17α-hydroxyprogesterone caproate plus cerclage have cumulative effect in preventing recurrent preterm birth and improving perinatal outcome.

Clinical Pearls:    

·         Women receiving transvaginal cerclage plus 17α-hydroxyprogesterone caproate had a 69% relative reduction in delivery at less than 24 weeks of gestation when compared with women receiving cerclage alone. 

·         These women also delivered babies that were heavier (2,547±1,009 g) as compared to women with only cerclage (2,326±1,250 g). (P=.03)

·         They also had fewer neonates with with 5-minute Apgar score less than 7,10% in the cerclage plus 17α-hydroxyprogesterone caproate cohort compared with 20% in the control cohort (P=.04).

·         There was no significant difference in delivery at less than 28 and less than 37 weeks of gestation, neonatal complications and admission to NICU between the two cohorts. 

·         The pilot study results indicate that the two therapies, 17α-hydroxyprogesterone caproate and cerclage, appear to be cumulative in their benefit.

Preterm birth is a major cause of neonatal morbidity and mortality with most preterm-related deaths occurring among babies who were born very preterm (before 32 weeks). Preterm birth is also a leading cause of long-term neurological disabilities in children.[1]

As per WHO statistics every year nearly 15 million babies are born preterm (1 in 10 babies) and it was responsible for nearly 1 million deaths in 2013.

In India, 3,341,000 babies are born preterm each year and 361,600 children under five die due to direct preterm complications.[2] More than 90% of babies born before 28 weeks of gestation in developing countries succumb within first few days of birth while in developed countries less than 10% babies of the same gestation die.[3]

Beside other risk factors, a history of prior preterm birth is the single most important risk factor for subsequent preterm birth.

A meta-analysis by Berghella V et al published in obstetrics and gynecology journal compared the outcome in singleton gestations with prior preterm birth that were managed either by cervical length screening with cerclage for short cervical length or history-indicated cerclage. The study concluded that cerclage is not indicated in every woman with previous history of preterm birth but reserved for the minority of women who develop a short cervical length.[4]

ACOG February 2014 Practice Bulletin reviews the guidelines for cervical cerclage in women with a history of preterm birth based on history, physical examination, and ultrasonographic findings.[5]

The second modality of treatment for women with a prior preterm birth is 17α-hydroxyprogesterone caproate. A study by Meis  PJ et al showed that weekly  injection of 250 mg 17 alpha-hydroxyprogesterone caproate reduced the risk of preterm birth before 37 weeks by nearly 34%.[6]

The additive effects of cerclage plus 17 alpha-hydroxyprogesterone caproate versus only cerclage in patients with a prior spontaneous preterm delivery has not been studied.  

The recent study published in obstetrics and gynecology November 2016 issue compared the prolongation of pregnancy and perinatal outcome in   among women with a prior preterm birth who received cerclage compared with cerclage plus 17α-hydroxyprogesterone caproate.

This retrospective cohort study recruited patients with vaginal cerclage and prior history of preterm birth between 16-36 weeks of gestation were identified over a course of 10-year period from July 2002 to May 2012.

A total of 411 women with cerclage were identified out of whom 260 met the inclusion criteria.  Of these, the control arm of 171 women continued the pregnancy with cerclage alone while 89 women in the study arm received 250 mg of 17α-hydroxyprogesterone caproate injections weekly along with the cerclage. In 46 women with a history based cerclage the injections were started prior to surgery and in 43 patients they were started after the procedure.

The primary outcome was delivery before 24 weeks while the secondary outcomes were delivery at less than 28 and less than 37 weeks of gestation as well as preterm prelabor rupture of membranes (PROM), delivery mode, neonatal intensive care unit admission, 5-minute Apgar score less than 7, necrotizing enterocolitis, grade 3 or 4 intraventricular hemorrhage, and birth weight.

The two groups were identical in terms of maternal demographics and gestational age of receiving cerclage.

It was seen that women receiving transvaginal cerclage plus 17α-hydroxyprogesterone caproate had a 69% relative reduction in delivery at less than 24 weeks of gestation when compared with women receiving cerclage alone. 

These women also delivered babies that were heavier (2,547±1,009 g) as compared to women with only cerclage (2,326±1,250 g). (P=.03)

They also had fewer neonates with with 5-minute Apgar score less than 7. 10% in the cerclage plus 17α-hydroxyprogesterone caproate cohort compared with 20% in the control cohort (P=.04).

There was no significant difference in delivery at less than 28 and less than 37 weeks of gestation between the two cohorts. 

 Both the cohorts also have similar mode of delivery, neonatal intensive care unit admission, intraventricular hemorrhage (grade 3 or 4), or necrotizing enterocolitis.

A secondary analysis studies the relationship between examination and ultrasound indicated cerclage with the additive effect of 17α-hydroxyprogesterone caproate as compared to history indicated cerclage. There was a 91% and 89% reduction in delivery at less than 24 and less than 28 weeks of gestation, respectively when progesterone was continued.

The study has multiple strengths and limitations. The investigators understand that the study had a small sample size and limitations of adjusting for several variables. They also caution the readers to interpret the results of the study carefully as more large, adequately powered multicenter prospective trial studies are needed before a recommendation can be made.

The pilot study results indicate that the two therapies, 17α-hydroxyprogesterone caproate and cerclage, appear to be cumulative in their benefit.

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[1]http://www.cdc.gov/reproductivehealth/maternalinfanthealth/pretermbirth.htm

[2] http://www.everypreemie.org/wp-content/uploads/2016/02/India-revJan2016.pdf

[3] http://www.who.int/mediacentre/factsheets/fs363/en/

[4] http://journals.lww.com/greenjournal/Abstract/2011/07000/Cervical_Length_Screening_With.20.aspx

[5] Cerclage for the management of cervical insufficiency. Practice Bulletin No. 142. American College of Obstetricians and Gynecologists. Obstet Gynecol 2014;123:372–9.

[6] https://www.ncbi.nlm.nih.gov/pubmed/12802023

Adverse pregnancy and neonatal outcomes seen in obese pregnant women even in the absence of chronic diseases.

According to a recent study published Ahead of Print in journal of obstetrics and gynecology, women who are obese have higher risk of adverse pregnancy and neonatal outcome.

The study was conducted as a retrospective cohort study using the medical records obtained from the Consortium on Safe Labor, from the year 2002-2008. 

Dr. Sung Soo Kim and her colleagues from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, examined records of singleton pregnancies among US women without any pre-pregnancy disease for obstetrics and neonatal complications based on prepregnancy BMI of mother.

The mothers were put into either of the 5 categories according to the BMI as normal weight (18.5-24.9 kg/m²), overweight (25-29.9), obese class I (30-34.9), obese class II (35-39.9), or obese class III (40 or greater).

The investigators looked in to 112,309 deliveries among 106,552 women.

The relative risk for developing gestational diabetes compared to normal weight women was 1.99 for overweight women, 2.94 for obese class I women, 3.97 for obese class II women, and 5.47 for obese class III women.

A similar risk profile was noted for gestational hypertensive disorders, gestational diabetes, cesarean delivery, and induction that increased in a dose response manner.

The neonatal risks also increase with increasing BMI like preterm birth at less than 32 weeks of gestation, large for gestational age (LGA), transient tachypnea, sepsis, and intensive care unit admission.

The percentage of LGA infants born to normal weight women was 7.9% that increased to 17.3% among obese class III women and relative risks increased to 1.52 (1.45-1.58), 1.74 (1.65-1.83), 1.93 (1.79-2.07), and 2.32 (2.14-2.52) as BMI category increased.

When all these adverse outcomes were grouped together and analyzed as a single composite variable, it was seen that obese women have a 18%-47% increased risk of any pregnancy complication than normal weight cohorts.

The researchers said “We found increased risks of relatively rare outcomes that other studies could not observe, including maternal acute cardiovascular events and neonatal transient tachypnea, necrotizing enterocolitis, peri- and intraventricular hemorrhage, and retinopathy of prematurity among deliveries to overweight or obese women.” 

References:

http://journals.lww.com/greenjournal/Abstract/publishahead/Obstetric_and_Neonatal_Risks_Among_Obese_Women.98718.aspx

Water Birth or Land Birth! What is more safe for babies? A systemic review and meta-analysis.

Immersion in water during labor or delivery has gained popularity in recent years in many parts of world and has been suggested as a better alternative to delivering in hospital labor wards.

Many Hospitals in U.K are offering women a choice between traditional hospital delivery vs laboring in water. In fact, a 2006 joint statement from the Royal College of Obstetricians and Gynaecologists and Royal College of Midwives supported immersion in water during labor for uncomplicated pregnancies and stressed that the organization should provide infrastructure and system to develop best practice for underwater birthing.

A latest review published on April 28, in online edition of Archives of Disease inChildhood - Fetal and Neonatal Edition quotes that in U.K.  about 9% of total deliveries occurred under water in year 2015.

Professor Alastair Sutcliffe and his colleagues conducted a systemic review and meta-analysis and pooled the data from 29 studies amounting a total of 39,000 labors.

All these studies were small, observational studies conducted mostly at small hospitals in Europe and other wealthy countries. They are many a time based on personal opinion and published in journals that are not peer reviewed. The studies also differ on the way the labor is conducted and “underwater” in some studies meant only the first stage in water and other included the second stage underwater too.

However, in these studies it was observed that the babies did have slightly higher Apgar scores but the difference was not significant.

There are many perceived benefits of labor underwater less painful contractions and less need for pharmacological analgesia, shorter labor, less need for augmentation. A 2009 Cochrane systemic review of RCTs involving   immersion in the first stage of labor documented no such benefits. Only the need for epidural, spinal or paracervical anesthesia was slightly reduced in study group. But, the incidence of perineal trauma or tears remained the same in the two groups.

No increased fetal respiratory complications were seen in these review which reported “there is no evidence of increased adverse effects to the fetus/neonate or woman from laboring in water or water birth.”

Several other small studies and case reports have reported higher risk of maternal and neonatal infections, particularly with ruptured membranes; difficulties in neonatal thermoregulation; Umbilical cord avulsion; severe respiratory distress, increased NICU admissions and tub water aspiration.

However, the present study as well as 2009 Cochrane review did not report any of these increased neonatal complications.

RCOG and Royal college of Midwives U.K advocate that “All healthy women with uncomplicated pregnancies at term should have the option of water birth available to them and should be able to proceed to a water birth if they wish.” 

In the U.S., however, the American College of Obstetricians and Gynecologists and the American Academy of Pediatrics recommend against underwater deliveries due to potential complications for babies such as infections, breathing difficulties and drowning.

ACOG does take an equivocal stance on immersion during first stage of labor, which may   be associated with decreased pain or use of anesthesia and decreased duration of labor. However, it stresses the need of routine maternal and fetal monitoring even if the mother is in birthing pool/tub.

It does not support the second stage of labor underwater and only advocates its use in context of clinical trials as an experimental procedure with written consent.  

ACOG also insist the need of rigorous protocols for candidate selection to maintenance and cleaning of tubs and immersion pools, infection control procedures, monitoring of mothers and fetuses at appropriate intervals while immersed, and protocols for moving women from tubs if urgent maternal or fetal concerns develop.

In all, the current review and meta-analysis failed to document that underwater labor is safe or unsafe and Dr. Alastair Sutcliffe opines that “Whilst it is a good plan to try labor in water, my advice is to wait until there is more convincing evidence of safety before having the actual delivery in water."

References:

Cluett ER, Burns E. Immersion in water in labour and birth. Cochrane Database of Systematic Reviews 2009, Issue 2. Art. No.: CD000111

http://www.waterbirth.org/assets/documents/rcog_rcm_birth_in_water.pdf accessed May 8, 2016.

http://www.waterbirth.org/assets/documents/rcog_rcm_birth_in_water.pdf

http://fn.bmj.com/content/early/2016/04/28/archdischild-2015-309600.short?rss=1

Stillbirths and the ACOG 39 weeks rule----Does it need to be revisited?

The 39-week rule – was established in 2009 that restricts labor induction in the 37^th and 38^th week of pregnancy (i.e., in the “early-term period”) unless an accepted/approved “indication” is present.

The 39-week rule is now a strict clinical guideline that is enforced by professional organizations, governmental agencies and the medical insurance industry in US. 

In November 2013, ACOG  and Society for Maternal and Fetal medicine(SMFM)  made a recommendation of  replacing the use of “ term”  pregnancy which accommodated gestations between 37 wks to 42 wks with the following designations:

•  Early term: 37 weeks through 38 weeks and 6 days
 •  Full term: 39 weeks through 40 weeks and 6 days
 •  Late term: 41 weeks through 41 weeks and 6 days
 •  Postterm: 42 weeks and beyond

These changes were made by growing research evidence, a part of which has been led by Eunice Kennedy Shriver National Institute of Child Health and Human Development, indicating that key developmental process for the fetus continue well beyond 37 wks till 39 wks. They also advocated that “Babies born at or after 39 weeks have the best chance at healthy outcomes compared to those born before 39 weeks.”

It was seen that the percentage of infants born preterm declined for the seventh straight year in 2013. The NIH  also published a report that shows a decline in induction of labor for singleton birth in year 2011 (23.7%) and 2012 (23.3%),after 20 years of consecutive increases. There was also a decline in Early Elective Deliveries across the United States, from 17% of babies in the United States were delivered before 39 weeks in 2010 to a sharp decline to 4.6% in 2013. 

But, two recent studies, one by Dr. Nicholson presented at Society for Maternal-Fetal Medicine (SMFM) 2016 Pregnancy Meeting and the other by Dr Jason Salemi, assistant professor of family and community medicine at Baylor and lead author of the study advise caution against the universal application of the rule.  

According to  paper presented at SMFM 2016 Pregnancy Meeting Dr Nicholson said that  “Investigators found that the proportion of term stillbirths rose from 1.103 per 1000 deliveries before the rule was adopted to 1.177 per 1000 after. He further added "This study raises the possibility that the 39-week rule may be causing serious unintended harm."

According to Dr Nicholson "Term stillbirth is clearly one of worst obstetrical outcomes, and it occurs with relatively high frequency — in one per 1000 deliveries that reach 37 weeks," he explained. "We should place a high priority on determining the causes, developing preventive interventions, and studying factors suspected of producing this truly horrible outcome.

He advocated an urgent need of high quality research in this area, and until we get the evidence the forced imposition of the 39-week rule should be looked into. The 39 weeks rule was put into action after results of many studies, but he said that all those studies were flawed; they suffered from incorrect modeling, were retrospective cohort studies and the confounders were not corrected for.

He further went to add that "the studies failed to consider ecological fallacy, which is that we should not determine the treatment of an individual patient based on studies that examine population-based data," he said. "Ecological cohort studies should rarely be used to generate policy, yet that's what I think we did."

Dr. Nicholson and his colleagues requested the state health department to provide them with data on term still births and term births segregated according to the weeks of gestation for 3 years before and 3 years after the rule was in enforced. The data clearly showed an increase in deliveries at 39 weeks. He said that "The greatest increases in term stillbirth occurred at 37, 38, and 39 weeks of gestation," he noted, which is "right where the 39-week rule is working."

The team observed a clear increase in number of stillbirths when the rule  was  implemented,  1.103 per 1000 deliveries in 2007-2009 to 1.177 per 1000 in 2011-2013. He further estimated that it accounts for additional 335 more term stillbirths in 2013 than in 2007. He acknowledged some shortcoming of his retrospective cohort study, saying it only identifies association, not causation.

A study published in JAMA paediatric, documented that  during this period admission to NICU increased sharply.

The paper was a topic of hot debate and some physicians suggest that benefit of the rule outweigh the risk. 
Dr. Baxi from New York University Langone Medical Center in New York City Opined that timing of delivery is refined decision depending on many variable and it should be individualized according to the circumstances and not governed by a rule .

She also emphasized the need to understand more about the pathophysiology of the stillbirths. "Unless we know the cause, we can't say it's related to the 39-week rule," Dr Baxi pointed out. "Over time, we have fewer 'unrecognized causes,' but there still are some.

Dr Jason also saw limitations in many studies used to justify the 39-week rule. They conducted a retrospective cohort study, used state health data on  675,000 infants and found equivocal results in elective cesarean sections at 37-38 weeks and those delivered after  39 weeks.

“Each pregnancy is unique,” He said. “I cannot overstate the importance of open and ongoing communication between pregnant women and their healthcare providers so that the potential risks and benefits of any pregnancy-related decision are understood fully.”

Many other studies also have challenged the “39 weeks rule”. A study by Hart et al published in ACOG challenged the application of rule in Women who had prior C-sections. They conclude that their findings suggest the optimal time for scheduled delivery of women with 2 previous cesarean section deliveries is between 38 wks 0 and 38wk 6 days and between 37 wks 0 and 37 wks 6 days for women with ≥ 3 previous cesarean section deliveries

Some physicians said that they do not think that the rule should be dropped entirely but needs to be revisited.

 References:

http://www.cdc.gov/nchs/data/databriefs/db155.htm

http://www.nih.gov/news/health/jul2015/nichd-10.htm

http://www.cmaj.ca/content/early/2014/04/14/cmaj.109-4766.short?rss=1

https://www.nichd.nih.gov/Pages/index.aspx

https://www.bcm.edu/news/reproductive-health/research-goes-against-39-week-pregnancy-rule

Hart L, Refuerzo J, Sibai B, Blackwell S. Abstract 40: Should the “39 week rule” apply to women with multiple prior cesarean deliveries? American Journal of Obstetrics & Gynecology 2014; 210(1 Supplement): S27, January 2014