophy and other genitourinary symptoms causing dysparunia. Local estrogens increase blood hormonal level even in the lowest possible dose  and systemic hormone therapy has its own shortcoming. 

A study published in December issue of Menopause by Labrie F et al aims to confirm the local beneficial effects of intravaginal dehydroepiandrosterone (DHEA, Prasterone) on moderate to severe dyspareunia or pain at sexual activity, the most frequent symptom of vulvovaginal atrophy.

This is a prospective, randomized, double-blind, and placebo-controlled phase III clinical trial.

325 women were registered as the study subjects and they used daily intravaginal 0.5% DHEA (6.5 mg) as suppositories for 12 weeks while 157 women who served as control used placebo.

There was a significant improvement in all the parameters tested like dysparunia, vaginal dryness and vaginal pH.

At physical examination the gynecologists saw an improvement in vaginal secretions, epithelial integrity, epithelial surface thickness, and color all by 86% to 121% over placebo (P < 0.0001).

Vaginal pH decreased by 0.66 pH unit over placebo (P < 0.0001) on a scale of 0-3.

Serum steroid level also remained in the menopausal range.

Local DHES, through local androgen and estrogen formation, causes a rapid and efficient reversal of all the symptoms and signs of vaginal atrophy with no or minimal changes in serum steroids, which remain well within the normal postmenopausal range. This approach avoids the fear of systemic effects common to all presently available estrogen formulations and adds a novel physiological androgenic component to therapy.


Tuesday, January 12, 2016

USPSTF recommends biennial breast cancer screening beginning at age 50.

The USPSTF today once more made an important update to its 2009 U.S. Preventive Services Task Force (USPSTF) recommendation on screening for breast cancer. The USPSTF recommends biennial screening mammography for women aged 50 to 74 years. (B recommendation).These recommendations were published in the on-line issue of Annals of Internal Medicine on January 12, 2016.

Breast Cancer Screening Recommendations for Average-Risk Women

Agency issuing guidelines

40–49 years
Screening decision should be an informed, individual one, after she weighs the potential benefit against the potential harms.( C recommendations )
50–74 years
Mammography every 2 years (B recommendation)
≥75 years
Data were not sufficient to establish the benefits of mammography screening in women aged 75 years or older.( I statement)

40 years ≥
Annual mammograms beginning at age 40.

 45 years
Annual screening beginning at age 45
45-54 years
Annual screening
55 and older
Transition to biennial screening or have the opportunity to continue screening annually depending upon personal preference. Women should continue screening mammography as long as their overall health is good and they have a life expectancy of 10 years or longer

40 years ≥
Clinical breast exam every 6-12 + annual mammogram beginning at age 40years.

Upper age limit for screening not established; screening can continue if the woman is in good health and is expected to live at least 10 more years

Breast cancer is the second-leading cause of cancer death among women in the United States.

In 2015, an estimated 232 000 women were diagnosed with the disease and 40,000 women died of it.

There are approximately 125 new cases of breast cancer and about 22 deaths per 100 000 U.S. women each year. The mean age at diagnosis has remained unchanged at 64 years since the late 1970s.

It is most frequently diagnosed among women aged 55 to 64 years, and the median age of death from breast cancer is 68 years.

Across all ages, screening mammography has a sensitivity of approximately 77% to 95% and a specificity of about 94% to 97%

Dr.Christine Laine praises the USPSTF in an accompanying editorial saying that “The USPSTF did a difficult job well, considering updated evidence reviews, fuller panoply of potential harms, and tradeoffs of different screening strategies.”

She also said that “ Although for many years the dogma was that women should have mammograms “once a year for a lifetime” starting at age 40 years, current evidence shows that the balance of risks and benefits of screening, particularly among women in their 40s, warrants more nuanced decision making. Potential harms of over diagnosis and overtreatment of lesions with little progressive potential and harms of false-positive screening results with unnecessary biopsies and multiple repeated examinations must be considered”.

The following recommendation (originally issued in 2009) still stands: Each average-risk woman between the ages of 40 and 49 years should make her own decision about whether to have a mammogram, based on her personal balancing of the benefits and harms of screening (a grade “C” recommendation).

Benefit of Screening

Over a 10-year period, screening 10 000 women aged 60 to 69 years will result in 21 (95% CI, 11 to 32) fewer breast cancer deaths. The benefit is smaller in younger women: Screening 10 000 women aged 50 to 59 years will result in 8 (CI, 2 to 17) fewer breast cancer deaths, and screening 10 000 women aged 40 to 49 years will result in 3 (CI, 0 to 9) fewer breast cancer deaths.

Harms of screening

The harms of screening are over diagnosis and over screening that is diagnosis and treatment of non invasive and invasive cancer that would never have been detected in the absence of screening. Existing technology does not allow us to segregate with precision about how much is over diagnosis and how much was real diagnosis.

The best estimates from randomized, controlled trials (RCTs) evaluating the effect of mammography screening on breast cancer mortality suggest that 1 in 5 women diagnosed with breast cancer over approximately 10 years will be over diagnosed.

Based on data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program: The baseline breast cancer incidence rate was 105 to 111 cases per 100 000 women (depending on whether one considers invasive disease or invasive plus noninvasive disease together). With the widespread diffusion of mammography screening in last 30 years, this rate increased to 165 cases of noninvasive plus invasive disease per 100 000 women in 2011 (an excess of 54 to 60 cases per 100 000 women, or about a 50% increase).

Breast cancer mortality rates have declined at a slower rate, from 31 to 22 cases (or a reduction of 9 deaths) per 100,000 women over the same time period.

The USPSTF concludes that while there are harms of mammography, the benefit of screening mammography outweighs the harms by at least a moderate amount from age 50 to 74 years and is greatest for women in their 60s. For women in their 40s, the number who benefit from starting regular screening mammography is smaller and the number experiencing harm is larger compared with older women.

The current recommendations by USPSTF are based upon modeling studies conducted in support by the Cancer Intervention and Surveillance Modeling Network (CISNET). The investigators at CISNET evaluated data from six models that were grouped according to various screening strategies, various starting age and frequency.  The model with no screening served as reference.

It was seen that strategies involving screening every 2 years were consistently the most efficient for women at average risk for breast cancer.

The models showed that for women in the age group 50 to 74 years, biennial screening would prevent a median of seven breast-cancer deaths, compared with no screening vs. if the screening started at age 40, three additional breast cancer deaths would be prevented, but there would be 1988 more false-positive results and seven more over diagnoses for every 1000 women screened.

Dissatisfaction with the updated guidelines.

Many of the National agencies like National Comprehensive Cancer Network (NCCN) and M.D. Anderson Cancer Center are continue to screen women annually beginning at age 40 till she is within a decade of the predicted end of her life according to Therese Bevers, MD, medical director of the Cancer Prevention Center at the M.D. Anderson Cancer Center in Houston, and chair of NCCN guideline panels on breast cancer screening and diagnosis and breast cancer risk reduction.

National breast cancer screening programs in other countries like the United Kingdom,  Netherlands, Switzerland, Poland, Norway, Luxembourg, Germany, Finland, Denmark, and Belgium offer mammography screening every 2 to 3 years for women aged 50 up to 74 years.