CERVICAL CANCER SCREENING- IS LIQUID BASED CYTOLOGY BETTER THAN CONVENTIONAL PAP SMEAR?

Worldwide, cervical cancer is the second most common cause of death amongst women with cancer.  Fortunately, the incidence of cervical cancer has decreased by more than 50% in the past 30 years, largely due to the increasing use of cervical cancer screening with cervical cytology.

Although worldwide cervical cancer rates have decreased dramatically with the increase in screening efforts, incidence and prevalence in developing countries remains high due to lack of screening programs.

 

Cervical cancer screening methods

The conventional pap smear (CPS)

The mainstay of cervical cancer screening for the last 60+ years has been the Papanicolaou test. The Papanicolaou test, also known as the Pap smear, was developed in the 1940s by Georgios Papanikolaou. It involves exfoliating cells from the transformation zone of the cervix to enable examination of these cells microscopically for detection of cancerous or precancerous lesions. The cervical cells obtained is directly transfer onto a microscope slide for evaluation.

The conventional papanicolaou (Pap) test is considered suboptimal due to false-negative and false-positive test results.  This is caused by the poor quality of sampling and preparation (obscuration by blood or inflammation, bad cell fixation, and inhomogeneous distribution of cells) and by errors in detection and interpretation. All these contributed to an unsatisfactory smear and need for repeat test albeit a small incidence of 1%.

Liquid based cytology (LBC)

Liquid-based cytology was developed as an alternative to conventional pap smear. This method involves the collection of cervical cells using a traditional sampling device and rinsed into a vial with preservation solution rather than being smeared on a slide.  It is centrifuged to filter out cervical cells from other contaminants and the product is then analyzed in the cytology lab.  Because only a representative portion of the sample is used, the residual material in the vial may be used for ancillary testing such as reflex human papillomavirus (HPV) testing and other tests.

 

Is the liquid based cytology superior to CPS?

Siebers et al (JAMA 2008) had conducted a large prospective trial with 90000 women, comparing the screening performance of the two screening methods.   The results showed no differences were found in the cytological test positivity rates between methods. He concluded that liquid-based cytology was not superior to conventional Pap test regarding detection rates of histologically confirmed outcomes (gold standard). A reduced unsatisfactory rate was found when using liquid-based cytology even though the added value was limited because the unsatisfactory rates were already low. On the other hand, liquid-based cytology tests cost more money than a conventional Pap test.

The results of a systematic review and meta-analysis by Arbyn (2008), utilizing strict criteria had similarly found that liquid-based cervical cytology is neither more sensitive nor more specific for detection of high-grade cervical intraepithelial neoplasia (abnormal premalignant cervical cells) compared with the conventional Pap test.

Despite the above findings, Schiffman and Solomon (2009) observed that liquid-based cytology often results in fewer unsatisfactory specimens and allows for HPV testing on the same sample.  They also observed that liquid-based cytology has virtually replaced conventional Pap smears in the United States.  Although liquid-based cytology is more expensive, its ease of use allows laboratories to process slides more quickly and efficiently makes it the preferred method at the expense of a limited public program funding.

The bigger question, however, is how liquid based cytology screening itself will fit into the broader picture of cervical cancer prevention in low resource countries, where cervical cancer is more prevalent couple with lack of adequate screening.  Saraiya (2010) argued that findings of Siebers et al validated the practices of clinicians and laboratories that have continued to use conventional cytology.

 

Conclusions

Both conventional cytology and liquid-based cytology have been shown to have similar sensitivity and specificity for cervical dysplasia (premalignant cervical cells).  In addition, both types of cytological screening are considered acceptable by the American College of Obstetricians and Gynecologists.

 

References

Arbyn M et al., Liquid compared with conventional cervical cytology.  Obstet Gynecol (2008);111(1): 167-177

Schiffmans et al., Screening and prevention methods in cervical cancer. JAMA (2009);302(16):1809-1810

Siebers AG et al., Cytological detection of cervical abnormalities using liquid-based compared with conventional cytology .  Obstet Gynecol (2008);112(6): 1327-1334.

Suraiya et al., To the Editor: Liquid based cytology versus conventional cytology in detecting cervical cancer. JAMA(2009);303(11):1034

INFLUENZA VACCINATION AND PREGNANCY

Influenza or seasonal flu is cause by a virus, namely Influenza A or B.  To most healthy people, flu is an unpleasant experience characterized by symptoms of fever, muscle pain, nasal congestion and discharge.  It is usually a self-limiting disease and recovery is expected within a week.  Pregnant mothers, those with pre-existing medical condition, the very young and old population are prone to the more serious complications of influenza infection.  These complications include bronchitis, pneumonia, ear infection, sepsis, meningitis and encephalitis.

Influenza vaccine – risks and benefits

There is strong evidence that influenza vaccination for women who are pregnant is both efficacious and safe, with no increased incidence of miscarriages, fetal anomalies or neurodevelopmental disorders (Tamma 2009). There is also evidence that infants born to mothers vaccinated against influenza during pregnancy, compared with those not vaccinated, had lower rates of laboratory-confirmed influenza (4% versus 10%) and febrile respiratory illness (69% versus 97%) up to 24 months of age (Zaman K 2008).

The influenza vaccine can be safely taken at any stage of the pregnancy.  The injectable vaccine consists of inactivated virus (harmless as it does not contain live virus) and is not associated with adverse maternal or fetal outcome. The vaccine needs to be repeated annually due to the rapid viral mutation.  Its reported effectiveness is between 25-75%.

Despite the above benefits, the current vaccine uptake by pregnant mothers are low.  This is partly due to safety concern, poor patient awareness and lack of healthcare professional recommendation Koul 2014).

Conclusions

Pregnant women are at high risk of morbidity and mortality from influenza infection.  The current professional consensus strongly advocates influenza vaccine in pregnancy (ACOG 2014, RANZCOG 2014,WHO).

(Notes: At the time of writing, there is no known local guideline on influenza vaccine in pregnancy.)

 

References

ACOG committee Opinion 608. Influenza vaccination during pregnancy. Obstet Gynecol 2014

Koul PA et al., Poor uptake of influenza vaccination in pregnancy in northern India. Int J Obstet Gynecol 2014

RANZCOG. College statement: Influenza vaccine during pregnancy 2013.

Tamma PD et al., Safety of influenza vaccination during pregnancy. Am J Obstet Gynecol. 2009.

World Health Organization. Influenza (seasonal) fact sheet number 211.

Zaman K et al., Effectiveness of maternal influenza immunization in mothers and infants. NEJM 2008.

DELIVERY AFTER MYOMECTOMY

Uterine fibroid is the commonest benign tumor of the uterus.  It can be associated with difficulty to conceive.  For those women who have uterine fibroid in pregnancy, it may cause pain due to degeneration, fetal malpresentation, or placenta previa. Most women with uterine fibroid may have undergone a myomectomy (surgical removal of the fibroid) prior to conception.  The scar from myomectomy surgery may be associated with the uterine wall weakness and increases the risk of uterine rupture.

How common is uterine rupture after a myomectomy?

Uterine rupture is an obstetrical emergency that can be catastrophic for the mother and fetus. Previous uterine surgery, including previous cesarean delivery or myomectomy, is an established risk factor, although the exact magnitude of the associated risk remains uncertain.

The consequences of uterine rupture affect both the mother and the fetus. Maternal consequences of uterine rupture include severe internal bleeding (hypovolaemic shock), genitourinary injury, potential need for hysterectomy, and maternal death. The fetal sequelae include fetal hypoxia and fetal or neonatal death. In 2003, Chauhan (2003) estimated that the overall rate of hysterectomy secondary to uterine rupture is 0.09% with a perinatal mortality rate of 0.04% and a maternal mortality rate of 0.02%.

 

The reported prevalence of uterine rupture following a Caesarean section is about 1%.  The frequency of uterine rupture is generally lower in developed countries compared undeveloped countries.  Meanwhile, the incidence of uterine rupture following myomectomy  is 0.79 %, which is comparable with that after cesarean section.

This risk is estimated to be lower than a classical Caesarean scar (incision on the muscular part of uterus).  The American College of Obstetricians and Gynecologists (ACOG) has cited a uterine rupture risk of 4%-9% for women with prior classical caesarean and a trial of vaginal delivery is contraindicated.

 

The current available evidence shows no significant difference between the incidences of a rupture during pregnancy following a laparoscopic (1.2 %) versus an open myomectomy (0.4 %).  The location, size of the fibroids and breach of the uterine cavity, surgical skills and technique (of suturing) also affect the likelihood of uterine rupture following previous myomectomy.

 

However, most studies on the safety of vaginal delivery after a myomectomy have several important limitations including non prospective, selection bias, under-reporting of iatrogenic complications and publication bias.  The under-estimated true risk of uterine rupture, a potentially life-threatening event is possibly contributed by more primary Caesarean section performed to avert medicolegal litigation.

 

Should women with myomectomy have trial of vaginal delivery?

 

The mode of delivery following myomectomy is controversial. Though the risk for uterine rupture is low (less than 1%) following a myomectomy, regardless of the technique used, the evidence is not robust.  It is clear that randomized studies are needed to study the effectiveness of laparoscopic myomectomy for the adverse outcome of uterine rupture before conclusive evidence can be used to present evidence-based recommendations for daily clinical practice.

 

This estimation of the incidence might be used for counseling women wishing to conceive after a myomectomy, but it should be done with utmost caution.

Some physicians will allow labor, as long as the uterine cavity has not been breached or less 50 percent of the uterine wall has been incised during myomectomy. However, ACOG currently recommends cesarean section following myomectomy be performed between 37 and 38 week to decrease the chance of the patient first going into labor with its risk of uterine rupture

Milton (2015) states that although there are limited data to support an elective Caesarean delivery, it should be offered to pregnant women who had myomectomies, in which large defects in the active segment of the uterus were created by removal of the fibroids. He feels that the total extent of the defect has a more significant impact on the risk of rupture compare to breach of the uterine cavity during the procedure.

There is currently insufficient evidence to determine the recommended mode of delivery following myomectomy. Some women are offered an elective Caesarean delivery by clinicians with the intention of reducing the risk of uterine rupture.

Conclusions

Uterine rupture during subsequent pregnancy seems to be a rare event.  Due to paucity of robust evidence and given the potentially devastating consequences of uterine rupture, a scheduled delivery at 38 weeks should be offered to women with myomectomy. However, this does not preclude a trial of vaginal delivery after an informed decision.

References

  1. ACOG Practice Bulletin, 2004.
  2. Bernardi TS et al., Archives of Gynecology & Obstetrics. 2014
  3. Chauhan SP et al., American J Obstet Gyne 2003.
  4. Milton, SH. In: eMedicine, ME Rivlin (ed). 2015

 

 

 

 

 

 

 

ADVANCED MATERNAL AGE AND PREGNANCY RISKS

There is currently an increasing trend towards delay childbearing across the world. Among the reasons are delay due to longer schooling, late marriage, shift in life priority, financial security, availability of contraception and women exercising their choices.  The consequence of this shift has led to more elderly pregnant mothers.

The commonly accepted definition of advanced maternal age (elderly) is 35 years or more. Studies have shown that pregnancy in this group of women is associated with a higher complication risk to both the mother and baby. Women should be supported in their decisions of whether to have children or not and when to plan childbearing. They should also be aware that the fertility and pregnancy outcomes change with age. For these reasons, women are encouraged to consider having families during the period of optimum fertility.

Pregnancy risks

Maternal age has been shown to affect pregnancy from conception to delivery. Biologically, the best period for pregnancy is between 20–35 years of age. The spontaneous conception rate is 75% in women aged 30 compared to 66% in those aged 35 years old (Leridon 2004). The pregnancy rate in elderly women is lower due to poorer egg quality associated with aging.  There is also a higher risk of spontaneous miscarriage. The reported miscarriage rate at 22 years old is 8.2%, but increases to 20% among women at 35 years of age.

Elderly mother has an increased risk of fetal chromosomal abnormalities and congenital anomalies. The risk of Down syndrome, the commonest cause of mental retardation is significantly increased from 1 in 1000 when the pregnant woman is 25 years of age compared to 1 in 250 at 35 years.

There is also a higher association of preterm birth, small for gestational age (small baby and intrauterine growth restriction, IUGR) among elderly mothers. The preterm delivery may be unexplained or iatrogenic, due to intervention following maternal complications (see below). Elderly mother may be associated with poorer placental perfusion or transplacental flux of nutrients. This led to an increased likelihood of a small for gestational age baby.  All these complications are associated with a higher neonatal intensive care unit admission and higher morbidity.

 

Increase perinatal morbidity and mortality

The risk of stillbirth (fetal demise after 28weeks gestation) is significantly higher in older women, partly due to the risks of aneuploidy (chromosomal anomalies) and fatal congenital anomalies.  The increased incidence of small for gestational age babies in the older women further contributes to the increased stillbirth rate.

 

Maternal complications

Older women are more likely to have pre-existing medical disorders such as diabetes mellitus or hypertension, which further complicate the pregnancy. There is an increased incidence of antepartum haemorrhage, malpresentation, pre-eclampsia and gestational diabetes mellitus.  All these complications lead to a higher operative vaginal delivery and Caesarean section.

 

Conclusions

Pregnant women aged ≥35 years are at increased risk of complications in pregnancy compared with younger women. Although women should be supported in their life choices, they should be aware of the possible problems that older mothers may encounter. Adherent to frequent antenatal visits, under an experienced obstetrician and increased fetal surveillance are some measures that may help to ensure a better outcome.

 

References

  1. Huang L et al., CMAJ 2008.
  2. Leridon H. Human Reproduction 2004
  3. RCOG statement on later maternity age 2009

 

VAGINAL SEEDING FOR CAESAREAN BABY!!

Vaginal seeding is a practice used for babies born by caesarean section that aims to mimic the exposure to bacteria that would have occurred during a normal vaginal delivery.  It involves rubbing vaginal fluid on the baby’s mouth, face and body, with the intention of exposing it to the “healthy” bacteria it would be exposed to in a vaginal birth.

This is not a standard practice.  It first hits the news in the United States in 2015.  It is believed that the practice of vaginal seeding improves the baby’s immunity.

The origin of this practice came from reports that found associations between being born by caesarean section and a “modest” increased risk of obesityasthma and autoimmune diseases. Other observational studies have shown associations between these conditions and changes in the different varieties of micro-organisms, such as bacteria normally present on and in the body.  These and other animal studies suggest exposure to these bacteria may play a role in developing a healthy immune system and reducing the risk of certain non-infectious diseases.

Despite the lack of studies proving cause and effect, many women in Australia and the UK are reportedly requesting the procedure after reading about it in the news.

Besides its unproven benefits, the vaginal seeding may risk the babies developing serious infections from potentially harmful bacteria (Group B Streptococcus, Chlamydia, Gonorrhea) or viruses (Hepatitis B, Genital herpes) from unaware mothers.

The current medical consensus is not to perform the procedure because there is no evidence of any benefits. The risk of harm cannot be justified. However, if the mothers have made an informed decision for vaginal seeding, their wishes should be respected.

Finally, the practice of breastfeeding and limiting exposure to antibiotics are both recommended ways to help the child obtain a wide variety of normal bacteria needed to build a strong immune system.  In summary, the practice of vaginal seeding lacks evidence to be routinely instituted on Caesarean birth babies.

LATEST ON UTERINE TRANSPLANT- A DISAPPOINTING OUTCOME FOR THE FIRST UTERINE TRANSPLANT IN U.S.

The recent achievement of successful uterine transplant by Professor Brannstrom from Europe opens up a new excitement in the field of reproductive medicine.  This new surgical technology gives hope to women with uterine factor infertility, to conceive. Currently, the European team had reported five babies born to mothers with transplanted uteruses

On February 25th, 2016, the Cleveland Clinic in United States, similarly reported its successful uterine transplant, using a uterus from deceased donor.  However, the recipient developed complications within a week.  This had led to removal of the transplanted uterus on March 8th.  The preliminary report showed that the complication was due to infection that compromised the blood supply to the newly transplanted uterus.  The US team is actively looking into improving the protocols to reduce the risk of this complication in the future.

MRI GUIDED FOCUSED ULTRASOUND (MRIGFUS)- A NOVEL APPROACH TO THE TREATMENT OF UTERINE FIBROID?

Uterine fibroid is one of the commonest benign tumor amongst women.  It is present in 30%  of premenopausal women and is the main indication for hysterectomy.  Currently, there is no effective medical treatment available.  The uterine artery ablation has been offered as alternatives to surgical treatment (hysterectomy) but its clinical application is limited.

The MRI guided focused ultrasound is a minimally invasive fibroid treatment that uses a tightly focused ultrasound waves to deliver heat that instantaneously destroys fibroid tissue.  It is performed as an outpatient procedure with sedation.  The fibroid location is identified using T2-weighted MR imaging followed by a pretreatment planning and application of multiple therapeutic sonications to a temperature of at least 65 degree Celsius.  The heat generated basically ablates the fibroid tissue. The whole procedure takes about two to three hours.  The recovery time of about one to three days appears promising as a viable alternative to the current surgical option.

There are many reports of the experience with this treatment modality.  These reports were not from a high quality study design and occasionally sponsored by industry that are prone to bias and confounding.

There is only one randomized, placebo-controlled trial (PROMISe) to date, that assess the effectiveness of MRIgFUS therapy.  This is a high quality study and has a post treatment follow-up period of 2 years duration.  The result shows there is no diffence between MRIgFUS and placebo group, in terms of symptom improvement and quality of life at 4 to 12 weeks post procedure.  However, about a third (30%) of all women who had MRIgFUS therapy opted for hysterectomy by 2 years post treatment.

In summary, the MRIgFUS treatment for uterine seems promising and avoids the need for surgery.  Currently, the available results suggest its role as a temporary alternative treatment prior to the decision for hysterectomy, at best.

Reference

PROMISe trial (Pilot Randomized trial of MRIgFUS for symptomatic fibroid) trial. Fert Steril 2016

Alternative therapies in management of leiomyomas. Fert Steril 2014

Clinical improvement and shrinkage of uterine fibroids after thermal ablation by magnetic resonance-guided focused ultrasound surgery. Ultrasound Obstet Gynecol 2007.

Clinical outcomes of focused ultrasound surgery for the treatment of uterine fibroids.  Fert Steril 2006