When to make the diagnosis of failed induction of labor after Oxytocin and Rupture of membranes?

Clinical Pearls:

• In Nulliparous women 12 hours of Oxytocin and Rupture of membranes is optimum before diagnosing an unsuccessful induction. The neonates of women who remained in latent phase past 12 hours have increased rate of NICU admissions.
• In Multiparous women 15 hours of Oxytocin and Rupture of membranes is optimum before diagnosing an unsuccessful induction. The neonates of women who remained in latent phase past 15 hours have increased rate of NICU admissions.
• The longer women remained in latent phase with Oxytocin and Rupture of Membranes, the risk of maternal and neonatal complication increased.

According to CDC between 1990 and 2011 the rate for labor induction have more than doubled rising from 9.5% to 23.2%. About 762,000 induction of labor were performed making it one of the most commonly performed obstetric procedure in US.[1]

There is no accepted definition of “failed induction of labor”, although the ACOG in its statement to bring down the cesarean section rate does quote “cesarean deliveries for failed induction of labor in the latent phase can be avoided by... requiring that oxytocin be administered for at least 12–18 hours after membrane rupture before deeming the induction a failure.”[2] However this recommendation by ACOG is based on limited studies with very small study population. [3] In the two studies on which the recommendation is based 17- 60% of the women had vaginal delivery after still being in latent phase after 12 hours. [4] [5]

A Joint statement issued by Eunice Kennedy Shriver National Institute of Child Health and Human Development, Society for Maternal-Fetal Medicine, and American College of Obstetricians and Gynecologists Workshop quotes that “The diagnosis of failed induction should only be made after an adequate attempt. Failed induction is defined as failure to generate regular (eg, every 3 minutes) contractions and cervical change after at least 24 hours of oxytocin administration with artificial membrane rupture if feasible.”[6] But, with the latent phase extending long, maternal and neonatal safety concerns are constantly raised.

A recent retrospective cohort study published in Journal of Obstetrics and Gynecology compared neonatal and maternal outcome in relation to oxytocin induction and rupture of membranes before the active phase of labor (Cervical dilatation > 6 cm). This large study used the data from Consortiumon Safe Labor (CSL) which is a consortium of 12 clinical institutions providing data on labor and newborn to create a perinatal database with more than 200,000 deliveries. The de-identified database is than used for secondary data analysis to answer several obstetrics questions.

The study data included 9,763 nulliparous and 8,379 multiparous women, carrying singleton term pregnancies, with unfavorable cervix. In all these women labor was induced at 2 cm dilatation or less to 6 cm dilatation with rupture of membrane.  6 cm was taken as cut-off because women entered into active phase of labor once they crossed the 6 cm dilatation. No cervical ripening agent was used in the women included in the study.

The clinical outcomes evaluated included vaginal delivery rates, maternal and neonatal morbidity including NICU admissions. Women were assessed at fixed intervals of 6, 9, 12, 15, and 18 hours post oxytocin and rupture of membranes in regards to cervical dilatation, contraction, vaginal delivery or cesarean delivery. Time was marked zero hour when oxytocin and rupture of membrane both were present.

Hypertensive disorders of pregnancy were the most common indication for induction of labor in nulliparous (21.8%) and multiparous patients (10.7%) followed by post-date pregnancy.

At the end of 12 hours most of the nulliparous women have entered the active phase or have delivered with only 6.5% still in the latent phase, while at 15 hours only .6% multiparous women were still in the latent phase.

Eventually, out of this group 36.6% of the nulliparous and 50.0% of multiparous women had vaginal birth.  Those nulliparous women who still were in latent phase of labor at the end of 12 or 15 hours had high rates of maternal and neonatal complications. For multiparous patients who were still laboring at the end of 15 hours had increased maternal complications but the rate of NICU admission were not statistically significant.

The longer the patients remained in the latent phase with rupture of membranes and oxytocin, chances of vaginal delivery decreased proportionately and maternal and neonatal complications increased as time progressed. Maternal complications include chorioamnionitis, PPH and endometritis while neonatal complications include neonatal sepsis and NICU admissions.

The large cohort of patient’s data drawn from diverse population powered the study sufficiently to study a variety of outcomes including neonatal morbidity and NICU admission associated with longer duration of oxytocin and rupture of membranes. It also increased the generalizability of the study. Labor management is not standardized across the hospitals which may have led to cesarean deliveries in latent phase without waiting longer.

It was seen that the longer women remained in latent phase with Oxytocin and Rupture of Membranes, the risk of maternal and neonatal complication increased. Because of the retrospective nature of the data, diagnosis of failed induction cannot be made but 12 hours of Oxytocin and rupture of membranes in Nulliparous and 15 hours in Multiparous patient is a reasonable cutoff, because neonatal morbidity rises after that.

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[1] http://www.cdc.gov/nchs/fastats/obstetrical-procedures.htm

[2] Safe prevention of the primary cesarean delivery. Obstetric Care Consensus No. 1. American College of Obstetricians and Gynecologists. Obstet Gynecol 2014;123:693–711

[3] http://www.acog.org/Resources-And-Publications/Obstetric-Care-Consensus-Series/Safe-Prevention-of-the-Primary-Cesarean-Delivery

[4] Rouse DJ, Owen J, Hauth JC. Criteria for failed labor induction: prospective evaluation of a standard protocol. Obstet Gynecol 2000;96:671–7

[5] Simon CE, Grobman WA. When has an induction failed? Obstet Gynecol 2005;105:705–9

[6] http://journals.lww.com/greenjournal/Fulltext/2012/11000/Preventing_the_First_Cesarean_Delivery__Summary_of.26.aspx

Moderate intensity physical activity for an hour mitigates the risk of death associated with sedentary lifestyle: A Meta-analysis.

Clinical Pearls:

• Intense to moderate physical activity for 60-75 minutes’ can eliminate the effects of prolonged sitting (> 8 hours).
• This equals to brisk walking at 5.6 km/h or cycling for pleasure at 16 km/h.

The association of sedentary lifestyle and many chronic conditions and colorectal cancer is well known and physical inactivity is an important modifiable risk factors in the causation of many chronic condition.  Prolonged sitting is one of the important cause of premature mortality.

But, according to a Meta-analysis involving about a million people, intense to moderate physical activity for 60-75 minutes’ can undermine the effects of prolonged sitting. This study was published online in the Lancet on July 27, 2016.[1] Examples of physical activity were brisk walking at 5.6 km/h or cycling for pleasure at 16 km/h.

This is a second in the series of articles published on physical inactivity by Lancet, the first was published in 2012, sending a message that physical inactivity is a global pandemic killer-responsible for 5.3 million premature deaths worldwide. The number equals the deaths caused by smoking and twice the deaths caused by obesity.

This is the first harmonized meta-analysis that compares the relationship between all-cause mortality and sedentary life style and different levels of physical inactivity.

A systematic review of literature identified about 16 studies out of which 13 were identified by the researchers as providing data on sitting time and all-cause mortality.

The combined study data generated data on pool of 1,005,791 individuals from different countries, who were followed up for 2-18 years.

The study participants were divided into quartiles according to the time spent being physically active and ranged from less than 5 minutes/day to 60-75 minutes/day. The daily sitting and TV viewing time was also divided into 4 standardized protocol.

It was seen that those who very active (60-75 minutes/day), the amount of sitting time does not increase the mortality. But, the risk of death increases as the activity time decreases. WHO guidelines also recommends at least 150 minutes of physical activity per week, which is far less than what the study recommends.[2]

"A clear dose-response association was observed, with an almost curvilinear augmented risk for all-cause mortality with increased sitting time in combination with lower levels of activity," the researchers noted.

For the purpose of estimating the hazard ratio(HR), the most active individuals were used as the reference group. (HR=1).

People who exercised the least (less than 5 min/day) were at highest risk, even if they did not spend much time sitting (less than 4 h/day). In this group the hazard of premature death was 1.27. This was way higher than those group of individuals who were most active physically (60-75 min/day) but also spent more than 8 hours sitting (HR=1.04). This was very close to the referent group, which led the researchers to conclude that physical inactivity is the root cause of premature deaths, independent of the hours of sitting.

The findings of this study emphasized the importance of physical activity, even if you have a job that demands prolonged sitting.

The study also draws attention towards relationship with TV watching and premature death. Watching TV for more than 3 hours per day is associated with premature death regardless of physical activity except in the most active quartile. In this group the mortality was only increased if you watch more than 5 hours of TV. The benefit of physical activity is not very strong in people watching TV because of “residual confounding”. Dr. Ekelund points that perhaps these people have unhealthy life- style that include snacking or drinking that increases the risks.

Ekelund pointed out in a London press conference [3]  that the average amount of time adults in the United Kingdom spend watching TV is three hours and six minutes. “I don’t know if it’s too much to ask that maybe a little of those three hours be devoted to physical activity,” he said. The general rule of thumb, as Ekelund succinctly advised: “Sit less and move more, and the more the better.”

He also emphasized the message about "moving more," suggesting that people should walk as much as they can and that if they do need to sit for prolonged periods, they should break up those periods with short bursts of activity, such as walking for 5 minutes every hour.

The full Lancet podcast about the series can be heard here.

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[1] http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30370-1/fulltext

[2]  http://www.who.int/dietphysicalactivity/factsheet_recommendations/en/

[3] http://press.thelancet.com/PhysicalactivityMEDIA.mp3

Induction of labor does not hike the risk for Autism Spectrum disorders.

Clinical Pearls:

• Contrary to the findings of earlier study, Induction of labor does not increase the risk for development of Autism Spectrum disorders(ASD).

Autism Spectrum disorders(ASD) is a group of complex developmental disability that affects a person ability to interact and communicate socially. It includes several conditions that were earlier diagnosed separately and include autistic disorder, pervasive developmental disorder not otherwise specified (PDD-NOS), and Asperger syndrome.

According to CDC about 1% of world population have ASD. It is the fastest growing developmental disability in US and the current prevalence is 1 in 64 births and has increased 119.4 percent from 2000 (1 in 150) to 2010 (1 in 68).[1] An article published in JAMA Pediatric 2014 by Buescher et al. estimated that about 3.5 million people in US live with ASD.[2]

Numerous pregnancy related risk factors have been attributed in putting the children at high risk for ASD like children that were born to older parents,  were preterm or low birth weight, born with other chromosomal disorders like  Down syndrome, fragile X syndrome, tuberous sclerosis and  those delivered by cesarean section.

A study published in Annals of Epidemiology attributed three perinatal risk factors like being born too early, too small, and/or by Cesarean delivery to be responsible for 12-13% of ASD in children.[3]

Many other studies have examined the mother’s use of  serotonin uptake  inhibitors (SSRIs) and increasing use of ART as a causative factor for  sudden increase in prevalence of ASD.

Another large population based study published in JAMA pediatrics in October,2013 concluded that “Compared with children born to mothers who received neither labor induction nor augmentation, children born to mothers who were induced and augmented, induced only, or augmented only experienced increased odds of autism after controlling for potential confounders related to socioeconomic status, maternal health, pregnancy-related events and conditions, and birth year. The observed associations between labor induction/augmentation were particularly pronounced in male children.”[4]

This study sparked a widespread debate between physicians and researchers and the lead author of the study Dr. Gregory proposed the culprit to be oxytocin in induced or augmented labors, putting these children at high risk for ASD. After this controversy ACOG put out a committee opinion (597) in 2014 stating that “Current evidence does not support a conclusion that labor induction or augmentation causes autism spectrum disorder (ASD) in newborns, available evidence is inconsistent and does not demonstrate causation.”[5]

A recent study conducted by researchers at Harvard T.H. Chan School of public health in Boston and published in JAMA pediatrics online first on July 25, 2016 found no association between induction of labor and ASD. This large nationwide study performed in Sweden, followed up a cohort of 1,362,950 children born between 1992-2005. Out of which 1.6% (22077) children were diagnosed with ASD by ages 8 years through 21 years.  

In 11% of the mothers’ labor induction was done due to preeclampsia, gestational diabetes and chronic hypertension. After the statistical analysis, the study found an association between labor induction and ASD but when the analysis was performed between siblings and close relatives the association was not documented.

Siblings share many genetic, socioeconomic and maternal characteristics that may increase the risk for development of ASD, so if association is not documented when comparing with them, the association probably does not exist.

The finding of this large study suggests that if clinically indicated, decision to induce labor should not be withheld in fear of baby developing ASD. Not to induce the labor when indicated may have adverse neonatal consequences.

Dr. Bateman concludes "Overall, these findings should provide reassurance to women who are about to give birth, that having their labor induced will not increase their child's risk of developing autism spectrum disorders."

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[1] https://www.cdc.gov/ncbddd/autism/facts.html

[2] http://www.ncbi.nlm.nih.gov/pubmed/24911948

[3] Schieve LA, Tian LH, Baio J, Rankin K, Rosenberg D, Wiggins L, Maenner MJ, Yeargin-Allsopp M, Durkin M, Rice C, King L, Kirby RS, Wingate MS, Devine O. Annals of Epidemiology. January 2014. [epub ahead of print]

[4] Gregory SG, Anthopolos R, Osgood CE, Grotegut CA, Miranda M. Association of Autism With Induced or Augmented Childbirth in North Carolina Birth Record (1990-1998) and Education Research (1997-2007) Databases. JAMA Pediatr.2013;167(10):959-966. doi:10.1001/jamapediatrics.2013.2904.

[5] http://www.acog.org/Resources-And-Publications/Committee-Opinions/Committee-on-Obstetric-Practice/Labor-Induction-or-Augmentation-and-Autism

Iron deficiency in Pregnancy linked to hypothyroidism!

Clinical Pearls:

• The study findings show that prevalence of iron deficiency is still 35% in a developed country like Belgium.
• 10% of pregnant women with iron deficiency will have thyroid autoimmunity and 20% will have subclinical hypothyroidism.

According to WHO the prevalence of anemia in pregnancy is nearly 40% worldwide, with iron deficiency being the major cause.[1]

A small Belgian study published in European Journal of Endocrinology on July 22, 2016 linked low serum iron with increased risk of thyroid autoimmunity and hypothyroidism in pregnancy.[2] It was a nested cross sectional study as a part of ongoing data collection on pregnant woman at a single tertiary center in Université Libre de Bruxelles in Belgium.

The analysis included 1900 study participants in the first trimester of pregnancy. Iron deficiency was diagnosed when ferritin levels were < 15 μg/L, subclinical hypothyroidism was defined as a TSH level > 2.5 mIU/L and thyroid peroxidase antibodies(TPO-abs) was > 60 kIU/L defined thyroid autoimmunity(TAI).

Iron is necessary for the normal functioning of thyroid peroxidase(TPO) which is a  heme-containing enzyme catalyzing the two initial steps in thyroid hormone synthesis.

Nearly one third of the women suffered from iron deficiency, and in these women significant association was found between low iron and thyroid autoimmunity (10% versus 6%) and subclinical hypothyroidism (20% versus 16%) as compared to women with normal iron levels.

The study co-author Kris Poppe, MD, an endocrinologist opined that in his daily practice,  those women who are often referred to him  for thyroid  dysfunction often seems to  have low iron levels concurrently. 

It is a very small study which does not have significant impact on clinical practice, nor does it proves causation. Low Ferritin levels might be due to other nutritional deficiency or poor diet. But, it does emphasize on the need for replicating the study in different population, with larger data.

Dr. Kris Poppe also stressed the need for checking the iron levels in first trimester of pregnancy or before planning the pregnancy so that any nutritional deficiency could be corrected.

The researchers are planning to design studies that look into impact of low iron and thyroid dysfunction on pregnancy outcomes.

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[1] http://www.who.int/vmnis/anaemia/prevalence/summary/anaemia_data_status_t2/en/

[2] http://www.eje-online.org/content/early/2016/07/22/EJE-16-0288.abstract

First female to male sexual transmission of Zika virus documented in New York.

Yet another very important update on sexual transmission of Zika virus from CDC was published online in CDC's Morbidity and Mortality Weekly Report[1]

Till now it was known that sexual transmission of ZIKA virus only takes place from male to female partner. But, The New York City Department of Health and Mental Hygiene (DOHMH) today identified the first case of a female transmitting the Zika virus to a man through sex in New York city.

This surprising new announcement have prompted the CDC to update its guidelines on the sexual mode of transmission of the virus.

A 20-year-old non-pregnant woman had condomless vaginal intercourse with male partner on the day she returned from a country where Zika virus infection is ongoing. She was completely symptomless on the day of return, but was down with Zika-like symptoms, including fever, rash, fatigue and muscle pain, along with numbness and tingling in her fingers and toes. On the next day she visited her primary health care provider, who confirmed the illness as Zika virus after getting the results of her urine and blood test. ((rRT-PCR). 

A week after the sexual contact, the male partner also had similar symptoms and was also diagnosed with Zika infection. On detailed history he ruled out other mode of Zika transmission. He has not travelled outside the country since 1 year, only had one sexual encounter since a week and did not have any mosquito bite.

Both the partners tested negative for Zika virus IgM antibodies by the CDC Zika MAC-ELISA assay performed at the New York State Department of Health Wadsworth Center.

CDC report concluded that “The timing and sequence of events support female-to-male Zika virus transmission through condomless vaginal intercourse.” The woman was most likely viremic when she had sex with her partner, and the virus was transmitted through uretral mucosa or penile abrasion or cut from woman’s vaginal or menstrual blood.   

A case report published on May 2016 in Lancet has already documented the presence of Zika virus in female genital tract.[2] Non-Human studies in primates have shown the presence of the virus in genital tract up to 7 days after subcutaneous inoculation.[3]

This case is very important from public health perspective as until now, it was assumed that the Virus is transmitted from a male partner to a receptive partner, now ongoing surveillance will be needed to combat the additional risk of reverse transmission. CDC is also advising protection for pregnant women with female sex partners who might have travelled to Zika endemic areas, though woman to woman transmission is not known till now.

The report stressed the need for further studies to determine the amount of time of virus survives in female genital tract.

The Aedes aegypti mosquitos still is the major source of infection.

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[1] http://www.cdc.gov/mmwr/volumes/65/wr/mm6528e2.htm?s_cid=mm6528e2_w

[2] http://www.thelancet.com/journals/laninf/article/PIIS1473-3099%2816%2930193-1/fulltext

[3] Dudley DM, Aliota MT, Mohr EL, et al. A rhesus macaque model of Asian-lineage Zika virus infection. Nat Commun 2016;7:12204

Multivitamin supplements ‘Is a waste of money’ for most women during pregnancy.

Multivitamins Courtesy Pixabay 

The drug market is flooded with myriad combinations of prenatal multivitamins and nearly all women are routinely prescribed these at prenatal visit to healthcare provider. It has long been claimed that taking a daily multi translate into better health for women and her unborn child.

Maternal deficiency of certain nutrients is linked with congenital malformations and poor pregnancy outcomes like preeclampsia, IUGR, skeletal deformities and neural tube defects.

This has given rise to billion-dollar pharma industry manufacturing and marketing products targeted at antenatal women and her baby. Globally the retail value sales of Prenatal Vitamin grew by 34% between 2008 and 2013 to reach its current market value of US$ 4.7 billion worldwide and is expected to rise continuously.[1]

According to the researchers, a typical prenatal Multi(MV) contains at least 20 different vitamins and minerals and sometimes the dose exceeds 100% RDS value. The average cost of daily prenatal MV is $20 per month.

A recent review[2]  published in British Medical Journal's Drug and Therapeutics Bulletin have refuted the need of Multivitamin supplements in pregnancy, the authors say “For most women who are planning to become pregnant or who are pregnant, complex multivitamin and mineral preparations promoted for use during pregnancy are unlikely to be needed and are an unnecessary expense.”

“The marketing of such products does not appear to be supported by evidence of improvement in child or maternal outcomes. Pregnant women may be vulnerable to messages about giving their baby the best start in life, regardless of cost,” the review further adds.

We found no evidence to recommend that all pregnant women should take prenatal multi-nutrient supplements beyond the nationally advised folic acid and vitamin D supplements, generic versions of which can be purchased relatively inexpensively," they say.

"Pregnancy multivitamins are a waste of money because most mothers-to-be do not need them, according to researchers," BBC News reports[3]

The researchers also looked at individual vitamins and supplements taken during pregnancy like Vitamin A, C, D and E, iron and folic acid. Strong evidence was only found in favor of supplementing Vitamin D and folic acid.

They have also cautioned against the excessive intake of Vitamin A which may be teratogenic to the fetus.

The researchers in this review have further confirmed the NICE guidelines:

• Folic acid (400 micrograms) should be taken when trying to conceive and for the first 12 weeks of pregnancy to protect against neural tube defects (NTD), such as spina bifida, in babies. 
• Folic acid dose is increased to 5 milligrams of folic acid a day where there is a family history of neural tube defects or where they have diabetes or have had a previous baby with a neural tube defect.
• 10 micrograms of vitamin D which equals 400 I.U each day throughout pregnancy that has to be continued while breastfeeding.

ACOG currently advises a pregnant woman to eat a well-balanced diet that includes foods from five groups: grains, fruits, vegetables, protein foods and dairy. Women who are pregnant requires extra folic acid and iron, which can be sourced from taking a prenatal Multivitamin but "a well-rounded diet should supply all of the other vitamins and minerals."[4]

Janet Fyle, from the Royal College of Midwives also dispelled the myth for eating for ‘two’ in pregnancy.

"We would also stress that there is no need for pregnant women to 'eat for two'."This is a myth, and all that is required is a normal balanced amount of food."

This news has angered the pharmaceutical industry, who are arguing that the prenatal vitamins are prescribed to fill in the gaps in the diet and not to cure any specific disease.

Two earlier studies and an expert editorial published in Annals of Internal Medicine have dispelled that myth too.  "The message is simple: Most supplements do not prevent chronic disease or death, their use is not justified, and they should be avoided," says the editorial, signed by two researchers from Johns Hopkins University in Baltimore, one British researcher and one of the journal's senior editors.[5]

The review may not be systematic, but it provides data supporting the current recommendation of NHS. The researchers also argue that most studies favoring Multivitamin supplementation in pregnancy are from developing countries, where women are deficient in many key nutrients. Hence, the same recommendation does not hold true for developed countries.

However, according to current evidence, eating a good balanced diet, along with folic acid and Vitamin D supplementation ensures the best possible outcome for pregnant woman and her unborn child.

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[1] http://blog.euromonitor.com/2014/05/optimizing-development-the-growing-paediatric-and-prenatal-supplements-market.html

[2] http://dtb.bmj.com/content/early/2016/07/11/dtb.2016.7.0414

[3] http://www.bbc.com/news/health-36765161

[4] http://www.acog.org/Patients/FAQs/Nutrition-During-Pregnancy#extra

[5] http://annals.org/article.aspx?articleid=1789253

Angiogenesis related biomarkers as a prognostic indicator in women with preterm preeclampsia.

Clinical Pearls:

• Studies and reviews have demonstrated that maternal serum levels of soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF) and sEng correlate with preeclampsia disease activity and are increased well before the onset of clinical signs and symptoms.
• Among the many markers evaluated, it was seen that a single angiogenesis related biomarker (PlGF, sFlt-1, or endoglin) alone can be used as an important diagnostic test for the primary endpoint in women with preterm preeclampsia.

The incidence of preeclampsia and related hypertensive disorders of pregnancy is 5-8% of all births in the United State while globally it is estimated that about 10,0000 women develop preeclampsia, and about 76,000 women succumb to preeclampsia, eclampsia and hypertensive disorders of pregnancy each year. [1]

According to WHO a woman in developing country is seven times more likely to develop preeclampsia than a woman in developed country. [2]

While preeclampsia presents itself clinically anytime between second trimester and postpartum, the pathological changes antedates it and begin at the end of first trimester and consist of abnormal remodeling of the spiral arteries.

While researchers all around the world have tried to develop various tests to accurately predict the women at risk of developing preeclampsia, but the current ability and availability of clinical test is still limited. Evidence suggests that preeclampsia develops because of endothelial injury, which sets forth a cascade of coagulation, vasoconstriction, and intravascular fluid redistribution.[3]Altered placentation and subsequent ischemia plays an important role in disease development. 

Among the sea of vast number of biomarkers, large number of studies and reviews have demonstrated that maternal serum levels of soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF) and sEng correlate with preeclampsia disease activity and are increased well before the onset of clinical signs and symptoms. But clinical applications of these have not been materialized in actual clinical practice.[4]

Only few guidelines have included them in daily practice. The German guidelines have recently included the sFlt-1/PlGF ratio as aiding in the diagnosis of preeclampsia.

Earlier studies have demonstrated the use of sFlt-1/PlGF ratio to predict adverse pregnancy outcome. Rana et al showed that in cases evaluated under 34 weeks of gestation, delivery took place in the two weeks following its determination in 86% of patients with a sFlt-1/PlGF ratio ≥85, compared with only 16% of women with a sFlt-1/PlGF <85.[5]

Measuring the sFlt-1/PlGF ration as a prognostic indicator have been adopted in large hospitals in Spain and if results are good, they can be used for risk stratifications and management.

A recent study published in the forthcoming issue of Journal of Obstetrics and Gynecology evaluated 47 biomarkers individually as well as in combination with placental growth factor (PlGF) as a prognostic marker requiring delivery within 14 days in women with suspected preterm preeclampsia.

It was a prospective, multicenter observational study recruiting 423 women presenting with suspected preterm preeclampsia categorized into two groups (less than 35 weeks and 35 0/7 - 36 6/7 weeks based on gestational dating.

The primary endpoint in the study was preeclampsia requiring delivery within 14 days.  

In both the groups, the combination of markers was not statistically better than a single biomarker used alone. Among the many markers evaluated, it was seen that a single angiogenesis related biomarker (PlGF, sFlt-1, or endoglin) alone can be used as an important diagnostic test for the primary endpoint in women with preterm preeclampsia.

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[1] Villar J, Say L, Gulmezoglu AM, Meraldi M, Lindheimer MD, Betran AP, Piaggio G; Eclampsia and pre-eclampsia: a health problem for 2000 years. In Pre-eclampsia, Critchly H, MacLean A, Poston L, Walker J, eds. London, RCOG Press, 2003, pp 189-207.

[2] Maternal mortality in 2005: estimates developed by WHO, UNICEF, UNIFPA and the World Bank, Geneva, World Health Organization, 2007.

[3] Roberts, J. M., Taylor, R. N., Musci, T. J., Rodgers, G. M., Hubel, C. A., & McLaughlin, M. K. (1989). Preeclampsia: an endothelial cell disorder.American journal of obstetrics and gynecology, 161(5), 1200-1204.

[4] Levine, R. J., Maynard, S. E., Qian, C., Lim, K. H., England, L. J., Yu, K. F., ... & Sibai, B. M. (2004). Circulating angiogenic factors and the risk of preeclampsia. New England Journal of Medicine, 350(7), 672-683.

[5] Rana S., Powe C.E., Salahuddin S., Verlohren S., Perschel F.H., Levine R.J., Lim K.H., Wenger J.B., Thadhani R., Karumanchi S.A. Angiogenic factors and the risk of adverse outcomes in women with suspected preeclampsia. Circulation. 2012;125:911–919. doi: 10.1161/CIRCULATIONAHA.111.054361.

New Use of old drug: Sildenafil Citrate ( Viagra) in treatment of preeclampsia.

photo courtesy: Avon Pharmacy

Preeclampsia is a leading cause of maternal and neonatal morbidity and mortality, and early-onset preeclampsia is responsible for long lasting consequences for the fetus.

A recent study published online July 07, 2016 in journal of obstetrics and gynecology concluded that treatment with sildenafil citrate prolonged pregnancy by an average of 4 days compared with placebo.

Sildenafil citrate, is a specific phosphodiesterase-5 inhibitor, augments the vasodilatory effects of NO by preventing the degradation of cGMP causing vasodilatation. Phosphodiesterase-5 is present in the human feto-placental circulation and sildenafil mediates vasodilatation and improve fetoplacental circulation by the same mechanism of action.[1]

This randomized, double blind placebo controlled trial recruited 100 patients with preeclampsia between 24 and 33 weeks of gestation, into two groups, one received 50 mg oral sildenafil citrate every 8 hours and other was put on placebo.

The patients also received additional antihypertensive treatment in the form of α-methyldopa (500 - 1500 mg/day) along with pindolol (10 - 30 mg/per day) as needed. Those patients who anticipated to go in labor received full corticosteroid coverage within 72 hours.

Patients in the treatment group on an average gained 4 days (14.4 days) as compared to the placebo group (10.4 days). This group also observed an improvement in blood flow in uterine and umbilical arteries (P< .001). and a significant reduction in Maternal Arterial Pressure within 24 hrs of randomization (P < .05).

Patients in placebo group required increased dose of the primary drug or addition of the new drug (P < .001).

Both groups were comparable in terms of perinatal morbidity, mortality, or adverse effects between groups. Each extra day gained between 24 and 32 weeks of gestations helps to improve the infant mortality statistics.

To confirm the benefits to the infant, "studies with a larger number of patients and an earlier start of medication are required," the authors opined.

The lead author Alberto Trapani Jr, MD, PhD, quoted that "Reduction in maternal [mean arterial pressure], without compromising uterine artery blood flow, provides reassurance that sildenafil may be useful as an antihypertensive drug in the context of placental vascular insufficiency."

Preliminary studies have demonstrated use of sildenafil citrate in early onset preeclampsia to improve fetal growth retardation, but more randomized trials and meta-analysis are needed before a recommendation for its use can be made in clinical practice.  [2] A randomized trial in 2009 demonstrated that although sildenafil does not prolong pregnancy but it was well tolerated without any maternal or fetal adverse effects in the escalating dose regimen 20-80 mg tid.[3]

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[1] Maharaj CH, O’Toole D, Lynch T, et al. Effects and mechanisms of action of sildenafil citrate in human chorionic arteries. Reproductive Biology and Endocrinology : RB&E. 2009;7:34. doi:10.1186/1477-7827-7-34.

[2] Sildenafil citrate therapy for severe early-onset intrauterine growth restriction.

P. von Dadelszen, S. Dwinnell, L. A. Magee, B. C. Carleton, A. Gruslin, B. Lee, K. I. Lim, R. M. Liston, S. P. Miller, D. Rurak, et al.

BJOG. 2011 April; 118(5): 624–628. doi: 10.1111/j.1471-0528.2010.02879.x

[3] http://www.ncbi.nlm.nih.gov/pubmed/19843000