Combination of labor induction agents almost halves the time to delivery.

The cascade of spontaneous events that sets the wheels of labor in motion has remained a mystery despite all the recent advances in the field of maternal and fetal medicine. Researchers hypothesize that it’s blend of physiology and magic that sets the ball rolling. Maternal and fetal signals both play a part in starting the process.

The history of labor induction dates to time of Hippocrates' when mammary stimulation and mechanical cervical dilatation was used to bring about uterine contraction.[1]

Induction of labor for singleton births has seen a slight decline from 23.8% in 2010 and 23.3% in 2012 after seeing a steady increase in past 20 years. [2]  This translate to 932,000 women undergoing induction of labor for various maternal and fetal indication.

Various mechanical and chemical methods singly or in combination have been in use since long. The choice of method depends on state of cervix, previous obstetric history, indication of induction and gestational age at induction. Foley’s balloon catheter, Prostaglandin E2 and misoprostol are common methods used for cervical ripening. Amniotomy and oxytocin are used when the cervix is already ripened.[3]

A recent paper published on November 03, 2016 in Journal of Obstetrics & Gynecology evaluated the effectiveness of the four most commonly used method. [4] The paper was also presented at the Pregnancy Meeting, the 2016 Annual Meeting of the Society for Maternal-Fetal Medicine (SMFM).

Dr. Lisa Levine, MD, University of Pennsylvania’s Perelman School of Medicine, Philadelphia, Pennsylvania, and colleagues said in their presentation “This randomized trial is one of the first of its kind to compare 4 different induction methods in a head-to-head trial. We found that combination induction methods resulted in delivery in half the amount of time as single agents with no difference in caesarean delivery rates.”

The study called as Foley or Misoprostol for the Management of Induction (FOR MOMI) trial was a 4-armed randomized trial conducted between May 2013 and June 2015. The study recruited 492 women with singleton full-term pregnancy (37 weeks of gestation or greater), vertex-presentation, with no contraindication to vaginal delivery, intact membranes, Bishop score 6 or less, and cervical dilation 2 cm or less. These women were assigned to receive either misoprostol alone; or Foley catheter alone; Foley catheter and Pitocin concurrently or misoprostol and cervical Foley catheter concurrently.

The primary outcome measured was reduction in time to delivery with a reduction of more than 4 hours considered significant. Numerous secondary outcomes like time to vaginal delivery, rate of caesarean deliveries, time in active labor, defined as cervical dilation of 5 cm or more, delivery within 12 or 24 hours, and maternal length of stay were also looked at.

The demographics and clinical characteristics of the study participants were quite similar with a mean age of 27 years, 72% being nullipara, mean gestational age at induction being 39 weeks with mean bishop score 3 and mean cervical dilatation 1.

The median time to delivery for nulliparous and multiparous women in various arms of the study are (P<.001):

misoprostol–Foley group       13.1 hours

oxytocin–Foley group            14.5 hours

misoprostol only                    17.6 hours

Foley-only group                   17.7 hours

When the data was adjusted for parity and only vaginal deliveries analyzed, women in the misoprostol-Foley group where twice as likely to deliver earlier (HR=1.92) with reference to misoprostol only or Foley-only group.

  

Women in the combination arms of the study also had the maximum chance of delivering in 24 hours. (88% of women in the misoprostol/Foley group and 84% in the oxytocin/Foley group).

Rates of cesarean section and other maternal morbidities like perineal lacerations, endometritis, wound infection and dehiscence, readmission or length of stay were comparable in all the groups. No significant difference was found in neonatal morbidities too.

The authors opined that “This study has significant clinical implications for obstetric care. The ability to shorten the length of time women spend in labor without increasing morbidity has large clinical and financial implications given the cost and known maternal–neonatal risks associated with both prolonged labor and cesarean delivery."

The only study limitation was lack of blinding, because women had to be examined for application of different methods in 4 study arms. Also, individual arm lacked the statistical power to compare the cesarean section, maternal and neonatal morbidities across different groups.

In all, the findings could help millions of women and shorten thousands of hours in labor across the world. It is estimated that nearly 20% or 932,000 women undergo induction of labor in USA. If combination method is used in all of them, then there would be more than 3 million fewer hours, or more than 125,000 fewer days that women spend in labor in the United States alone. 

This has huge financial and health care utilization implications.

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[1] www.glowm.com/section_view/heading/Induction%20of%20Labor/item/130

[2] http://www.cdc.gov/nchs/data/databriefs/db155.pdf

[3] https://sogc.org/wp-content/uploads/2013/08/September2013-CPG296-ENG-Online_REV-D.pdf

[4] http://journals.lww.com/greenjournal/Abstract/publishahead/Mechanical_and_Pharmacologic_Methods_of_Labor.98564.aspx

New Use of old PAP test: Prenatal Genetic Screening

photo courtesy:Wikimedia commons 

Noninvasive prenatal testing (NIPT) used for antenatal detection of fetal aneuploidy is expanding worldwide. NIPT is the most recent addition to the growing armament of methods available for diagnosing chromosomal malformations. The test detects the fetal circulating DNA in maternal blood.

In USA, cell-free DNA analysis became clinically available in 2011 and the American College of Obstetricians and Gynecologists and the Society for Maternal–Fetal Medicine recommended it as a screening option for women at increased risk of fetal aneuploidy. Its use has since been expanded as a screening tool in general obstetric population.[1]

Fetal circulating cell free DNA is derived mostly from placenta and is present in maternal blood for testing as early as 10 weeks of gestation. Different laboratories have validated different techniques and mainly rely on next-generation sequencing technologies and advanced bioinformatic analyses.[2]

Cell free DNA is commonly used to screen for only the common trisomies and, if requested, sex chromosome composition. The sensitivity and specificity as well as the negative predictive value of the method is >99% for trisomy 21 (Down syndrome), with slightly lower performance for trisomy 13 and 18.[3]

However, this test is sometimes limited by low fetal cell fraction in the collected sample. The other two most commonly used test are both invasive. (amniocentesis and chorionic villus sampling).

A recent paper published by Jain et al in Science translational medicine describes a method for still earlier detection of trophoblastic cells, carrying fetal DNA by Papanicolaou smear. It is possible to analyze fetal DNA as early as 5 weeks without any of the invasive tests.[4]

Incidence of fetal aneuploidies are on the rise because of more and more women delaying pregnancies till late thirties or early forties.

The new technique was shown to be effective in correctly picking up cell free DNA from cells collected from maternal endocervical canal in 20 consecutive samples.

Chandni V. Jain, PhD, a research associate in the laboratory of Sascha Drewlo, PhD, and D. Randall Armant, PhD, and colleagues at Wayne State University School of Medicine, Detroit, Michigan, devised a "nuclear isolation protocol" to exclude most maternal DNA from ECC samples.[5]

The investigator quoted “a straightforward alternative that uses a Pap smear to capture intact fetal trophoblast cells in numbers sufficient for next-generation sequencing as early as 5 weeks of gestation." 

The average fetal cell free DNA fraction was 92.2% ± 6.5%, way more than 4% to 10% obtained from maternal blood at 10 weeks for Noninvasive prenatal testing (NIPT).

This test has got tremendous commercial potential as it utilizes existing technology in a novel way.

The limitation at present are small sample size (20) and placental mosaicism.

James Byrne, MD, maternal-fetal medicine specialist and chair of the Department of Obstetrics and Gynecology at the Santa Clara Valley Medical Center and affiliated clinical professor, Stanford University School of Medicine, California opined that the technique is simple, safe and will be accepted widely by patients and physician once it is endorsed by national organization like American Congress of Obstetricians and Gynecologists and Society for Maternal and Fetal Medicine.

Larger studies with large sample size are awaited before it can be used for screening of all pregnant women, who are at average risk. It’s also very suitable for genetic testing, which targets high-risk groups, such as women over age 35 or with a family history of a detectable genetic or chromosomal condition.

A perfect example of new use of old technology. 

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[1] http://www.acog.org/Resources-And-Publications/Committee-Opinions/Committee-on-Genetics/Cell-free-DNA-Screening-for-Fetal-Aneuploidy

[2] Zimmermann B, Hill M, Gemelos G, Demko Z, Banjevic M, Baner J, et al. Noninvasive prenatal aneuploidy testing of chromosomes 13, 18, 21, X, and Y, using targeted sequencing of polymorphic loci. Prenat Diagn 2012;32:1233–41

[3] http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0156088

[4] http://stm.sciencemag.org/content/8/363/363re4

[5] Prenatal Genetic Screening Through Pap Smear?. Medscape. Nov 02, 2016.

Five viruses, a chemical, and a metallic element added to the list of human carcinogens.

 The U.S. Department of Health and Human Services 14th Report on Human Carcinogens was released today bringing the total to 248.

Image courtesy: Pixabay

The 5 viruses include human immunodeficiency virus type 1, human T-cell lymphotropic virus type 1, Epstein-Barr virus, Kaposi sarcoma-associated herpesvirus, and Merkel cell polyomavirus. People with weak immunity or on immunosuppression drugs are more likely to develop these cancers.

Linda Birnbaum, Ph.D., director of the National Institute of Environmental Health Sciences (NIEHS) and National Toxicology Program (NTP) said in a press release that "Given that approximately 12 percent of human cancers worldwide may be attributed to viruses, and there are no vaccines currently available for these five viruses, prevention strategies to reduce the infections that can lead to cancer are even more critical."[1]

These viruses are responsible for causing 20 different cancers in humans. All the viruses are transmitted through body fluids and saliva. In addition, 3 out of 5 are also spread because of unprotected sexual activity namely human immunodeficiency virus type 1, human T-cell lymphotropic virus type 1 and Kaposi sarcoma-associated herpesvirus (KSHV).

The chemical in the list is Trichloroethylene (TCE), It is an industrial solvent used primarily to make hydrofluorocarbon chemicals, especially refrigerants. Earlier it was in the list of suspected carcinogen but recent studies have proved causation between TCE exposure and an increased risk for kidney cancer. It makes its way into air, water and soil at places where it is manufactured or used. People can be exposed by multiple routes especially underground drinking sources. It’s especially abundant in soil and water in military areas and practice grounds.

The metallic element listed as carcinogen is cobalt and cobalt compounds that release ions into the body. Cobalt is a natural occurring element used in military equipment and rechargeable batteries. Humans can be exposed to it at workplace and due to failed surgical implants.

In our body cobalt is present as an important component of vitamin B-12, also called cobalamin which plays a key role in normal functioning of nervous system and needed for erythropoiesis. However, it is not toxic in our body since it is chemically bound to protein and does not release cobalt ions in the body.

All these cancers can be prevented by minimizing the exposure to the listed carcinogens. Dr. Linda Birnbaum quoted in the news release “The listings in this report, particularly the viruses, bring attention to the important role that prevention can play in reducing the world's cancer burden. There are also things people can do to reduce their exposure to cobalt and TCE.”

As always practicing safe sex, not sharing needles and contacting your health care provider if you have been already exposed to any of the viruses listed goes a long way in minimizing your risk for cancers due to these viruses.[2]

Exposure to TCE can be reduced at work places and military settlements by wearing protective gear and properly using respirators. If it is known to be present in the underground water sources than such water should not be used for drinking. [3]

Cobalt exposure can be reduced by using the same measures that for TCE. In addition, children living near the dumpsites containing cobalt should wash their hands frequently before eating.[4]

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[1] http://www.niehs.nih.gov/news/newsroom/releases/2016/november3/index.cfm

[2] http://www.niehs.nih.gov/health/materials/5_viruses_508.pdf

[3] http://www.niehs.nih.gov/health/materials/tce_508.pdf

[4] http://www.niehs.nih.gov/health/materials/cobalt_508.pdf