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Proclivity ID
18811001
Unpublish
Citation Name
OBG Manag
Specialty Focus
Obstetrics
Gynecology
Surgery
Negative Keywords
gaming
gambling
compulsive behaviors
ammunition
assault rifle
black jack
Boko Haram
bondage
child abuse
cocaine
Daech
drug paraphernalia
explosion
gun
human trafficking
ISIL
ISIS
Islamic caliphate
Islamic state
mixed martial arts
MMA
molestation
national rifle association
NRA
nsfw
pedophile
pedophilia
poker
porn
pornography
psychedelic drug
recreational drug
sex slave rings
slot machine
terrorism
terrorist
Texas hold 'em
UFC
substance abuse
abuseed
abuseer
abusees
abuseing
abusely
abuses
aeolus
aeolused
aeoluser
aeoluses
aeolusing
aeolusly
aeoluss
ahole
aholeed
aholeer
aholees
aholeing
aholely
aholes
alcohol
alcoholed
alcoholer
alcoholes
alcoholing
alcoholly
alcohols
allman
allmaned
allmaner
allmanes
allmaning
allmanly
allmans
alted
altes
alting
altly
alts
analed
analer
anales
analing
anally
analprobe
analprobeed
analprobeer
analprobees
analprobeing
analprobely
analprobes
anals
anilingus
anilingused
anilinguser
anilinguses
anilingusing
anilingusly
anilinguss
anus
anused
anuser
anuses
anusing
anusly
anuss
areola
areolaed
areolaer
areolaes
areolaing
areolaly
areolas
areole
areoleed
areoleer
areolees
areoleing
areolely
areoles
arian
arianed
arianer
arianes
arianing
arianly
arians
aryan
aryaned
aryaner
aryanes
aryaning
aryanly
aryans
asiaed
asiaer
asiaes
asiaing
asialy
asias
ass
ass hole
ass lick
ass licked
ass licker
ass lickes
ass licking
ass lickly
ass licks
assbang
assbanged
assbangeded
assbangeder
assbangedes
assbangeding
assbangedly
assbangeds
assbanger
assbanges
assbanging
assbangly
assbangs
assbangsed
assbangser
assbangses
assbangsing
assbangsly
assbangss
assed
asser
asses
assesed
asseser
asseses
assesing
assesly
assess
assfuck
assfucked
assfucker
assfuckered
assfuckerer
assfuckeres
assfuckering
assfuckerly
assfuckers
assfuckes
assfucking
assfuckly
assfucks
asshat
asshated
asshater
asshates
asshating
asshatly
asshats
assholeed
assholeer
assholees
assholeing
assholely
assholes
assholesed
assholeser
assholeses
assholesing
assholesly
assholess
assing
assly
assmaster
assmastered
assmasterer
assmasteres
assmastering
assmasterly
assmasters
assmunch
assmunched
assmuncher
assmunches
assmunching
assmunchly
assmunchs
asss
asswipe
asswipeed
asswipeer
asswipees
asswipeing
asswipely
asswipes
asswipesed
asswipeser
asswipeses
asswipesing
asswipesly
asswipess
azz
azzed
azzer
azzes
azzing
azzly
azzs
babeed
babeer
babees
babeing
babely
babes
babesed
babeser
babeses
babesing
babesly
babess
ballsac
ballsaced
ballsacer
ballsaces
ballsacing
ballsack
ballsacked
ballsacker
ballsackes
ballsacking
ballsackly
ballsacks
ballsacly
ballsacs
ballsed
ballser
ballses
ballsing
ballsly
ballss
barf
barfed
barfer
barfes
barfing
barfly
barfs
bastard
bastarded
bastarder
bastardes
bastarding
bastardly
bastards
bastardsed
bastardser
bastardses
bastardsing
bastardsly
bastardss
bawdy
bawdyed
bawdyer
bawdyes
bawdying
bawdyly
bawdys
beaner
beanered
beanerer
beaneres
beanering
beanerly
beaners
beardedclam
beardedclamed
beardedclamer
beardedclames
beardedclaming
beardedclamly
beardedclams
beastiality
beastialityed
beastialityer
beastialityes
beastialitying
beastialityly
beastialitys
beatch
beatched
beatcher
beatches
beatching
beatchly
beatchs
beater
beatered
beaterer
beateres
beatering
beaterly
beaters
beered
beerer
beeres
beering
beerly
beeyotch
beeyotched
beeyotcher
beeyotches
beeyotching
beeyotchly
beeyotchs
beotch
beotched
beotcher
beotches
beotching
beotchly
beotchs
biatch
biatched
biatcher
biatches
biatching
biatchly
biatchs
big tits
big titsed
big titser
big titses
big titsing
big titsly
big titss
bigtits
bigtitsed
bigtitser
bigtitses
bigtitsing
bigtitsly
bigtitss
bimbo
bimboed
bimboer
bimboes
bimboing
bimboly
bimbos
bisexualed
bisexualer
bisexuales
bisexualing
bisexually
bisexuals
bitch
bitched
bitcheded
bitcheder
bitchedes
bitcheding
bitchedly
bitcheds
bitcher
bitches
bitchesed
bitcheser
bitcheses
bitchesing
bitchesly
bitchess
bitching
bitchly
bitchs
bitchy
bitchyed
bitchyer
bitchyes
bitchying
bitchyly
bitchys
bleached
bleacher
bleaches
bleaching
bleachly
bleachs
blow job
blow jobed
blow jober
blow jobes
blow jobing
blow jobly
blow jobs
blowed
blower
blowes
blowing
blowjob
blowjobed
blowjober
blowjobes
blowjobing
blowjobly
blowjobs
blowjobsed
blowjobser
blowjobses
blowjobsing
blowjobsly
blowjobss
blowly
blows
boink
boinked
boinker
boinkes
boinking
boinkly
boinks
bollock
bollocked
bollocker
bollockes
bollocking
bollockly
bollocks
bollocksed
bollockser
bollockses
bollocksing
bollocksly
bollockss
bollok
bolloked
bolloker
bollokes
bolloking
bollokly
bolloks
boner
bonered
bonerer
boneres
bonering
bonerly
boners
bonersed
bonerser
bonerses
bonersing
bonersly
bonerss
bong
bonged
bonger
bonges
bonging
bongly
bongs
boob
boobed
boober
boobes
boobies
boobiesed
boobieser
boobieses
boobiesing
boobiesly
boobiess
boobing
boobly
boobs
boobsed
boobser
boobses
boobsing
boobsly
boobss
booby
boobyed
boobyer
boobyes
boobying
boobyly
boobys
booger
boogered
boogerer
boogeres
boogering
boogerly
boogers
bookie
bookieed
bookieer
bookiees
bookieing
bookiely
bookies
bootee
booteeed
booteeer
booteees
booteeing
booteely
bootees
bootie
bootieed
bootieer
bootiees
bootieing
bootiely
booties
booty
bootyed
bootyer
bootyes
bootying
bootyly
bootys
boozeed
boozeer
boozees
boozeing
boozely
boozer
boozered
boozerer
boozeres
boozering
boozerly
boozers
boozes
boozy
boozyed
boozyer
boozyes
boozying
boozyly
boozys
bosomed
bosomer
bosomes
bosoming
bosomly
bosoms
bosomy
bosomyed
bosomyer
bosomyes
bosomying
bosomyly
bosomys
bugger
buggered
buggerer
buggeres
buggering
buggerly
buggers
bukkake
bukkakeed
bukkakeer
bukkakees
bukkakeing
bukkakely
bukkakes
bull shit
bull shited
bull shiter
bull shites
bull shiting
bull shitly
bull shits
bullshit
bullshited
bullshiter
bullshites
bullshiting
bullshitly
bullshits
bullshitsed
bullshitser
bullshitses
bullshitsing
bullshitsly
bullshitss
bullshitted
bullshitteded
bullshitteder
bullshittedes
bullshitteding
bullshittedly
bullshitteds
bullturds
bullturdsed
bullturdser
bullturdses
bullturdsing
bullturdsly
bullturdss
bung
bunged
bunger
bunges
bunging
bungly
bungs
busty
bustyed
bustyer
bustyes
bustying
bustyly
bustys
butt
butt fuck
butt fucked
butt fucker
butt fuckes
butt fucking
butt fuckly
butt fucks
butted
buttes
buttfuck
buttfucked
buttfucker
buttfuckered
buttfuckerer
buttfuckeres
buttfuckering
buttfuckerly
buttfuckers
buttfuckes
buttfucking
buttfuckly
buttfucks
butting
buttly
buttplug
buttpluged
buttpluger
buttpluges
buttpluging
buttplugly
buttplugs
butts
caca
cacaed
cacaer
cacaes
cacaing
cacaly
cacas
cahone
cahoneed
cahoneer
cahonees
cahoneing
cahonely
cahones
cameltoe
cameltoeed
cameltoeer
cameltoees
cameltoeing
cameltoely
cameltoes
carpetmuncher
carpetmunchered
carpetmuncherer
carpetmuncheres
carpetmunchering
carpetmuncherly
carpetmunchers
cawk
cawked
cawker
cawkes
cawking
cawkly
cawks
chinc
chinced
chincer
chinces
chincing
chincly
chincs
chincsed
chincser
chincses
chincsing
chincsly
chincss
chink
chinked
chinker
chinkes
chinking
chinkly
chinks
chode
chodeed
chodeer
chodees
chodeing
chodely
chodes
chodesed
chodeser
chodeses
chodesing
chodesly
chodess
clit
clited
cliter
clites
cliting
clitly
clitoris
clitorised
clitoriser
clitorises
clitorising
clitorisly
clitoriss
clitorus
clitorused
clitoruser
clitoruses
clitorusing
clitorusly
clitoruss
clits
clitsed
clitser
clitses
clitsing
clitsly
clitss
clitty
clittyed
clittyer
clittyes
clittying
clittyly
clittys
cocain
cocaine
cocained
cocaineed
cocaineer
cocainees
cocaineing
cocainely
cocainer
cocaines
cocaining
cocainly
cocains
cock
cock sucker
cock suckered
cock suckerer
cock suckeres
cock suckering
cock suckerly
cock suckers
cockblock
cockblocked
cockblocker
cockblockes
cockblocking
cockblockly
cockblocks
cocked
cocker
cockes
cockholster
cockholstered
cockholsterer
cockholsteres
cockholstering
cockholsterly
cockholsters
cocking
cockknocker
cockknockered
cockknockerer
cockknockeres
cockknockering
cockknockerly
cockknockers
cockly
cocks
cocksed
cockser
cockses
cocksing
cocksly
cocksmoker
cocksmokered
cocksmokerer
cocksmokeres
cocksmokering
cocksmokerly
cocksmokers
cockss
cocksucker
cocksuckered
cocksuckerer
cocksuckeres
cocksuckering
cocksuckerly
cocksuckers
coital
coitaled
coitaler
coitales
coitaling
coitally
coitals
commie
commieed
commieer
commiees
commieing
commiely
commies
condomed
condomer
condomes
condoming
condomly
condoms
coon
cooned
cooner
coones
cooning
coonly
coons
coonsed
coonser
coonses
coonsing
coonsly
coonss
corksucker
corksuckered
corksuckerer
corksuckeres
corksuckering
corksuckerly
corksuckers
cracked
crackwhore
crackwhoreed
crackwhoreer
crackwhorees
crackwhoreing
crackwhorely
crackwhores
crap
craped
craper
crapes
craping
craply
crappy
crappyed
crappyer
crappyes
crappying
crappyly
crappys
cum
cumed
cumer
cumes
cuming
cumly
cummin
cummined
cumminer
cummines
cumming
cumminged
cumminger
cumminges
cumminging
cummingly
cummings
cummining
cumminly
cummins
cums
cumshot
cumshoted
cumshoter
cumshotes
cumshoting
cumshotly
cumshots
cumshotsed
cumshotser
cumshotses
cumshotsing
cumshotsly
cumshotss
cumslut
cumsluted
cumsluter
cumslutes
cumsluting
cumslutly
cumsluts
cumstain
cumstained
cumstainer
cumstaines
cumstaining
cumstainly
cumstains
cunilingus
cunilingused
cunilinguser
cunilinguses
cunilingusing
cunilingusly
cunilinguss
cunnilingus
cunnilingused
cunnilinguser
cunnilinguses
cunnilingusing
cunnilingusly
cunnilinguss
cunny
cunnyed
cunnyer
cunnyes
cunnying
cunnyly
cunnys
cunt
cunted
cunter
cuntes
cuntface
cuntfaceed
cuntfaceer
cuntfacees
cuntfaceing
cuntfacely
cuntfaces
cunthunter
cunthuntered
cunthunterer
cunthunteres
cunthuntering
cunthunterly
cunthunters
cunting
cuntlick
cuntlicked
cuntlicker
cuntlickered
cuntlickerer
cuntlickeres
cuntlickering
cuntlickerly
cuntlickers
cuntlickes
cuntlicking
cuntlickly
cuntlicks
cuntly
cunts
cuntsed
cuntser
cuntses
cuntsing
cuntsly
cuntss
dago
dagoed
dagoer
dagoes
dagoing
dagoly
dagos
dagosed
dagoser
dagoses
dagosing
dagosly
dagoss
dammit
dammited
dammiter
dammites
dammiting
dammitly
dammits
damn
damned
damneded
damneder
damnedes
damneding
damnedly
damneds
damner
damnes
damning
damnit
damnited
damniter
damnites
damniting
damnitly
damnits
damnly
damns
dick
dickbag
dickbaged
dickbager
dickbages
dickbaging
dickbagly
dickbags
dickdipper
dickdippered
dickdipperer
dickdipperes
dickdippering
dickdipperly
dickdippers
dicked
dicker
dickes
dickface
dickfaceed
dickfaceer
dickfacees
dickfaceing
dickfacely
dickfaces
dickflipper
dickflippered
dickflipperer
dickflipperes
dickflippering
dickflipperly
dickflippers
dickhead
dickheaded
dickheader
dickheades
dickheading
dickheadly
dickheads
dickheadsed
dickheadser
dickheadses
dickheadsing
dickheadsly
dickheadss
dicking
dickish
dickished
dickisher
dickishes
dickishing
dickishly
dickishs
dickly
dickripper
dickrippered
dickripperer
dickripperes
dickrippering
dickripperly
dickrippers
dicks
dicksipper
dicksippered
dicksipperer
dicksipperes
dicksippering
dicksipperly
dicksippers
dickweed
dickweeded
dickweeder
dickweedes
dickweeding
dickweedly
dickweeds
dickwhipper
dickwhippered
dickwhipperer
dickwhipperes
dickwhippering
dickwhipperly
dickwhippers
dickzipper
dickzippered
dickzipperer
dickzipperes
dickzippering
dickzipperly
dickzippers
diddle
diddleed
diddleer
diddlees
diddleing
diddlely
diddles
dike
dikeed
dikeer
dikees
dikeing
dikely
dikes
dildo
dildoed
dildoer
dildoes
dildoing
dildoly
dildos
dildosed
dildoser
dildoses
dildosing
dildosly
dildoss
diligaf
diligafed
diligafer
diligafes
diligafing
diligafly
diligafs
dillweed
dillweeded
dillweeder
dillweedes
dillweeding
dillweedly
dillweeds
dimwit
dimwited
dimwiter
dimwites
dimwiting
dimwitly
dimwits
dingle
dingleed
dingleer
dinglees
dingleing
dinglely
dingles
dipship
dipshiped
dipshiper
dipshipes
dipshiping
dipshiply
dipships
dizzyed
dizzyer
dizzyes
dizzying
dizzyly
dizzys
doggiestyleed
doggiestyleer
doggiestylees
doggiestyleing
doggiestylely
doggiestyles
doggystyleed
doggystyleer
doggystylees
doggystyleing
doggystylely
doggystyles
dong
donged
donger
donges
donging
dongly
dongs
doofus
doofused
doofuser
doofuses
doofusing
doofusly
doofuss
doosh
dooshed
doosher
dooshes
dooshing
dooshly
dooshs
dopeyed
dopeyer
dopeyes
dopeying
dopeyly
dopeys
douchebag
douchebaged
douchebager
douchebages
douchebaging
douchebagly
douchebags
douchebagsed
douchebagser
douchebagses
douchebagsing
douchebagsly
douchebagss
doucheed
doucheer
douchees
doucheing
douchely
douches
douchey
doucheyed
doucheyer
doucheyes
doucheying
doucheyly
doucheys
drunk
drunked
drunker
drunkes
drunking
drunkly
drunks
dumass
dumassed
dumasser
dumasses
dumassing
dumassly
dumasss
dumbass
dumbassed
dumbasser
dumbasses
dumbassesed
dumbasseser
dumbasseses
dumbassesing
dumbassesly
dumbassess
dumbassing
dumbassly
dumbasss
dummy
dummyed
dummyer
dummyes
dummying
dummyly
dummys
dyke
dykeed
dykeer
dykees
dykeing
dykely
dykes
dykesed
dykeser
dykeses
dykesing
dykesly
dykess
erotic
eroticed
eroticer
erotices
eroticing
eroticly
erotics
extacy
extacyed
extacyer
extacyes
extacying
extacyly
extacys
extasy
extasyed
extasyer
extasyes
extasying
extasyly
extasys
fack
facked
facker
fackes
facking
fackly
facks
fag
faged
fager
fages
fagg
fagged
faggeded
faggeder
faggedes
faggeding
faggedly
faggeds
fagger
fagges
fagging
faggit
faggited
faggiter
faggites
faggiting
faggitly
faggits
faggly
faggot
faggoted
faggoter
faggotes
faggoting
faggotly
faggots
faggs
faging
fagly
fagot
fagoted
fagoter
fagotes
fagoting
fagotly
fagots
fags
fagsed
fagser
fagses
fagsing
fagsly
fagss
faig
faiged
faiger
faiges
faiging
faigly
faigs
faigt
faigted
faigter
faigtes
faigting
faigtly
faigts
fannybandit
fannybandited
fannybanditer
fannybandites
fannybanditing
fannybanditly
fannybandits
farted
farter
fartes
farting
fartknocker
fartknockered
fartknockerer
fartknockeres
fartknockering
fartknockerly
fartknockers
fartly
farts
felch
felched
felcher
felchered
felcherer
felcheres
felchering
felcherly
felchers
felches
felching
felchinged
felchinger
felchinges
felchinging
felchingly
felchings
felchly
felchs
fellate
fellateed
fellateer
fellatees
fellateing
fellately
fellates
fellatio
fellatioed
fellatioer
fellatioes
fellatioing
fellatioly
fellatios
feltch
feltched
feltcher
feltchered
feltcherer
feltcheres
feltchering
feltcherly
feltchers
feltches
feltching
feltchly
feltchs
feom
feomed
feomer
feomes
feoming
feomly
feoms
fisted
fisteded
fisteder
fistedes
fisteding
fistedly
fisteds
fisting
fistinged
fistinger
fistinges
fistinging
fistingly
fistings
fisty
fistyed
fistyer
fistyes
fistying
fistyly
fistys
floozy
floozyed
floozyer
floozyes
floozying
floozyly
floozys
foad
foaded
foader
foades
foading
foadly
foads
fondleed
fondleer
fondlees
fondleing
fondlely
fondles
foobar
foobared
foobarer
foobares
foobaring
foobarly
foobars
freex
freexed
freexer
freexes
freexing
freexly
freexs
frigg
frigga
friggaed
friggaer
friggaes
friggaing
friggaly
friggas
frigged
frigger
frigges
frigging
friggly
friggs
fubar
fubared
fubarer
fubares
fubaring
fubarly
fubars
fuck
fuckass
fuckassed
fuckasser
fuckasses
fuckassing
fuckassly
fuckasss
fucked
fuckeded
fuckeder
fuckedes
fuckeding
fuckedly
fuckeds
fucker
fuckered
fuckerer
fuckeres
fuckering
fuckerly
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Maternal oxygen in labor: False reassurance?

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Wed, 11/11/2020 - 10:30
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Maternal oxygen in labor:
False reassurance?

 

 

CASE Heart rate tracing suggests fetal distress

Ms. M. presents for elective induction of labor at 39 weeks’ gestation. During the course of her labor, a Category II fetal heart rate (FHR) tracing is noted, and maternal oxygen is administered as part of the intrauterine resuscitative efforts. Her infant ultimately was delivered vaginally with an arterial cord blood pH of 7.1 and Apgar scores of 5 and 7.

Should intrauterine resuscitation include maternal oxygen administration?

It is a common sight on labor and delivery: An FHR monitoring strip is noted to be a Category II tracing. There may be fetal tachycardia, late decelerations, or perhaps decreased variability. The nurse or physician goes to the laboring mother’s room, checks cervical dilation, changes the patient’s position, and puts an oxygen mask over her face.

The American College of Obstetricians and Gynecologists (ACOG) lists maternal oxygen administration, most commonly at 10 L/min via a nonrebreather face mask, as an intrauterine resuscitative measure for Category II or Category III FHR tracings.1 Maternal oxygen is used to treat abnormal FHR tracings in approximately half of all births in the United States.2 Despite these recommendations and the frequency of its use, however, evidence is limited that maternal oxygenation improves neonatal outcome. In fact, there is emerging evidence of potential harm.

Why use oxygen?

The use of maternal oxygen supplementation intuitively makes sense. We know that certain abnormalities in FHR tracings can signal fetal hypoxia. Left untreated, the hypoxia could lead to fetal acidemia and associated neonatal sequelae. Theoretically, the administration of maternal oxygen should lead to improved fetal oxygenation and improved fetal outcome. This is supported by studies from the 1960s that demonstrate improved FHR tracings after maternal oxygen administration.3

This idea was further supported by studies that demonstrated an increase in fetal oxygen levels when maternal oxygen is administered. Haydon and colleagues evaluated the administration of maternal oxygen in women with nonreassuring FHR tracings.4 Their data showed that maternal oxygen administration increased fetal oxygen as measured by fetal pulse oximetry. The lower the initial fetal oxygen levels prior to oxygen administration, the greater the increase.

Despite these findings, evidence for improved neonatal outcomes is lacking.5 While heart rate tracings and fetal oxygen saturation may be improved with maternal oxygen supplementation, neonatal morbidity appears to remain unchanged (FIGURE). In fact, newer research suggests potential harm. Although an improved FHR tracing may be comforting to the clinician, the end result may be less so. Given these findings on maternal oxygen supplementation, it is time to break this practice habit.

Maternal cardiovascular effects

Most of the literature on maternal hyperoxygenation focuses on fetal response. Before examining the effects on the fetus, however, we must consider the effect on the mother. Cardiovascular changes occur during and after maternal oxygen administration that should be taken into account.

McHugh and colleagues measured the hemodynamic changes in 46 pregnant and 20 nonpregnant women before, immediately, and 10 minutes after a 30-minute period of high-flow oxygen administration.6 While there were no changes in the nonpregnant women’s parameters, in the pregnant women heart rate and stroke volume were decreased after oxygen administration. Additionally, systemic vascular resistance increased and did not return to baseline by 10 minutes postadministration.

Since the purpose of the maternal oxygen administration is to increase oxygen to the fetus, this decrease in cardiac output and increase in systemic vascular resistance is concerning. These results may negate the intended effect of increased oxygen delivery to the fetus.

Continue to: Maternal and fetal oxidative stress...

 

 

Maternal and fetal oxidative stress

Assuming that the abnormal FHR tracing in our case patient is actually due to fetal hypoxia, it would seem prudent to increase fetal oxygenation. However, fetal hyperoxygenation may lead to free radical damage that could worsen neonatal outcomes. Oxidative stress, which can be caused by both hypoxia and hyperoxia, can lead to endothelial and cell receptor damage. This is known to contribute to the cerebral damage of hypoxic-ischemic encephalopathy.

In a randomized trial, Khaw and colleagues measured lipid peroxidases as a “free radical footprint” in women undergoing elective cesarean delivery who were administered oxygen or room air.7 Maternal and fetal oxygen levels were higher in the oxygen-supplementation group, but lipid peroxidases also were elevated. This finding suggests that the excess oxygen results in free radical formation and potentially negative effects on the neonate.

Although maternal oxygen supplementation frequently is viewed as harmless, this research shows that free radical damage may occur in the mother as well.

Additional research shows that longer durations of oxygen administration are correlated with worsening neonatal outcomes. In a study of liberal versus indicated oxygen use, the average time was approximately 90 minutes.8 Use for longer than 176 minutes was associated with lower oxygen levels in fetal blood. A proposed mechanism for this response is placental vasoconstriction thought to protect the fetus from free radical damage.

Again, if the goal is to increase oxygenation, prolonged maternal oxygen supplementation appears to produce the opposite effect.

Fetal acidemia and neonatal morbidity

If a fetus with an abnormal FHR tracing is thought to be hypoxic or acidemic, adding the potentially harmful effects of free radicals could worsen this condition. This is exactly what Raghuraman and colleagues demonstrated in a large prospective cohort analysis.9 While there was no difference in neonatal morbidity between those receiving oxygen and those on room air, there was a significant difference among infants with acidemia and hyperoxia. Composite morbidity (mechanical ventilation, hypothermic therapy, meconium aspiration, and death) was significantly increased in neonates with both hyperoxia and acidemia compared with nonacidemic hyperoxic infants.9 This is further supported by reports of an increased need for neonatal resuscitation and a fourfold increase in umbilical cord pH of less than 7.2.10

While intrauterine and extrauterine life certainly differ, these findings align with the pediatric literature that supports neonatal resuscitation with room air rather than 100% oxygen.11 Additionally, the intrauterine environment is relatively hypoxic, which may make free radical damage more severe.

Continue to: Oxygen use during the COVID-19 pandemic...

 

 

Oxygen use during the COVID-19 pandemic

While high-flow oxygen by mask is not considered an aerosol-generating procedure according to the Centers for Disease Control and Prevention, data are limited regarding the cleaning and filtering of oxygen. It is unknown if high-flow oxygen by mask increases the risk of infectious disease transmission to care providers. Therefore, in the midst of the COVID-19 pandemic, ACOG currently recommends against using supplemental oxygen for Category II and Category III tracings, since the benefits are not well established and the possibility of harm to providers may be increased.12 Oxygen supplementation still should be used in mothers with hypoxia.

Other intrauterine resuscitation options

Maternal oxygen administration does not appear beneficial for neonatal outcomes, but other methods can be used. An intravenous fluid bolus and lateral positioning of the mother, for example, are both associated with increased fetal oxygenation. Reducing uterine activity by discontinuing oxytocin or cervical ripening agents or by administering a tocolytic also can improve FHR abnormalities. Oxygen use should be reserved for patients with maternal hypoxia.

The bottom line

The liberal use of maternal oxygenation for the management of abnormal FHR tracings should be stopped. Clear evidence of its benefit is lacking, and the real possibility of fetal and maternal harm remains. This may be especially true during the COVID-19 pandemic. ●

References
  1. American College of Obstetricians and Gynecologists. Practice bulletin No. 116. Management of intrapartum fetal heart rate tracings. Obstet Gynecol. 2010;116:1232-1240. 
  2. Hamel MS, Anderson BL, Rouse DJ. Oxygen for intrauterine resuscitation: of unproved benefit and potentially harmful. Am J Obstet Gynecol. 2014;211:124-127. 
  3. Althabe O, Schwarcz RL, Pose SV, et al. Effects on fetal heart rate and fetal pO2 of oxygen administration to the mother. Am J Obstet Gynecol. 1967;98:858-870. 
  4. Haydon ML, Gorenberg DM, Nageotte MP, et al. The effect of maternal oxygen administration on fetal pulse oximetry during labor in fetuses with nonreassuring fetal heart rate patterns. Am J Obstet Gynecol. 2006;195:735-738. 
  5. Fawole B, Hofmeyr GJ. Maternal oxygen administration for fetal distress. Cochrane Database Syst Rev. 2012;12:CD0000136. 
  6. McHugh A, El-Khuffash A, Bussmann N, et al. Hyperoxygenation in pregnancy exerts a more profound effect on cardiovascular hemodynamics than is observed in the nonpregnant state. Am J Obstet Gynecol. 2019;220:397.e1-397.e8. 
  7. Khaw KS, Wang CC, Ngan Kee WD, et al. Effects of high inspired oxygen fraction during elective caesarean section under spinal anaesthesia on maternal and fetal oxygenation and lipid peroxidation. Br J Anaesth. 2002;88:18-23. 
  8. Watkins VY, Martin S, Macones GA, et al. The duration of intrapartum supplemental oxygen administration and umbilical cord oxygen content. Am J Obstet Gynecol. 2020;223:440.e1-440.e7. 
  9. Raghuraman N, Temming LA, Stout MJ, et al. Intrauterine hyperoxemia and risk of neonatal morbidity. Obstet Gynecol. 2017;129:676-682. 
  10. Thorp JA, Trobough T, Evans R, et al. The effect of maternal oxygen administration during the second stage of labor on umbilical cord blood gas values: a randomized controlled prospective trial. Am J Obstet Gynecol. 1995;172(2 pt 1):465-474. 
  11. Rabi Y, Rabi D, Yee W. Room air resuscitation of the depressed newborn: a systematic review and meta-analysis. Resuscitation. 2007;72:353-363. 
  12. COVID-19 FAQs for Obstetrician-Gynecologists, Obstetrics. https://www.acog.org/clinical-information/physician-faqs/covid-19-faqs-for-ob-gyns-obstetrics. Accessed October 15, 2020.
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Dr. Harris is a Resident, Prisma Health Upstate Obstetrics and Gynecology Resident Program, Greenville, South Carolina. 

Dr. Ragonetti-Zebell is an academic generalist, Department of Obstetrics and Gynecology, Prisma Health Upstate, Greenville.  

The authors report no financial relationships relevant to this article. 
 

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Dr. Harris is a Resident, Prisma Health Upstate Obstetrics and Gynecology Resident Program, Greenville, South Carolina. 

Dr. Ragonetti-Zebell is an academic generalist, Department of Obstetrics and Gynecology, Prisma Health Upstate, Greenville.  

The authors report no financial relationships relevant to this article. 
 

Author and Disclosure Information

Dr. Harris is a Resident, Prisma Health Upstate Obstetrics and Gynecology Resident Program, Greenville, South Carolina. 

Dr. Ragonetti-Zebell is an academic generalist, Department of Obstetrics and Gynecology, Prisma Health Upstate, Greenville.  

The authors report no financial relationships relevant to this article. 
 

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CASE Heart rate tracing suggests fetal distress

Ms. M. presents for elective induction of labor at 39 weeks’ gestation. During the course of her labor, a Category II fetal heart rate (FHR) tracing is noted, and maternal oxygen is administered as part of the intrauterine resuscitative efforts. Her infant ultimately was delivered vaginally with an arterial cord blood pH of 7.1 and Apgar scores of 5 and 7.

Should intrauterine resuscitation include maternal oxygen administration?

It is a common sight on labor and delivery: An FHR monitoring strip is noted to be a Category II tracing. There may be fetal tachycardia, late decelerations, or perhaps decreased variability. The nurse or physician goes to the laboring mother’s room, checks cervical dilation, changes the patient’s position, and puts an oxygen mask over her face.

The American College of Obstetricians and Gynecologists (ACOG) lists maternal oxygen administration, most commonly at 10 L/min via a nonrebreather face mask, as an intrauterine resuscitative measure for Category II or Category III FHR tracings.1 Maternal oxygen is used to treat abnormal FHR tracings in approximately half of all births in the United States.2 Despite these recommendations and the frequency of its use, however, evidence is limited that maternal oxygenation improves neonatal outcome. In fact, there is emerging evidence of potential harm.

Why use oxygen?

The use of maternal oxygen supplementation intuitively makes sense. We know that certain abnormalities in FHR tracings can signal fetal hypoxia. Left untreated, the hypoxia could lead to fetal acidemia and associated neonatal sequelae. Theoretically, the administration of maternal oxygen should lead to improved fetal oxygenation and improved fetal outcome. This is supported by studies from the 1960s that demonstrate improved FHR tracings after maternal oxygen administration.3

This idea was further supported by studies that demonstrated an increase in fetal oxygen levels when maternal oxygen is administered. Haydon and colleagues evaluated the administration of maternal oxygen in women with nonreassuring FHR tracings.4 Their data showed that maternal oxygen administration increased fetal oxygen as measured by fetal pulse oximetry. The lower the initial fetal oxygen levels prior to oxygen administration, the greater the increase.

Despite these findings, evidence for improved neonatal outcomes is lacking.5 While heart rate tracings and fetal oxygen saturation may be improved with maternal oxygen supplementation, neonatal morbidity appears to remain unchanged (FIGURE). In fact, newer research suggests potential harm. Although an improved FHR tracing may be comforting to the clinician, the end result may be less so. Given these findings on maternal oxygen supplementation, it is time to break this practice habit.

Maternal cardiovascular effects

Most of the literature on maternal hyperoxygenation focuses on fetal response. Before examining the effects on the fetus, however, we must consider the effect on the mother. Cardiovascular changes occur during and after maternal oxygen administration that should be taken into account.

McHugh and colleagues measured the hemodynamic changes in 46 pregnant and 20 nonpregnant women before, immediately, and 10 minutes after a 30-minute period of high-flow oxygen administration.6 While there were no changes in the nonpregnant women’s parameters, in the pregnant women heart rate and stroke volume were decreased after oxygen administration. Additionally, systemic vascular resistance increased and did not return to baseline by 10 minutes postadministration.

Since the purpose of the maternal oxygen administration is to increase oxygen to the fetus, this decrease in cardiac output and increase in systemic vascular resistance is concerning. These results may negate the intended effect of increased oxygen delivery to the fetus.

Continue to: Maternal and fetal oxidative stress...

 

 

Maternal and fetal oxidative stress

Assuming that the abnormal FHR tracing in our case patient is actually due to fetal hypoxia, it would seem prudent to increase fetal oxygenation. However, fetal hyperoxygenation may lead to free radical damage that could worsen neonatal outcomes. Oxidative stress, which can be caused by both hypoxia and hyperoxia, can lead to endothelial and cell receptor damage. This is known to contribute to the cerebral damage of hypoxic-ischemic encephalopathy.

In a randomized trial, Khaw and colleagues measured lipid peroxidases as a “free radical footprint” in women undergoing elective cesarean delivery who were administered oxygen or room air.7 Maternal and fetal oxygen levels were higher in the oxygen-supplementation group, but lipid peroxidases also were elevated. This finding suggests that the excess oxygen results in free radical formation and potentially negative effects on the neonate.

Although maternal oxygen supplementation frequently is viewed as harmless, this research shows that free radical damage may occur in the mother as well.

Additional research shows that longer durations of oxygen administration are correlated with worsening neonatal outcomes. In a study of liberal versus indicated oxygen use, the average time was approximately 90 minutes.8 Use for longer than 176 minutes was associated with lower oxygen levels in fetal blood. A proposed mechanism for this response is placental vasoconstriction thought to protect the fetus from free radical damage.

Again, if the goal is to increase oxygenation, prolonged maternal oxygen supplementation appears to produce the opposite effect.

Fetal acidemia and neonatal morbidity

If a fetus with an abnormal FHR tracing is thought to be hypoxic or acidemic, adding the potentially harmful effects of free radicals could worsen this condition. This is exactly what Raghuraman and colleagues demonstrated in a large prospective cohort analysis.9 While there was no difference in neonatal morbidity between those receiving oxygen and those on room air, there was a significant difference among infants with acidemia and hyperoxia. Composite morbidity (mechanical ventilation, hypothermic therapy, meconium aspiration, and death) was significantly increased in neonates with both hyperoxia and acidemia compared with nonacidemic hyperoxic infants.9 This is further supported by reports of an increased need for neonatal resuscitation and a fourfold increase in umbilical cord pH of less than 7.2.10

While intrauterine and extrauterine life certainly differ, these findings align with the pediatric literature that supports neonatal resuscitation with room air rather than 100% oxygen.11 Additionally, the intrauterine environment is relatively hypoxic, which may make free radical damage more severe.

Continue to: Oxygen use during the COVID-19 pandemic...

 

 

Oxygen use during the COVID-19 pandemic

While high-flow oxygen by mask is not considered an aerosol-generating procedure according to the Centers for Disease Control and Prevention, data are limited regarding the cleaning and filtering of oxygen. It is unknown if high-flow oxygen by mask increases the risk of infectious disease transmission to care providers. Therefore, in the midst of the COVID-19 pandemic, ACOG currently recommends against using supplemental oxygen for Category II and Category III tracings, since the benefits are not well established and the possibility of harm to providers may be increased.12 Oxygen supplementation still should be used in mothers with hypoxia.

Other intrauterine resuscitation options

Maternal oxygen administration does not appear beneficial for neonatal outcomes, but other methods can be used. An intravenous fluid bolus and lateral positioning of the mother, for example, are both associated with increased fetal oxygenation. Reducing uterine activity by discontinuing oxytocin or cervical ripening agents or by administering a tocolytic also can improve FHR abnormalities. Oxygen use should be reserved for patients with maternal hypoxia.

The bottom line

The liberal use of maternal oxygenation for the management of abnormal FHR tracings should be stopped. Clear evidence of its benefit is lacking, and the real possibility of fetal and maternal harm remains. This may be especially true during the COVID-19 pandemic. ●

 

 

CASE Heart rate tracing suggests fetal distress

Ms. M. presents for elective induction of labor at 39 weeks’ gestation. During the course of her labor, a Category II fetal heart rate (FHR) tracing is noted, and maternal oxygen is administered as part of the intrauterine resuscitative efforts. Her infant ultimately was delivered vaginally with an arterial cord blood pH of 7.1 and Apgar scores of 5 and 7.

Should intrauterine resuscitation include maternal oxygen administration?

It is a common sight on labor and delivery: An FHR monitoring strip is noted to be a Category II tracing. There may be fetal tachycardia, late decelerations, or perhaps decreased variability. The nurse or physician goes to the laboring mother’s room, checks cervical dilation, changes the patient’s position, and puts an oxygen mask over her face.

The American College of Obstetricians and Gynecologists (ACOG) lists maternal oxygen administration, most commonly at 10 L/min via a nonrebreather face mask, as an intrauterine resuscitative measure for Category II or Category III FHR tracings.1 Maternal oxygen is used to treat abnormal FHR tracings in approximately half of all births in the United States.2 Despite these recommendations and the frequency of its use, however, evidence is limited that maternal oxygenation improves neonatal outcome. In fact, there is emerging evidence of potential harm.

Why use oxygen?

The use of maternal oxygen supplementation intuitively makes sense. We know that certain abnormalities in FHR tracings can signal fetal hypoxia. Left untreated, the hypoxia could lead to fetal acidemia and associated neonatal sequelae. Theoretically, the administration of maternal oxygen should lead to improved fetal oxygenation and improved fetal outcome. This is supported by studies from the 1960s that demonstrate improved FHR tracings after maternal oxygen administration.3

This idea was further supported by studies that demonstrated an increase in fetal oxygen levels when maternal oxygen is administered. Haydon and colleagues evaluated the administration of maternal oxygen in women with nonreassuring FHR tracings.4 Their data showed that maternal oxygen administration increased fetal oxygen as measured by fetal pulse oximetry. The lower the initial fetal oxygen levels prior to oxygen administration, the greater the increase.

Despite these findings, evidence for improved neonatal outcomes is lacking.5 While heart rate tracings and fetal oxygen saturation may be improved with maternal oxygen supplementation, neonatal morbidity appears to remain unchanged (FIGURE). In fact, newer research suggests potential harm. Although an improved FHR tracing may be comforting to the clinician, the end result may be less so. Given these findings on maternal oxygen supplementation, it is time to break this practice habit.

Maternal cardiovascular effects

Most of the literature on maternal hyperoxygenation focuses on fetal response. Before examining the effects on the fetus, however, we must consider the effect on the mother. Cardiovascular changes occur during and after maternal oxygen administration that should be taken into account.

McHugh and colleagues measured the hemodynamic changes in 46 pregnant and 20 nonpregnant women before, immediately, and 10 minutes after a 30-minute period of high-flow oxygen administration.6 While there were no changes in the nonpregnant women’s parameters, in the pregnant women heart rate and stroke volume were decreased after oxygen administration. Additionally, systemic vascular resistance increased and did not return to baseline by 10 minutes postadministration.

Since the purpose of the maternal oxygen administration is to increase oxygen to the fetus, this decrease in cardiac output and increase in systemic vascular resistance is concerning. These results may negate the intended effect of increased oxygen delivery to the fetus.

Continue to: Maternal and fetal oxidative stress...

 

 

Maternal and fetal oxidative stress

Assuming that the abnormal FHR tracing in our case patient is actually due to fetal hypoxia, it would seem prudent to increase fetal oxygenation. However, fetal hyperoxygenation may lead to free radical damage that could worsen neonatal outcomes. Oxidative stress, which can be caused by both hypoxia and hyperoxia, can lead to endothelial and cell receptor damage. This is known to contribute to the cerebral damage of hypoxic-ischemic encephalopathy.

In a randomized trial, Khaw and colleagues measured lipid peroxidases as a “free radical footprint” in women undergoing elective cesarean delivery who were administered oxygen or room air.7 Maternal and fetal oxygen levels were higher in the oxygen-supplementation group, but lipid peroxidases also were elevated. This finding suggests that the excess oxygen results in free radical formation and potentially negative effects on the neonate.

Although maternal oxygen supplementation frequently is viewed as harmless, this research shows that free radical damage may occur in the mother as well.

Additional research shows that longer durations of oxygen administration are correlated with worsening neonatal outcomes. In a study of liberal versus indicated oxygen use, the average time was approximately 90 minutes.8 Use for longer than 176 minutes was associated with lower oxygen levels in fetal blood. A proposed mechanism for this response is placental vasoconstriction thought to protect the fetus from free radical damage.

Again, if the goal is to increase oxygenation, prolonged maternal oxygen supplementation appears to produce the opposite effect.

Fetal acidemia and neonatal morbidity

If a fetus with an abnormal FHR tracing is thought to be hypoxic or acidemic, adding the potentially harmful effects of free radicals could worsen this condition. This is exactly what Raghuraman and colleagues demonstrated in a large prospective cohort analysis.9 While there was no difference in neonatal morbidity between those receiving oxygen and those on room air, there was a significant difference among infants with acidemia and hyperoxia. Composite morbidity (mechanical ventilation, hypothermic therapy, meconium aspiration, and death) was significantly increased in neonates with both hyperoxia and acidemia compared with nonacidemic hyperoxic infants.9 This is further supported by reports of an increased need for neonatal resuscitation and a fourfold increase in umbilical cord pH of less than 7.2.10

While intrauterine and extrauterine life certainly differ, these findings align with the pediatric literature that supports neonatal resuscitation with room air rather than 100% oxygen.11 Additionally, the intrauterine environment is relatively hypoxic, which may make free radical damage more severe.

Continue to: Oxygen use during the COVID-19 pandemic...

 

 

Oxygen use during the COVID-19 pandemic

While high-flow oxygen by mask is not considered an aerosol-generating procedure according to the Centers for Disease Control and Prevention, data are limited regarding the cleaning and filtering of oxygen. It is unknown if high-flow oxygen by mask increases the risk of infectious disease transmission to care providers. Therefore, in the midst of the COVID-19 pandemic, ACOG currently recommends against using supplemental oxygen for Category II and Category III tracings, since the benefits are not well established and the possibility of harm to providers may be increased.12 Oxygen supplementation still should be used in mothers with hypoxia.

Other intrauterine resuscitation options

Maternal oxygen administration does not appear beneficial for neonatal outcomes, but other methods can be used. An intravenous fluid bolus and lateral positioning of the mother, for example, are both associated with increased fetal oxygenation. Reducing uterine activity by discontinuing oxytocin or cervical ripening agents or by administering a tocolytic also can improve FHR abnormalities. Oxygen use should be reserved for patients with maternal hypoxia.

The bottom line

The liberal use of maternal oxygenation for the management of abnormal FHR tracings should be stopped. Clear evidence of its benefit is lacking, and the real possibility of fetal and maternal harm remains. This may be especially true during the COVID-19 pandemic. ●

References
  1. American College of Obstetricians and Gynecologists. Practice bulletin No. 116. Management of intrapartum fetal heart rate tracings. Obstet Gynecol. 2010;116:1232-1240. 
  2. Hamel MS, Anderson BL, Rouse DJ. Oxygen for intrauterine resuscitation: of unproved benefit and potentially harmful. Am J Obstet Gynecol. 2014;211:124-127. 
  3. Althabe O, Schwarcz RL, Pose SV, et al. Effects on fetal heart rate and fetal pO2 of oxygen administration to the mother. Am J Obstet Gynecol. 1967;98:858-870. 
  4. Haydon ML, Gorenberg DM, Nageotte MP, et al. The effect of maternal oxygen administration on fetal pulse oximetry during labor in fetuses with nonreassuring fetal heart rate patterns. Am J Obstet Gynecol. 2006;195:735-738. 
  5. Fawole B, Hofmeyr GJ. Maternal oxygen administration for fetal distress. Cochrane Database Syst Rev. 2012;12:CD0000136. 
  6. McHugh A, El-Khuffash A, Bussmann N, et al. Hyperoxygenation in pregnancy exerts a more profound effect on cardiovascular hemodynamics than is observed in the nonpregnant state. Am J Obstet Gynecol. 2019;220:397.e1-397.e8. 
  7. Khaw KS, Wang CC, Ngan Kee WD, et al. Effects of high inspired oxygen fraction during elective caesarean section under spinal anaesthesia on maternal and fetal oxygenation and lipid peroxidation. Br J Anaesth. 2002;88:18-23. 
  8. Watkins VY, Martin S, Macones GA, et al. The duration of intrapartum supplemental oxygen administration and umbilical cord oxygen content. Am J Obstet Gynecol. 2020;223:440.e1-440.e7. 
  9. Raghuraman N, Temming LA, Stout MJ, et al. Intrauterine hyperoxemia and risk of neonatal morbidity. Obstet Gynecol. 2017;129:676-682. 
  10. Thorp JA, Trobough T, Evans R, et al. The effect of maternal oxygen administration during the second stage of labor on umbilical cord blood gas values: a randomized controlled prospective trial. Am J Obstet Gynecol. 1995;172(2 pt 1):465-474. 
  11. Rabi Y, Rabi D, Yee W. Room air resuscitation of the depressed newborn: a systematic review and meta-analysis. Resuscitation. 2007;72:353-363. 
  12. COVID-19 FAQs for Obstetrician-Gynecologists, Obstetrics. https://www.acog.org/clinical-information/physician-faqs/covid-19-faqs-for-ob-gyns-obstetrics. Accessed October 15, 2020.
References
  1. American College of Obstetricians and Gynecologists. Practice bulletin No. 116. Management of intrapartum fetal heart rate tracings. Obstet Gynecol. 2010;116:1232-1240. 
  2. Hamel MS, Anderson BL, Rouse DJ. Oxygen for intrauterine resuscitation: of unproved benefit and potentially harmful. Am J Obstet Gynecol. 2014;211:124-127. 
  3. Althabe O, Schwarcz RL, Pose SV, et al. Effects on fetal heart rate and fetal pO2 of oxygen administration to the mother. Am J Obstet Gynecol. 1967;98:858-870. 
  4. Haydon ML, Gorenberg DM, Nageotte MP, et al. The effect of maternal oxygen administration on fetal pulse oximetry during labor in fetuses with nonreassuring fetal heart rate patterns. Am J Obstet Gynecol. 2006;195:735-738. 
  5. Fawole B, Hofmeyr GJ. Maternal oxygen administration for fetal distress. Cochrane Database Syst Rev. 2012;12:CD0000136. 
  6. McHugh A, El-Khuffash A, Bussmann N, et al. Hyperoxygenation in pregnancy exerts a more profound effect on cardiovascular hemodynamics than is observed in the nonpregnant state. Am J Obstet Gynecol. 2019;220:397.e1-397.e8. 
  7. Khaw KS, Wang CC, Ngan Kee WD, et al. Effects of high inspired oxygen fraction during elective caesarean section under spinal anaesthesia on maternal and fetal oxygenation and lipid peroxidation. Br J Anaesth. 2002;88:18-23. 
  8. Watkins VY, Martin S, Macones GA, et al. The duration of intrapartum supplemental oxygen administration and umbilical cord oxygen content. Am J Obstet Gynecol. 2020;223:440.e1-440.e7. 
  9. Raghuraman N, Temming LA, Stout MJ, et al. Intrauterine hyperoxemia and risk of neonatal morbidity. Obstet Gynecol. 2017;129:676-682. 
  10. Thorp JA, Trobough T, Evans R, et al. The effect of maternal oxygen administration during the second stage of labor on umbilical cord blood gas values: a randomized controlled prospective trial. Am J Obstet Gynecol. 1995;172(2 pt 1):465-474. 
  11. Rabi Y, Rabi D, Yee W. Room air resuscitation of the depressed newborn: a systematic review and meta-analysis. Resuscitation. 2007;72:353-363. 
  12. COVID-19 FAQs for Obstetrician-Gynecologists, Obstetrics. https://www.acog.org/clinical-information/physician-faqs/covid-19-faqs-for-ob-gyns-obstetrics. Accessed October 15, 2020.
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Syphilis: Cutting risk through primary prevention and prenatal screening

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CASE Pregnant woman with positive Treponema pallidum antibody test

A 30-year-old primigravida at 10 weeks and 4 days of gestation by her last menstrual period presents to your office for her initial prenatal visit. She expresses no concerns. You order the standard set of laboratory tests, including a sexually transmitted infection (STI) screening panel. Consistent with your institution’s use of the reverse algorithm for syphilis screening, you obtain a Treponema pallidum antibody test, which reflexes to the rapid plasma reagin (RPR) test. Three days later, you receive a notification that this patient’s T pallidum antibody result was positive, followed by negative RPR test results. The follow-up T pallidum particle agglutination (TP-PA) test also was negative. Given these findings, you consider:

  • What is the correct interpretation of the patient’s sequence of test results?
  • Is she infected, and does she require treatment?

Meet our perpetrator

Syphilis has plagued society since the late 15th century, although its causative agent, the spirochete T pallidum, was not recognized until 1905.1,2T pallidum bacteria are transmitted via sexual contact, as well as through vertical transmission during pregnancy or delivery. Infection with syphilis is reported in 50% to 60% of sexual partners after a single exposure to an infected individual with early syphilis, and the mean incubation period is 21 days.3T pallidum can cross the placenta and infect a fetus as early as the sixth week of gestation.3 Congenital syphilis infections occur in the neonates of 50% to 80% of women with untreated primary, secondary, or early latent syphilis infections; maternal syphilis is associated with a 21% increased risk of stillbirth, a 6% increased risk of preterm delivery, and a 9% increased risk of neonatal death.4,5 Additionally, syphilis infection is associated with a high risk of HIV infection, as well as coinfection with other STIs.1

Given the highly infective nature of T pallidum, as well as the severity of the potential consequences of infection for both mothers and babies, primary prevention, education of at-risk populations, and early recognition of clinical features of syphilis infection are of utmost importance in preventing morbidity and mortality. In this article, we review the epidemiology and extensive clinical manifestations of syphilis, as well as current screening recommendations and treatment for pregnant women.

The extent of the problem today

Although US rates of syphilis have ebbed and flowed for the past several decades, the current incidence has grown exponentially in recent years, with the number of cases reported to the Centers for Disease Control and Prevention (CDC) increasing by 71% from 2014 to 2018.6 During this time period, reported cases of primary and secondary syphilis in women more than doubled (172.7% and 165.4%, respectively) according to CDC data, accompanied by a parallel rise in reported cases of congenital syphilis in both live and stillborn infants.6 In 2018, the CDC reported a national rate of congenital syphilis of 33.1 cases per 100,000 live births, a 39.7% rise compared with data from 2017.6

Those most at risk. Risk factors for syphilis infection include age younger than 30 years, low socioeconomic status, substance abuse, HIV infection, concurrent STIs, and high-risk sexual activity (sex with multiple high-risk partners).3 Additionally, reported rates of primary and secondary syphilis infections, as well as congenital syphilis infections, are more elevated among women who identify as Black, American Indian/Alaska Native, and/or Hispanic.6 Congenital infections in the United States are correlated with a lack of prenatal care, which has been similarly linked with racial and socioeconomic disparities, as well as with untreated mental health and substance use disorders and recent immigration to the United States.5,7

Continue to: The many phases of syphilis...

 

 

The many phases of syphilis

The characteristic lesion of primary syphilis is a chancre, which is a painless, ulcerative lesion with raised borders and a clean, indurated base appearing at the site of spirochete entry (FIGURE 1). Chancres most commonly appear in the genital area, with the most frequent sites in females being within the vaginal canal or on the cervix. Primary chancres tend to heal spontaneously within 3 to 6 weeks, even without treatment, and frequently are accompanied by painless inguinal lymphadenopathy. Given that the most common chancre sites are not immediately apparent, primary infections in women often go undetected.3 In fact, it is essential for clinicians to recognize that, in our routine practice, most patients with syphilis will not be symptomatic at all, and the diagnosis will only be made by serologic screening.

Following resolution of the primary phase, the patient may enter the secondary stage of T pallidum infection. During this stage, spirochetes may disseminate throughout the bloodstream to infect all major organ systems. The principal manifestations of secondary syphilis include a diffuse maculopapular rash that begins on the trunk and proximal extremities and spreads to include the palms and soles (FIGURE 2); mucosal lesions, such as mucous patches and condyloma lata (FIGURE 3); nonscarring alopecia; periostitis; generalized lymphadenopathy; and, in some cases, hepatitis or nephritis.1,3


Secondary syphilis usually clears within 2 to 6 weeks, with the patient then entering the early latent stage of syphilis. During this period, up to 25% of patients are subject to flares of secondary syphilitic lesions but otherwise are asymptomatic.1,3,4 These recurrences tend to occur within 1 year, hence the distinction between early and late latent stages. Once a year has passed, patients are not contagious by sexual transmission and are unlikely to suffer a relapse of secondary symptoms.1,3 However, late latent syphilis is characterized by periods of intermittent bacteremia that allow for seeding of the placenta and infection in about 10% of fetuses.5
 


Untreated, about 40% of patients will progress to the tertiary stage of syphilis, which is characterized by gummas affecting the skin and mucous membranes (FIGURE 4) and cardiovascular manifestations including arterial aneurysms and aortic insufficiency.3

Neurologic manifestations of syphilis may arise during any of the above stages, though the most characteristic manifestations tend to appear decades after the primary infection. Early neurosyphilis may present as meningitis, with or without concomitant ocular syphilis (uveitis, retinitis) and/or as otic syphilis (hearing loss, persistent tinnitus).1,5 Patients with late (tertiary) neurosyphilis tend to exhibit meningovascular symptoms similar to stroke (aphasia, hemiplegia, seizures) and/or parenchymal effects such as general paresis. Tabes dorsalis (manifestations of which include urinary and rectal incontinence, lightning pains, and ataxia) is a late-onset manifestation.1,3

Congenital syphilis can be subdivided into an early and late stage. The first stage, in which clinical findings occur within the first 2 years of life, commonly features a desquamating rash, hepatomegaly, and rhinitis. Anemia, thrombocytopenia, periostitis, and osteomyelitis also have been documented.5 Of note, two-thirds of infants are asymptomatic at birth and may not develop such clinical manifestations for 3 to 8 weeks.3 If untreated, early congenital infection may progress to late manifestations, such as Hutchinson teeth, mulberry molars, interstitial keratitis, deafness, saddle nose, saber shins, and such neurologic abnormalities as developmental delay and general paresis.3

Continue to: Prenatal screening and diagnosis...

 

 

Prenatal screening and diagnosis

Current recommendations issued by the CDC and the American College of Obstetricians and Gynecologists state that all pregnant women should be screened for syphilis infection at their first presentation to care, with repeat screening between 28 and 32 weeks of gestation and at birth, for women living in areas with a high prevalence of syphilis and/or with any of the aforementioned risk factors.3,5 Given that providers may be unfamiliar with the prevalence of syphilis in their area, and that patients may acquire or develop an infection later on in their pregnancy, researchers have begun to investigate the feasibility of universal third-trimester screening. While the cost-effectiveness of such a protocol is disputed, recent studies suggest that it may result in a substantial decrease in adverse maternal and fetal outcomes.8,9

Diagnostic tests

The traditional algorithm for the diagnosis of syphilis infection begins with a nontreponemal screening test, such as the RPR or the Venereal Disease Research Laboratory test. If positive, these screening tests are followed by a confirmatory treponemal test, such as the fluorescent treponemal antibody (FTA) test or the TP-PA (FIGURE 5).

The “reverse” screening algorithm begins with the FTA and, if positive, reflexes to the RPR. A reactive RPR indicates an active infection, and the patient should be treated. A negative RPR should be followed by the TP-PA to rule out a false-positive immunoglobulin G test. If the TP-PA test result is positive, the diagnosis of syphilis is confirmed (FIGURE 6). It is crucial to understand, however, that treponemal antibodies will remain positive for a patient’s lifetime, and someone who may have been treated for syphilis in the past also will screen positive. Once 2 treponemal tests are positive, physicians should take a careful history to assess prior infection risk and treatment status. A negative TP-PA excludes a diagnosis of syphilis.

Advantages of the reverse screening algorithm. Nontreponemal tests are inexpensive and easy to perform, and titers allow for identification of a baseline to evaluate response to treatment.11 However, given the fluctuation of RPR sensitivity (depending on stage of disease and a decreased ability to detect primary and latent stages of syphilis), there has been a resurgence of interest in the reverse algorithm.11 While reverse screening has been found to incur higher costs, and may result in overtreatment and increased stress due to false-positive results,12 there is evidence to suggest that this algorithm is more sensitive for primary and latent infections.8,11,13-15

Given the rise in prevalence of syphilis infections in the United States over the past decade, and therefore a higher pretest probability of syphilis in the population, we favor the reverse screening algorithm in obstetrics, particularly given the risks of adverse maternal and fetal outcomes.

Treating syphilis in pregnancy

Parenteral benzathine penicillin G is the only currently recommended medication for the treatment of syphilis in pregnancy. This drug is effective in treating maternal infection and in preventing fetal infections, as well as in treating established fetal infections.3,5 Regimens differ depending on the stage of syphilis infection (TABLE). Treatment for presumed early syphilis is recommended for women who have had sexual contact with a partner diagnosed with primary, secondary, or early latent syphilis within 3 months of their current pregnancy.5 Any patient with diagnosed syphilis who demonstrates clinical signs of neurologic involvement should undergo lumbar puncture to assess for evidence of neurosyphilis.3 CDC guidelines recommend that patients who report an allergy to penicillin undergo desensitization therapy in a controlled setting, as other antibiotics that have been investigated in the treatment of syphilis are either not appropriate due to teratogenicity or due to suboptimal fetal treatment.3,5

Syphilotherapy may lead to the Jarisch-Herxheimer reaction, which is an acute systemic reaction to inflammatory cytokines produced in response to lipopolysaccharide released by dying spirochetes.5 This reaction is characterized by fever, chills, myalgia, headache, hypotension, and worsening of cutaneous lesions. Preterm labor and delivery and fetal heart rate tracing abnormalities also have been documented in pregnant women experiencing this reaction, particularly during the second half of pregnancy.16 Prior to the start of treatment, a detailed sonographic assessment should be performed to assess the fetus for signs of early syphilis, including hepatomegaly, elevated peak systolic velocity of the middle cerebral artery (indicative of fetal anemia), polyhydramnios, placentomegaly, or hydrops.5,7

CASE Resolved

The combination of the patient’s test results—positive FTA, negative RPR, and negative TP-PA—suggest a false-positive treponemal assay. This sequence of tests excludes a diagnosis of syphilis; therefore, no treatment is necessary. Depending on the prevalence of syphilis in the patient’s geographic location, as well as her sexual history, rescreening between 28 and 32 weeks may be warranted. ●

References
  1. Ghanem KG, Ram S, Rice PA. The modern epidemic of syphilis. N Engl J Med. 2020;382:845-854.  
  2. Barnett R. Syphilis. Lancet. 2018;391:1471. 
  3. Duff P. Maternal and fetal infections. In: Resnik R, Lockwood CJ, Moore T, et al. Creasy and Resnik's Maternal-Fetal Medicine: Principles and Practice. 8th ed. Philadelphia, PA: Elsevier; 2018:862-919. 
  4. Gomez GB, Kamb ML, Newman LM, et al. Untreated maternal syphilis and adverse outcomes of pregnancy: a systematic review and meta-analysis. Bull World Health Organ. 2013;91:217-226. 
  5. Adhikari EH. Syphilis in pregnancy. Obstet Gynecol. 2020;135:1121-1135. 
  6. Syphilis. CDC website. https://www.cdc.gov/std/stats18/syphilis.htm. Published October 1, 2019. Accessed October 6, 2020. 
  7. Rac MF, Revell PA, Eppes CS. Syphilis during pregnancy: a preventable threat to maternal-fetal health. Am J Obstet Gynecol. 2017;4:352-363. 
  8. Dunseth CD, Ford BA, Krasowski MD. Traditional versus reverse syphilis algorithms: a comparison at a large academic medical center. Pract Lab Med. 2017;8:52-59. 
  9. Hersh AR, Megli CJ, Caughey AB. Repeat screening for syphilis in the third trimester of pregnancy: a cost-effectiveness analysis. Obstet Gynecol. 2018;132:699-706. 
  10. Albright CM, Emerson JB, Werner EF, et al. Third trimester prenatal syphilis screening: a cost-effectiveness analysis. Obstet Gynecol. 2015;126:479-485. 
  11. Seña AC, White BL, Sparling PF. Novel Treponema pallidum serologic tests: a paradigm shift in syphilis screening for the 21st century. Clin Infect Dis. 2010;51:700-708.  
  12. Owusu-Edusei K Jr, Peterman TA, Ballard RC. Serologic testing for syphilis in the United States: a cost-effectiveness analysis of two screening algorithms. Sex Transm Dis. 2011;38:1-7. 
  13. Huh HJ, Chung JW, Park SY, et al. Comparison of automated treponemal and nontreponemal test algorithms as first-line syphilis screening assays. Ann Lab Med. 2016;36:23-27.  
  14. Centers for Disease Control and Prevention. Syphilis testing algorithms using treponemal test for initial screening-four laboratories. New York City, 2005-2006. MMWR Morb Mortal Wkly Rep. 2008;57:872-875. 
  15. Mishra S, Boily MC, Ng V, et al. The laboratory impact of changing syphilis screening from the rapid-plasma reagin to a treponemal enzyme immunoassay: a case-study from the greater Toronto area. Sex Transm Dis. 2011;38:190-196. 
  16. Klein VR, Cox SM, Mitchell MD, et al. The Jarisch-Herzheimer reaction complicating syphilotherapy in pregnancy. Obstet Gynecol. 1990;75:375-380.
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CASE Pregnant woman with positive Treponema pallidum antibody test

A 30-year-old primigravida at 10 weeks and 4 days of gestation by her last menstrual period presents to your office for her initial prenatal visit. She expresses no concerns. You order the standard set of laboratory tests, including a sexually transmitted infection (STI) screening panel. Consistent with your institution’s use of the reverse algorithm for syphilis screening, you obtain a Treponema pallidum antibody test, which reflexes to the rapid plasma reagin (RPR) test. Three days later, you receive a notification that this patient’s T pallidum antibody result was positive, followed by negative RPR test results. The follow-up T pallidum particle agglutination (TP-PA) test also was negative. Given these findings, you consider:

  • What is the correct interpretation of the patient’s sequence of test results?
  • Is she infected, and does she require treatment?

Meet our perpetrator

Syphilis has plagued society since the late 15th century, although its causative agent, the spirochete T pallidum, was not recognized until 1905.1,2T pallidum bacteria are transmitted via sexual contact, as well as through vertical transmission during pregnancy or delivery. Infection with syphilis is reported in 50% to 60% of sexual partners after a single exposure to an infected individual with early syphilis, and the mean incubation period is 21 days.3T pallidum can cross the placenta and infect a fetus as early as the sixth week of gestation.3 Congenital syphilis infections occur in the neonates of 50% to 80% of women with untreated primary, secondary, or early latent syphilis infections; maternal syphilis is associated with a 21% increased risk of stillbirth, a 6% increased risk of preterm delivery, and a 9% increased risk of neonatal death.4,5 Additionally, syphilis infection is associated with a high risk of HIV infection, as well as coinfection with other STIs.1

Given the highly infective nature of T pallidum, as well as the severity of the potential consequences of infection for both mothers and babies, primary prevention, education of at-risk populations, and early recognition of clinical features of syphilis infection are of utmost importance in preventing morbidity and mortality. In this article, we review the epidemiology and extensive clinical manifestations of syphilis, as well as current screening recommendations and treatment for pregnant women.

The extent of the problem today

Although US rates of syphilis have ebbed and flowed for the past several decades, the current incidence has grown exponentially in recent years, with the number of cases reported to the Centers for Disease Control and Prevention (CDC) increasing by 71% from 2014 to 2018.6 During this time period, reported cases of primary and secondary syphilis in women more than doubled (172.7% and 165.4%, respectively) according to CDC data, accompanied by a parallel rise in reported cases of congenital syphilis in both live and stillborn infants.6 In 2018, the CDC reported a national rate of congenital syphilis of 33.1 cases per 100,000 live births, a 39.7% rise compared with data from 2017.6

Those most at risk. Risk factors for syphilis infection include age younger than 30 years, low socioeconomic status, substance abuse, HIV infection, concurrent STIs, and high-risk sexual activity (sex with multiple high-risk partners).3 Additionally, reported rates of primary and secondary syphilis infections, as well as congenital syphilis infections, are more elevated among women who identify as Black, American Indian/Alaska Native, and/or Hispanic.6 Congenital infections in the United States are correlated with a lack of prenatal care, which has been similarly linked with racial and socioeconomic disparities, as well as with untreated mental health and substance use disorders and recent immigration to the United States.5,7

Continue to: The many phases of syphilis...

 

 

The many phases of syphilis

The characteristic lesion of primary syphilis is a chancre, which is a painless, ulcerative lesion with raised borders and a clean, indurated base appearing at the site of spirochete entry (FIGURE 1). Chancres most commonly appear in the genital area, with the most frequent sites in females being within the vaginal canal or on the cervix. Primary chancres tend to heal spontaneously within 3 to 6 weeks, even without treatment, and frequently are accompanied by painless inguinal lymphadenopathy. Given that the most common chancre sites are not immediately apparent, primary infections in women often go undetected.3 In fact, it is essential for clinicians to recognize that, in our routine practice, most patients with syphilis will not be symptomatic at all, and the diagnosis will only be made by serologic screening.

Following resolution of the primary phase, the patient may enter the secondary stage of T pallidum infection. During this stage, spirochetes may disseminate throughout the bloodstream to infect all major organ systems. The principal manifestations of secondary syphilis include a diffuse maculopapular rash that begins on the trunk and proximal extremities and spreads to include the palms and soles (FIGURE 2); mucosal lesions, such as mucous patches and condyloma lata (FIGURE 3); nonscarring alopecia; periostitis; generalized lymphadenopathy; and, in some cases, hepatitis or nephritis.1,3


Secondary syphilis usually clears within 2 to 6 weeks, with the patient then entering the early latent stage of syphilis. During this period, up to 25% of patients are subject to flares of secondary syphilitic lesions but otherwise are asymptomatic.1,3,4 These recurrences tend to occur within 1 year, hence the distinction between early and late latent stages. Once a year has passed, patients are not contagious by sexual transmission and are unlikely to suffer a relapse of secondary symptoms.1,3 However, late latent syphilis is characterized by periods of intermittent bacteremia that allow for seeding of the placenta and infection in about 10% of fetuses.5
 


Untreated, about 40% of patients will progress to the tertiary stage of syphilis, which is characterized by gummas affecting the skin and mucous membranes (FIGURE 4) and cardiovascular manifestations including arterial aneurysms and aortic insufficiency.3

Neurologic manifestations of syphilis may arise during any of the above stages, though the most characteristic manifestations tend to appear decades after the primary infection. Early neurosyphilis may present as meningitis, with or without concomitant ocular syphilis (uveitis, retinitis) and/or as otic syphilis (hearing loss, persistent tinnitus).1,5 Patients with late (tertiary) neurosyphilis tend to exhibit meningovascular symptoms similar to stroke (aphasia, hemiplegia, seizures) and/or parenchymal effects such as general paresis. Tabes dorsalis (manifestations of which include urinary and rectal incontinence, lightning pains, and ataxia) is a late-onset manifestation.1,3

Congenital syphilis can be subdivided into an early and late stage. The first stage, in which clinical findings occur within the first 2 years of life, commonly features a desquamating rash, hepatomegaly, and rhinitis. Anemia, thrombocytopenia, periostitis, and osteomyelitis also have been documented.5 Of note, two-thirds of infants are asymptomatic at birth and may not develop such clinical manifestations for 3 to 8 weeks.3 If untreated, early congenital infection may progress to late manifestations, such as Hutchinson teeth, mulberry molars, interstitial keratitis, deafness, saddle nose, saber shins, and such neurologic abnormalities as developmental delay and general paresis.3

Continue to: Prenatal screening and diagnosis...

 

 

Prenatal screening and diagnosis

Current recommendations issued by the CDC and the American College of Obstetricians and Gynecologists state that all pregnant women should be screened for syphilis infection at their first presentation to care, with repeat screening between 28 and 32 weeks of gestation and at birth, for women living in areas with a high prevalence of syphilis and/or with any of the aforementioned risk factors.3,5 Given that providers may be unfamiliar with the prevalence of syphilis in their area, and that patients may acquire or develop an infection later on in their pregnancy, researchers have begun to investigate the feasibility of universal third-trimester screening. While the cost-effectiveness of such a protocol is disputed, recent studies suggest that it may result in a substantial decrease in adverse maternal and fetal outcomes.8,9

Diagnostic tests

The traditional algorithm for the diagnosis of syphilis infection begins with a nontreponemal screening test, such as the RPR or the Venereal Disease Research Laboratory test. If positive, these screening tests are followed by a confirmatory treponemal test, such as the fluorescent treponemal antibody (FTA) test or the TP-PA (FIGURE 5).

The “reverse” screening algorithm begins with the FTA and, if positive, reflexes to the RPR. A reactive RPR indicates an active infection, and the patient should be treated. A negative RPR should be followed by the TP-PA to rule out a false-positive immunoglobulin G test. If the TP-PA test result is positive, the diagnosis of syphilis is confirmed (FIGURE 6). It is crucial to understand, however, that treponemal antibodies will remain positive for a patient’s lifetime, and someone who may have been treated for syphilis in the past also will screen positive. Once 2 treponemal tests are positive, physicians should take a careful history to assess prior infection risk and treatment status. A negative TP-PA excludes a diagnosis of syphilis.

Advantages of the reverse screening algorithm. Nontreponemal tests are inexpensive and easy to perform, and titers allow for identification of a baseline to evaluate response to treatment.11 However, given the fluctuation of RPR sensitivity (depending on stage of disease and a decreased ability to detect primary and latent stages of syphilis), there has been a resurgence of interest in the reverse algorithm.11 While reverse screening has been found to incur higher costs, and may result in overtreatment and increased stress due to false-positive results,12 there is evidence to suggest that this algorithm is more sensitive for primary and latent infections.8,11,13-15

Given the rise in prevalence of syphilis infections in the United States over the past decade, and therefore a higher pretest probability of syphilis in the population, we favor the reverse screening algorithm in obstetrics, particularly given the risks of adverse maternal and fetal outcomes.

Treating syphilis in pregnancy

Parenteral benzathine penicillin G is the only currently recommended medication for the treatment of syphilis in pregnancy. This drug is effective in treating maternal infection and in preventing fetal infections, as well as in treating established fetal infections.3,5 Regimens differ depending on the stage of syphilis infection (TABLE). Treatment for presumed early syphilis is recommended for women who have had sexual contact with a partner diagnosed with primary, secondary, or early latent syphilis within 3 months of their current pregnancy.5 Any patient with diagnosed syphilis who demonstrates clinical signs of neurologic involvement should undergo lumbar puncture to assess for evidence of neurosyphilis.3 CDC guidelines recommend that patients who report an allergy to penicillin undergo desensitization therapy in a controlled setting, as other antibiotics that have been investigated in the treatment of syphilis are either not appropriate due to teratogenicity or due to suboptimal fetal treatment.3,5

Syphilotherapy may lead to the Jarisch-Herxheimer reaction, which is an acute systemic reaction to inflammatory cytokines produced in response to lipopolysaccharide released by dying spirochetes.5 This reaction is characterized by fever, chills, myalgia, headache, hypotension, and worsening of cutaneous lesions. Preterm labor and delivery and fetal heart rate tracing abnormalities also have been documented in pregnant women experiencing this reaction, particularly during the second half of pregnancy.16 Prior to the start of treatment, a detailed sonographic assessment should be performed to assess the fetus for signs of early syphilis, including hepatomegaly, elevated peak systolic velocity of the middle cerebral artery (indicative of fetal anemia), polyhydramnios, placentomegaly, or hydrops.5,7

CASE Resolved

The combination of the patient’s test results—positive FTA, negative RPR, and negative TP-PA—suggest a false-positive treponemal assay. This sequence of tests excludes a diagnosis of syphilis; therefore, no treatment is necessary. Depending on the prevalence of syphilis in the patient’s geographic location, as well as her sexual history, rescreening between 28 and 32 weeks may be warranted. ●

 

 

CASE Pregnant woman with positive Treponema pallidum antibody test

A 30-year-old primigravida at 10 weeks and 4 days of gestation by her last menstrual period presents to your office for her initial prenatal visit. She expresses no concerns. You order the standard set of laboratory tests, including a sexually transmitted infection (STI) screening panel. Consistent with your institution’s use of the reverse algorithm for syphilis screening, you obtain a Treponema pallidum antibody test, which reflexes to the rapid plasma reagin (RPR) test. Three days later, you receive a notification that this patient’s T pallidum antibody result was positive, followed by negative RPR test results. The follow-up T pallidum particle agglutination (TP-PA) test also was negative. Given these findings, you consider:

  • What is the correct interpretation of the patient’s sequence of test results?
  • Is she infected, and does she require treatment?

Meet our perpetrator

Syphilis has plagued society since the late 15th century, although its causative agent, the spirochete T pallidum, was not recognized until 1905.1,2T pallidum bacteria are transmitted via sexual contact, as well as through vertical transmission during pregnancy or delivery. Infection with syphilis is reported in 50% to 60% of sexual partners after a single exposure to an infected individual with early syphilis, and the mean incubation period is 21 days.3T pallidum can cross the placenta and infect a fetus as early as the sixth week of gestation.3 Congenital syphilis infections occur in the neonates of 50% to 80% of women with untreated primary, secondary, or early latent syphilis infections; maternal syphilis is associated with a 21% increased risk of stillbirth, a 6% increased risk of preterm delivery, and a 9% increased risk of neonatal death.4,5 Additionally, syphilis infection is associated with a high risk of HIV infection, as well as coinfection with other STIs.1

Given the highly infective nature of T pallidum, as well as the severity of the potential consequences of infection for both mothers and babies, primary prevention, education of at-risk populations, and early recognition of clinical features of syphilis infection are of utmost importance in preventing morbidity and mortality. In this article, we review the epidemiology and extensive clinical manifestations of syphilis, as well as current screening recommendations and treatment for pregnant women.

The extent of the problem today

Although US rates of syphilis have ebbed and flowed for the past several decades, the current incidence has grown exponentially in recent years, with the number of cases reported to the Centers for Disease Control and Prevention (CDC) increasing by 71% from 2014 to 2018.6 During this time period, reported cases of primary and secondary syphilis in women more than doubled (172.7% and 165.4%, respectively) according to CDC data, accompanied by a parallel rise in reported cases of congenital syphilis in both live and stillborn infants.6 In 2018, the CDC reported a national rate of congenital syphilis of 33.1 cases per 100,000 live births, a 39.7% rise compared with data from 2017.6

Those most at risk. Risk factors for syphilis infection include age younger than 30 years, low socioeconomic status, substance abuse, HIV infection, concurrent STIs, and high-risk sexual activity (sex with multiple high-risk partners).3 Additionally, reported rates of primary and secondary syphilis infections, as well as congenital syphilis infections, are more elevated among women who identify as Black, American Indian/Alaska Native, and/or Hispanic.6 Congenital infections in the United States are correlated with a lack of prenatal care, which has been similarly linked with racial and socioeconomic disparities, as well as with untreated mental health and substance use disorders and recent immigration to the United States.5,7

Continue to: The many phases of syphilis...

 

 

The many phases of syphilis

The characteristic lesion of primary syphilis is a chancre, which is a painless, ulcerative lesion with raised borders and a clean, indurated base appearing at the site of spirochete entry (FIGURE 1). Chancres most commonly appear in the genital area, with the most frequent sites in females being within the vaginal canal or on the cervix. Primary chancres tend to heal spontaneously within 3 to 6 weeks, even without treatment, and frequently are accompanied by painless inguinal lymphadenopathy. Given that the most common chancre sites are not immediately apparent, primary infections in women often go undetected.3 In fact, it is essential for clinicians to recognize that, in our routine practice, most patients with syphilis will not be symptomatic at all, and the diagnosis will only be made by serologic screening.

Following resolution of the primary phase, the patient may enter the secondary stage of T pallidum infection. During this stage, spirochetes may disseminate throughout the bloodstream to infect all major organ systems. The principal manifestations of secondary syphilis include a diffuse maculopapular rash that begins on the trunk and proximal extremities and spreads to include the palms and soles (FIGURE 2); mucosal lesions, such as mucous patches and condyloma lata (FIGURE 3); nonscarring alopecia; periostitis; generalized lymphadenopathy; and, in some cases, hepatitis or nephritis.1,3


Secondary syphilis usually clears within 2 to 6 weeks, with the patient then entering the early latent stage of syphilis. During this period, up to 25% of patients are subject to flares of secondary syphilitic lesions but otherwise are asymptomatic.1,3,4 These recurrences tend to occur within 1 year, hence the distinction between early and late latent stages. Once a year has passed, patients are not contagious by sexual transmission and are unlikely to suffer a relapse of secondary symptoms.1,3 However, late latent syphilis is characterized by periods of intermittent bacteremia that allow for seeding of the placenta and infection in about 10% of fetuses.5
 


Untreated, about 40% of patients will progress to the tertiary stage of syphilis, which is characterized by gummas affecting the skin and mucous membranes (FIGURE 4) and cardiovascular manifestations including arterial aneurysms and aortic insufficiency.3

Neurologic manifestations of syphilis may arise during any of the above stages, though the most characteristic manifestations tend to appear decades after the primary infection. Early neurosyphilis may present as meningitis, with or without concomitant ocular syphilis (uveitis, retinitis) and/or as otic syphilis (hearing loss, persistent tinnitus).1,5 Patients with late (tertiary) neurosyphilis tend to exhibit meningovascular symptoms similar to stroke (aphasia, hemiplegia, seizures) and/or parenchymal effects such as general paresis. Tabes dorsalis (manifestations of which include urinary and rectal incontinence, lightning pains, and ataxia) is a late-onset manifestation.1,3

Congenital syphilis can be subdivided into an early and late stage. The first stage, in which clinical findings occur within the first 2 years of life, commonly features a desquamating rash, hepatomegaly, and rhinitis. Anemia, thrombocytopenia, periostitis, and osteomyelitis also have been documented.5 Of note, two-thirds of infants are asymptomatic at birth and may not develop such clinical manifestations for 3 to 8 weeks.3 If untreated, early congenital infection may progress to late manifestations, such as Hutchinson teeth, mulberry molars, interstitial keratitis, deafness, saddle nose, saber shins, and such neurologic abnormalities as developmental delay and general paresis.3

Continue to: Prenatal screening and diagnosis...

 

 

Prenatal screening and diagnosis

Current recommendations issued by the CDC and the American College of Obstetricians and Gynecologists state that all pregnant women should be screened for syphilis infection at their first presentation to care, with repeat screening between 28 and 32 weeks of gestation and at birth, for women living in areas with a high prevalence of syphilis and/or with any of the aforementioned risk factors.3,5 Given that providers may be unfamiliar with the prevalence of syphilis in their area, and that patients may acquire or develop an infection later on in their pregnancy, researchers have begun to investigate the feasibility of universal third-trimester screening. While the cost-effectiveness of such a protocol is disputed, recent studies suggest that it may result in a substantial decrease in adverse maternal and fetal outcomes.8,9

Diagnostic tests

The traditional algorithm for the diagnosis of syphilis infection begins with a nontreponemal screening test, such as the RPR or the Venereal Disease Research Laboratory test. If positive, these screening tests are followed by a confirmatory treponemal test, such as the fluorescent treponemal antibody (FTA) test or the TP-PA (FIGURE 5).

The “reverse” screening algorithm begins with the FTA and, if positive, reflexes to the RPR. A reactive RPR indicates an active infection, and the patient should be treated. A negative RPR should be followed by the TP-PA to rule out a false-positive immunoglobulin G test. If the TP-PA test result is positive, the diagnosis of syphilis is confirmed (FIGURE 6). It is crucial to understand, however, that treponemal antibodies will remain positive for a patient’s lifetime, and someone who may have been treated for syphilis in the past also will screen positive. Once 2 treponemal tests are positive, physicians should take a careful history to assess prior infection risk and treatment status. A negative TP-PA excludes a diagnosis of syphilis.

Advantages of the reverse screening algorithm. Nontreponemal tests are inexpensive and easy to perform, and titers allow for identification of a baseline to evaluate response to treatment.11 However, given the fluctuation of RPR sensitivity (depending on stage of disease and a decreased ability to detect primary and latent stages of syphilis), there has been a resurgence of interest in the reverse algorithm.11 While reverse screening has been found to incur higher costs, and may result in overtreatment and increased stress due to false-positive results,12 there is evidence to suggest that this algorithm is more sensitive for primary and latent infections.8,11,13-15

Given the rise in prevalence of syphilis infections in the United States over the past decade, and therefore a higher pretest probability of syphilis in the population, we favor the reverse screening algorithm in obstetrics, particularly given the risks of adverse maternal and fetal outcomes.

Treating syphilis in pregnancy

Parenteral benzathine penicillin G is the only currently recommended medication for the treatment of syphilis in pregnancy. This drug is effective in treating maternal infection and in preventing fetal infections, as well as in treating established fetal infections.3,5 Regimens differ depending on the stage of syphilis infection (TABLE). Treatment for presumed early syphilis is recommended for women who have had sexual contact with a partner diagnosed with primary, secondary, or early latent syphilis within 3 months of their current pregnancy.5 Any patient with diagnosed syphilis who demonstrates clinical signs of neurologic involvement should undergo lumbar puncture to assess for evidence of neurosyphilis.3 CDC guidelines recommend that patients who report an allergy to penicillin undergo desensitization therapy in a controlled setting, as other antibiotics that have been investigated in the treatment of syphilis are either not appropriate due to teratogenicity or due to suboptimal fetal treatment.3,5

Syphilotherapy may lead to the Jarisch-Herxheimer reaction, which is an acute systemic reaction to inflammatory cytokines produced in response to lipopolysaccharide released by dying spirochetes.5 This reaction is characterized by fever, chills, myalgia, headache, hypotension, and worsening of cutaneous lesions. Preterm labor and delivery and fetal heart rate tracing abnormalities also have been documented in pregnant women experiencing this reaction, particularly during the second half of pregnancy.16 Prior to the start of treatment, a detailed sonographic assessment should be performed to assess the fetus for signs of early syphilis, including hepatomegaly, elevated peak systolic velocity of the middle cerebral artery (indicative of fetal anemia), polyhydramnios, placentomegaly, or hydrops.5,7

CASE Resolved

The combination of the patient’s test results—positive FTA, negative RPR, and negative TP-PA—suggest a false-positive treponemal assay. This sequence of tests excludes a diagnosis of syphilis; therefore, no treatment is necessary. Depending on the prevalence of syphilis in the patient’s geographic location, as well as her sexual history, rescreening between 28 and 32 weeks may be warranted. ●

References
  1. Ghanem KG, Ram S, Rice PA. The modern epidemic of syphilis. N Engl J Med. 2020;382:845-854.  
  2. Barnett R. Syphilis. Lancet. 2018;391:1471. 
  3. Duff P. Maternal and fetal infections. In: Resnik R, Lockwood CJ, Moore T, et al. Creasy and Resnik's Maternal-Fetal Medicine: Principles and Practice. 8th ed. Philadelphia, PA: Elsevier; 2018:862-919. 
  4. Gomez GB, Kamb ML, Newman LM, et al. Untreated maternal syphilis and adverse outcomes of pregnancy: a systematic review and meta-analysis. Bull World Health Organ. 2013;91:217-226. 
  5. Adhikari EH. Syphilis in pregnancy. Obstet Gynecol. 2020;135:1121-1135. 
  6. Syphilis. CDC website. https://www.cdc.gov/std/stats18/syphilis.htm. Published October 1, 2019. Accessed October 6, 2020. 
  7. Rac MF, Revell PA, Eppes CS. Syphilis during pregnancy: a preventable threat to maternal-fetal health. Am J Obstet Gynecol. 2017;4:352-363. 
  8. Dunseth CD, Ford BA, Krasowski MD. Traditional versus reverse syphilis algorithms: a comparison at a large academic medical center. Pract Lab Med. 2017;8:52-59. 
  9. Hersh AR, Megli CJ, Caughey AB. Repeat screening for syphilis in the third trimester of pregnancy: a cost-effectiveness analysis. Obstet Gynecol. 2018;132:699-706. 
  10. Albright CM, Emerson JB, Werner EF, et al. Third trimester prenatal syphilis screening: a cost-effectiveness analysis. Obstet Gynecol. 2015;126:479-485. 
  11. Seña AC, White BL, Sparling PF. Novel Treponema pallidum serologic tests: a paradigm shift in syphilis screening for the 21st century. Clin Infect Dis. 2010;51:700-708.  
  12. Owusu-Edusei K Jr, Peterman TA, Ballard RC. Serologic testing for syphilis in the United States: a cost-effectiveness analysis of two screening algorithms. Sex Transm Dis. 2011;38:1-7. 
  13. Huh HJ, Chung JW, Park SY, et al. Comparison of automated treponemal and nontreponemal test algorithms as first-line syphilis screening assays. Ann Lab Med. 2016;36:23-27.  
  14. Centers for Disease Control and Prevention. Syphilis testing algorithms using treponemal test for initial screening-four laboratories. New York City, 2005-2006. MMWR Morb Mortal Wkly Rep. 2008;57:872-875. 
  15. Mishra S, Boily MC, Ng V, et al. The laboratory impact of changing syphilis screening from the rapid-plasma reagin to a treponemal enzyme immunoassay: a case-study from the greater Toronto area. Sex Transm Dis. 2011;38:190-196. 
  16. Klein VR, Cox SM, Mitchell MD, et al. The Jarisch-Herzheimer reaction complicating syphilotherapy in pregnancy. Obstet Gynecol. 1990;75:375-380.
References
  1. Ghanem KG, Ram S, Rice PA. The modern epidemic of syphilis. N Engl J Med. 2020;382:845-854.  
  2. Barnett R. Syphilis. Lancet. 2018;391:1471. 
  3. Duff P. Maternal and fetal infections. In: Resnik R, Lockwood CJ, Moore T, et al. Creasy and Resnik's Maternal-Fetal Medicine: Principles and Practice. 8th ed. Philadelphia, PA: Elsevier; 2018:862-919. 
  4. Gomez GB, Kamb ML, Newman LM, et al. Untreated maternal syphilis and adverse outcomes of pregnancy: a systematic review and meta-analysis. Bull World Health Organ. 2013;91:217-226. 
  5. Adhikari EH. Syphilis in pregnancy. Obstet Gynecol. 2020;135:1121-1135. 
  6. Syphilis. CDC website. https://www.cdc.gov/std/stats18/syphilis.htm. Published October 1, 2019. Accessed October 6, 2020. 
  7. Rac MF, Revell PA, Eppes CS. Syphilis during pregnancy: a preventable threat to maternal-fetal health. Am J Obstet Gynecol. 2017;4:352-363. 
  8. Dunseth CD, Ford BA, Krasowski MD. Traditional versus reverse syphilis algorithms: a comparison at a large academic medical center. Pract Lab Med. 2017;8:52-59. 
  9. Hersh AR, Megli CJ, Caughey AB. Repeat screening for syphilis in the third trimester of pregnancy: a cost-effectiveness analysis. Obstet Gynecol. 2018;132:699-706. 
  10. Albright CM, Emerson JB, Werner EF, et al. Third trimester prenatal syphilis screening: a cost-effectiveness analysis. Obstet Gynecol. 2015;126:479-485. 
  11. Seña AC, White BL, Sparling PF. Novel Treponema pallidum serologic tests: a paradigm shift in syphilis screening for the 21st century. Clin Infect Dis. 2010;51:700-708.  
  12. Owusu-Edusei K Jr, Peterman TA, Ballard RC. Serologic testing for syphilis in the United States: a cost-effectiveness analysis of two screening algorithms. Sex Transm Dis. 2011;38:1-7. 
  13. Huh HJ, Chung JW, Park SY, et al. Comparison of automated treponemal and nontreponemal test algorithms as first-line syphilis screening assays. Ann Lab Med. 2016;36:23-27.  
  14. Centers for Disease Control and Prevention. Syphilis testing algorithms using treponemal test for initial screening-four laboratories. New York City, 2005-2006. MMWR Morb Mortal Wkly Rep. 2008;57:872-875. 
  15. Mishra S, Boily MC, Ng V, et al. The laboratory impact of changing syphilis screening from the rapid-plasma reagin to a treponemal enzyme immunoassay: a case-study from the greater Toronto area. Sex Transm Dis. 2011;38:190-196. 
  16. Klein VR, Cox SM, Mitchell MD, et al. The Jarisch-Herzheimer reaction complicating syphilotherapy in pregnancy. Obstet Gynecol. 1990;75:375-380.
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Which hormonal management approach for women with premature ovarian insufficiency is best for bone?

Article Type
Changed
Wed, 11/04/2020 - 10:59

Carvalho Gazarra LB, Bonacordi CL, Yela DA, et al. Bone mass in women with premature ovarian insufficiency: a comparative study between hormone therapy and combined oral contraceptives. Menopause. 2020;27:1110-1116.

EXPERT COMMENTARY

Premature ovarian insufficiency (POI) refers to a condition in women in whom ovarian function ceases prior to age 40 years. Although hormone therapy (HT) is a mainstay of treatment for women with POI, it is uncertain which approach to HT is most effective in terms of bone mineral density (BMD). Investigators recently published their results of an observational study that aimed to evaluate the use of combined oral contraceptives (COCs) for preserving BMD in women with POI.

Details of the study

At an academic center in Brazil, Carvalho Gazarra and colleagues identified women with POI who had undergone 2 or more BMD assessments performed 2 or more years apart.1 HT regimens (all of which were taken continuously) employed the following: a COC with ethinyl estradiol (EE) 30 µg and levonorgestrel; low-dose estrogen plus progestin therapy (EPT, conjugated equine estrogen [CEE] 0.625 mg with medroxyprogesterone acetate or estradiol 1.0 mg with norethindrone acetate); or high-dose estrogen plus progestin (CEE 1.25 mg or estradiol 2.0 mg combined with the same progestins).

Results. Among 119 evaluable women with POI (mean age, 30.3 years), the use of COC was associated with the most positive BMD trends. For women using COC or high-dose EPT, BMD at the lumbar spine increased. By contrast, BMD of the lumbar spine declined in women who used no treatment or low-dose EPT.1

Other studies’ take on dose, route of administration, and cost considerations

Sequelae of POI include infertility, bothersome hot flashes, vaginal dryness, sexual dysfunction, mood disorders, and an elevated risk of cardiovascular disease, dementia, Parkinson’s disease, and osteoporosis. Importantly, clinicians and patients need to understand that the results from the Women’s Health Initiative studies do not apply to women with POI.2 Physiologic doses of HT (that is, doses higher than those used to treat menopausal symptoms in women with normal/spontaneous menopause) are appropriate for women with POI, at least until they reach the normal age of menopause (51 to 52 years).

A clinical trial conducted in Scotland in women with POI found that high-dose transdermal estrogen (application of one to two 0.1-mg estradiol patches) daily had an impact on BMD that was more positive than that of an oral contraceptive formulated with EE 30 µg.3 Likewise, a trial in the United States found that, among oligo-amenorrheic athletes, a hormone replacement regimen using a 0.1-mg estradiol patch had a more positive impact on BMD than an oral contraceptive formulated with EE 30 µg.4

Although Carvalho Gazarra and colleagues acknowledged awareness of reports suggesting the skeletal health benefits of high-dose estradiol patches, in the Brazilian public health system oral hormone therapy is less expensive and oral contraceptives are available at no charge.1

 

WHAT THIS EVIDENCE MEANS FOR PRACTICE
When replacing estrogen and progestin in young women who lack ovarian function, it is appropriate to use considerably higher doses than those used to treat bothersome vasomotor symptoms in women with normal/spontaneous menopause. From the perspective of venous thromboembolism risk, the transdermal route of administration is safer than the oral route,5 and the Scottish and US studies discussed here indicate that transdermal estradiol is an effective approach to maintaining skeletal health in young women without ovarian function. Accordingly, hormonal management with high-dose transdermal estradiol with a progestin (such as progesterone 200–300 mg at bedtime or medroxyprogesterone 5–10 mg daily) represents an appropriate strategy. In situations where transdermal estradiol plus oral progestin treatment is not covered by health insurance or acceptable to the patient, an oral estrogen-progestin contraceptive formulated with EE 30 or 35 µg will provide protection against bone loss.
References
  1. Carvalho Gazarra LB, Bonacordi CL, Yela DA, et al. Bone mass in women with premature ovarian insufficiency: a comparative study between hormone therapy and combined oral contraceptives. Menopause. 2020;27:1110-1116. 
  2. Jiang XD. Bone health and beyond in women with primary ovarian insufficiency: time to narrow the knowledge-action gap in care. Menopause. 2020;27:1101-1103. 
  3. Crofton PM, Evans N, Bath LE, et al. Physiological versus standard sex steroid replacement in young women with premature ovarian failure: effects on bone mass acquisition and turnover. Clin Endocrinol (Oxf). 2010;73:707-714. 
  4. Ackerman KE, Singhal V, Baskaran C, et al. Oestrogen replacement improves bone mineral density in oligo-amenorrhoeic athletes: a randomised clinical trial. Br J Sports Med. 2019;53:229-236. 
  5. Vinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases. BMJ. 2019;364:k4810.
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Andrew M. Kaunitz, MD, is Professor and Associate Chairman, Department of Obstetrics and Gynecology, University of Florida College of Medicine–Jacksonville; Medical Director and Director of Menopause and Gynecologic Ultrasound Services, UF Women’s Health Specialists at Emerson, Jacksonville. He serves on the OBG Management Board of Editors.

 

The author reports serving on the advisory boards of Pfizer (contraception) and Mithra, and that the University of Florida has received clinical trial support from Mithra.  
 

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Andrew M. Kaunitz, MD, is Professor and Associate Chairman, Department of Obstetrics and Gynecology, University of Florida College of Medicine–Jacksonville; Medical Director and Director of Menopause and Gynecologic Ultrasound Services, UF Women’s Health Specialists at Emerson, Jacksonville. He serves on the OBG Management Board of Editors.

 

The author reports serving on the advisory boards of Pfizer (contraception) and Mithra, and that the University of Florida has received clinical trial support from Mithra.  
 

Author and Disclosure Information

Andrew M. Kaunitz, MD, is Professor and Associate Chairman, Department of Obstetrics and Gynecology, University of Florida College of Medicine–Jacksonville; Medical Director and Director of Menopause and Gynecologic Ultrasound Services, UF Women’s Health Specialists at Emerson, Jacksonville. He serves on the OBG Management Board of Editors.

 

The author reports serving on the advisory boards of Pfizer (contraception) and Mithra, and that the University of Florida has received clinical trial support from Mithra.  
 

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Carvalho Gazarra LB, Bonacordi CL, Yela DA, et al. Bone mass in women with premature ovarian insufficiency: a comparative study between hormone therapy and combined oral contraceptives. Menopause. 2020;27:1110-1116.

EXPERT COMMENTARY

Premature ovarian insufficiency (POI) refers to a condition in women in whom ovarian function ceases prior to age 40 years. Although hormone therapy (HT) is a mainstay of treatment for women with POI, it is uncertain which approach to HT is most effective in terms of bone mineral density (BMD). Investigators recently published their results of an observational study that aimed to evaluate the use of combined oral contraceptives (COCs) for preserving BMD in women with POI.

Details of the study

At an academic center in Brazil, Carvalho Gazarra and colleagues identified women with POI who had undergone 2 or more BMD assessments performed 2 or more years apart.1 HT regimens (all of which were taken continuously) employed the following: a COC with ethinyl estradiol (EE) 30 µg and levonorgestrel; low-dose estrogen plus progestin therapy (EPT, conjugated equine estrogen [CEE] 0.625 mg with medroxyprogesterone acetate or estradiol 1.0 mg with norethindrone acetate); or high-dose estrogen plus progestin (CEE 1.25 mg or estradiol 2.0 mg combined with the same progestins).

Results. Among 119 evaluable women with POI (mean age, 30.3 years), the use of COC was associated with the most positive BMD trends. For women using COC or high-dose EPT, BMD at the lumbar spine increased. By contrast, BMD of the lumbar spine declined in women who used no treatment or low-dose EPT.1

Other studies’ take on dose, route of administration, and cost considerations

Sequelae of POI include infertility, bothersome hot flashes, vaginal dryness, sexual dysfunction, mood disorders, and an elevated risk of cardiovascular disease, dementia, Parkinson’s disease, and osteoporosis. Importantly, clinicians and patients need to understand that the results from the Women’s Health Initiative studies do not apply to women with POI.2 Physiologic doses of HT (that is, doses higher than those used to treat menopausal symptoms in women with normal/spontaneous menopause) are appropriate for women with POI, at least until they reach the normal age of menopause (51 to 52 years).

A clinical trial conducted in Scotland in women with POI found that high-dose transdermal estrogen (application of one to two 0.1-mg estradiol patches) daily had an impact on BMD that was more positive than that of an oral contraceptive formulated with EE 30 µg.3 Likewise, a trial in the United States found that, among oligo-amenorrheic athletes, a hormone replacement regimen using a 0.1-mg estradiol patch had a more positive impact on BMD than an oral contraceptive formulated with EE 30 µg.4

Although Carvalho Gazarra and colleagues acknowledged awareness of reports suggesting the skeletal health benefits of high-dose estradiol patches, in the Brazilian public health system oral hormone therapy is less expensive and oral contraceptives are available at no charge.1

 

WHAT THIS EVIDENCE MEANS FOR PRACTICE
When replacing estrogen and progestin in young women who lack ovarian function, it is appropriate to use considerably higher doses than those used to treat bothersome vasomotor symptoms in women with normal/spontaneous menopause. From the perspective of venous thromboembolism risk, the transdermal route of administration is safer than the oral route,5 and the Scottish and US studies discussed here indicate that transdermal estradiol is an effective approach to maintaining skeletal health in young women without ovarian function. Accordingly, hormonal management with high-dose transdermal estradiol with a progestin (such as progesterone 200–300 mg at bedtime or medroxyprogesterone 5–10 mg daily) represents an appropriate strategy. In situations where transdermal estradiol plus oral progestin treatment is not covered by health insurance or acceptable to the patient, an oral estrogen-progestin contraceptive formulated with EE 30 or 35 µg will provide protection against bone loss.

Carvalho Gazarra LB, Bonacordi CL, Yela DA, et al. Bone mass in women with premature ovarian insufficiency: a comparative study between hormone therapy and combined oral contraceptives. Menopause. 2020;27:1110-1116.

EXPERT COMMENTARY

Premature ovarian insufficiency (POI) refers to a condition in women in whom ovarian function ceases prior to age 40 years. Although hormone therapy (HT) is a mainstay of treatment for women with POI, it is uncertain which approach to HT is most effective in terms of bone mineral density (BMD). Investigators recently published their results of an observational study that aimed to evaluate the use of combined oral contraceptives (COCs) for preserving BMD in women with POI.

Details of the study

At an academic center in Brazil, Carvalho Gazarra and colleagues identified women with POI who had undergone 2 or more BMD assessments performed 2 or more years apart.1 HT regimens (all of which were taken continuously) employed the following: a COC with ethinyl estradiol (EE) 30 µg and levonorgestrel; low-dose estrogen plus progestin therapy (EPT, conjugated equine estrogen [CEE] 0.625 mg with medroxyprogesterone acetate or estradiol 1.0 mg with norethindrone acetate); or high-dose estrogen plus progestin (CEE 1.25 mg or estradiol 2.0 mg combined with the same progestins).

Results. Among 119 evaluable women with POI (mean age, 30.3 years), the use of COC was associated with the most positive BMD trends. For women using COC or high-dose EPT, BMD at the lumbar spine increased. By contrast, BMD of the lumbar spine declined in women who used no treatment or low-dose EPT.1

Other studies’ take on dose, route of administration, and cost considerations

Sequelae of POI include infertility, bothersome hot flashes, vaginal dryness, sexual dysfunction, mood disorders, and an elevated risk of cardiovascular disease, dementia, Parkinson’s disease, and osteoporosis. Importantly, clinicians and patients need to understand that the results from the Women’s Health Initiative studies do not apply to women with POI.2 Physiologic doses of HT (that is, doses higher than those used to treat menopausal symptoms in women with normal/spontaneous menopause) are appropriate for women with POI, at least until they reach the normal age of menopause (51 to 52 years).

A clinical trial conducted in Scotland in women with POI found that high-dose transdermal estrogen (application of one to two 0.1-mg estradiol patches) daily had an impact on BMD that was more positive than that of an oral contraceptive formulated with EE 30 µg.3 Likewise, a trial in the United States found that, among oligo-amenorrheic athletes, a hormone replacement regimen using a 0.1-mg estradiol patch had a more positive impact on BMD than an oral contraceptive formulated with EE 30 µg.4

Although Carvalho Gazarra and colleagues acknowledged awareness of reports suggesting the skeletal health benefits of high-dose estradiol patches, in the Brazilian public health system oral hormone therapy is less expensive and oral contraceptives are available at no charge.1

 

WHAT THIS EVIDENCE MEANS FOR PRACTICE
When replacing estrogen and progestin in young women who lack ovarian function, it is appropriate to use considerably higher doses than those used to treat bothersome vasomotor symptoms in women with normal/spontaneous menopause. From the perspective of venous thromboembolism risk, the transdermal route of administration is safer than the oral route,5 and the Scottish and US studies discussed here indicate that transdermal estradiol is an effective approach to maintaining skeletal health in young women without ovarian function. Accordingly, hormonal management with high-dose transdermal estradiol with a progestin (such as progesterone 200–300 mg at bedtime or medroxyprogesterone 5–10 mg daily) represents an appropriate strategy. In situations where transdermal estradiol plus oral progestin treatment is not covered by health insurance or acceptable to the patient, an oral estrogen-progestin contraceptive formulated with EE 30 or 35 µg will provide protection against bone loss.
References
  1. Carvalho Gazarra LB, Bonacordi CL, Yela DA, et al. Bone mass in women with premature ovarian insufficiency: a comparative study between hormone therapy and combined oral contraceptives. Menopause. 2020;27:1110-1116. 
  2. Jiang XD. Bone health and beyond in women with primary ovarian insufficiency: time to narrow the knowledge-action gap in care. Menopause. 2020;27:1101-1103. 
  3. Crofton PM, Evans N, Bath LE, et al. Physiological versus standard sex steroid replacement in young women with premature ovarian failure: effects on bone mass acquisition and turnover. Clin Endocrinol (Oxf). 2010;73:707-714. 
  4. Ackerman KE, Singhal V, Baskaran C, et al. Oestrogen replacement improves bone mineral density in oligo-amenorrhoeic athletes: a randomised clinical trial. Br J Sports Med. 2019;53:229-236. 
  5. Vinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases. BMJ. 2019;364:k4810.
References
  1. Carvalho Gazarra LB, Bonacordi CL, Yela DA, et al. Bone mass in women with premature ovarian insufficiency: a comparative study between hormone therapy and combined oral contraceptives. Menopause. 2020;27:1110-1116. 
  2. Jiang XD. Bone health and beyond in women with primary ovarian insufficiency: time to narrow the knowledge-action gap in care. Menopause. 2020;27:1101-1103. 
  3. Crofton PM, Evans N, Bath LE, et al. Physiological versus standard sex steroid replacement in young women with premature ovarian failure: effects on bone mass acquisition and turnover. Clin Endocrinol (Oxf). 2010;73:707-714. 
  4. Ackerman KE, Singhal V, Baskaran C, et al. Oestrogen replacement improves bone mineral density in oligo-amenorrhoeic athletes: a randomised clinical trial. Br J Sports Med. 2019;53:229-236. 
  5. Vinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases. BMJ. 2019;364:k4810.
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9vHPV vaccine: Prevention of oropharyngeal cancer

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Tue, 11/10/2020 - 12:46

Surprisingly, in the United States, the most common cancer associated with human papillomavirus (HPV) is oropharyngeal squamous cell cancer (SCC), with one study reporting 15,479 cases among men and 3,428 cases among women in 2015.1 In the same year, the investigators reported 11,788 cases of cervical cancer.1 A public health concern is that cases of oropharyngeal SCC are increasing, while cases of cervical cancer are decreasing. From 1999 to 2015, the rate of oropharyngeal SCC increased annually among both men and women, at rates of 2.7% and 0.8% per year, respectively. By contrast, the rate of cervical cancer decreased by 1.6% per year.1

Although the incidence of HPV-negative oropharyngeal SCC (cases associated with cigarette smoking) has declined by 50% from 1988 to 2004, the incidence of HPV-positive oropharyngeal SCC has increased by 225%, with much of the increase occurring among young, white men.2 HPV infection is a major cause of oropharyngeal SCC at the base of the tongue and tonsils, but not in the soft palate or oropharyngeal walls.3

Most physicians and parents recognize that the 9-valent (9v)HPV vaccine prevents the majority of cervical cancers and precancers in women. Far fewer people realize that there is an important opportunity to prevent a large number of oropharyngeal cancers by improving 9vHPV vaccination in men and women.

Which HPV types are associated with oropharyngeal cancer?

HPV16 is the most common HPV type associated with oropharyngeal SCC. Among these cancer types, greater than 80% harbor HPV16, with greater than 90% harboring HPV16 or 18 and less than 10% of tumors associated with HPV types 31, 33, 45, 52, or 58.4-7

The high prevalence of HPV16 in patients with oropharyngeal cancer raises the question of the HPV status of the intimate partner of the index patient. In one study of 164 people with HPV detected in their oropharyngeal, the partner of the index patient had a low prevalence of high-risk HPV types (1.2%) in oral rinse and gargle samples, similar to the rate in the general population (1.3%).7 This finding is reassuring and suggests that intimate partners of patients with HPV-positive oropharyngeal cancer effectively clear high-risk HPV virus from the oropharynx. The HPV status of the genital tissue of the intimate partner of an index patient with oropharyngeal SCC has not been adequately studied.

Men are more likely than women to harbor oral HPV

Among a sample of 5,501 men and women aged 14 to 69 years from the National Health and Nutrition Examination Survey, oral rinses were obtained and analyzed for the presence of HPV.8 The prevalence of any oral HPV and any oral high-risk HPV was 6.9% and 3.7%, respectively. Oral HPV-16 was detected in 1.6% of men and 0.3% of women. The prevalence of HPV was higher among current smokers, heavy alcohol drinkers, and people with a history of a greater number of sexual partners. In men and women reporting more than 20 lifetime sexual partners, the prevalence of oral HPV was 20%.

In a study of 2,627 men and women aged 18 to 33 years, the prevalence of oral HPV 16/18/6/11 was lower among those vaccinated versus those unvaccinated (0.11% and 1.6%, respectively; P = .008).9 Among men, oral HPV 16/18/6/11 was lower among those vaccinated versus unvaccinated (0.0% and 2.13%, respectively; P = .007).9 The results of this observational study support the important role of vaccination in reducing oral HPV infection.

9vHPV vaccine: Indications and immunization schedule

In 2020, the US Food and Drug Administration (FDA) approved the 9-valent human papillomavirus (9vHPV) vaccine for the prevention of oropharyngeal cancer. The 9vHPV vaccine contains inactive L1 capsid proteins for 9 HPV types, including types 6, 11, 16, 18, 31, 33, 45, 52, and 58. The vaccine stimulates the production of neutralizing antibodies to the capsid protein.

9vHPV is approved for females aged 9 to 45 years to prevent cancers and precancers of the cervix, vulva, vagina, and anus caused by HPV types 16, 18, 31, 33, 45, 52, and 58.1 It is also approved for males aged 9 to 45 years to prevent cancer and precancers of the anus caused by those viral types. In 2020 the 9vHPV vaccine was approved by the FDA to prevent oropharyngeal cancer in males and females. Of note, the FDA reported that, “the oropharyngeal and head and neck cancer indication is approved under accelerated approval based on effectiveness in preventing HPV-related anogenital disease. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.”2

The Advisory Committee on Immunization Practices (ACIP) recommends routine vaccination of girls and boys, 11 to 12 years of age.1 Children with a history of sexual abuse or assault can start the vaccine at 9 years of age. Catch-up vaccination is recommended for all females and males through age 26 years. The ACIP recommends shared clinical decision-making regarding vaccination for some adults 27 to 45 years of age. Gynecologists with routine exposure to HPV may have occupational risk that warrants HPV vaccination3 (see “As a gynecologist, should you receive the 9vHPV vaccine?”).

For most individuals who start the vaccine series before age 15, two doses of 9vHPV vaccine are recommended, with the second dose 6 to 12 months following the first dose. For teens and adults aged 15 to 26 years, 3 doses of 9vHPV vaccine are recommended, with the second dose 1 to 2 months later and the third dose 6 months following the first dose. Immunocompromised individuals 9 to 26 years of age, including those with HIV infection, should receive 3 doses of the vaccine.

References

1. Meites E, Szilagyi PG, Chesson HW, et al. Human papillomavirus vaccination for adults: updated recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2019;68:698-702.

2. Gardasil 9 [package insert]. Whitehouse Station, NJ: Merck & Co. Inc; 2020.

3. Stockdale CK, Einstein MH, Huh WK. ASCCP recommends HPV vaccination for providers. February 19, 2020. https://www.asccp.org/Assets/d3abdb05-25c5-4e58-9cec-05c11fb2b920/637177876310030000/hpv-vaccinemember-announcment-02-19-20-pdf. Accessed October 23, 2020.

Continue to: Vaccinate boys and girls to prevent cancer...

 

 

Vaccinate boys and girls to prevent cancer

Most population studies report that males are less likely to receive an HPV vaccine than females. For example, based on the National Health Interview Survey of people aged 18 to 26, the percentage of women who self-reported receiving at least one dose of HPV vaccine was 37% in 2013 and 54% in 2018.10 By contrast, among men, the rates of self-reported vaccination were much lower—8% in 2013 and 27% in 2018.10

The percentage of women who received the recommended number of doses of HPV vaccine (see “9vHPV vaccine: Indications and immunization schedule”) was 26% in 2013 and 35% in 2018.10 For men, these percentages were 2% in 2013 and 9% in 2018.10 These data indicate that, compared with women, men are less likely to receive an HPV vaccination and far less likely to have received the recommended number of doses.

It is heartening that there has been a slow and steady increase in the prevalence of HPV vaccination. In fact, increasing the HPV vaccination rate among both boys and girls has the potential to markedly reduce the incidence of oropharyngeal cancer.

The reasons for the female-male gap in vaccination rates are not fully characterized. For one, parental awareness of the importance of HPV vaccination to prevent cancer among men is limited, and represents an important opportunity for additional public health education. In a qualitative interview study of mothers with children aged 11 to 19, the investigators reported that most mothers were aware that HPV vaccination could prevent cervical cancer in women, but most mothers did not know that HPV causes cancer of the mouth and that vaccination could prevent oropharyngeal cancer in boys and girls.11 Because of this lack of knowledge, the mothers did not think their sons needed to have an HPV vaccine. The research report is aptly titled, “I don’t think he needs the HPV vaccine cause boys can’t have cervical cancer.”11

Clinicians are highly influential in guiding parents to accept HPV vaccination of their children. Offering consistent messaging to parents that HPV vaccination prevents cancer in both women and men, and reducing the out-of-pocket cost of vaccination surely will result in an increase in the vaccination rate of boys and girls. ●

As a gynecologist, should you receive the 9vHPV vaccine?

Surgical treatment of tissues infected with human papillomavirus (HPV) often involves the use of laser or electrosurgical devices that generate smoke, which is known to contain HPV nucleic acid sequences and may contain infective virions.1 It is known that HPV nucleic acid sequences are present in surgical smoke. In one study plantar warts were treated with a carbon dioxide laser or electrocoagulation. The vapor produced from the surgery was collected with a dry filter apparatus. Five of 8 laser-derived vapors and 4 of 7 electrocoagulation-derived vapors were positive for HPV DNA. The concentration of HPV DNA was greater with laser than with electrocoagulation treatment.2

It is not known if surgical smoke derived from treatment of HPV-infected tissues contains infective HPV virions. In an experimental bovine model, smoke generated by laser ablation of fibropapillomas was collected. Injection of the contents of the smoke caused cutaneous papillomavirus lesions when inoculated into calves, suggesting that the smoke contained infective HPV virions.3 Although this animal experiment is a proof of principle that surgical smoke generated from treatment of HPVinfected tissue contain virions, it is unclear if surgical smoke generated in gynecologic practice contains HPV virions.

To investigate the prevalence of nasal HPV DNA among gynecologists, 700 physicians in Zhejiang Province, China, completed a questionnaire and provided a nasal swab for HPV DNA analysis.4 Among gynecologists who performed or did not perform LEEP, the prevalence of HPV DNA in the nose was 10% and 3%, respectively. The most common HPV types detected were HPV16 (76%), HPV31 (10%), HPV58 (5%), HPV55 (5%), HPV56 (2%), and HPV59 (2%).4 Among gynecologists who performed LEEP procedures, the prevalence of HPV DNA was 19% for those who did not use a surgical mask, 8% for clinicians who used a standard surgical mask, and 0% for those who used an N95 filtering facepiece respirator, suggesting that an N95 respirator provides the greatest protection from surgical smoke.4 Over 24 months of follow-up, all the gynecologists who had initially tested positive for HPV DNA no longer had detectable nasal HPV DNA. In this study, no gynecologist was diagnosed with an HPV-associated oropharyngeal disease. The investigators concluded that surgical masks, especially an N95 respirator, should be used by gynecologists performing LEEP procedures.

Investigators also have evaluated for the presence of HPV DNA in matched samples from the cervix of 134 patients undergoing loop electrosurgical excision procedure (LEEP) for cervical dysplasia, as well as the smoke generated during the procedure and nasal swabs from the surgeon performing the LEEP.5 HPV DNA was detected in 95% of the cervical samples, 30% of the surgical smoke samples, and 1.5% of the surgeons’ nasal swabs.5 At 6 months of follow-up, the two surgeons who initially had HPV-positive nasal swabs no longer had detected HPV DNA.

Of concern is that otolaryngologists have reported sporadic cases of oropharyngeal squamous cell cancer6 and laryngeal papillomatosis7 in health care workers with frequent and repetitive exposure to HPVs. For example, in one case report, a 53-year-old male gynecologist, nonsmoker, presented to his physician with a lump on the neck.6 The gynecologist had performed more than 3,000 laser ablation or LEEP procedures of dysplastic cervical, vaginal, and vulvar lesions over a span of 20 years.6 Most of the procedures were performed without wearing a mask and in a poorly ventilated procedure room. A computed tomography scan demonstrated a 2.2-cm soft tissue lesion in the right tonsil extending to the right soft palate and a level-2 lymph node. A biopsy of the tonsil confirmed invasive squamous cell carcinoma containing HPV16. He was treated with 35 fractions of radiotherapy and adjuvant cisplatin. Treatment adverse effects included dysphagia and xerostomia, and the patient lost 40 pounds.

Available interventions to reduce exposure of clinicians to HPV virions that may be present in surgical smoke include:

  • wearing a fit-tested N95 respirator  
  • routinely using a smoke evacuation device, and
  • ensuring sufficient ventilation in the procedure room.

A new recommendation is to consider 9vHPV vaccination for clinicians who are routinely exposed to HPV virions.8,9 In February 2020, the American Society for Colposcopy and Cervical Pathology recommended that clinicians who are routinely exposed to HPVs consider 9vHPV vaccination.8 This recommendation pertains to all members of the clinical team in the procedure room, including physicians, nurses, and staff. Based on the available data, gynecologists who have not been vaccinated will need to weigh the benefits and costs of receiving a 9vHPV vaccine to protect themselves against an occupational exposure that may adversely impact their health.

References

  1. Liu Y, Song Y, Hu X, et al. Awareness of surgical smoke hazards and enhancement of surgical smoke prevention among gynecologists. J Cancer. 2019;10:2788-2799.
  2. Sawchuk WS, Weber PJ, Lowy DR, et al. Infectious papillomavirus in the vapor of warts treated with carbon dioxide laser or electrocoagulation: detection and protection. J Am Acad Dermatol. 1989;21:41-49.
  3. Garden JM, O’Banion MK, Bakus AD, et al. Viral transmitted by laser-generated plume (aerosol). Arch Dermatol. 2002;138:1303-1307.
  4. Hu X, Zhou Q, Yu J, et al. Prevalence of HPV infections in surgical smoke exposed gynecologists. Int Arch Occup Environ Health. 2020; Epub September 1. doi: 10.1007 /s00420-020-01568-9.
  5. Zhou Q, Hu X, Zhou J, et al. Human papillomavirus DNA in surgical smoke during cervical loop electrosurgical excision procedures and its impact on the surgeon. Cancer Manag Res. 2019;11:3643-3654.
  6. Rioux M, Garland A, Webster D, et al. HPV-positive tonsillar cancer in two laser surgeons: case reports. J Otolaryngol Head Neck Surg. 2013;42:54-57.
  7. Hallmo P, Naess O. Laryngeal papillomatosis with human papillomavirus DNA contracted by a laser surgeon. Eur Arch Otorhinolaryngol. 1991;248:425-427.
  8. Stockdale CK, Einstein MH, Huh WK. ASCCP recommends HPV vaccination for providers. February 19, 2020. www.asccp.org/Assets/d3abdb05-25c5-4e58-%209cec-05c11fb2b920/637177876310030000/hpv-vaccinemember-announcment-02-19-20-pdf. Accessed October 23, 2020.

  9. Harrison R, Huh W. Occupational exposure to human papillomavirus and vaccination for health care workers. Obstet Gynecol. 2020;136:663-665

 

 

References
  1. Van Dyne EA, Henley SJ, Saraiya M, et al. Trends in human papillomavirus-associated cancers--United States, 1999-2015. MMWR. 2018;67:918-924. 
  2. Chaturvedi AK, Engels EA, Pfeiffer RM, et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol. 2011;29:4294-4301. 
  3. Haeggblom L, Ramqvist T, Tommasino M, et al. Time to change perspective on HPV in oropharyngeal cancer. A systematic review of HPV prevalence per oropharyngeal sub-site the last 3 years. Papillomavirus Research. 2017;4:1-11. 
  4. Kreimer AR, Clifford GM, Boyle P, et al. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev. 2005;14:467-475.  
  5. D'Souza G, Kreimer AR, Viscidi R, et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med. 2007;356:1944-1956. 
  6. de Martel C, Plummer M, Vignat J, et al. Worldwide burden of cancer attributable to HPV by site, country and HPV type. Int J Cancer. 2017;141:664-670. 
  7. D'Souza G, Gross ND, Pai SI, et al. Oral human papillomavirus infection in HPV-positive patients with oropharyngeal cancer and their partners. J Clin Oncol. 2014;32:2408-2415. 
  8. Gillison ML, Broutian T, Pickard RK, et al. Prevalence of oral HPV infection in the United States, 2009-2010. JAMA. 2012;307:693. 
  9. Chaturvedi AK, Graubard BI, Broutian T, et al. Effect of prophylactic human papillomavirus vaccination on oral HPV infections among young adults in the United States. J Clin Oncol. 2018;36:262-267. 
  10. Boersma P, Black LI. Human papillomavirus vaccination among adults aged 18 to 26, 2013-2018. NCHS Data Brief. 2020:1-8. 
  11. Lindsay AC, Delgado D, Valdez MJ, et al. "I don't think he needs the HPV vaccine cause boys can't have cervical cancer": a qualitative study of Latina mothers' (Mis) understandings about human papillomavirus transmission, associated cancers and the vaccine. J Cancer Educ. July 11, 2020. doi: 10.1007/s13187-020-01824-z.
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Harvard Medical School
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Harvard Medical School
Boston, Massachusetts

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Harvard Medical School
Boston, Massachusetts

Dr. Barbieri reports no financial relationships relevant to this article.

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Surprisingly, in the United States, the most common cancer associated with human papillomavirus (HPV) is oropharyngeal squamous cell cancer (SCC), with one study reporting 15,479 cases among men and 3,428 cases among women in 2015.1 In the same year, the investigators reported 11,788 cases of cervical cancer.1 A public health concern is that cases of oropharyngeal SCC are increasing, while cases of cervical cancer are decreasing. From 1999 to 2015, the rate of oropharyngeal SCC increased annually among both men and women, at rates of 2.7% and 0.8% per year, respectively. By contrast, the rate of cervical cancer decreased by 1.6% per year.1

Although the incidence of HPV-negative oropharyngeal SCC (cases associated with cigarette smoking) has declined by 50% from 1988 to 2004, the incidence of HPV-positive oropharyngeal SCC has increased by 225%, with much of the increase occurring among young, white men.2 HPV infection is a major cause of oropharyngeal SCC at the base of the tongue and tonsils, but not in the soft palate or oropharyngeal walls.3

Most physicians and parents recognize that the 9-valent (9v)HPV vaccine prevents the majority of cervical cancers and precancers in women. Far fewer people realize that there is an important opportunity to prevent a large number of oropharyngeal cancers by improving 9vHPV vaccination in men and women.

Which HPV types are associated with oropharyngeal cancer?

HPV16 is the most common HPV type associated with oropharyngeal SCC. Among these cancer types, greater than 80% harbor HPV16, with greater than 90% harboring HPV16 or 18 and less than 10% of tumors associated with HPV types 31, 33, 45, 52, or 58.4-7

The high prevalence of HPV16 in patients with oropharyngeal cancer raises the question of the HPV status of the intimate partner of the index patient. In one study of 164 people with HPV detected in their oropharyngeal, the partner of the index patient had a low prevalence of high-risk HPV types (1.2%) in oral rinse and gargle samples, similar to the rate in the general population (1.3%).7 This finding is reassuring and suggests that intimate partners of patients with HPV-positive oropharyngeal cancer effectively clear high-risk HPV virus from the oropharynx. The HPV status of the genital tissue of the intimate partner of an index patient with oropharyngeal SCC has not been adequately studied.

Men are more likely than women to harbor oral HPV

Among a sample of 5,501 men and women aged 14 to 69 years from the National Health and Nutrition Examination Survey, oral rinses were obtained and analyzed for the presence of HPV.8 The prevalence of any oral HPV and any oral high-risk HPV was 6.9% and 3.7%, respectively. Oral HPV-16 was detected in 1.6% of men and 0.3% of women. The prevalence of HPV was higher among current smokers, heavy alcohol drinkers, and people with a history of a greater number of sexual partners. In men and women reporting more than 20 lifetime sexual partners, the prevalence of oral HPV was 20%.

In a study of 2,627 men and women aged 18 to 33 years, the prevalence of oral HPV 16/18/6/11 was lower among those vaccinated versus those unvaccinated (0.11% and 1.6%, respectively; P = .008).9 Among men, oral HPV 16/18/6/11 was lower among those vaccinated versus unvaccinated (0.0% and 2.13%, respectively; P = .007).9 The results of this observational study support the important role of vaccination in reducing oral HPV infection.

9vHPV vaccine: Indications and immunization schedule

In 2020, the US Food and Drug Administration (FDA) approved the 9-valent human papillomavirus (9vHPV) vaccine for the prevention of oropharyngeal cancer. The 9vHPV vaccine contains inactive L1 capsid proteins for 9 HPV types, including types 6, 11, 16, 18, 31, 33, 45, 52, and 58. The vaccine stimulates the production of neutralizing antibodies to the capsid protein.

9vHPV is approved for females aged 9 to 45 years to prevent cancers and precancers of the cervix, vulva, vagina, and anus caused by HPV types 16, 18, 31, 33, 45, 52, and 58.1 It is also approved for males aged 9 to 45 years to prevent cancer and precancers of the anus caused by those viral types. In 2020 the 9vHPV vaccine was approved by the FDA to prevent oropharyngeal cancer in males and females. Of note, the FDA reported that, “the oropharyngeal and head and neck cancer indication is approved under accelerated approval based on effectiveness in preventing HPV-related anogenital disease. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.”2

The Advisory Committee on Immunization Practices (ACIP) recommends routine vaccination of girls and boys, 11 to 12 years of age.1 Children with a history of sexual abuse or assault can start the vaccine at 9 years of age. Catch-up vaccination is recommended for all females and males through age 26 years. The ACIP recommends shared clinical decision-making regarding vaccination for some adults 27 to 45 years of age. Gynecologists with routine exposure to HPV may have occupational risk that warrants HPV vaccination3 (see “As a gynecologist, should you receive the 9vHPV vaccine?”).

For most individuals who start the vaccine series before age 15, two doses of 9vHPV vaccine are recommended, with the second dose 6 to 12 months following the first dose. For teens and adults aged 15 to 26 years, 3 doses of 9vHPV vaccine are recommended, with the second dose 1 to 2 months later and the third dose 6 months following the first dose. Immunocompromised individuals 9 to 26 years of age, including those with HIV infection, should receive 3 doses of the vaccine.

References

1. Meites E, Szilagyi PG, Chesson HW, et al. Human papillomavirus vaccination for adults: updated recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2019;68:698-702.

2. Gardasil 9 [package insert]. Whitehouse Station, NJ: Merck & Co. Inc; 2020.

3. Stockdale CK, Einstein MH, Huh WK. ASCCP recommends HPV vaccination for providers. February 19, 2020. https://www.asccp.org/Assets/d3abdb05-25c5-4e58-9cec-05c11fb2b920/637177876310030000/hpv-vaccinemember-announcment-02-19-20-pdf. Accessed October 23, 2020.

Continue to: Vaccinate boys and girls to prevent cancer...

 

 

Vaccinate boys and girls to prevent cancer

Most population studies report that males are less likely to receive an HPV vaccine than females. For example, based on the National Health Interview Survey of people aged 18 to 26, the percentage of women who self-reported receiving at least one dose of HPV vaccine was 37% in 2013 and 54% in 2018.10 By contrast, among men, the rates of self-reported vaccination were much lower—8% in 2013 and 27% in 2018.10

The percentage of women who received the recommended number of doses of HPV vaccine (see “9vHPV vaccine: Indications and immunization schedule”) was 26% in 2013 and 35% in 2018.10 For men, these percentages were 2% in 2013 and 9% in 2018.10 These data indicate that, compared with women, men are less likely to receive an HPV vaccination and far less likely to have received the recommended number of doses.

It is heartening that there has been a slow and steady increase in the prevalence of HPV vaccination. In fact, increasing the HPV vaccination rate among both boys and girls has the potential to markedly reduce the incidence of oropharyngeal cancer.

The reasons for the female-male gap in vaccination rates are not fully characterized. For one, parental awareness of the importance of HPV vaccination to prevent cancer among men is limited, and represents an important opportunity for additional public health education. In a qualitative interview study of mothers with children aged 11 to 19, the investigators reported that most mothers were aware that HPV vaccination could prevent cervical cancer in women, but most mothers did not know that HPV causes cancer of the mouth and that vaccination could prevent oropharyngeal cancer in boys and girls.11 Because of this lack of knowledge, the mothers did not think their sons needed to have an HPV vaccine. The research report is aptly titled, “I don’t think he needs the HPV vaccine cause boys can’t have cervical cancer.”11

Clinicians are highly influential in guiding parents to accept HPV vaccination of their children. Offering consistent messaging to parents that HPV vaccination prevents cancer in both women and men, and reducing the out-of-pocket cost of vaccination surely will result in an increase in the vaccination rate of boys and girls. ●

As a gynecologist, should you receive the 9vHPV vaccine?

Surgical treatment of tissues infected with human papillomavirus (HPV) often involves the use of laser or electrosurgical devices that generate smoke, which is known to contain HPV nucleic acid sequences and may contain infective virions.1 It is known that HPV nucleic acid sequences are present in surgical smoke. In one study plantar warts were treated with a carbon dioxide laser or electrocoagulation. The vapor produced from the surgery was collected with a dry filter apparatus. Five of 8 laser-derived vapors and 4 of 7 electrocoagulation-derived vapors were positive for HPV DNA. The concentration of HPV DNA was greater with laser than with electrocoagulation treatment.2

It is not known if surgical smoke derived from treatment of HPV-infected tissues contains infective HPV virions. In an experimental bovine model, smoke generated by laser ablation of fibropapillomas was collected. Injection of the contents of the smoke caused cutaneous papillomavirus lesions when inoculated into calves, suggesting that the smoke contained infective HPV virions.3 Although this animal experiment is a proof of principle that surgical smoke generated from treatment of HPVinfected tissue contain virions, it is unclear if surgical smoke generated in gynecologic practice contains HPV virions.

To investigate the prevalence of nasal HPV DNA among gynecologists, 700 physicians in Zhejiang Province, China, completed a questionnaire and provided a nasal swab for HPV DNA analysis.4 Among gynecologists who performed or did not perform LEEP, the prevalence of HPV DNA in the nose was 10% and 3%, respectively. The most common HPV types detected were HPV16 (76%), HPV31 (10%), HPV58 (5%), HPV55 (5%), HPV56 (2%), and HPV59 (2%).4 Among gynecologists who performed LEEP procedures, the prevalence of HPV DNA was 19% for those who did not use a surgical mask, 8% for clinicians who used a standard surgical mask, and 0% for those who used an N95 filtering facepiece respirator, suggesting that an N95 respirator provides the greatest protection from surgical smoke.4 Over 24 months of follow-up, all the gynecologists who had initially tested positive for HPV DNA no longer had detectable nasal HPV DNA. In this study, no gynecologist was diagnosed with an HPV-associated oropharyngeal disease. The investigators concluded that surgical masks, especially an N95 respirator, should be used by gynecologists performing LEEP procedures.

Investigators also have evaluated for the presence of HPV DNA in matched samples from the cervix of 134 patients undergoing loop electrosurgical excision procedure (LEEP) for cervical dysplasia, as well as the smoke generated during the procedure and nasal swabs from the surgeon performing the LEEP.5 HPV DNA was detected in 95% of the cervical samples, 30% of the surgical smoke samples, and 1.5% of the surgeons’ nasal swabs.5 At 6 months of follow-up, the two surgeons who initially had HPV-positive nasal swabs no longer had detected HPV DNA.

Of concern is that otolaryngologists have reported sporadic cases of oropharyngeal squamous cell cancer6 and laryngeal papillomatosis7 in health care workers with frequent and repetitive exposure to HPVs. For example, in one case report, a 53-year-old male gynecologist, nonsmoker, presented to his physician with a lump on the neck.6 The gynecologist had performed more than 3,000 laser ablation or LEEP procedures of dysplastic cervical, vaginal, and vulvar lesions over a span of 20 years.6 Most of the procedures were performed without wearing a mask and in a poorly ventilated procedure room. A computed tomography scan demonstrated a 2.2-cm soft tissue lesion in the right tonsil extending to the right soft palate and a level-2 lymph node. A biopsy of the tonsil confirmed invasive squamous cell carcinoma containing HPV16. He was treated with 35 fractions of radiotherapy and adjuvant cisplatin. Treatment adverse effects included dysphagia and xerostomia, and the patient lost 40 pounds.

Available interventions to reduce exposure of clinicians to HPV virions that may be present in surgical smoke include:

  • wearing a fit-tested N95 respirator  
  • routinely using a smoke evacuation device, and
  • ensuring sufficient ventilation in the procedure room.

A new recommendation is to consider 9vHPV vaccination for clinicians who are routinely exposed to HPV virions.8,9 In February 2020, the American Society for Colposcopy and Cervical Pathology recommended that clinicians who are routinely exposed to HPVs consider 9vHPV vaccination.8 This recommendation pertains to all members of the clinical team in the procedure room, including physicians, nurses, and staff. Based on the available data, gynecologists who have not been vaccinated will need to weigh the benefits and costs of receiving a 9vHPV vaccine to protect themselves against an occupational exposure that may adversely impact their health.

References

  1. Liu Y, Song Y, Hu X, et al. Awareness of surgical smoke hazards and enhancement of surgical smoke prevention among gynecologists. J Cancer. 2019;10:2788-2799.
  2. Sawchuk WS, Weber PJ, Lowy DR, et al. Infectious papillomavirus in the vapor of warts treated with carbon dioxide laser or electrocoagulation: detection and protection. J Am Acad Dermatol. 1989;21:41-49.
  3. Garden JM, O’Banion MK, Bakus AD, et al. Viral transmitted by laser-generated plume (aerosol). Arch Dermatol. 2002;138:1303-1307.
  4. Hu X, Zhou Q, Yu J, et al. Prevalence of HPV infections in surgical smoke exposed gynecologists. Int Arch Occup Environ Health. 2020; Epub September 1. doi: 10.1007 /s00420-020-01568-9.
  5. Zhou Q, Hu X, Zhou J, et al. Human papillomavirus DNA in surgical smoke during cervical loop electrosurgical excision procedures and its impact on the surgeon. Cancer Manag Res. 2019;11:3643-3654.
  6. Rioux M, Garland A, Webster D, et al. HPV-positive tonsillar cancer in two laser surgeons: case reports. J Otolaryngol Head Neck Surg. 2013;42:54-57.
  7. Hallmo P, Naess O. Laryngeal papillomatosis with human papillomavirus DNA contracted by a laser surgeon. Eur Arch Otorhinolaryngol. 1991;248:425-427.
  8. Stockdale CK, Einstein MH, Huh WK. ASCCP recommends HPV vaccination for providers. February 19, 2020. www.asccp.org/Assets/d3abdb05-25c5-4e58-%209cec-05c11fb2b920/637177876310030000/hpv-vaccinemember-announcment-02-19-20-pdf. Accessed October 23, 2020.

  9. Harrison R, Huh W. Occupational exposure to human papillomavirus and vaccination for health care workers. Obstet Gynecol. 2020;136:663-665

 

 

Surprisingly, in the United States, the most common cancer associated with human papillomavirus (HPV) is oropharyngeal squamous cell cancer (SCC), with one study reporting 15,479 cases among men and 3,428 cases among women in 2015.1 In the same year, the investigators reported 11,788 cases of cervical cancer.1 A public health concern is that cases of oropharyngeal SCC are increasing, while cases of cervical cancer are decreasing. From 1999 to 2015, the rate of oropharyngeal SCC increased annually among both men and women, at rates of 2.7% and 0.8% per year, respectively. By contrast, the rate of cervical cancer decreased by 1.6% per year.1

Although the incidence of HPV-negative oropharyngeal SCC (cases associated with cigarette smoking) has declined by 50% from 1988 to 2004, the incidence of HPV-positive oropharyngeal SCC has increased by 225%, with much of the increase occurring among young, white men.2 HPV infection is a major cause of oropharyngeal SCC at the base of the tongue and tonsils, but not in the soft palate or oropharyngeal walls.3

Most physicians and parents recognize that the 9-valent (9v)HPV vaccine prevents the majority of cervical cancers and precancers in women. Far fewer people realize that there is an important opportunity to prevent a large number of oropharyngeal cancers by improving 9vHPV vaccination in men and women.

Which HPV types are associated with oropharyngeal cancer?

HPV16 is the most common HPV type associated with oropharyngeal SCC. Among these cancer types, greater than 80% harbor HPV16, with greater than 90% harboring HPV16 or 18 and less than 10% of tumors associated with HPV types 31, 33, 45, 52, or 58.4-7

The high prevalence of HPV16 in patients with oropharyngeal cancer raises the question of the HPV status of the intimate partner of the index patient. In one study of 164 people with HPV detected in their oropharyngeal, the partner of the index patient had a low prevalence of high-risk HPV types (1.2%) in oral rinse and gargle samples, similar to the rate in the general population (1.3%).7 This finding is reassuring and suggests that intimate partners of patients with HPV-positive oropharyngeal cancer effectively clear high-risk HPV virus from the oropharynx. The HPV status of the genital tissue of the intimate partner of an index patient with oropharyngeal SCC has not been adequately studied.

Men are more likely than women to harbor oral HPV

Among a sample of 5,501 men and women aged 14 to 69 years from the National Health and Nutrition Examination Survey, oral rinses were obtained and analyzed for the presence of HPV.8 The prevalence of any oral HPV and any oral high-risk HPV was 6.9% and 3.7%, respectively. Oral HPV-16 was detected in 1.6% of men and 0.3% of women. The prevalence of HPV was higher among current smokers, heavy alcohol drinkers, and people with a history of a greater number of sexual partners. In men and women reporting more than 20 lifetime sexual partners, the prevalence of oral HPV was 20%.

In a study of 2,627 men and women aged 18 to 33 years, the prevalence of oral HPV 16/18/6/11 was lower among those vaccinated versus those unvaccinated (0.11% and 1.6%, respectively; P = .008).9 Among men, oral HPV 16/18/6/11 was lower among those vaccinated versus unvaccinated (0.0% and 2.13%, respectively; P = .007).9 The results of this observational study support the important role of vaccination in reducing oral HPV infection.

9vHPV vaccine: Indications and immunization schedule

In 2020, the US Food and Drug Administration (FDA) approved the 9-valent human papillomavirus (9vHPV) vaccine for the prevention of oropharyngeal cancer. The 9vHPV vaccine contains inactive L1 capsid proteins for 9 HPV types, including types 6, 11, 16, 18, 31, 33, 45, 52, and 58. The vaccine stimulates the production of neutralizing antibodies to the capsid protein.

9vHPV is approved for females aged 9 to 45 years to prevent cancers and precancers of the cervix, vulva, vagina, and anus caused by HPV types 16, 18, 31, 33, 45, 52, and 58.1 It is also approved for males aged 9 to 45 years to prevent cancer and precancers of the anus caused by those viral types. In 2020 the 9vHPV vaccine was approved by the FDA to prevent oropharyngeal cancer in males and females. Of note, the FDA reported that, “the oropharyngeal and head and neck cancer indication is approved under accelerated approval based on effectiveness in preventing HPV-related anogenital disease. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.”2

The Advisory Committee on Immunization Practices (ACIP) recommends routine vaccination of girls and boys, 11 to 12 years of age.1 Children with a history of sexual abuse or assault can start the vaccine at 9 years of age. Catch-up vaccination is recommended for all females and males through age 26 years. The ACIP recommends shared clinical decision-making regarding vaccination for some adults 27 to 45 years of age. Gynecologists with routine exposure to HPV may have occupational risk that warrants HPV vaccination3 (see “As a gynecologist, should you receive the 9vHPV vaccine?”).

For most individuals who start the vaccine series before age 15, two doses of 9vHPV vaccine are recommended, with the second dose 6 to 12 months following the first dose. For teens and adults aged 15 to 26 years, 3 doses of 9vHPV vaccine are recommended, with the second dose 1 to 2 months later and the third dose 6 months following the first dose. Immunocompromised individuals 9 to 26 years of age, including those with HIV infection, should receive 3 doses of the vaccine.

References

1. Meites E, Szilagyi PG, Chesson HW, et al. Human papillomavirus vaccination for adults: updated recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2019;68:698-702.

2. Gardasil 9 [package insert]. Whitehouse Station, NJ: Merck & Co. Inc; 2020.

3. Stockdale CK, Einstein MH, Huh WK. ASCCP recommends HPV vaccination for providers. February 19, 2020. https://www.asccp.org/Assets/d3abdb05-25c5-4e58-9cec-05c11fb2b920/637177876310030000/hpv-vaccinemember-announcment-02-19-20-pdf. Accessed October 23, 2020.

Continue to: Vaccinate boys and girls to prevent cancer...

 

 

Vaccinate boys and girls to prevent cancer

Most population studies report that males are less likely to receive an HPV vaccine than females. For example, based on the National Health Interview Survey of people aged 18 to 26, the percentage of women who self-reported receiving at least one dose of HPV vaccine was 37% in 2013 and 54% in 2018.10 By contrast, among men, the rates of self-reported vaccination were much lower—8% in 2013 and 27% in 2018.10

The percentage of women who received the recommended number of doses of HPV vaccine (see “9vHPV vaccine: Indications and immunization schedule”) was 26% in 2013 and 35% in 2018.10 For men, these percentages were 2% in 2013 and 9% in 2018.10 These data indicate that, compared with women, men are less likely to receive an HPV vaccination and far less likely to have received the recommended number of doses.

It is heartening that there has been a slow and steady increase in the prevalence of HPV vaccination. In fact, increasing the HPV vaccination rate among both boys and girls has the potential to markedly reduce the incidence of oropharyngeal cancer.

The reasons for the female-male gap in vaccination rates are not fully characterized. For one, parental awareness of the importance of HPV vaccination to prevent cancer among men is limited, and represents an important opportunity for additional public health education. In a qualitative interview study of mothers with children aged 11 to 19, the investigators reported that most mothers were aware that HPV vaccination could prevent cervical cancer in women, but most mothers did not know that HPV causes cancer of the mouth and that vaccination could prevent oropharyngeal cancer in boys and girls.11 Because of this lack of knowledge, the mothers did not think their sons needed to have an HPV vaccine. The research report is aptly titled, “I don’t think he needs the HPV vaccine cause boys can’t have cervical cancer.”11

Clinicians are highly influential in guiding parents to accept HPV vaccination of their children. Offering consistent messaging to parents that HPV vaccination prevents cancer in both women and men, and reducing the out-of-pocket cost of vaccination surely will result in an increase in the vaccination rate of boys and girls. ●

As a gynecologist, should you receive the 9vHPV vaccine?

Surgical treatment of tissues infected with human papillomavirus (HPV) often involves the use of laser or electrosurgical devices that generate smoke, which is known to contain HPV nucleic acid sequences and may contain infective virions.1 It is known that HPV nucleic acid sequences are present in surgical smoke. In one study plantar warts were treated with a carbon dioxide laser or electrocoagulation. The vapor produced from the surgery was collected with a dry filter apparatus. Five of 8 laser-derived vapors and 4 of 7 electrocoagulation-derived vapors were positive for HPV DNA. The concentration of HPV DNA was greater with laser than with electrocoagulation treatment.2

It is not known if surgical smoke derived from treatment of HPV-infected tissues contains infective HPV virions. In an experimental bovine model, smoke generated by laser ablation of fibropapillomas was collected. Injection of the contents of the smoke caused cutaneous papillomavirus lesions when inoculated into calves, suggesting that the smoke contained infective HPV virions.3 Although this animal experiment is a proof of principle that surgical smoke generated from treatment of HPVinfected tissue contain virions, it is unclear if surgical smoke generated in gynecologic practice contains HPV virions.

To investigate the prevalence of nasal HPV DNA among gynecologists, 700 physicians in Zhejiang Province, China, completed a questionnaire and provided a nasal swab for HPV DNA analysis.4 Among gynecologists who performed or did not perform LEEP, the prevalence of HPV DNA in the nose was 10% and 3%, respectively. The most common HPV types detected were HPV16 (76%), HPV31 (10%), HPV58 (5%), HPV55 (5%), HPV56 (2%), and HPV59 (2%).4 Among gynecologists who performed LEEP procedures, the prevalence of HPV DNA was 19% for those who did not use a surgical mask, 8% for clinicians who used a standard surgical mask, and 0% for those who used an N95 filtering facepiece respirator, suggesting that an N95 respirator provides the greatest protection from surgical smoke.4 Over 24 months of follow-up, all the gynecologists who had initially tested positive for HPV DNA no longer had detectable nasal HPV DNA. In this study, no gynecologist was diagnosed with an HPV-associated oropharyngeal disease. The investigators concluded that surgical masks, especially an N95 respirator, should be used by gynecologists performing LEEP procedures.

Investigators also have evaluated for the presence of HPV DNA in matched samples from the cervix of 134 patients undergoing loop electrosurgical excision procedure (LEEP) for cervical dysplasia, as well as the smoke generated during the procedure and nasal swabs from the surgeon performing the LEEP.5 HPV DNA was detected in 95% of the cervical samples, 30% of the surgical smoke samples, and 1.5% of the surgeons’ nasal swabs.5 At 6 months of follow-up, the two surgeons who initially had HPV-positive nasal swabs no longer had detected HPV DNA.

Of concern is that otolaryngologists have reported sporadic cases of oropharyngeal squamous cell cancer6 and laryngeal papillomatosis7 in health care workers with frequent and repetitive exposure to HPVs. For example, in one case report, a 53-year-old male gynecologist, nonsmoker, presented to his physician with a lump on the neck.6 The gynecologist had performed more than 3,000 laser ablation or LEEP procedures of dysplastic cervical, vaginal, and vulvar lesions over a span of 20 years.6 Most of the procedures were performed without wearing a mask and in a poorly ventilated procedure room. A computed tomography scan demonstrated a 2.2-cm soft tissue lesion in the right tonsil extending to the right soft palate and a level-2 lymph node. A biopsy of the tonsil confirmed invasive squamous cell carcinoma containing HPV16. He was treated with 35 fractions of radiotherapy and adjuvant cisplatin. Treatment adverse effects included dysphagia and xerostomia, and the patient lost 40 pounds.

Available interventions to reduce exposure of clinicians to HPV virions that may be present in surgical smoke include:

  • wearing a fit-tested N95 respirator  
  • routinely using a smoke evacuation device, and
  • ensuring sufficient ventilation in the procedure room.

A new recommendation is to consider 9vHPV vaccination for clinicians who are routinely exposed to HPV virions.8,9 In February 2020, the American Society for Colposcopy and Cervical Pathology recommended that clinicians who are routinely exposed to HPVs consider 9vHPV vaccination.8 This recommendation pertains to all members of the clinical team in the procedure room, including physicians, nurses, and staff. Based on the available data, gynecologists who have not been vaccinated will need to weigh the benefits and costs of receiving a 9vHPV vaccine to protect themselves against an occupational exposure that may adversely impact their health.

References

  1. Liu Y, Song Y, Hu X, et al. Awareness of surgical smoke hazards and enhancement of surgical smoke prevention among gynecologists. J Cancer. 2019;10:2788-2799.
  2. Sawchuk WS, Weber PJ, Lowy DR, et al. Infectious papillomavirus in the vapor of warts treated with carbon dioxide laser or electrocoagulation: detection and protection. J Am Acad Dermatol. 1989;21:41-49.
  3. Garden JM, O’Banion MK, Bakus AD, et al. Viral transmitted by laser-generated plume (aerosol). Arch Dermatol. 2002;138:1303-1307.
  4. Hu X, Zhou Q, Yu J, et al. Prevalence of HPV infections in surgical smoke exposed gynecologists. Int Arch Occup Environ Health. 2020; Epub September 1. doi: 10.1007 /s00420-020-01568-9.
  5. Zhou Q, Hu X, Zhou J, et al. Human papillomavirus DNA in surgical smoke during cervical loop electrosurgical excision procedures and its impact on the surgeon. Cancer Manag Res. 2019;11:3643-3654.
  6. Rioux M, Garland A, Webster D, et al. HPV-positive tonsillar cancer in two laser surgeons: case reports. J Otolaryngol Head Neck Surg. 2013;42:54-57.
  7. Hallmo P, Naess O. Laryngeal papillomatosis with human papillomavirus DNA contracted by a laser surgeon. Eur Arch Otorhinolaryngol. 1991;248:425-427.
  8. Stockdale CK, Einstein MH, Huh WK. ASCCP recommends HPV vaccination for providers. February 19, 2020. www.asccp.org/Assets/d3abdb05-25c5-4e58-%209cec-05c11fb2b920/637177876310030000/hpv-vaccinemember-announcment-02-19-20-pdf. Accessed October 23, 2020.

  9. Harrison R, Huh W. Occupational exposure to human papillomavirus and vaccination for health care workers. Obstet Gynecol. 2020;136:663-665

 

 

References
  1. Van Dyne EA, Henley SJ, Saraiya M, et al. Trends in human papillomavirus-associated cancers--United States, 1999-2015. MMWR. 2018;67:918-924. 
  2. Chaturvedi AK, Engels EA, Pfeiffer RM, et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol. 2011;29:4294-4301. 
  3. Haeggblom L, Ramqvist T, Tommasino M, et al. Time to change perspective on HPV in oropharyngeal cancer. A systematic review of HPV prevalence per oropharyngeal sub-site the last 3 years. Papillomavirus Research. 2017;4:1-11. 
  4. Kreimer AR, Clifford GM, Boyle P, et al. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev. 2005;14:467-475.  
  5. D'Souza G, Kreimer AR, Viscidi R, et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med. 2007;356:1944-1956. 
  6. de Martel C, Plummer M, Vignat J, et al. Worldwide burden of cancer attributable to HPV by site, country and HPV type. Int J Cancer. 2017;141:664-670. 
  7. D'Souza G, Gross ND, Pai SI, et al. Oral human papillomavirus infection in HPV-positive patients with oropharyngeal cancer and their partners. J Clin Oncol. 2014;32:2408-2415. 
  8. Gillison ML, Broutian T, Pickard RK, et al. Prevalence of oral HPV infection in the United States, 2009-2010. JAMA. 2012;307:693. 
  9. Chaturvedi AK, Graubard BI, Broutian T, et al. Effect of prophylactic human papillomavirus vaccination on oral HPV infections among young adults in the United States. J Clin Oncol. 2018;36:262-267. 
  10. Boersma P, Black LI. Human papillomavirus vaccination among adults aged 18 to 26, 2013-2018. NCHS Data Brief. 2020:1-8. 
  11. Lindsay AC, Delgado D, Valdez MJ, et al. "I don't think he needs the HPV vaccine cause boys can't have cervical cancer": a qualitative study of Latina mothers' (Mis) understandings about human papillomavirus transmission, associated cancers and the vaccine. J Cancer Educ. July 11, 2020. doi: 10.1007/s13187-020-01824-z.
References
  1. Van Dyne EA, Henley SJ, Saraiya M, et al. Trends in human papillomavirus-associated cancers--United States, 1999-2015. MMWR. 2018;67:918-924. 
  2. Chaturvedi AK, Engels EA, Pfeiffer RM, et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol. 2011;29:4294-4301. 
  3. Haeggblom L, Ramqvist T, Tommasino M, et al. Time to change perspective on HPV in oropharyngeal cancer. A systematic review of HPV prevalence per oropharyngeal sub-site the last 3 years. Papillomavirus Research. 2017;4:1-11. 
  4. Kreimer AR, Clifford GM, Boyle P, et al. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev. 2005;14:467-475.  
  5. D'Souza G, Kreimer AR, Viscidi R, et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med. 2007;356:1944-1956. 
  6. de Martel C, Plummer M, Vignat J, et al. Worldwide burden of cancer attributable to HPV by site, country and HPV type. Int J Cancer. 2017;141:664-670. 
  7. D'Souza G, Gross ND, Pai SI, et al. Oral human papillomavirus infection in HPV-positive patients with oropharyngeal cancer and their partners. J Clin Oncol. 2014;32:2408-2415. 
  8. Gillison ML, Broutian T, Pickard RK, et al. Prevalence of oral HPV infection in the United States, 2009-2010. JAMA. 2012;307:693. 
  9. Chaturvedi AK, Graubard BI, Broutian T, et al. Effect of prophylactic human papillomavirus vaccination on oral HPV infections among young adults in the United States. J Clin Oncol. 2018;36:262-267. 
  10. Boersma P, Black LI. Human papillomavirus vaccination among adults aged 18 to 26, 2013-2018. NCHS Data Brief. 2020:1-8. 
  11. Lindsay AC, Delgado D, Valdez MJ, et al. "I don't think he needs the HPV vaccine cause boys can't have cervical cancer": a qualitative study of Latina mothers' (Mis) understandings about human papillomavirus transmission, associated cancers and the vaccine. J Cancer Educ. July 11, 2020. doi: 10.1007/s13187-020-01824-z.
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Unrecognized placenta accreta spectrum: Intraoperative management

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Wed, 11/04/2020 - 10:11

 

 

CASE Concerning finding on repeat CD

A 30-year-old woman with a history of 1 prior cesarean delivery (CD) presents to labor and delivery at 38 weeks of gestation with symptoms of mild cramping. Her prenatal care was uncomplicated. The covering team made a decision to proceed with a repeat CD. A Pfannenstiel incision is made to enter the abdomen, and inspection of the lower uterine segment is concerning for a placenta accreta spectrum (PAS) (FIGURE).

What would be your next steps?

 

Placenta accreta spectrum describes the range of disorders of placental implantation, including placenta accreta, increta, and percreta. PAS is a significant cause of severe maternal morbidity and mortality, primarily due to massive hemorrhage at the time of delivery. The incidence of PAS continues to rise along with the CD rate. The authors of a recent meta-analysis reported a pooled prevalence rate of 1 in 588 women.1 Notably, in women with PAS, the rate of hysterectomy is 52.2%, and the transfusion-dependent hemorrhage rate is 46.9%.1

Ideally, PAS should be diagnosed or at least suspected antenatally during prenatal ultrasonography, leading to delivery planning by a multidisciplinary team.2 The presence of a multidisciplinary team—in addition to the primary obstetric and surgical teams—composed of experienced anesthesiologists, a blood bank able to respond to massive transfusion needs, critical care specialists, and interventional radiologists is associated with improved outcomes.3-5

Occasionally, a patient is found to have an advanced PAS (increta or percreta) at the time of delivery. In these situations, it is paramount that the appropriate resources be assembled as expeditiously as possible to optimize maternal outcomes. Surgical management can be challenging even for experienced pelvic surgeons, and appropriate resuscitation cannot be provided by a single anesthesiologist working alone. A cavalier attitude of proceeding with the delivery “as usual” in the face of an unexpected PAS situation can lead to disastrous consequences, including maternal death.

In this article, we review the important steps to take when faced with the unexpected situation of a PAS at the time of CD.

 

Continue to: Stop and collect your multidisciplinary team...

 

 

Stop and collect your multidisciplinary team

Once the diagnosis of an advanced PAS is suspected, the first step is to stop and request the presence of your institution’s multidisciplinary surgical team. This team typically includes a maternal-fetal specialist or, if not available, an experienced obstetrician, and an expert pelvic surgeon, which varies by institution (gynecologic oncologist, trauma surgeon, urologist, urogynecologist, vascular surgeon). An interventional radiology team is an additional useful resource that can assist with the control of pelvic hemorrhage using embolization techniques.

In our opinion, it is not appropriate to have a surgical backup team available only as needed at a certain distance from the hospital or even in the building. Because of the acuity and magnitude of bleeding that can occur in a short time, the most appropriate approach is to have your surgical team scrubbed and ready to assist or take over the procedure immediately if indicated.

Additional support staff also may be required. A single circulating nurse may not be sufficient, and available nursing staff may need to be called. The surgical technician scrubbed on the case may be familiar only with uncomplicated CDs and can be overwhelmed during a PAS case. Having a more experienced surgical technologist can optimize the availability of the appropriate instruments for the surgical team.

If a multidisciplinary surgical team with PAS management expertise is not available at your institution and the patient is stable, it is appropriate to consider transferring her to the nearest center that can meet the high-risk needs of this situation.6

Prepare for resuscitation

While you are calling your multidisciplinary team members, implement plans for resuscitation by notifying the anesthesiologist about the PAS findings. This will allow the gathering of needed resources that may include calling on additional anesthesiologists with experience in high-risk obstetrics, trauma, or critical care.

Placing large-bore intravenous lines or a central line to allow rapid transfusion is essential. Strongly consider inserting an arterial line for hemodynamic monitoring and intraoperative blood draws to monitor blood loss, blood gases, electrolytes, and coagulation parameters, which can guide resuscitative efforts and replacement therapies.

Simultaneously, inform the blood bank to prepare blood and blood products for possible activation of a massive transfusion protocol. It is imperative to have the products available in the operating room (OR) prior to proceeding with the surgery. Our current practice is to have 10 units of packed red blood cells and fresh frozen plasma available in the OR for all our prenatally diagnosed electively planned PAS cases.

Optimize exposure of the surgical field

Appropriate exposure of the surgical field is essential and should include exposure of the uterine fundus and the pelvic sidewalls. The uterine incision should avoid the placenta; typically it is placed at the level of the uterine fundus. Exposure of the pelvic sidewalls is needed to open the retroperitoneum and identify the ureter and the iliac vessels.

Vertical extension of the fascial incision probably will be needed to achieve appropriate exposure. Although at times this can be done without a concomitant vertical skin incision, often an inverted T incision is required. Be mindful that PAS is a life-threatening condition and that aesthetics are not a priority. After extending the fascial incision, adequate exposure can be achieved with any of the commonly used retractors or wound protectors (depending on institutional availability and surgeon preference) or by the surgical assistants using body wall retractors.

We routinely place the patient in lithotomy position. This allows us to monitor for vaginal bleeding (often a site of unrecognized massive hemorrhage) during the surgery, facilitate retrograde bladder filling, and provide a vaginal access to the pelvis. In addition, the lithotomy position allows for cystoscopy and placement of ureteral stents, which can be performed before starting the surgery to help prevent urinary tract injuries or at the end of the procedure in case one is suspected.7

 

Continue to: Performing the hysterectomy...

 

 

 

Performing the hysterectomy

A complete review of all surgical techniques for managing PAS is beyond the scope of this article. However, we briefly cover important procedural steps and offer suggestions on how to minimize the risk of bleeding.

In our experience. The areas with the highest risk of massive bleeding that can be difficult to control include the pelvic sidewall when there is lateral extension of the PAS, the vesicouterine space, and placenta previa vaginally. Be mindful of these areas at risk and have a plan in place in case of bleeding.

Uterine incision

Avoid the placenta when making the uterine incision, which is typically done in the fundal part of the uterus. Cut and tie the cord and return it to the uterine cavity. Close the incision in a single layer. Use of a surgical stapler can be used for the hysterotomy and can decrease the amount of blood loss.8

Superior attachments of the uterus

The superior attachments of the uterus include the round ligament, the utero-ovarian ligament, and the fallopian tubes. With meticulous dissection, develop an avascular space underneath these structures and, in turn, individually divide and suture ligate; this is typically achieved with minimal blood loss.

In addition, isolate the engorged veins of the broad ligament and divide them in a similar fashion.

In our experience. Use of a vessel-sealing device can facilitate division of all the former structures. Simply excise the fallopian tubes with the vessel-sealing device either at this time or after the uterus is removed.

Pelvic sidewall

Once the superior attachments of the uterus have been divided, the next step involves exposing the pelvic sidewall structures, that is, the ureter and the pelvic vessels. Expose the ureter from the pelvic brim to the level of the uterine artery. The hypogastric artery is exposed as well in this process and the pararectal space developed.

When the PAS has extended laterally, perform stepwise division of the lateral attachments of the placenta to the pelvic sidewall using a combination of electrocautery, hemoclips, and the vessel-sealing device. In laterally extended PAS cases, it often is necessary to divide the uterine artery either at its origin or at the level of the ureter to allow for the completion of the separation of the placenta from the pelvic sidewall.

In our experience. During this lateral dissection, significant bleeding may be encountered from the neovascular network that has developed in the pelvic sidewall. The bleeding may be diffuse and difficult to control with the methods described above. In this situation, we have found that placing hemostatic agents in this area and packing the sidewall with laparotomy pads can achieve hemostasis in most cases, thus allowing the surgery to proceed.

Steps in managing a cesarean delivery with placenta accreta spectrum

1. Stop and collect your multidisciplinary team. If required resources are not available at your institution and the patient is stable, consider transferring her to the nearest center of expertise

2. Prepare for resuscitation: Have blood products available in the operating room and optimize IV access and arterial line

3. Optimize exposure of the surgical field: place in lithotomy position, extend fascial incision, perform hysterotomy to avoid the placenta, and expose pelvic sidewall and ureters

4. Be mindful of likely sources of massive bleeding: pelvic sidewall, bladder/vesicouterine space, and/or placenta previa vaginally

5. Proceed with meticulous dissection to minimize the risk of hemorrhage, retrograde fill the bladder, be mindful of the utility of packing

6. Be prepared to move to an expeditious hysterectomy in case of massive bleeding

Continue to: Bladder dissection...

 

 

Bladder dissection

The next critical part of the surgery involves developing the vesicovaginal space to mobilize the bladder. Prior to initiating the bladder dissection, we routinely retrograde fill the bladder with 180 to 240 mL of saline mixed with methylene blue. This delineates the superior edge of the bladder and indicates the appropriate level to start the dissection. Then slowly develop the vesicouterine space using a combination of electrocautery and a vessel-sealing device until the bladder is mobilized to the level of the anterior vaginal wall. Many vascular connections are encountered at that level, and meticulous dissection and patience is required to systematically divide them all.

In our experience. This part of the surgery presents several challenges. The bladder wall may be invaded by the placenta, which will lead to an increased risk of bleeding and cystotomy during the dissection. In these cases, it might be preferable to create an intentional cystotomy to guide the dissection; at times, a limited excision of the involved bladder wall may be required. In other cases, even in the absence of bladder wall invasion, the bladder may be densely adherent to the uterine wall (usually due to a history of prior CDs), and bladder mobilization may be complicated by bleeding from the neovascular network that has developed between the placenta and bladder.

Uterine arteries and cervix

Once the placenta is separated from its lateral attachments and the bladder is mobilized, the next steps are similar to those in a standard abdominal hysterectomy. If the uterine arteries were not yet divided during the pelvic sidewall dissection, they are clamped, divided, and suture ligated at the level of the uterine isthmus. The decision whether to perform a supracervical or total hysterectomy depends on the level of cervical involvement by the placenta, surgeon preference, anatomic distortion, and bleeding from the cervix and anterior vaginal wall.

Responding to massive bleeding

Not uncommonly, and despite the best efforts to avoid it, massive bleeding may develop from the areas at risk as noted above. If the bleeding is significant and originates from multiple areas (including vaginal bleeding from placenta previa), we recommend proceeding with an expeditious hysterectomy to remove the specimen, and then reassess the pelvic field for hemostatic control and any organ damage that may have occurred.

The challenge of PAS

Surgical management of PAS is one the most challenging procedures in pelvic surgery. Successful outcomes require a multidisciplinary team approach and an experienced team dedicated to the management of this condition.9 By contrast, proceeding “as usual” in the face of an unexpected PAS situation can lead to disastrous consequences in terms of maternal morbidity and mortality. ●

References
  1. Jauniaux E, Bunce C, Gronbeck L, et al. Prevalence and main outcomes of placenta accreta spectrum: a systematic review and meta-analysis. Am J Obstet Gynecol. 2019;221:208-218. 
  2. Society of Gynecologic Oncology, American College of Obstetricians and Gynecologists, Society for Maternal-Fetal Medicine, et al. Placenta accreta spectrum. Am J Obstet Gynecol. 2018;219:B2-B16. 
  3. Eller AG, Bennett MA, Sharshiner M, et al. Maternal morbidity in cases of placenta accreta managed by a multidisciplinary care team compared with standard obstetric care. Obstet Gynecol. 2011;117(2 pt 1):331-337. 
  4. Shamshirsaz AA, Fox KA, Salmanian B, et al. Maternal morbidity in patients with morbidly adherent placenta treated with and without a standardized multidisciplinary approach. Am J Obstet Gynecol. 2015;212:218.e1-9. 
  5. Collins SL, Alemdar B, van Beekhuizen HJ, et al; International Society for Abnormally Invasive Placenta. Evidence-based guidelines for the management of abnormally invasive placenta: recommendations from the International Society for Abnormally Invasive Placenta. Am J Obstet Gynecol. 2019;220:511-526. 
  6. Silver RM, Fox KA, Barton JR, et al. Center of excellence for placenta accreta. Am J Obstet Gynecol. 2015;212:561-568. 
  7. Tam Tam KB, Dozier J, Martin JN Jr. Approaches to reduce urinary tract injury during management of placenta accreta, increta, and percreta: a systematic review. J Matern Fetal Neonatal Med. 2012;25:329-334. 
  8. Belfort MA, Shamshiraz AA, Fox K. Minimizing blood loss at cesarean-hysterectomy for placenta previa percreta. Am J Obstet Gynecol. 2017;216:78.e1-78.e2. 
  9. Shamshirsaz AA, Fox KA, Erfani H, et al. Multidisciplinary team learning in the management of the morbidly adherent placenta: outcome improvements over time. Am J Obstet Gynecol. 2017;216:612.e1-612.e5.
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Dr. Gamble is Fellow in the Division of Gynecologic Oncology, New York-Presbyterian/Weill Cornell Medical Center, and Columbia University Medical Center, New York, New York. 

Dr. Khoury-Collado is Assistant Professor of Obstetrics and Gynecology, Division of Gynecologic Oncology, Columbia University Irving Medical Center/New York Presbyterian Hospital, New York. 

 

The authors report no financial relationships relevant to this article. 
 

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Dr. Gamble is Fellow in the Division of Gynecologic Oncology, New York-Presbyterian/Weill Cornell Medical Center, and Columbia University Medical Center, New York, New York. 

Dr. Khoury-Collado is Assistant Professor of Obstetrics and Gynecology, Division of Gynecologic Oncology, Columbia University Irving Medical Center/New York Presbyterian Hospital, New York. 

 

The authors report no financial relationships relevant to this article. 
 

Author and Disclosure Information

Dr. Gamble is Fellow in the Division of Gynecologic Oncology, New York-Presbyterian/Weill Cornell Medical Center, and Columbia University Medical Center, New York, New York. 

Dr. Khoury-Collado is Assistant Professor of Obstetrics and Gynecology, Division of Gynecologic Oncology, Columbia University Irving Medical Center/New York Presbyterian Hospital, New York. 

 

The authors report no financial relationships relevant to this article. 
 

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CASE Concerning finding on repeat CD

A 30-year-old woman with a history of 1 prior cesarean delivery (CD) presents to labor and delivery at 38 weeks of gestation with symptoms of mild cramping. Her prenatal care was uncomplicated. The covering team made a decision to proceed with a repeat CD. A Pfannenstiel incision is made to enter the abdomen, and inspection of the lower uterine segment is concerning for a placenta accreta spectrum (PAS) (FIGURE).

What would be your next steps?

 

Placenta accreta spectrum describes the range of disorders of placental implantation, including placenta accreta, increta, and percreta. PAS is a significant cause of severe maternal morbidity and mortality, primarily due to massive hemorrhage at the time of delivery. The incidence of PAS continues to rise along with the CD rate. The authors of a recent meta-analysis reported a pooled prevalence rate of 1 in 588 women.1 Notably, in women with PAS, the rate of hysterectomy is 52.2%, and the transfusion-dependent hemorrhage rate is 46.9%.1

Ideally, PAS should be diagnosed or at least suspected antenatally during prenatal ultrasonography, leading to delivery planning by a multidisciplinary team.2 The presence of a multidisciplinary team—in addition to the primary obstetric and surgical teams—composed of experienced anesthesiologists, a blood bank able to respond to massive transfusion needs, critical care specialists, and interventional radiologists is associated with improved outcomes.3-5

Occasionally, a patient is found to have an advanced PAS (increta or percreta) at the time of delivery. In these situations, it is paramount that the appropriate resources be assembled as expeditiously as possible to optimize maternal outcomes. Surgical management can be challenging even for experienced pelvic surgeons, and appropriate resuscitation cannot be provided by a single anesthesiologist working alone. A cavalier attitude of proceeding with the delivery “as usual” in the face of an unexpected PAS situation can lead to disastrous consequences, including maternal death.

In this article, we review the important steps to take when faced with the unexpected situation of a PAS at the time of CD.

 

Continue to: Stop and collect your multidisciplinary team...

 

 

Stop and collect your multidisciplinary team

Once the diagnosis of an advanced PAS is suspected, the first step is to stop and request the presence of your institution’s multidisciplinary surgical team. This team typically includes a maternal-fetal specialist or, if not available, an experienced obstetrician, and an expert pelvic surgeon, which varies by institution (gynecologic oncologist, trauma surgeon, urologist, urogynecologist, vascular surgeon). An interventional radiology team is an additional useful resource that can assist with the control of pelvic hemorrhage using embolization techniques.

In our opinion, it is not appropriate to have a surgical backup team available only as needed at a certain distance from the hospital or even in the building. Because of the acuity and magnitude of bleeding that can occur in a short time, the most appropriate approach is to have your surgical team scrubbed and ready to assist or take over the procedure immediately if indicated.

Additional support staff also may be required. A single circulating nurse may not be sufficient, and available nursing staff may need to be called. The surgical technician scrubbed on the case may be familiar only with uncomplicated CDs and can be overwhelmed during a PAS case. Having a more experienced surgical technologist can optimize the availability of the appropriate instruments for the surgical team.

If a multidisciplinary surgical team with PAS management expertise is not available at your institution and the patient is stable, it is appropriate to consider transferring her to the nearest center that can meet the high-risk needs of this situation.6

Prepare for resuscitation

While you are calling your multidisciplinary team members, implement plans for resuscitation by notifying the anesthesiologist about the PAS findings. This will allow the gathering of needed resources that may include calling on additional anesthesiologists with experience in high-risk obstetrics, trauma, or critical care.

Placing large-bore intravenous lines or a central line to allow rapid transfusion is essential. Strongly consider inserting an arterial line for hemodynamic monitoring and intraoperative blood draws to monitor blood loss, blood gases, electrolytes, and coagulation parameters, which can guide resuscitative efforts and replacement therapies.

Simultaneously, inform the blood bank to prepare blood and blood products for possible activation of a massive transfusion protocol. It is imperative to have the products available in the operating room (OR) prior to proceeding with the surgery. Our current practice is to have 10 units of packed red blood cells and fresh frozen plasma available in the OR for all our prenatally diagnosed electively planned PAS cases.

Optimize exposure of the surgical field

Appropriate exposure of the surgical field is essential and should include exposure of the uterine fundus and the pelvic sidewalls. The uterine incision should avoid the placenta; typically it is placed at the level of the uterine fundus. Exposure of the pelvic sidewalls is needed to open the retroperitoneum and identify the ureter and the iliac vessels.

Vertical extension of the fascial incision probably will be needed to achieve appropriate exposure. Although at times this can be done without a concomitant vertical skin incision, often an inverted T incision is required. Be mindful that PAS is a life-threatening condition and that aesthetics are not a priority. After extending the fascial incision, adequate exposure can be achieved with any of the commonly used retractors or wound protectors (depending on institutional availability and surgeon preference) or by the surgical assistants using body wall retractors.

We routinely place the patient in lithotomy position. This allows us to monitor for vaginal bleeding (often a site of unrecognized massive hemorrhage) during the surgery, facilitate retrograde bladder filling, and provide a vaginal access to the pelvis. In addition, the lithotomy position allows for cystoscopy and placement of ureteral stents, which can be performed before starting the surgery to help prevent urinary tract injuries or at the end of the procedure in case one is suspected.7

 

Continue to: Performing the hysterectomy...

 

 

 

Performing the hysterectomy

A complete review of all surgical techniques for managing PAS is beyond the scope of this article. However, we briefly cover important procedural steps and offer suggestions on how to minimize the risk of bleeding.

In our experience. The areas with the highest risk of massive bleeding that can be difficult to control include the pelvic sidewall when there is lateral extension of the PAS, the vesicouterine space, and placenta previa vaginally. Be mindful of these areas at risk and have a plan in place in case of bleeding.

Uterine incision

Avoid the placenta when making the uterine incision, which is typically done in the fundal part of the uterus. Cut and tie the cord and return it to the uterine cavity. Close the incision in a single layer. Use of a surgical stapler can be used for the hysterotomy and can decrease the amount of blood loss.8

Superior attachments of the uterus

The superior attachments of the uterus include the round ligament, the utero-ovarian ligament, and the fallopian tubes. With meticulous dissection, develop an avascular space underneath these structures and, in turn, individually divide and suture ligate; this is typically achieved with minimal blood loss.

In addition, isolate the engorged veins of the broad ligament and divide them in a similar fashion.

In our experience. Use of a vessel-sealing device can facilitate division of all the former structures. Simply excise the fallopian tubes with the vessel-sealing device either at this time or after the uterus is removed.

Pelvic sidewall

Once the superior attachments of the uterus have been divided, the next step involves exposing the pelvic sidewall structures, that is, the ureter and the pelvic vessels. Expose the ureter from the pelvic brim to the level of the uterine artery. The hypogastric artery is exposed as well in this process and the pararectal space developed.

When the PAS has extended laterally, perform stepwise division of the lateral attachments of the placenta to the pelvic sidewall using a combination of electrocautery, hemoclips, and the vessel-sealing device. In laterally extended PAS cases, it often is necessary to divide the uterine artery either at its origin or at the level of the ureter to allow for the completion of the separation of the placenta from the pelvic sidewall.

In our experience. During this lateral dissection, significant bleeding may be encountered from the neovascular network that has developed in the pelvic sidewall. The bleeding may be diffuse and difficult to control with the methods described above. In this situation, we have found that placing hemostatic agents in this area and packing the sidewall with laparotomy pads can achieve hemostasis in most cases, thus allowing the surgery to proceed.

Steps in managing a cesarean delivery with placenta accreta spectrum

1. Stop and collect your multidisciplinary team. If required resources are not available at your institution and the patient is stable, consider transferring her to the nearest center of expertise

2. Prepare for resuscitation: Have blood products available in the operating room and optimize IV access and arterial line

3. Optimize exposure of the surgical field: place in lithotomy position, extend fascial incision, perform hysterotomy to avoid the placenta, and expose pelvic sidewall and ureters

4. Be mindful of likely sources of massive bleeding: pelvic sidewall, bladder/vesicouterine space, and/or placenta previa vaginally

5. Proceed with meticulous dissection to minimize the risk of hemorrhage, retrograde fill the bladder, be mindful of the utility of packing

6. Be prepared to move to an expeditious hysterectomy in case of massive bleeding

Continue to: Bladder dissection...

 

 

Bladder dissection

The next critical part of the surgery involves developing the vesicovaginal space to mobilize the bladder. Prior to initiating the bladder dissection, we routinely retrograde fill the bladder with 180 to 240 mL of saline mixed with methylene blue. This delineates the superior edge of the bladder and indicates the appropriate level to start the dissection. Then slowly develop the vesicouterine space using a combination of electrocautery and a vessel-sealing device until the bladder is mobilized to the level of the anterior vaginal wall. Many vascular connections are encountered at that level, and meticulous dissection and patience is required to systematically divide them all.

In our experience. This part of the surgery presents several challenges. The bladder wall may be invaded by the placenta, which will lead to an increased risk of bleeding and cystotomy during the dissection. In these cases, it might be preferable to create an intentional cystotomy to guide the dissection; at times, a limited excision of the involved bladder wall may be required. In other cases, even in the absence of bladder wall invasion, the bladder may be densely adherent to the uterine wall (usually due to a history of prior CDs), and bladder mobilization may be complicated by bleeding from the neovascular network that has developed between the placenta and bladder.

Uterine arteries and cervix

Once the placenta is separated from its lateral attachments and the bladder is mobilized, the next steps are similar to those in a standard abdominal hysterectomy. If the uterine arteries were not yet divided during the pelvic sidewall dissection, they are clamped, divided, and suture ligated at the level of the uterine isthmus. The decision whether to perform a supracervical or total hysterectomy depends on the level of cervical involvement by the placenta, surgeon preference, anatomic distortion, and bleeding from the cervix and anterior vaginal wall.

Responding to massive bleeding

Not uncommonly, and despite the best efforts to avoid it, massive bleeding may develop from the areas at risk as noted above. If the bleeding is significant and originates from multiple areas (including vaginal bleeding from placenta previa), we recommend proceeding with an expeditious hysterectomy to remove the specimen, and then reassess the pelvic field for hemostatic control and any organ damage that may have occurred.

The challenge of PAS

Surgical management of PAS is one the most challenging procedures in pelvic surgery. Successful outcomes require a multidisciplinary team approach and an experienced team dedicated to the management of this condition.9 By contrast, proceeding “as usual” in the face of an unexpected PAS situation can lead to disastrous consequences in terms of maternal morbidity and mortality. ●

 

 

CASE Concerning finding on repeat CD

A 30-year-old woman with a history of 1 prior cesarean delivery (CD) presents to labor and delivery at 38 weeks of gestation with symptoms of mild cramping. Her prenatal care was uncomplicated. The covering team made a decision to proceed with a repeat CD. A Pfannenstiel incision is made to enter the abdomen, and inspection of the lower uterine segment is concerning for a placenta accreta spectrum (PAS) (FIGURE).

What would be your next steps?

 

Placenta accreta spectrum describes the range of disorders of placental implantation, including placenta accreta, increta, and percreta. PAS is a significant cause of severe maternal morbidity and mortality, primarily due to massive hemorrhage at the time of delivery. The incidence of PAS continues to rise along with the CD rate. The authors of a recent meta-analysis reported a pooled prevalence rate of 1 in 588 women.1 Notably, in women with PAS, the rate of hysterectomy is 52.2%, and the transfusion-dependent hemorrhage rate is 46.9%.1

Ideally, PAS should be diagnosed or at least suspected antenatally during prenatal ultrasonography, leading to delivery planning by a multidisciplinary team.2 The presence of a multidisciplinary team—in addition to the primary obstetric and surgical teams—composed of experienced anesthesiologists, a blood bank able to respond to massive transfusion needs, critical care specialists, and interventional radiologists is associated with improved outcomes.3-5

Occasionally, a patient is found to have an advanced PAS (increta or percreta) at the time of delivery. In these situations, it is paramount that the appropriate resources be assembled as expeditiously as possible to optimize maternal outcomes. Surgical management can be challenging even for experienced pelvic surgeons, and appropriate resuscitation cannot be provided by a single anesthesiologist working alone. A cavalier attitude of proceeding with the delivery “as usual” in the face of an unexpected PAS situation can lead to disastrous consequences, including maternal death.

In this article, we review the important steps to take when faced with the unexpected situation of a PAS at the time of CD.

 

Continue to: Stop and collect your multidisciplinary team...

 

 

Stop and collect your multidisciplinary team

Once the diagnosis of an advanced PAS is suspected, the first step is to stop and request the presence of your institution’s multidisciplinary surgical team. This team typically includes a maternal-fetal specialist or, if not available, an experienced obstetrician, and an expert pelvic surgeon, which varies by institution (gynecologic oncologist, trauma surgeon, urologist, urogynecologist, vascular surgeon). An interventional radiology team is an additional useful resource that can assist with the control of pelvic hemorrhage using embolization techniques.

In our opinion, it is not appropriate to have a surgical backup team available only as needed at a certain distance from the hospital or even in the building. Because of the acuity and magnitude of bleeding that can occur in a short time, the most appropriate approach is to have your surgical team scrubbed and ready to assist or take over the procedure immediately if indicated.

Additional support staff also may be required. A single circulating nurse may not be sufficient, and available nursing staff may need to be called. The surgical technician scrubbed on the case may be familiar only with uncomplicated CDs and can be overwhelmed during a PAS case. Having a more experienced surgical technologist can optimize the availability of the appropriate instruments for the surgical team.

If a multidisciplinary surgical team with PAS management expertise is not available at your institution and the patient is stable, it is appropriate to consider transferring her to the nearest center that can meet the high-risk needs of this situation.6

Prepare for resuscitation

While you are calling your multidisciplinary team members, implement plans for resuscitation by notifying the anesthesiologist about the PAS findings. This will allow the gathering of needed resources that may include calling on additional anesthesiologists with experience in high-risk obstetrics, trauma, or critical care.

Placing large-bore intravenous lines or a central line to allow rapid transfusion is essential. Strongly consider inserting an arterial line for hemodynamic monitoring and intraoperative blood draws to monitor blood loss, blood gases, electrolytes, and coagulation parameters, which can guide resuscitative efforts and replacement therapies.

Simultaneously, inform the blood bank to prepare blood and blood products for possible activation of a massive transfusion protocol. It is imperative to have the products available in the operating room (OR) prior to proceeding with the surgery. Our current practice is to have 10 units of packed red blood cells and fresh frozen plasma available in the OR for all our prenatally diagnosed electively planned PAS cases.

Optimize exposure of the surgical field

Appropriate exposure of the surgical field is essential and should include exposure of the uterine fundus and the pelvic sidewalls. The uterine incision should avoid the placenta; typically it is placed at the level of the uterine fundus. Exposure of the pelvic sidewalls is needed to open the retroperitoneum and identify the ureter and the iliac vessels.

Vertical extension of the fascial incision probably will be needed to achieve appropriate exposure. Although at times this can be done without a concomitant vertical skin incision, often an inverted T incision is required. Be mindful that PAS is a life-threatening condition and that aesthetics are not a priority. After extending the fascial incision, adequate exposure can be achieved with any of the commonly used retractors or wound protectors (depending on institutional availability and surgeon preference) or by the surgical assistants using body wall retractors.

We routinely place the patient in lithotomy position. This allows us to monitor for vaginal bleeding (often a site of unrecognized massive hemorrhage) during the surgery, facilitate retrograde bladder filling, and provide a vaginal access to the pelvis. In addition, the lithotomy position allows for cystoscopy and placement of ureteral stents, which can be performed before starting the surgery to help prevent urinary tract injuries or at the end of the procedure in case one is suspected.7

 

Continue to: Performing the hysterectomy...

 

 

 

Performing the hysterectomy

A complete review of all surgical techniques for managing PAS is beyond the scope of this article. However, we briefly cover important procedural steps and offer suggestions on how to minimize the risk of bleeding.

In our experience. The areas with the highest risk of massive bleeding that can be difficult to control include the pelvic sidewall when there is lateral extension of the PAS, the vesicouterine space, and placenta previa vaginally. Be mindful of these areas at risk and have a plan in place in case of bleeding.

Uterine incision

Avoid the placenta when making the uterine incision, which is typically done in the fundal part of the uterus. Cut and tie the cord and return it to the uterine cavity. Close the incision in a single layer. Use of a surgical stapler can be used for the hysterotomy and can decrease the amount of blood loss.8

Superior attachments of the uterus

The superior attachments of the uterus include the round ligament, the utero-ovarian ligament, and the fallopian tubes. With meticulous dissection, develop an avascular space underneath these structures and, in turn, individually divide and suture ligate; this is typically achieved with minimal blood loss.

In addition, isolate the engorged veins of the broad ligament and divide them in a similar fashion.

In our experience. Use of a vessel-sealing device can facilitate division of all the former structures. Simply excise the fallopian tubes with the vessel-sealing device either at this time or after the uterus is removed.

Pelvic sidewall

Once the superior attachments of the uterus have been divided, the next step involves exposing the pelvic sidewall structures, that is, the ureter and the pelvic vessels. Expose the ureter from the pelvic brim to the level of the uterine artery. The hypogastric artery is exposed as well in this process and the pararectal space developed.

When the PAS has extended laterally, perform stepwise division of the lateral attachments of the placenta to the pelvic sidewall using a combination of electrocautery, hemoclips, and the vessel-sealing device. In laterally extended PAS cases, it often is necessary to divide the uterine artery either at its origin or at the level of the ureter to allow for the completion of the separation of the placenta from the pelvic sidewall.

In our experience. During this lateral dissection, significant bleeding may be encountered from the neovascular network that has developed in the pelvic sidewall. The bleeding may be diffuse and difficult to control with the methods described above. In this situation, we have found that placing hemostatic agents in this area and packing the sidewall with laparotomy pads can achieve hemostasis in most cases, thus allowing the surgery to proceed.

Steps in managing a cesarean delivery with placenta accreta spectrum

1. Stop and collect your multidisciplinary team. If required resources are not available at your institution and the patient is stable, consider transferring her to the nearest center of expertise

2. Prepare for resuscitation: Have blood products available in the operating room and optimize IV access and arterial line

3. Optimize exposure of the surgical field: place in lithotomy position, extend fascial incision, perform hysterotomy to avoid the placenta, and expose pelvic sidewall and ureters

4. Be mindful of likely sources of massive bleeding: pelvic sidewall, bladder/vesicouterine space, and/or placenta previa vaginally

5. Proceed with meticulous dissection to minimize the risk of hemorrhage, retrograde fill the bladder, be mindful of the utility of packing

6. Be prepared to move to an expeditious hysterectomy in case of massive bleeding

Continue to: Bladder dissection...

 

 

Bladder dissection

The next critical part of the surgery involves developing the vesicovaginal space to mobilize the bladder. Prior to initiating the bladder dissection, we routinely retrograde fill the bladder with 180 to 240 mL of saline mixed with methylene blue. This delineates the superior edge of the bladder and indicates the appropriate level to start the dissection. Then slowly develop the vesicouterine space using a combination of electrocautery and a vessel-sealing device until the bladder is mobilized to the level of the anterior vaginal wall. Many vascular connections are encountered at that level, and meticulous dissection and patience is required to systematically divide them all.

In our experience. This part of the surgery presents several challenges. The bladder wall may be invaded by the placenta, which will lead to an increased risk of bleeding and cystotomy during the dissection. In these cases, it might be preferable to create an intentional cystotomy to guide the dissection; at times, a limited excision of the involved bladder wall may be required. In other cases, even in the absence of bladder wall invasion, the bladder may be densely adherent to the uterine wall (usually due to a history of prior CDs), and bladder mobilization may be complicated by bleeding from the neovascular network that has developed between the placenta and bladder.

Uterine arteries and cervix

Once the placenta is separated from its lateral attachments and the bladder is mobilized, the next steps are similar to those in a standard abdominal hysterectomy. If the uterine arteries were not yet divided during the pelvic sidewall dissection, they are clamped, divided, and suture ligated at the level of the uterine isthmus. The decision whether to perform a supracervical or total hysterectomy depends on the level of cervical involvement by the placenta, surgeon preference, anatomic distortion, and bleeding from the cervix and anterior vaginal wall.

Responding to massive bleeding

Not uncommonly, and despite the best efforts to avoid it, massive bleeding may develop from the areas at risk as noted above. If the bleeding is significant and originates from multiple areas (including vaginal bleeding from placenta previa), we recommend proceeding with an expeditious hysterectomy to remove the specimen, and then reassess the pelvic field for hemostatic control and any organ damage that may have occurred.

The challenge of PAS

Surgical management of PAS is one the most challenging procedures in pelvic surgery. Successful outcomes require a multidisciplinary team approach and an experienced team dedicated to the management of this condition.9 By contrast, proceeding “as usual” in the face of an unexpected PAS situation can lead to disastrous consequences in terms of maternal morbidity and mortality. ●

References
  1. Jauniaux E, Bunce C, Gronbeck L, et al. Prevalence and main outcomes of placenta accreta spectrum: a systematic review and meta-analysis. Am J Obstet Gynecol. 2019;221:208-218. 
  2. Society of Gynecologic Oncology, American College of Obstetricians and Gynecologists, Society for Maternal-Fetal Medicine, et al. Placenta accreta spectrum. Am J Obstet Gynecol. 2018;219:B2-B16. 
  3. Eller AG, Bennett MA, Sharshiner M, et al. Maternal morbidity in cases of placenta accreta managed by a multidisciplinary care team compared with standard obstetric care. Obstet Gynecol. 2011;117(2 pt 1):331-337. 
  4. Shamshirsaz AA, Fox KA, Salmanian B, et al. Maternal morbidity in patients with morbidly adherent placenta treated with and without a standardized multidisciplinary approach. Am J Obstet Gynecol. 2015;212:218.e1-9. 
  5. Collins SL, Alemdar B, van Beekhuizen HJ, et al; International Society for Abnormally Invasive Placenta. Evidence-based guidelines for the management of abnormally invasive placenta: recommendations from the International Society for Abnormally Invasive Placenta. Am J Obstet Gynecol. 2019;220:511-526. 
  6. Silver RM, Fox KA, Barton JR, et al. Center of excellence for placenta accreta. Am J Obstet Gynecol. 2015;212:561-568. 
  7. Tam Tam KB, Dozier J, Martin JN Jr. Approaches to reduce urinary tract injury during management of placenta accreta, increta, and percreta: a systematic review. J Matern Fetal Neonatal Med. 2012;25:329-334. 
  8. Belfort MA, Shamshiraz AA, Fox K. Minimizing blood loss at cesarean-hysterectomy for placenta previa percreta. Am J Obstet Gynecol. 2017;216:78.e1-78.e2. 
  9. Shamshirsaz AA, Fox KA, Erfani H, et al. Multidisciplinary team learning in the management of the morbidly adherent placenta: outcome improvements over time. Am J Obstet Gynecol. 2017;216:612.e1-612.e5.
References
  1. Jauniaux E, Bunce C, Gronbeck L, et al. Prevalence and main outcomes of placenta accreta spectrum: a systematic review and meta-analysis. Am J Obstet Gynecol. 2019;221:208-218. 
  2. Society of Gynecologic Oncology, American College of Obstetricians and Gynecologists, Society for Maternal-Fetal Medicine, et al. Placenta accreta spectrum. Am J Obstet Gynecol. 2018;219:B2-B16. 
  3. Eller AG, Bennett MA, Sharshiner M, et al. Maternal morbidity in cases of placenta accreta managed by a multidisciplinary care team compared with standard obstetric care. Obstet Gynecol. 2011;117(2 pt 1):331-337. 
  4. Shamshirsaz AA, Fox KA, Salmanian B, et al. Maternal morbidity in patients with morbidly adherent placenta treated with and without a standardized multidisciplinary approach. Am J Obstet Gynecol. 2015;212:218.e1-9. 
  5. Collins SL, Alemdar B, van Beekhuizen HJ, et al; International Society for Abnormally Invasive Placenta. Evidence-based guidelines for the management of abnormally invasive placenta: recommendations from the International Society for Abnormally Invasive Placenta. Am J Obstet Gynecol. 2019;220:511-526. 
  6. Silver RM, Fox KA, Barton JR, et al. Center of excellence for placenta accreta. Am J Obstet Gynecol. 2015;212:561-568. 
  7. Tam Tam KB, Dozier J, Martin JN Jr. Approaches to reduce urinary tract injury during management of placenta accreta, increta, and percreta: a systematic review. J Matern Fetal Neonatal Med. 2012;25:329-334. 
  8. Belfort MA, Shamshiraz AA, Fox K. Minimizing blood loss at cesarean-hysterectomy for placenta previa percreta. Am J Obstet Gynecol. 2017;216:78.e1-78.e2. 
  9. Shamshirsaz AA, Fox KA, Erfani H, et al. Multidisciplinary team learning in the management of the morbidly adherent placenta: outcome improvements over time. Am J Obstet Gynecol. 2017;216:612.e1-612.e5.
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Apps for applying to ObGyn residency programs in the era of virtual interviews

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The coronavirus disease 2019 (COVID-19) pandemic has upended the traditional 2020–2021 application season for ObGyn residency programs. In May 2020, the 2 national ObGyn education organizations, the Association of Professors of Gynecology and Obstetrics (APGO) and Council on Resident Education in ObGyn (CREOG), issued guidelines to ensure a fair and equitable application process.1 These guidelines are consistent with recommendations from the Association of American Medical Colleges (AAMC) and the Coalition for Physician Accountability. Important recommendations include:

  • limiting away rotations
  • being flexible in the number of specialty-specific letters of recommendation required
  • encouraging residency programs to develop alternate means of conveying information about their curriculum.

In addition, these statements provide timing on when programs should release interview offers and when to begin interviews. Finally, programs are required to commit to online interviews and virtual visits for all applicants, including local students, rather than in-person interviews.

Here, we focus on identifying apps that students can use to help them with the application process—apps for the nuts and bolts of applying and interviewing and apps to learn more about individual programs.

Students must use the Electronic Residency Application Service (ERAS) platform from AAMC to enter their information and register with the National Resident Matching Program (NRMP). Students also must use the ERAS to submit their applications to their selected residency programs. The ERAS platform does not include an app to aid in the completion or submission of an application. The NRMP has developed the MATCH PRISM app, but this does not allow students to register for the match or submit their rank list. To learn about how to schedule interviews, residency programs may use one of the following sources: ERAS, Interview Broker, or Thalamus. Moreover, APGO/CREOG has partnered with Thalamus for the upcoming application cycle, which provides residency programs and applicants tools for application management, interview scheduling, and itinerary building. Thalamus offers a free app.

This year offers some unique challenges. The application process for ObGyn residencies is likely to be more competitive, and students face the added stress of having to navigate the interview season:

  • without away rotations (audition interviews)
  • without in-person visits of the city/hospital/program or social events before or after interview day
  • with an all-virtual interview day.

Continue to: To find information on individual residency programs...

 

 

To find information on individual residency programs, the APGO website lists the FREIDA and APGO Residency Directories, which are not apps. Students are also aware of the Doximity Residency Navigator, which does include an app. The NRMP MATCH PRISM app is another resource, as it provides students with a directory of residency programs and information about each program.

The American College of Obstetricians and Gynecologists (ACOG) recognizes that residency program websites and social media will be crucial in helping applicants learn about individual programs, faculty, and residents. As such, ACOG hosted a Virtual Residency Showcase in September 2020 in which programs posted content on Instagram and Twitter using the hashtag #ACOG-ResWeek20.2 Similarly, APGO and CREOG produced a report containing a social media directory, which lists individual residency programs and whether or not they have a social media handle/account.3 In a recent webinar,4 Drs. Sarah Santiago and Elizabeth Southworth noted that the number of residency programs that have an Instagram account more than doubled (from 60 to 128) between May and September 2020.



We present 2 tables describing the important features and caveats of apps available to students to assist them with residency applications this year—TABLE 1 summarizes apps to aid with applications and interviews; TABLE 2 lists apps designed for students to learn more about individual residency programs. We wish all of this year’s students every success in their search for the right program. ●

References
  1. Association of Professors of Gynecology and Obstetrics, Council on Resident Education in ObGyn. Updated APGO and CREOG Residency Application Response to COVID-19. https://www.apgo.org/wp-content/uploads/2020/05 /Updated-APGO-CREOG-Residency-Response-to -COVID-19-.pdf. Accessed October 27, 2020.
  2. https://www.acog.org/education-and-events/webinars /virtual-residency-showcase. Accessed October 4, 2020.
  3. Social media directory-ObGyn. https://docs.google.com /spreadsheets/d/e/2PACX-1vQ6boyn7FWV9tEhfQp1o3 XJgNIPNBQ3qCYf4IpV-rOPcd212J-HNR84p0r85nXrAz MvOmcNlgjywDP/pubhtml?gid=1472916499&single =true. Accessed October 27, 2020.
  4. APGO webinar: Virtual interviews best practices. September 9, 2020. https://zoom.us/rec/play/KqxMT6Wnb F6qaMnFMoer_czOszRGRT89o364GHDzhFpjXodgSyGZpj 0BaCvKnXtxD7IH-u1IU4QIzHBT.etDUC4znlfNcgG7T?start Time=1599696020000. Accessed October 4, 2020.
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Author and Disclosure Information

Dr. Nentin is Program Director and Assistant Professor of Obstetrics, Gynecology, and Reproductive Science, Icahn School of Medicine at Mount Sinai, New York, New York.

Dr. Chen is Vice-Chair of Ob-Gyn Education for the Mount Sinai Health System and Professor of Obstetrics, Gynecology, and Reproductive Science and Medical Education, Icahn School of Medicine at Mount Sinai. She is an OBG Management Contributing Editor.

Dr. Nentin reports no financial relationships relevant to this article. Dr. Chen reports being an advisory board member for and receiving royalties from UpToDate, Inc.

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Dr. Nentin is Program Director and Assistant Professor of Obstetrics, Gynecology, and Reproductive Science, Icahn School of Medicine at Mount Sinai, New York, New York.

Dr. Chen is Vice-Chair of Ob-Gyn Education for the Mount Sinai Health System and Professor of Obstetrics, Gynecology, and Reproductive Science and Medical Education, Icahn School of Medicine at Mount Sinai. She is an OBG Management Contributing Editor.

Dr. Nentin reports no financial relationships relevant to this article. Dr. Chen reports being an advisory board member for and receiving royalties from UpToDate, Inc.

Author and Disclosure Information

Dr. Nentin is Program Director and Assistant Professor of Obstetrics, Gynecology, and Reproductive Science, Icahn School of Medicine at Mount Sinai, New York, New York.

Dr. Chen is Vice-Chair of Ob-Gyn Education for the Mount Sinai Health System and Professor of Obstetrics, Gynecology, and Reproductive Science and Medical Education, Icahn School of Medicine at Mount Sinai. She is an OBG Management Contributing Editor.

Dr. Nentin reports no financial relationships relevant to this article. Dr. Chen reports being an advisory board member for and receiving royalties from UpToDate, Inc.

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The coronavirus disease 2019 (COVID-19) pandemic has upended the traditional 2020–2021 application season for ObGyn residency programs. In May 2020, the 2 national ObGyn education organizations, the Association of Professors of Gynecology and Obstetrics (APGO) and Council on Resident Education in ObGyn (CREOG), issued guidelines to ensure a fair and equitable application process.1 These guidelines are consistent with recommendations from the Association of American Medical Colleges (AAMC) and the Coalition for Physician Accountability. Important recommendations include:

  • limiting away rotations
  • being flexible in the number of specialty-specific letters of recommendation required
  • encouraging residency programs to develop alternate means of conveying information about their curriculum.

In addition, these statements provide timing on when programs should release interview offers and when to begin interviews. Finally, programs are required to commit to online interviews and virtual visits for all applicants, including local students, rather than in-person interviews.

Here, we focus on identifying apps that students can use to help them with the application process—apps for the nuts and bolts of applying and interviewing and apps to learn more about individual programs.

Students must use the Electronic Residency Application Service (ERAS) platform from AAMC to enter their information and register with the National Resident Matching Program (NRMP). Students also must use the ERAS to submit their applications to their selected residency programs. The ERAS platform does not include an app to aid in the completion or submission of an application. The NRMP has developed the MATCH PRISM app, but this does not allow students to register for the match or submit their rank list. To learn about how to schedule interviews, residency programs may use one of the following sources: ERAS, Interview Broker, or Thalamus. Moreover, APGO/CREOG has partnered with Thalamus for the upcoming application cycle, which provides residency programs and applicants tools for application management, interview scheduling, and itinerary building. Thalamus offers a free app.

This year offers some unique challenges. The application process for ObGyn residencies is likely to be more competitive, and students face the added stress of having to navigate the interview season:

  • without away rotations (audition interviews)
  • without in-person visits of the city/hospital/program or social events before or after interview day
  • with an all-virtual interview day.

Continue to: To find information on individual residency programs...

 

 

To find information on individual residency programs, the APGO website lists the FREIDA and APGO Residency Directories, which are not apps. Students are also aware of the Doximity Residency Navigator, which does include an app. The NRMP MATCH PRISM app is another resource, as it provides students with a directory of residency programs and information about each program.

The American College of Obstetricians and Gynecologists (ACOG) recognizes that residency program websites and social media will be crucial in helping applicants learn about individual programs, faculty, and residents. As such, ACOG hosted a Virtual Residency Showcase in September 2020 in which programs posted content on Instagram and Twitter using the hashtag #ACOG-ResWeek20.2 Similarly, APGO and CREOG produced a report containing a social media directory, which lists individual residency programs and whether or not they have a social media handle/account.3 In a recent webinar,4 Drs. Sarah Santiago and Elizabeth Southworth noted that the number of residency programs that have an Instagram account more than doubled (from 60 to 128) between May and September 2020.



We present 2 tables describing the important features and caveats of apps available to students to assist them with residency applications this year—TABLE 1 summarizes apps to aid with applications and interviews; TABLE 2 lists apps designed for students to learn more about individual residency programs. We wish all of this year’s students every success in their search for the right program. ●

 

The coronavirus disease 2019 (COVID-19) pandemic has upended the traditional 2020–2021 application season for ObGyn residency programs. In May 2020, the 2 national ObGyn education organizations, the Association of Professors of Gynecology and Obstetrics (APGO) and Council on Resident Education in ObGyn (CREOG), issued guidelines to ensure a fair and equitable application process.1 These guidelines are consistent with recommendations from the Association of American Medical Colleges (AAMC) and the Coalition for Physician Accountability. Important recommendations include:

  • limiting away rotations
  • being flexible in the number of specialty-specific letters of recommendation required
  • encouraging residency programs to develop alternate means of conveying information about their curriculum.

In addition, these statements provide timing on when programs should release interview offers and when to begin interviews. Finally, programs are required to commit to online interviews and virtual visits for all applicants, including local students, rather than in-person interviews.

Here, we focus on identifying apps that students can use to help them with the application process—apps for the nuts and bolts of applying and interviewing and apps to learn more about individual programs.

Students must use the Electronic Residency Application Service (ERAS) platform from AAMC to enter their information and register with the National Resident Matching Program (NRMP). Students also must use the ERAS to submit their applications to their selected residency programs. The ERAS platform does not include an app to aid in the completion or submission of an application. The NRMP has developed the MATCH PRISM app, but this does not allow students to register for the match or submit their rank list. To learn about how to schedule interviews, residency programs may use one of the following sources: ERAS, Interview Broker, or Thalamus. Moreover, APGO/CREOG has partnered with Thalamus for the upcoming application cycle, which provides residency programs and applicants tools for application management, interview scheduling, and itinerary building. Thalamus offers a free app.

This year offers some unique challenges. The application process for ObGyn residencies is likely to be more competitive, and students face the added stress of having to navigate the interview season:

  • without away rotations (audition interviews)
  • without in-person visits of the city/hospital/program or social events before or after interview day
  • with an all-virtual interview day.

Continue to: To find information on individual residency programs...

 

 

To find information on individual residency programs, the APGO website lists the FREIDA and APGO Residency Directories, which are not apps. Students are also aware of the Doximity Residency Navigator, which does include an app. The NRMP MATCH PRISM app is another resource, as it provides students with a directory of residency programs and information about each program.

The American College of Obstetricians and Gynecologists (ACOG) recognizes that residency program websites and social media will be crucial in helping applicants learn about individual programs, faculty, and residents. As such, ACOG hosted a Virtual Residency Showcase in September 2020 in which programs posted content on Instagram and Twitter using the hashtag #ACOG-ResWeek20.2 Similarly, APGO and CREOG produced a report containing a social media directory, which lists individual residency programs and whether or not they have a social media handle/account.3 In a recent webinar,4 Drs. Sarah Santiago and Elizabeth Southworth noted that the number of residency programs that have an Instagram account more than doubled (from 60 to 128) between May and September 2020.



We present 2 tables describing the important features and caveats of apps available to students to assist them with residency applications this year—TABLE 1 summarizes apps to aid with applications and interviews; TABLE 2 lists apps designed for students to learn more about individual residency programs. We wish all of this year’s students every success in their search for the right program. ●

References
  1. Association of Professors of Gynecology and Obstetrics, Council on Resident Education in ObGyn. Updated APGO and CREOG Residency Application Response to COVID-19. https://www.apgo.org/wp-content/uploads/2020/05 /Updated-APGO-CREOG-Residency-Response-to -COVID-19-.pdf. Accessed October 27, 2020.
  2. https://www.acog.org/education-and-events/webinars /virtual-residency-showcase. Accessed October 4, 2020.
  3. Social media directory-ObGyn. https://docs.google.com /spreadsheets/d/e/2PACX-1vQ6boyn7FWV9tEhfQp1o3 XJgNIPNBQ3qCYf4IpV-rOPcd212J-HNR84p0r85nXrAz MvOmcNlgjywDP/pubhtml?gid=1472916499&single =true. Accessed October 27, 2020.
  4. APGO webinar: Virtual interviews best practices. September 9, 2020. https://zoom.us/rec/play/KqxMT6Wnb F6qaMnFMoer_czOszRGRT89o364GHDzhFpjXodgSyGZpj 0BaCvKnXtxD7IH-u1IU4QIzHBT.etDUC4znlfNcgG7T?start Time=1599696020000. Accessed October 4, 2020.
References
  1. Association of Professors of Gynecology and Obstetrics, Council on Resident Education in ObGyn. Updated APGO and CREOG Residency Application Response to COVID-19. https://www.apgo.org/wp-content/uploads/2020/05 /Updated-APGO-CREOG-Residency-Response-to -COVID-19-.pdf. Accessed October 27, 2020.
  2. https://www.acog.org/education-and-events/webinars /virtual-residency-showcase. Accessed October 4, 2020.
  3. Social media directory-ObGyn. https://docs.google.com /spreadsheets/d/e/2PACX-1vQ6boyn7FWV9tEhfQp1o3 XJgNIPNBQ3qCYf4IpV-rOPcd212J-HNR84p0r85nXrAz MvOmcNlgjywDP/pubhtml?gid=1472916499&single =true. Accessed October 27, 2020.
  4. APGO webinar: Virtual interviews best practices. September 9, 2020. https://zoom.us/rec/play/KqxMT6Wnb F6qaMnFMoer_czOszRGRT89o364GHDzhFpjXodgSyGZpj 0BaCvKnXtxD7IH-u1IU4QIzHBT.etDUC4znlfNcgG7T?start Time=1599696020000. Accessed October 4, 2020.
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Safety and efficiency in the laparoscopic hysterectomy: Techniques to optimize the surgical approach

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Safety and efficiency in the laparoscopic hysterectomy: Techniques to optimize the surgical approach
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Dr. Lauer is Fellow in Minimally Invasive Gynecologic Surgery, Columbia University, New York, New York.

Dr. Kim is Assistant Professor, Department of Obstetrics and Gynecology, Division of Gynecologic Specialty Surgery, Columbia University, New York, New York.

Dr. Advincula is Levine Family Professor of Women’s Health; Vice-Chair, Department of Obstetrics and Gynecology; and Chief of Gynecologic Specialty Surgery, Columbia University Medical Center, New York, New York.

Dr. Advincula reports serving as a consultant to AbbVie, Baxter, ConMed, CooperSurgical, Eximis Surgical, Titan Medical, and Intuitive Surgical; on the surgeon advisory boards of ConMed and Titan Medical; and receiving royalties from CooperSurgical. Dr. Kim reports serving as a consultant to Empress Medical. Dr. Lauer reports no financial relationships relevant to this video.

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Dr. Advincula is Levine Family Professor of Women’s Health; Vice-Chair, Department of Obstetrics and Gynecology; and Chief of Gynecologic Specialty Surgery, Columbia University Medical Center, New York, New York.

Dr. Advincula reports serving as a consultant to AbbVie, Baxter, ConMed, CooperSurgical, Eximis Surgical, Titan Medical, and Intuitive Surgical; on the surgeon advisory boards of ConMed and Titan Medical; and receiving royalties from CooperSurgical. Dr. Kim reports serving as a consultant to Empress Medical. Dr. Lauer reports no financial relationships relevant to this video.

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Dr. Kim is Assistant Professor, Department of Obstetrics and Gynecology, Division of Gynecologic Specialty Surgery, Columbia University, New York, New York.

Dr. Advincula is Levine Family Professor of Women’s Health; Vice-Chair, Department of Obstetrics and Gynecology; and Chief of Gynecologic Specialty Surgery, Columbia University Medical Center, New York, New York.

Dr. Advincula reports serving as a consultant to AbbVie, Baxter, ConMed, CooperSurgical, Eximis Surgical, Titan Medical, and Intuitive Surgical; on the surgeon advisory boards of ConMed and Titan Medical; and receiving royalties from CooperSurgical. Dr. Kim reports serving as a consultant to Empress Medical. Dr. Lauer reports no financial relationships relevant to this video.

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It’s not time to abandon routine screening mammography in average-risk women in their 40s

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In the 1970s and early 1980s, population-based screening mammography was studied in numerous randomized control trials (RCTs), with the primary outcome of reduced breast cancer mortality. Although technology and the sensitivity of mammography in the 1980s was somewhat rudimentary compared with current screening, a meta-analysis of these RCTs demonstrated a clear mortality benefit for screening mammography.1 As a result, widespread population-based mammography was introduced in the mid-1980s in the United States and has become a standard for breast cancer screening.

Since that time, few RCTs of screening mammography versus observation have been conducted because of the ethical challenges of entering women into such studies as well as the difficulty and expense of long-term follow-up to measure the effect of screening on breast cancer mortality. Without ongoing RCTs of mammography, retrospective, observational, and computer simulation trials of the efficacy and harms of screening mammography have been conducted using proxy measures of mortality (such as stage at diagnosis), and some have questioned the overall benefit of screening mammography.2,3

To further complicate this controversy, some national guidelines have recommended against routinely recommending screening mammography for women aged 40 to 49 based on concerns that the harms (callbacks, benign breast biopsies, overdiagnosis) exceed the potential benefits (earlier diagnosis, possible decrease in needed treatments, reduced breast cancer mortality).4 This has resulted in a confusing morass of national recommendations with uncertainty regarding the question of whether to routinely offer screening mammography for women in their 40s at average risk for breast cancer.4-6

Recently, to address this question Duffy and colleagues conducted a large RCT of women in their 40s to evaluate the long-term effect of mammography on breast cancer mortality.7 Here, I review the study in depth and offer some guidance to clinicians and women struggling with screening decisions.

Breast cancer mortality significantly lower in the screening group

The RCT, known as the UK Age trial, was conducted in England, Wales, and Scotland and enrolled 160,921 women from 1990 through 1997.7 Women were randomly assigned in a 2:1 ratio to observation or annual screening mammogram beginning at age 39–41 until age 48. (In the United Kingdom, all women are screened starting at age 50.) Study enrollees were followed for a median of 22.8 years, and the primary outcome was breast cancer mortality.

The study results showed a 25% relative risk (RR) reduction in breast cancer mortality at 10 years of follow-up in the mammography group compared with the unscreened women (83 breast cancer deaths in the mammography group vs 219 in the observation group [RR, 0.75; 95% confidence interval (CI), 0.58–0.97; P = .029]). Based on the prevalence of breast cancer in women in their 40s, this 25% relative risk reduction translates into approximately 1 less death per 1,000 women who undergo routine screening in their 40s.

While there was no additional significant mortality reduction beyond 10 years of follow-up, as noted mammography is offered routinely starting at age 50 to all women in the United Kingdom. The authors concluded that “reducing the lower age limit for screening from 50 to 40 years [of age] could potentially reduce breast cancer mortality.”

Was overdiagnosis a concern? Another finding in this trial was related to overdiagnosis of breast cancer in the screened group. Overdiagnosis refers to mammographic-only diagnosis (that is, no clinical findings) of nonaggressive breast cancer, which would remain indolent and not harm the patient. The study results demonstrated essentially no overdiagnosis in women screened at age 40 compared with the unscreened group.

Continue to: Large trial, long follow-up are key strengths...

 

 

Large trial, long follow-up are key strengths

The UK Age trial’s primary strength is its study design: a large population-based RCT that included diverse participants with the critical study outcome for cancer screening (mortality). The study’s long-term follow-up is another key strength, since breast cancer mortality typically occurs 7 to 10 years after diagnosis. In addition, results were available for 99.9% of the women enrolled in the trial (that is, only 0.1% of women were lost to follow-up). Interestingly, the demonstrated mortality reduction with screening mammography for women in their 40s validates the mortality benefit demonstrated in other large RCTs of women in their 40s.1

Another strong point is that the study addresses the issue of whether screening women in their 40s results in overdiagnosis compared with women who start screening in their 50s. Further, this study validates a prior observational study that mammographic findings of nonprogressive cancers do not disappear, so nonaggressive cancers that present on mammography in women in their 40s still would be detected when women start screening in their 50s.8

Study limitations should be noted

The study has several limitations. For example, significant improvements have been made in breast cancer treatments that may mitigate against the positive impact of screening mammography. The impact of changed breast cancer management over the past 20 years could not be addressed with this study’s design since women would have been treated in the 1990s. In addition, substantial improvements have occurred in breast cancer screening standards (2 views vs the single view used in the study) and technology since the 1990s. Current mammography includes nearly uniform use of either digital mammography (DM) or digital breast tomosynthesis (DBT), both of which improve breast cancer detection for women in their 40s compared with the older film-screen technology. In addition, DBT reduces false-positive results by approximately 40%, resulting in fewer callbacks and biopsies. While improved cancer detection and reduced false-positive results are seen with DM and DBT, whether these technology improvements result in improved breast cancer mortality has not yet been sufficiently studied.

Perhaps the most important limitation in this study is that the women did not undergo routine risk assessment before trial entry to assure that they all were at “average risk.” As a result, both high- and average-risk women would have been included in this population-based trial. Without risk stratification, it remains uncertain whether the reduction in breast cancer mortality disproportionately exists within a high-risk subgroup (such as breast cancer gene mutation carriers).

Finally, the cost efficacy of routine screening mammography for women in their 40s was not evaluated in this study.

The UK Age trial in perspective

The good news is that there is the clear evidence that breast cancer mortality rates (deaths per 100,000) have decreased by about 40% over the past 50 years, likely due to improvements in breast cancer treatment and routine screening mammography.9 Breast cancer mortality reduction is particularly important because breast cancer remains the most common cancer and is the second leading cause of cancer death in women in the United States. In the past decade, considerable debate has arisen arguing whether this reduction in breast cancer mortality is due to improved treatments, routine screening mammography, or both. Authors of a retrospective trial in Australia, recently reviewed in OBG Management, suggested that the majority of improvement is due to improvements in treatment.3,10 However, as the authors pointed out, due to the trial’s retrospective design, causality only can be inferred. The current UK Age trial does add to the numerous prospective trials demonstrating mortality benefit for mammography in women in their 40s.11

What remains a challenge for clinicians, and for women struggling with the mammography question, is the absence of risk assessment in these long-term RCT trials as well as in the large retrospective database studies. Without risk stratification, these studies treated all the study population as “average risk.” Because breast cancer risk assessment is sporadically performed in clinical practice and there are no published RCTs of screening mammography in risk-assessed “average risk” women in their 40s, it remains uncertain whether the women benefiting from screening in their 40s are in a high-risk group or whether women of average risk in this age group also are benefiting from routine screening mammography.

Continue to: What’s next: Incorporate routine risk assessment into clinical practice...

 

 

What’s next: Incorporate routine risk assessment into clinical practice

It is not time to abandon screening mammography for all women in their 40s. Rather, routine risk assessment should be performed using one of many available validated or widely tested tools, a recommendation supported by the American College of Obstetricians and Gynecologists, the National Comprehensive Cancer Network, and the US Preventive Services Task Force.5,6,12

Ideally, these tools can be incorporated into an electronic health record and prepopulated using already available patient data (such as age, reproductive risk factors, current medications, breast density if available, and family history). Prepopulating available data into breast cancer risk calculators would allow clinicians to spend time on counseling women regarding breast cancer risk and appropriate screening methods. The TABLE provides a summary of useful breast cancer risk calculators and includes comments about their utility and significant limitations and benefits. In addition to breast cancer risk, the more comprehensive risk calculators (Tyrer-Cuzick and BOADICEA) allow calculation of ovarian cancer risk and gene mutation risk.



Routinely performing breast cancer risk assessment can guide discussions of screening mammography and can provide data for conducting a more individualized discussion on cancer genetic counseling and testing, risk reduction methods in high-risk women, and possible use of intensive breast cancer screening tools in identified high-risk women.

Ultimately, debating the question of whether all women should have routine breast cancer screening in their 40s should be passé. Ideally, all women should undergo breast cancer risk assessment in their 20s. Risk assessment results can then be used to guide the discussion of multiple potential interventions for women in their 40s (or earlier if appropriate), including routine screening mammography, cancer genetic counseling and testing in appropriate individuals, and intervention for women who are identified at high risk.

Absent breast cancer risk assessment, screening mammography still should be offered to women in their 40s, and the decision to proceed should be based on a discussion of risks, benefits, and the value the patient places on these factors.●

References
  1. Nelson HD, Fu R, Cantor A, et al. Effectiveness of breast cancer screening: systematic review and meta-analysis to update the 2009 US Preventive Services Task Force recommendation. Ann Intern Med. 2016;164:244-255.
  2. Bleyer A, Welch HG. Effect of three decades of screening mammography on breast-cancer incidence. N Engl J Med. 2012;367:1998-2005.
  3. Burton R, Stevenson C. Assessment of breast cancer mortality trends associated with mammographic screening and adjuvant therapy from 1986 to 2013 in the state of Victoria, Australia. JAMA Netw Open. 2020;3:e208249-e.
  4. Nelson HD, Cantor A, Humphrey L, et al. A systematic review to update the 2009 US Preventive Services Task Force recommendation. Evidence syntheses No. 124. AHRQ Publication No. 14-05201-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2016.
  5. Bevers TB, Helvie M, Bonaccio E, et al. Breast cancer screening and diagnosis, version 3.2018, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2018;16:1362-1389.
  6. ACOG Committee on Practice Bulletins–Gynecology. Breast cancer risk assessment and screening in average-risk women. Obstet Gynecol. 2017;130:e1-e16.
  7. Duffy SW, Vulkan D, Cuckle H, et al. Effect of mammographic screening from age 40 years on breast cancer mortality (UK Age trial): final results of a randomised, controlled trial. Lancet Oncol. 2020;21:1165-1172.
  8. Arleo EK, Monticciolo DL, Monsees B, et al. Persistent untreated screening-detected breast cancer: an argument against delaying screening or increasing the interval between screenings. J Am Coll Radiol. 2017;14:863-867.
  9. DeSantis CE, Ma J, Gaudet MM, et al. Breast cancer statistics, 2019. CA Cancer J Clin. 2019;69:438-451.
  10. Kaunitz AM. How effective is screening mammography for preventing breast cancer mortality? OBG Manag. 2020;32(8):17,49.
  11. Oeffinger KC, Fontham ET, Etzioni R, et al; American Cancer Society. Breast cancer screening for women at average risk: 2015 guideline update from the American Cancer Society. JAMA. 2015;314:1599-1614.
  12. US Preventive Services Task Force; Owens DK, Davidson KW, Krist AH, et al. Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer: US Preventive Services Task Force recommendation statement. JAMA. 2019;322:652-665.
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Professor Emeritus (Active), Department of Surgery

Michigan Medicine

Ann Arbor, Michigan

The author reports no financial relationships relevant to this article.

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Mark D. Pearlman, MD

Professor Emeritus (Active), Department of Obstetrics and Gynecology

Professor Emeritus (Active), Department of Surgery

Michigan Medicine

Ann Arbor, Michigan

The author reports no financial relationships relevant to this article.

In the 1970s and early 1980s, population-based screening mammography was studied in numerous randomized control trials (RCTs), with the primary outcome of reduced breast cancer mortality. Although technology and the sensitivity of mammography in the 1980s was somewhat rudimentary compared with current screening, a meta-analysis of these RCTs demonstrated a clear mortality benefit for screening mammography.1 As a result, widespread population-based mammography was introduced in the mid-1980s in the United States and has become a standard for breast cancer screening.

Since that time, few RCTs of screening mammography versus observation have been conducted because of the ethical challenges of entering women into such studies as well as the difficulty and expense of long-term follow-up to measure the effect of screening on breast cancer mortality. Without ongoing RCTs of mammography, retrospective, observational, and computer simulation trials of the efficacy and harms of screening mammography have been conducted using proxy measures of mortality (such as stage at diagnosis), and some have questioned the overall benefit of screening mammography.2,3

To further complicate this controversy, some national guidelines have recommended against routinely recommending screening mammography for women aged 40 to 49 based on concerns that the harms (callbacks, benign breast biopsies, overdiagnosis) exceed the potential benefits (earlier diagnosis, possible decrease in needed treatments, reduced breast cancer mortality).4 This has resulted in a confusing morass of national recommendations with uncertainty regarding the question of whether to routinely offer screening mammography for women in their 40s at average risk for breast cancer.4-6

Recently, to address this question Duffy and colleagues conducted a large RCT of women in their 40s to evaluate the long-term effect of mammography on breast cancer mortality.7 Here, I review the study in depth and offer some guidance to clinicians and women struggling with screening decisions.

Breast cancer mortality significantly lower in the screening group

The RCT, known as the UK Age trial, was conducted in England, Wales, and Scotland and enrolled 160,921 women from 1990 through 1997.7 Women were randomly assigned in a 2:1 ratio to observation or annual screening mammogram beginning at age 39–41 until age 48. (In the United Kingdom, all women are screened starting at age 50.) Study enrollees were followed for a median of 22.8 years, and the primary outcome was breast cancer mortality.

The study results showed a 25% relative risk (RR) reduction in breast cancer mortality at 10 years of follow-up in the mammography group compared with the unscreened women (83 breast cancer deaths in the mammography group vs 219 in the observation group [RR, 0.75; 95% confidence interval (CI), 0.58–0.97; P = .029]). Based on the prevalence of breast cancer in women in their 40s, this 25% relative risk reduction translates into approximately 1 less death per 1,000 women who undergo routine screening in their 40s.

While there was no additional significant mortality reduction beyond 10 years of follow-up, as noted mammography is offered routinely starting at age 50 to all women in the United Kingdom. The authors concluded that “reducing the lower age limit for screening from 50 to 40 years [of age] could potentially reduce breast cancer mortality.”

Was overdiagnosis a concern? Another finding in this trial was related to overdiagnosis of breast cancer in the screened group. Overdiagnosis refers to mammographic-only diagnosis (that is, no clinical findings) of nonaggressive breast cancer, which would remain indolent and not harm the patient. The study results demonstrated essentially no overdiagnosis in women screened at age 40 compared with the unscreened group.

Continue to: Large trial, long follow-up are key strengths...

 

 

Large trial, long follow-up are key strengths

The UK Age trial’s primary strength is its study design: a large population-based RCT that included diverse participants with the critical study outcome for cancer screening (mortality). The study’s long-term follow-up is another key strength, since breast cancer mortality typically occurs 7 to 10 years after diagnosis. In addition, results were available for 99.9% of the women enrolled in the trial (that is, only 0.1% of women were lost to follow-up). Interestingly, the demonstrated mortality reduction with screening mammography for women in their 40s validates the mortality benefit demonstrated in other large RCTs of women in their 40s.1

Another strong point is that the study addresses the issue of whether screening women in their 40s results in overdiagnosis compared with women who start screening in their 50s. Further, this study validates a prior observational study that mammographic findings of nonprogressive cancers do not disappear, so nonaggressive cancers that present on mammography in women in their 40s still would be detected when women start screening in their 50s.8

Study limitations should be noted

The study has several limitations. For example, significant improvements have been made in breast cancer treatments that may mitigate against the positive impact of screening mammography. The impact of changed breast cancer management over the past 20 years could not be addressed with this study’s design since women would have been treated in the 1990s. In addition, substantial improvements have occurred in breast cancer screening standards (2 views vs the single view used in the study) and technology since the 1990s. Current mammography includes nearly uniform use of either digital mammography (DM) or digital breast tomosynthesis (DBT), both of which improve breast cancer detection for women in their 40s compared with the older film-screen technology. In addition, DBT reduces false-positive results by approximately 40%, resulting in fewer callbacks and biopsies. While improved cancer detection and reduced false-positive results are seen with DM and DBT, whether these technology improvements result in improved breast cancer mortality has not yet been sufficiently studied.

Perhaps the most important limitation in this study is that the women did not undergo routine risk assessment before trial entry to assure that they all were at “average risk.” As a result, both high- and average-risk women would have been included in this population-based trial. Without risk stratification, it remains uncertain whether the reduction in breast cancer mortality disproportionately exists within a high-risk subgroup (such as breast cancer gene mutation carriers).

Finally, the cost efficacy of routine screening mammography for women in their 40s was not evaluated in this study.

The UK Age trial in perspective

The good news is that there is the clear evidence that breast cancer mortality rates (deaths per 100,000) have decreased by about 40% over the past 50 years, likely due to improvements in breast cancer treatment and routine screening mammography.9 Breast cancer mortality reduction is particularly important because breast cancer remains the most common cancer and is the second leading cause of cancer death in women in the United States. In the past decade, considerable debate has arisen arguing whether this reduction in breast cancer mortality is due to improved treatments, routine screening mammography, or both. Authors of a retrospective trial in Australia, recently reviewed in OBG Management, suggested that the majority of improvement is due to improvements in treatment.3,10 However, as the authors pointed out, due to the trial’s retrospective design, causality only can be inferred. The current UK Age trial does add to the numerous prospective trials demonstrating mortality benefit for mammography in women in their 40s.11

What remains a challenge for clinicians, and for women struggling with the mammography question, is the absence of risk assessment in these long-term RCT trials as well as in the large retrospective database studies. Without risk stratification, these studies treated all the study population as “average risk.” Because breast cancer risk assessment is sporadically performed in clinical practice and there are no published RCTs of screening mammography in risk-assessed “average risk” women in their 40s, it remains uncertain whether the women benefiting from screening in their 40s are in a high-risk group or whether women of average risk in this age group also are benefiting from routine screening mammography.

Continue to: What’s next: Incorporate routine risk assessment into clinical practice...

 

 

What’s next: Incorporate routine risk assessment into clinical practice

It is not time to abandon screening mammography for all women in their 40s. Rather, routine risk assessment should be performed using one of many available validated or widely tested tools, a recommendation supported by the American College of Obstetricians and Gynecologists, the National Comprehensive Cancer Network, and the US Preventive Services Task Force.5,6,12

Ideally, these tools can be incorporated into an electronic health record and prepopulated using already available patient data (such as age, reproductive risk factors, current medications, breast density if available, and family history). Prepopulating available data into breast cancer risk calculators would allow clinicians to spend time on counseling women regarding breast cancer risk and appropriate screening methods. The TABLE provides a summary of useful breast cancer risk calculators and includes comments about their utility and significant limitations and benefits. In addition to breast cancer risk, the more comprehensive risk calculators (Tyrer-Cuzick and BOADICEA) allow calculation of ovarian cancer risk and gene mutation risk.



Routinely performing breast cancer risk assessment can guide discussions of screening mammography and can provide data for conducting a more individualized discussion on cancer genetic counseling and testing, risk reduction methods in high-risk women, and possible use of intensive breast cancer screening tools in identified high-risk women.

Ultimately, debating the question of whether all women should have routine breast cancer screening in their 40s should be passé. Ideally, all women should undergo breast cancer risk assessment in their 20s. Risk assessment results can then be used to guide the discussion of multiple potential interventions for women in their 40s (or earlier if appropriate), including routine screening mammography, cancer genetic counseling and testing in appropriate individuals, and intervention for women who are identified at high risk.

Absent breast cancer risk assessment, screening mammography still should be offered to women in their 40s, and the decision to proceed should be based on a discussion of risks, benefits, and the value the patient places on these factors.●

In the 1970s and early 1980s, population-based screening mammography was studied in numerous randomized control trials (RCTs), with the primary outcome of reduced breast cancer mortality. Although technology and the sensitivity of mammography in the 1980s was somewhat rudimentary compared with current screening, a meta-analysis of these RCTs demonstrated a clear mortality benefit for screening mammography.1 As a result, widespread population-based mammography was introduced in the mid-1980s in the United States and has become a standard for breast cancer screening.

Since that time, few RCTs of screening mammography versus observation have been conducted because of the ethical challenges of entering women into such studies as well as the difficulty and expense of long-term follow-up to measure the effect of screening on breast cancer mortality. Without ongoing RCTs of mammography, retrospective, observational, and computer simulation trials of the efficacy and harms of screening mammography have been conducted using proxy measures of mortality (such as stage at diagnosis), and some have questioned the overall benefit of screening mammography.2,3

To further complicate this controversy, some national guidelines have recommended against routinely recommending screening mammography for women aged 40 to 49 based on concerns that the harms (callbacks, benign breast biopsies, overdiagnosis) exceed the potential benefits (earlier diagnosis, possible decrease in needed treatments, reduced breast cancer mortality).4 This has resulted in a confusing morass of national recommendations with uncertainty regarding the question of whether to routinely offer screening mammography for women in their 40s at average risk for breast cancer.4-6

Recently, to address this question Duffy and colleagues conducted a large RCT of women in their 40s to evaluate the long-term effect of mammography on breast cancer mortality.7 Here, I review the study in depth and offer some guidance to clinicians and women struggling with screening decisions.

Breast cancer mortality significantly lower in the screening group

The RCT, known as the UK Age trial, was conducted in England, Wales, and Scotland and enrolled 160,921 women from 1990 through 1997.7 Women were randomly assigned in a 2:1 ratio to observation or annual screening mammogram beginning at age 39–41 until age 48. (In the United Kingdom, all women are screened starting at age 50.) Study enrollees were followed for a median of 22.8 years, and the primary outcome was breast cancer mortality.

The study results showed a 25% relative risk (RR) reduction in breast cancer mortality at 10 years of follow-up in the mammography group compared with the unscreened women (83 breast cancer deaths in the mammography group vs 219 in the observation group [RR, 0.75; 95% confidence interval (CI), 0.58–0.97; P = .029]). Based on the prevalence of breast cancer in women in their 40s, this 25% relative risk reduction translates into approximately 1 less death per 1,000 women who undergo routine screening in their 40s.

While there was no additional significant mortality reduction beyond 10 years of follow-up, as noted mammography is offered routinely starting at age 50 to all women in the United Kingdom. The authors concluded that “reducing the lower age limit for screening from 50 to 40 years [of age] could potentially reduce breast cancer mortality.”

Was overdiagnosis a concern? Another finding in this trial was related to overdiagnosis of breast cancer in the screened group. Overdiagnosis refers to mammographic-only diagnosis (that is, no clinical findings) of nonaggressive breast cancer, which would remain indolent and not harm the patient. The study results demonstrated essentially no overdiagnosis in women screened at age 40 compared with the unscreened group.

Continue to: Large trial, long follow-up are key strengths...

 

 

Large trial, long follow-up are key strengths

The UK Age trial’s primary strength is its study design: a large population-based RCT that included diverse participants with the critical study outcome for cancer screening (mortality). The study’s long-term follow-up is another key strength, since breast cancer mortality typically occurs 7 to 10 years after diagnosis. In addition, results were available for 99.9% of the women enrolled in the trial (that is, only 0.1% of women were lost to follow-up). Interestingly, the demonstrated mortality reduction with screening mammography for women in their 40s validates the mortality benefit demonstrated in other large RCTs of women in their 40s.1

Another strong point is that the study addresses the issue of whether screening women in their 40s results in overdiagnosis compared with women who start screening in their 50s. Further, this study validates a prior observational study that mammographic findings of nonprogressive cancers do not disappear, so nonaggressive cancers that present on mammography in women in their 40s still would be detected when women start screening in their 50s.8

Study limitations should be noted

The study has several limitations. For example, significant improvements have been made in breast cancer treatments that may mitigate against the positive impact of screening mammography. The impact of changed breast cancer management over the past 20 years could not be addressed with this study’s design since women would have been treated in the 1990s. In addition, substantial improvements have occurred in breast cancer screening standards (2 views vs the single view used in the study) and technology since the 1990s. Current mammography includes nearly uniform use of either digital mammography (DM) or digital breast tomosynthesis (DBT), both of which improve breast cancer detection for women in their 40s compared with the older film-screen technology. In addition, DBT reduces false-positive results by approximately 40%, resulting in fewer callbacks and biopsies. While improved cancer detection and reduced false-positive results are seen with DM and DBT, whether these technology improvements result in improved breast cancer mortality has not yet been sufficiently studied.

Perhaps the most important limitation in this study is that the women did not undergo routine risk assessment before trial entry to assure that they all were at “average risk.” As a result, both high- and average-risk women would have been included in this population-based trial. Without risk stratification, it remains uncertain whether the reduction in breast cancer mortality disproportionately exists within a high-risk subgroup (such as breast cancer gene mutation carriers).

Finally, the cost efficacy of routine screening mammography for women in their 40s was not evaluated in this study.

The UK Age trial in perspective

The good news is that there is the clear evidence that breast cancer mortality rates (deaths per 100,000) have decreased by about 40% over the past 50 years, likely due to improvements in breast cancer treatment and routine screening mammography.9 Breast cancer mortality reduction is particularly important because breast cancer remains the most common cancer and is the second leading cause of cancer death in women in the United States. In the past decade, considerable debate has arisen arguing whether this reduction in breast cancer mortality is due to improved treatments, routine screening mammography, or both. Authors of a retrospective trial in Australia, recently reviewed in OBG Management, suggested that the majority of improvement is due to improvements in treatment.3,10 However, as the authors pointed out, due to the trial’s retrospective design, causality only can be inferred. The current UK Age trial does add to the numerous prospective trials demonstrating mortality benefit for mammography in women in their 40s.11

What remains a challenge for clinicians, and for women struggling with the mammography question, is the absence of risk assessment in these long-term RCT trials as well as in the large retrospective database studies. Without risk stratification, these studies treated all the study population as “average risk.” Because breast cancer risk assessment is sporadically performed in clinical practice and there are no published RCTs of screening mammography in risk-assessed “average risk” women in their 40s, it remains uncertain whether the women benefiting from screening in their 40s are in a high-risk group or whether women of average risk in this age group also are benefiting from routine screening mammography.

Continue to: What’s next: Incorporate routine risk assessment into clinical practice...

 

 

What’s next: Incorporate routine risk assessment into clinical practice

It is not time to abandon screening mammography for all women in their 40s. Rather, routine risk assessment should be performed using one of many available validated or widely tested tools, a recommendation supported by the American College of Obstetricians and Gynecologists, the National Comprehensive Cancer Network, and the US Preventive Services Task Force.5,6,12

Ideally, these tools can be incorporated into an electronic health record and prepopulated using already available patient data (such as age, reproductive risk factors, current medications, breast density if available, and family history). Prepopulating available data into breast cancer risk calculators would allow clinicians to spend time on counseling women regarding breast cancer risk and appropriate screening methods. The TABLE provides a summary of useful breast cancer risk calculators and includes comments about their utility and significant limitations and benefits. In addition to breast cancer risk, the more comprehensive risk calculators (Tyrer-Cuzick and BOADICEA) allow calculation of ovarian cancer risk and gene mutation risk.



Routinely performing breast cancer risk assessment can guide discussions of screening mammography and can provide data for conducting a more individualized discussion on cancer genetic counseling and testing, risk reduction methods in high-risk women, and possible use of intensive breast cancer screening tools in identified high-risk women.

Ultimately, debating the question of whether all women should have routine breast cancer screening in their 40s should be passé. Ideally, all women should undergo breast cancer risk assessment in their 20s. Risk assessment results can then be used to guide the discussion of multiple potential interventions for women in their 40s (or earlier if appropriate), including routine screening mammography, cancer genetic counseling and testing in appropriate individuals, and intervention for women who are identified at high risk.

Absent breast cancer risk assessment, screening mammography still should be offered to women in their 40s, and the decision to proceed should be based on a discussion of risks, benefits, and the value the patient places on these factors.●

References
  1. Nelson HD, Fu R, Cantor A, et al. Effectiveness of breast cancer screening: systematic review and meta-analysis to update the 2009 US Preventive Services Task Force recommendation. Ann Intern Med. 2016;164:244-255.
  2. Bleyer A, Welch HG. Effect of three decades of screening mammography on breast-cancer incidence. N Engl J Med. 2012;367:1998-2005.
  3. Burton R, Stevenson C. Assessment of breast cancer mortality trends associated with mammographic screening and adjuvant therapy from 1986 to 2013 in the state of Victoria, Australia. JAMA Netw Open. 2020;3:e208249-e.
  4. Nelson HD, Cantor A, Humphrey L, et al. A systematic review to update the 2009 US Preventive Services Task Force recommendation. Evidence syntheses No. 124. AHRQ Publication No. 14-05201-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2016.
  5. Bevers TB, Helvie M, Bonaccio E, et al. Breast cancer screening and diagnosis, version 3.2018, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2018;16:1362-1389.
  6. ACOG Committee on Practice Bulletins–Gynecology. Breast cancer risk assessment and screening in average-risk women. Obstet Gynecol. 2017;130:e1-e16.
  7. Duffy SW, Vulkan D, Cuckle H, et al. Effect of mammographic screening from age 40 years on breast cancer mortality (UK Age trial): final results of a randomised, controlled trial. Lancet Oncol. 2020;21:1165-1172.
  8. Arleo EK, Monticciolo DL, Monsees B, et al. Persistent untreated screening-detected breast cancer: an argument against delaying screening or increasing the interval between screenings. J Am Coll Radiol. 2017;14:863-867.
  9. DeSantis CE, Ma J, Gaudet MM, et al. Breast cancer statistics, 2019. CA Cancer J Clin. 2019;69:438-451.
  10. Kaunitz AM. How effective is screening mammography for preventing breast cancer mortality? OBG Manag. 2020;32(8):17,49.
  11. Oeffinger KC, Fontham ET, Etzioni R, et al; American Cancer Society. Breast cancer screening for women at average risk: 2015 guideline update from the American Cancer Society. JAMA. 2015;314:1599-1614.
  12. US Preventive Services Task Force; Owens DK, Davidson KW, Krist AH, et al. Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer: US Preventive Services Task Force recommendation statement. JAMA. 2019;322:652-665.
References
  1. Nelson HD, Fu R, Cantor A, et al. Effectiveness of breast cancer screening: systematic review and meta-analysis to update the 2009 US Preventive Services Task Force recommendation. Ann Intern Med. 2016;164:244-255.
  2. Bleyer A, Welch HG. Effect of three decades of screening mammography on breast-cancer incidence. N Engl J Med. 2012;367:1998-2005.
  3. Burton R, Stevenson C. Assessment of breast cancer mortality trends associated with mammographic screening and adjuvant therapy from 1986 to 2013 in the state of Victoria, Australia. JAMA Netw Open. 2020;3:e208249-e.
  4. Nelson HD, Cantor A, Humphrey L, et al. A systematic review to update the 2009 US Preventive Services Task Force recommendation. Evidence syntheses No. 124. AHRQ Publication No. 14-05201-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2016.
  5. Bevers TB, Helvie M, Bonaccio E, et al. Breast cancer screening and diagnosis, version 3.2018, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2018;16:1362-1389.
  6. ACOG Committee on Practice Bulletins–Gynecology. Breast cancer risk assessment and screening in average-risk women. Obstet Gynecol. 2017;130:e1-e16.
  7. Duffy SW, Vulkan D, Cuckle H, et al. Effect of mammographic screening from age 40 years on breast cancer mortality (UK Age trial): final results of a randomised, controlled trial. Lancet Oncol. 2020;21:1165-1172.
  8. Arleo EK, Monticciolo DL, Monsees B, et al. Persistent untreated screening-detected breast cancer: an argument against delaying screening or increasing the interval between screenings. J Am Coll Radiol. 2017;14:863-867.
  9. DeSantis CE, Ma J, Gaudet MM, et al. Breast cancer statistics, 2019. CA Cancer J Clin. 2019;69:438-451.
  10. Kaunitz AM. How effective is screening mammography for preventing breast cancer mortality? OBG Manag. 2020;32(8):17,49.
  11. Oeffinger KC, Fontham ET, Etzioni R, et al; American Cancer Society. Breast cancer screening for women at average risk: 2015 guideline update from the American Cancer Society. JAMA. 2015;314:1599-1614.
  12. US Preventive Services Task Force; Owens DK, Davidson KW, Krist AH, et al. Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer: US Preventive Services Task Force recommendation statement. JAMA. 2019;322:652-665.
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