preterm delivery and tocolytics nejm

7/23/2019 Preterm Delivery and Tocolytics NEJM

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DRUG THERAPY

Prevention of Preterm Delivery

Hyagriv N. Simhan, M.D., M.S.C.R., and Steve N. Caritis, M.D.

N Engl Med !""#$ %&#'(##)(*# A+g+st !, !""#D-' "."&/0NEMra"&"(%&

Preterm 1irth is de2ined as 1irth 1e23re the 43m5leti3n 32 %# 6ee7s 32 gestati3n.The 2re8+en4y 32 5reterm 1irth in the United States in4reased 2r3m ".#9 in::! t3 !.%9 in !""%. Preterm 1irths 4an 1e 4ateg3ri;ed as th3se +nderta7en1e4a+se 32 a s5e4i2i4 indi4ati3n 3r as s53ntane3+s 5reterm 1irths. -ndi4ated5reterm 1irths 344+r 6hen a health 4are 5r3vider delivers a 1a1y 1e4a+se 32medi4al 3r 31stetri4al 43m5li4ati3ns that <e35ardi;e the health 32 the m3ther 3rthe 2et+s. S53ntane3+s 5reterm 1irths 344+r as a 43nse8+en4e 32 s53ntane3+s

5reterm la13r 3r 5reterm r+5t+re 32 2etal mem1ranes 1e23re the 3nset 32 la13r.This revie6 234+ses 3n thera5e+ti4 strategies 23r the 5reventi3n and treatment 32s53ntane3+s 5reterm la13r and delivery.MECHANISMS OF PRETERM LABORPreterm 5art+riti3n is n3t ne4essarily the res+lt 32 5remat+re 5hysi3l3gi4a4tivati3n 32 5r34esses that n3rmally 344+r at term$ rather, 5reterm la13r43mm3nly res+lts 2r3m 5ath3l3gi4 5r34esses.!,%Regardless 32 6hen 5art+riti3n344+rs in gestati3n, the 5r34ess itsel2 is generally heralded 1y syn4hr3n3+s4hanges in the my3metri+m and 4ervi= that 5ermit e=5+lsi3n 32 the 2et+s. Them3le4+lar 5r34esses +nderlying 5art+riti3n 6ere re4ently 43m5rehensively

revie6ed 1y Smith in theJournal .(Pathophysiology of Preterm Birth

S53ntane3+s 5reterm 1irth is a 5hysi3l3gi4ally heter3gene3+s syndr3me.% The4as4ade 32 events that 4+lminate in s53ntane3+s 5reterm 1irth has several53ssi1le +nderlying 5ath6ays. >3+r 32 these 5ath6ays are s+553rted 1y a43nsidera1le 13dy 32 4lini4al and e=5erimental eviden4e' e=4essive my3metrialand 2etal mem1rane 3verdistenti3n, de4id+al hem3rrhage, 5re434i3+s 2etalend34rine a4tivati3n, and intra+terine in2e4ti3n 3r in2lammati3n.%,& These5ath6ays may 1e initiated 6ee7s t3 m3nths 1e23re 4lini4ally a55arent 5retermla13r. The 5r34esses leading t3 5reterm 5art+riti3n may 3riginate 2r3m 3ne 3rm3re 32 these 5ath6ays$ 23r e=am5le, intra+terine in2e4ti3n 3r in2lammati3n and5la4ental a1r+5ti3n 32ten 43e=ist in 5reterm 1irths./): De4id+al hem3rrhage andintra+terine in2e4ti3n share several in2lammat3ry m3le4+lar me4hanisms that43ntri1+te t3 5art+riti3n.")! +r +nderstanding 32 the nat+re 32 the m3le4+lar4r3ss)tal7 am3ng these 5ath6ays is in its in2an4y. The eti3l3gi4 heter3geneity 325reterm 1irth adds 43m5le=ity t3 thera5e+ti4 a55r3a4hes. Alth3+gh the +ltimate

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4lini4al 5resentati3n 32 63men 6ith 5reterm la13r may a55ear t3 1eh3m3gene3+s, the ante4edent 43ntri1+ting 2a4t3rs 5r31a1ly di22er 43nsidera1ly2r3m 63man t3 63man.Certain 4lini4al 5resentati3ns and ris7 2a4t3rs 5re2erentially 5redis53se thematernal?2etal +nit t3 5reterm 1irth in a 5ath6ay)s5e4i2i4 2ashi3n. >3r e=am5le,63men 6ith m+lti2etal 5regnan4ies are at 5arti4+lar ris7 23r 5reterm 1irth,5res+ma1ly 36ing t3 5ath3l3gi4 +terine 3verdistenti3n. @3men 6ith 5retermr+5t+re 32 mem1ranes 3r 5reterm la13r at a very early gestati3nal age e.g., !( t3!* 6ee7sB are at in4reased ris7 23r having +nderlying intra+terine in2e4ti3n$ the5re4ise nat+re 32 s+4h 5redis53siti3ns is n3t 7n36n at this time.Diagosis of A!"te Preterm La#or

>3r de4ades, the 4lini4al diagn3sis 32 5reterm la13r has 1een 1ased 3n the5resen4e 32 reg+lar, 5ain2+l +terine 43ntra4ti3ns a443m5anied 1y 4ervi4aldilatati3n 3r e22a4ement. -2 2ramed as s4reening 4riteria 23r the 3+t43me 32

5reterm 1irth, s+4h 2a4t3rs generally dem3nstrate 533r sensitivity ands5e4i2i4ity. The identi2i4ati3n 32 63men 6ith 5reterm 43ntra4ti3ns 6h3 6ill a4t+allydeliver 5reterm is an ine=a4t 5r34ess. A systemati4 revie6 sh36ed that ina55r3=imately %"9 32 5atients, 5reterm la13r res3lved s53ntane3+sly.% -ns+1se8+ent st+dies, &"9 32 5atients 6h3 6ere h3s5itali;ed 23r 5reterm la13ra4t+ally delivered at term.( The ina1ility t3 disting+ish a44+rately 1et6een63men in tr+e 5reterm la13r and th3se in 2alse la13r has greatly ham5eredthe assessment 32 thera5e+ti4 interventi3ns, sin4e +5 t3 &"9 32 +ntreated 3r5la4e13)treatedB s+1<e4ts d3 n3t a4t+ally deliver 5reterm.Part+riti3n is 4hara4teri;ed 1y m3le4+lar 4hanges in the my3metri+m, 4ervi=, and3ther gestati3nal tiss+es. These 4hanges 4ann3t r3+tinely 1e dete4ted 4lini4ally$th+s, s+rr3gate mar7ers e.g., either +terine 43ntra4ti3ns 3r 4ervi4al dilatati3n,s32tening, and sh3rteningB are +sed as indi4at3rs 32 the 1i34hemi4al events5revi3+sly des4ri1ed.( Un23rt+nately, these 4lini4al s+rr3gates are im5re4isemar7ers 32 an a4tivated 5r34ess 32 5art+riti3n. >3r e=am5le, 13th +terine43ntra4ti3ns and 4ervi4al 4hanges are 43mm3n, es5e4ially in 5ar3+s 63men 6h3d3 n3t deliver 5remat+rely. Meas+rement 32 a 1i34hemi4al mar7er, 2etal2i1r3ne4tin,& 31tained 2r3m vaginal 2l+id, and +ltras3n3gra5hy 32 the4ervi=,/ +sed either al3ne 3r t3gether t3 5redi4t the ris7 32 5reterm

delivery,# a55ear t3 h3ld 5r3mise 23r im5r3ving the diagn3sti4 a44+ra4y 1ey3nd4lini4al im5ressi3n al3ne.















TREATMENT STRATE$IES

e4a+se the 43ntra4ting +ter+s is the m3st 2re8+ently re43gni;ed

ante4edent 32 5reterm 1irth, st355ing 43ntra4ti3ns has 1een the 234+s 32

thera5e+ti4 a55r3a4hes. This strategy is 1ased 3n the naive ass+m5ti3n

that 4lini4ally a55arent 43ntra4ti3ns are 43mmens+rate 6ith the initiati3n 32 the 5r34ess 32 5art+riti3n$ 1y l3gi4al e=tensi3n, the s+44ess2+l inhi1iti3n 32

43ntra4ti3ns sh3+ld 5revent delivery. The inhi1iti3n 32 my3metrial

43ntra4ti3ns is 4alled t343lysis, and a dr+g administered t3 that end is

re2erred t3 as a t343lyti4 agent. The 2irst and 3nly agent a55r3ved 23r

t343lysis 1y the >33d and Dr+g Administrati3n >DAB 6as rit3drine. The

a55r3val 32 that dr+g in :*" initiated a 5eri3d 32 intense 4lini4al

e=5l3rati3n 23r 3ther agents that might inhi1it +terine 43ntra4ti3ns. The

>DA has n3t a55r3ved any 32 the additi3nal agents 23r the indi4ati3n 32

t343lysis. Fimited 5harma43l3gi4 in23rmati3n a13+t these dr+gs in5regnan4y e=ists. >e6 5la4e13)43ntr3lled trials inv3lving t343lyti4 agents

have 1een 43nd+4ted, and m3st agents 6ere assessed 1y 43m5aring

them 6ith rit3drine as the g3ld standard.

-n the three de4ades sin4e rit3drine 6as a55r3ved, n3ne 32 these agents

have lived +5 t3 the e=5e4tati3n that 5remat+rity rates 63+ld 1e red+4ed

1y t343lysis. Alth3+gh m3re than *"9 32 63men 6ith 5reterm la13r 6h3

are treated 6ith t343lyti4 agents have their 5regnan4ies maintained 23r !(

t3 (* h3+rs,* 2e6 data s+ggest that t343lysis maintains 5regnan4y 23r a

l3nger 5eri3d. T343lysis 5r31a1ly has limited s+44ess 1e4a+se 4+rrentlyavaila1le t343lyti4 dr+gs d3 n3t alter the 2+ndamental 5r34ess leading t3

my3metrial a4tivati3n.

Alth3+gh thera5y that inhi1its 43ntra4ti3ns d3es n3t 5revent 5reterm 1irth,

several g3als may still 1e a4hieved. ne 4riti4al g3al is t3 delay delivery

l3ng en3+gh t3 all36 23r the administrati3n 32 43rti43ster3ids, 6hi4h

red+4es the ris7s 32 the ne3natal res5irat3ry distress syndr3me,

intraventri4+lar hem3rrhage, ne4r3ti;ing enter343litis, and 3verall 5erinatal

death.: The initial 1ene2it 32 43rti43ster3id thera5y +s+ally 344+rs

a55r3=imately * h3+rs a2ter administrati3n 32 the 2irst d3se$ the ma=imal1ene2it 344+rs a13+t (* h3+rs a2ter the 2irst d3se. Th+s, treatment 32 a4+te

5reterm la13r may all36 time 23r the administrati3n and thera5e+ti4 e22e4t

32 43rti43ster3ids.!",! An3ther ma<3r g3al 32 treating a4+te 5reterm la13r is

t3 5ermit sa2e trans53rt 32 the m3ther, i2 indi4ated, t3 a regi3nal 2a4ility

s5e4iali;ing in the 4are 32 5remat+re ne3nates.









A variety 32 agents are +sed 23r the inhi1iti3n 32 a4+te 5reterm la13r.

Alth3+gh these agents di22er 6ith res5e4t t3 the me4hanism 32 a4ti3n,

d3se, r3+te 32 administrati3n, sa2ety, and side)e22e4t 5r32ile 23r m3ther and

1a1y, the 6h3le 4lass 32 la13r)inhi1iting dr+gs is largely ine22e4tive,

1e4a+se an attem5t t3 5araly;e the my3metri+m d3es n3t address the r33tstim+l+s 32 5reterm la13r in a 4a+se)s5e4i2i4 2ashi3n. The la13r)inhi1iting

agents +sed a1r3gate my3metrial 43ntra4tility 1y 3ne 32 t63 ma<3r

5ath6ays' thr3+gh generati3n 3r alterati3n 32 intra4ell+lar messengers 3r

1y inhi1iting the synthesis 3r 1l347ing the a4ti3n 32 a 7n36n my3metrial

stim+lant >ig+re FI$%RE & Sites 32 A4ti3n 32 C3mm3nly Used

T343lyti4 Dr+gs.B. Dr+gs a22e4ting intra4ell+lar messengers in4l+de )

adrenergi4?re4e5t3r ag3nists, agents that generate nitri4 3=ide nitri4 3=ided3n3rsB, magnesi+m s+l2ate, and 4al4i+m)4hannel 1l347ers. Dr+gs

1l347ing the synthesis 3r a4ti3n 32 7n36n my3metrial stim+lants in4l+de

5r3staglandin)synthesis inhi1it3rs and 3=yt34in antag3nists. >ig+re

ill+strates the me4hanisms 32 a4ti3n 32 these agents 3n the my3metrial

4ell.

The +ltimate g3al in 5reventing 5reterm 1irth is t3 eliminate the ris7s 32

ne3natal 43m5li4ati3ns and death. H36ever, individ+al trials 32 the e22i4a4y

32 t343lyti4 agents have 1een t33 small t3 assess these 3+t43mes.

S+rr3gate 3r se43ndary 3+t43mes that have 1een +sed in lie+ 32 ne3natalm3r1idity are the 5r3l3ngati3n 32 5regnan4y, 2re8+en4y 32 5reterm 1irth,

and gestati3nal age at 1irth. That 1eing said, several ty5es 32 agents are

availa1le.

'(A)reergi!*Re!eptor Agoists

The )adrenergi4?re4e5t3r ag3nists 4a+se my3metrial rela=ati3n 1y

1inding t3 !)adrenergi4 re4e5t3rs and s+1se8+ently in4reasing the levels

32 intra4ell+lar 4y4li4 AMP. An in4rease in intra4ell+lar 4y4li4 AMP a4tivates

5r3tein 7inase, 6hi4h ina4tivates my3sin light)4hain 7inase, th+s

diminishing my3metrial 43ntra4tility.!!)!( Availa1le meta)analyses s+ggestthat )adrenergi4?re4e5t3r ag3nists delay delivery and red+4e the

2re8+en4y 32 5reterm 1irth and l36 1irth 6eight, as 43m5ared 6ith

5la4e13.!& >3r e=am5le, a meta)analysis 1y An3tayan3nth et

al.!& 43nsidered rand3mi;ed, 43ntr3lled trials inv3lving %!" 63men

that 43m5ared )adrenergi4?re4e5t3r ag3nists 6ith 5la4e13. Am3ng the

63men 6ith 5reterm la13r 6h3 re4eived )adrenergi4?re4e5t3r ag3nists,

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2e6er gave 1irth 6ithin (* h3+rs relative ris7, "./%$ :&9 43n2iden4e

interval C-I, ".&% t3 ".#&B, 1+t there 6as n3 de4rease in the n+m1er 32

1irths 6ithin # days. This meta)analysis als3 sh36ed n3 1ene2it 32 )

adrenergi4?re4e5t3r ag3nists 6ith res5e4t t3 either the rate 32 5erinatal

death relative ris7, ".*($ :&9 C-, ".(/ t3 .&&B 3r, in 2ive trials enr3lling#( 63men, the rate 32 ne3natal death relative ris7, .""$ :&9 C-, ".(* t3

!.":B. Eight trials enr3lling !%: 63men did n3t sh36 any signi2i4ant e22e4t

32 )adrenergi4?re4e5t3r ag3nists 6ith res5e4t t3 the ne3natal res5irat3ry

distress syndr3me relative ris7, ".*#$ :&9 C-, ".# t3 ."*B.

Th+s, des5ite the 5r3l3ngati3n 32 5regnan4y and an a55arent red+4ti3n in

the immediate ris7 32 5reterm 1irth, a signi2i4ant red+4ti3n in 5erinatal

m3r1idity and m3rtality has n3t 1een dem3nstrated. The la47 32 eviden4e

23r a ne3natal 1ene2it may 1e an iss+e 32 sam5le si;e and may re2le4t the

in4l+si3n 4riteria 23r m3st st+dies 32 la13r)inhi1iting thera5y. -ndeed,alth3+gh deliveries at gestati3nal ages 2r3m %( t3 %/ 6ee7s are 5reterm,

1a1ies 13rn at these later 5reterm gestati3nal ages d3 n3t ty5i4ally have

high rates 32 43m5li4ati3ns. e4a+se a 533r ne3natal 3+t43me at later

5reterm gestati3nal ages is +n+s+al, it is di22i4+lt t3 dete4t an e22e4t 3n

m3r1idity in st+dies inv3lving small n+m1ers 32 s+1<e4ts.

Nitri! O+i)e Doors

Nitri4 3=ide, a vas3dilat3r that is essential 23r the maintenan4e 32 n3rmal

sm33th)m+s4le t3ne, is 5r3d+4ed in a variety 32 4ells. Nitri4 3=ide is

synthesi;ed d+ring the 3=idati3n 32 F)arginine an essential amin3 a4idB t3F)4itr+lline. This rea4ti3n is 4ataly;ed 1y the en;yme nitri4 3=ide synthase,

6hi4h e=ists in several is323rms. 3th ind+4i1le ty5e !B and 1rain ty5e B

nitri4 3=ide synthases are e=5ressed in my3metrial 4ells and 1l33d)vessel

end3thelial 4ells, 6hereas end3thelial ty5e %B nitri4 3=ide synthase is

e=5ressed e=4l+sively in 1l33d)vessel end3thelial 4ells.!/ The intera4ti3n

1et6een nitri4 3=ide and s3l+1le g+anylyl 4y4lase, 6hi4h is 5resent in

near1y e22e4t3r 4ells, re5resents a 6ides5read signal)transd+4ti3n

me4hanism that 43+5les diverse e=tra4ell+lar stim+li 32 nitri4 3=ide

23rmati3n t3 the synthesis 32 4y4li4 g+an3sine m3n35h3s5hate 4GMPB intarget 4ells.!# The in4rease in 4GMP 43ntent in sm33th)m+s4le 4ells

ina4tivates my3sin light)4hain 7inases, leading t3 sm33th)m+s4le

rela=ati3n.!*,!: -n a rand3mi;ed 43m5aris3n 32 intraven3+s nitr3gly4erin,

6hi4h is a nitri4 3=ide d3n3r, and magnesi+m s+l2ate, the latter 6as m3re

li7ely t3 delay delivery 23r at least ! h3+rs.%" H36ever, transdermal











nitr3gly4erin 6as s+5eri3r t3 5la4e13 in 5r3l3nging 5regnan4y 23r (* h3+rs

in a rand3mi;ed, 43ntr3lled trial inv3lving %% 63men.%

-n the largest rand3mi;ed, 43ntr3lled st+dy 32 t343lysis 6ith a nitri4 3=ide

d3n3r inv3lving !(& s+1<e4tsB, transdermal gly4eryl trinitrate 6as similar t3

rit3drine 6ith res5e4t t3 delaying delivery 23r (* h3+rs and 5r3l3nginggestati3n t3 %# 6ee7s.%! Smith et al.% rand3mly assigned &% 63men

6h3 6ere in la13r at !( t3 %! 6ee7s 32 gestati3n t3 re4eive either

transdermal nitr3gly4erin 3r 5la4e13 5at4hes. The 5rimary 3+t43me 6as a

43m53site 32 ne3natal 43m5li4ati3ns 4hr3ni4 l+ng disease, intraventri4+lar

hem3rrhage, 5eriventri4+lar le+73mala4ia, and ne4r3ti;ing enter343litisB

and death. The 43m53site 3+t43me 6as signi2i4antly red+4ed in in2ants

13rn t3 #( 63men 6h3 re4eived transdermal nitr3gly4erin, as 43m5ared

6ith th3se 13rn t3 #: 63men 6h3 re4eived 5la4e13 relative ris7, ".!:$

:&9 C-, "."* t3 .""$ PJ"."&B.(Magesi"m S"lfate

The 1asis 23r the 4lini4al +se 32 magnesi+m s+l2ate as a la13r)inhi1iting

agent is the 31servati3n 2r3m the :/"s that the agent 6as ass34iated 6ith

a red+4ti3n in h+man +terine 43ntra4tility 13th in viv3 and in vitr3.%% At a

5harma43l3gi4 43n4entrati3n & mm3l 5er literB, magnesi+m s+l2ate inhi1its

the 43ntra4tile res53nse and de4reases the intra4ell+lar 43n4entrati3n 32

4al4i+m in my3metrial stri5s 31tained 2r3m 5regnant 63men in a 5attern

that is 43nsistent 6ith 13th e=tra4ell+lar and intra4ell+lar me4hanisms 32

a4ti3n.%( This agent hy5er53lari;es the 5lasma mem1rane and inhi1itsmy3sin light)4hain 7inase a4tivity 1y 43m5eting 6ith intra4ell+lar 4al4i+m,

6hi4h in t+rn red+4es my3metrial 43ntra4tility.%&)%#

H36ever, the largest 5la4e13)43ntr3lled, rand3mi;ed trial 32 magnesi+m

s+l2ate as a t343lyti4 agent did n3t sh36 any 1ene2it 3ver 5la4e13 in the

5r3l3ngati3n 32 5regnan4y.%* A meta)analysis 32 trials%: 43m5aring the

3+t43me in ** 63men 6h3 re4eived magnesi+m s+l2ate, 5la4e13, 3r

an3ther a4tive dr+g sh36ed n3 signi2i4ant di22eren4e in the ris7 32 1irth

6ithin (* h3+rs a2ter administrati3n 32 magnesi+m s+l2ate relative ris7,

".*&$ :&9 C-, ".&* t3 .!&B. Magnesi+m s+l2ate a55eared t3 43n2er n31ene2it 6ith res5e4t t3 the ris7 32 5reterm 1irth at J%# 6ee7sB 3r very

5reterm 1irth at J%( 6ee7sB. -n seven trials inv3lving #!# in2ants, the ris7

32 death 13th 2etal and 5ediatri4B 6as in4reased 23r in2ants 6h3 had 1een

e=53sed t3 magnesi+m s+l2ate relative ris7, !.*!$ :&9 C-, .!" t3 /./!B.

Th+s, the literat+re d3es n3t s+553rt the e22i4a4y 32 magnesi+m s+l2ate,





















leading Grimes and Nanda t3 4all 23r the dis43ntin+ati3n 32 its +se as a

t343lyti4 agent.("@e agree 6ith this re43mmendati3n.

Cal!i"m(Chael Blo!,ers

Agents that 1l347 the 4al4i+m 4hannel dire4tly inhi1it the in2l+= 32 4al4i+m

i3ns thr3+gh the 4ell mem1rane and the release 32 intra4ell+lar 4al4i+m2r3m the sar435lasmi4 reti4+l+m. The ens+ing de4rease in intra4ell+lar 2ree

4al4i+m leads t3 the inhi1iti3n 32 my3sin light)4hain 7inase?mediated

5h3s5h3rylati3n, 6hi4h de5ends 3n 4al4i+m, and res+lts in my3metrial

rela=ati3n.(,(! Ni2edi5ine is the agent in this 4lass that has 1een +sed

m3st 43mm3nly t3 inhi1it la13r, 1+t n3 5la4e13)43ntr3lled trials have

st+died the e22i4a4y and sa2ety 32 the dr+g 23r this indi4ati3n. C3nse8+ently,

assessment 32 the e22i4a4y and sa2ety 32 ni2edi5ine 23r la13r inhi1iti3n is

1ased 3n 43m5arative trials, 6ith their inherent 1iases.

King et al. 4arried 3+t a systemati4 revie6 32 ! rand3mi;ed, 43ntr3lledtrials inv3lving "!: 63men.(% -n this meta)analysis, as 43m5ared 6ith any

3ther t343lyti4 agent mainly 1eta mimeti4sB, 4al4i+m)4hannel 1l347ers

red+4ed the n+m1er 32 63men giving 1irth 6ithin # days a2ter re4eiving

treatment relative ris7, ".#/$ :&9 C-, "./" t3 ".:#B and 1e23re %( 6ee7s 32

gestati3n relative ris7, ".*%$ :&9 C-, "./: t3 ".::B. King et al. als3 n3ted

that 4al4i+m)4hannel 1l347ers a55eared t3 red+4e the 2re8+en4y 32 the

ne3natal res5irat3ry distress syndr3me relative ris7, "./%$ :&9 C-, ".(/ t3

".**B, ne4r3ti;ing enter343litis relative ris7, ".!$ :&9 C-, "."& t3 ".:/B,

intraventri4+lar hem3rrhage relative ris7, ".&:$ :&9 C-, ".%/ t3 ".:*B, andne3natal <a+ndi4e relative ris7, ".#%$ :&9 C-, ".&# t3 ".:%B.(% H36ever,

the largest rand3mi;ed trial 32 4al4i+m)4hannel 1l347ers and )adrenergi4?

re4e5t3r ag3nist thera5y inv3lving *& s+1<e4tsB sh36ed the greatest

im5r3vement in 3+t43mes 6ith the +se 32 4al4i+m)4hannel 1l347ers,(( and

the in4l+si3n 32 this trial might have driven the res+lts 32 the meta)analysis.

Cy!loo+ygease Ihi#itors

Cy4l33=ygenase CL, 3r 5r3staglandin synthaseB, 6hi4h e=ists in t63

is323rms, CL) and CL)!, 43nverts ara4hid3ni4 a4id t3 5r3staglandin

H!, 6hi4h serves as a s+1strate 23r tiss+e)s5e4i2i4 en;ymes$ the 5r3d+4ts32 these en;ymes are 4riti4al in 5art+riti3n. Pr3staglandins enhan4e the

23rmati3n 32 my3metrial ga5 <+n4ti3ns and in4rease availa1le intra4ell+lar

4al4i+m 1y raising transmem1rane in2l+= and sar43lemmal release 32

4al4i+m.(& CL) is e=5ressed 43nstit+tively in h+man de4id+a,

my3metri+m, and 2etal mem1ranes, 6hereas CL)!, the ind+4i1le 23rm,















dramati4ally in4reases in the de4id+a and my3metri+m d+ring term and

5reterm la13r. CL inhi1it3rs de4rease 5r3staglandin 5r3d+4ti3n either 1y

general inhi1iti3n 32 CL 3r 1y s5e4i2i4 inhi1iti3n 32 CL)!, de5ending 3n

the agent. -nd3metha4in, a n3ns5e4i2i4 CL inhi1it3r, is the m3st

43mm3nly +sed t343lyti4 agent in this 4lass.-n a re4ent meta)analysis(/ 32 3+t43me data 2r3m 5la4e13, CL inhi1iti3n

6ith ind3metha4in 3nlyB res+lted in a red+4ti3n in 1irths 1e23re %# 6ee7s

32 gestati3n in 3ne trial inv3lving %/ 63men relative ris7, ".!B and an

in4rease in gestati3nal age 6eighted mean di22eren4e, %.&% 6ee7sB and

1irth 6eight 6eighted mean di22eren4e, #/ gB in t63 trials inv3lving /#

63men. As 43m5ared 6ith the +se 32 3ther a4tive agents, the +se 32 a

CL inhi1it3r res+lted in a red+4ti3n in 1irths 1e23re %# 6ee7s 32 gestati3n

in three trials inv3lving /* 63men relative ris7, ".&%B.

CL)! inhi1it3rs have 1e43me availa1le 23r 4lini4al +se m3re re4ently.Data 2r3m st+dies in animals s+ggest that CL)! inhi1it3rs red+4e

my3metrial 43ntra4tility and may delay 5reterm delivery.(#)(: ther data

sh36 that CL)! inhi1it3rs red+4e 5r3staglandin 5r3d+4ti3n in h+man

gestati3nal tiss+es.&" The literat+re 43ntains a 4ase re53rt 32 the +se 32 the

CL)! inhi1it3r nimes+lide 23r 5reterm la13r,& 1+t there is ins+22i4ient

eviden4e t3 re43mmend the +se 32 CL)! inhi1it3rs 23r this indi4ati3n.

O+yto!i(Re!eptor Atagoists

-n n3rmal 5art+riti3n, 3=yt34in stim+lates 43ntra4ti3ns 1y ind+4ing the

43nversi3n 32 5h3s5hatidylin3sit3l tri5h3s5hate t3 in3sit3l tri5h3s5hate,6hi4h 1inds t3 a 5r3tein in the sar435lasmi4 reti4+l+m, 4a+sing the release

32 4al4i+m int3 the 4yt35lasm. =yt34in)re4e5t3r antag3nists 43m5ete 6ith

3=yt34in 23r 1inding t3 re4e5t3rs in the my3metri+m and de4id+a, th+s

5reventing the in4rease in intra4ell+lar 2ree 4al4i+m that 344+rs 6ith

re4e5t3r 1inding.&!,&%

-n a re4ent meta)analysis 32 si= trials inv3lving /:& 63men,&( the

3=yt34in)re4e5t3r antag3nist at3si1an did n3t red+4e the in4iden4e 32

5reterm 1irth 3r im5r3ve the ne3natal 3+t43me, as 43m5ared 6ith 5la4e13.

T63 32 the 5la4e13)43ntr3lled trials&&,&/ inv3lving /% 63menB sh36edthat at3si1an 6as ass34iated 6ith l36er 1irth 6eight 6eighted mean

red+4ti3n, %* g$ :&9 C-, !* t3 !(:B and m3re maternal adverse dr+g

rea4ti3ns relative ris7, (."!$ :&9 C-, !."& t3 #.*&B than 6as 5la4e13. T63

3ther trials in4l+ded in this meta)analysis,&%,&# 6hi4h 43m5ared at3si1an

6ith )adrenergi4?re4e5t3r ag3nists in &#& in2ants, sh36ed that at3si1an

6as ass34iated 6ith an in4rease in the n+m1er 32 in2ants 6h3 6eighed



















less than &"" g at 1irth relative ris7, .:/$ :&9 C-, .& t3 %.%&B. -n a

5la4e13)43ntr3lled trial 1y R3mer3 et al.&/ inv3lving &% s+1<e4ts, at3si1an

6as ass34iated 6ith an in4rease in deaths in the 2irst year 32 li2e relative

ris7, /.&$ :&9 C-, .%: t3 !#.!!B. -n this trial, signi2i4antly m3re 63men

6ere rand3mly assigned t3 re4eive at3si1an 1e23re !/ 6ee7s 32 gestati3nthan 6ere assigned t3 re4eive 5la4e13, a 2a4t3r that 43+ld a443+nt 23r the

e=4ess in deaths am3ng the 1a1ies 32 63men 6h3 re4eived at3si1an.

Given the e=4ess 2etal and in2ant deaths 6ith the administrati3n 32 at3si1an

1e23re !* 6ee7s 32 gestati3n, the >DA has n3t a55r3ved the +se 32 this

dr+g 23r t343lysis.&/

IMPLICATIONS OF TREATMENT

Ea4h 4lass 32 agents in the 5re4eding dis4+ssi3n has a s5e4i2i4 5r32ile 32

side e22e4ts 6hen +sed 23r the inhi1iti3n 32 a4+te 5reterm la13r. Ta1le

TABLE & Side)E22e4t Pr32iles 32 T343lyti4 Agents. lists the side)

e22e4t 5r32iles 32 ea4h 32 these 4lasses 32 dr+gs 23r 13th 63men and their

2et+ses 3r ne3nates. -t is 63rth6hile t3 43nsider the sa2ety 32 inhi1iti3n 32

5reterm la13r, in general. As 5revi3+sly n3ted, 5reterm la13r, 5arti4+larly at

gestati3nal ages 1e23re %! 6ee7s, is li7ely t3 res+lt 2r3m intra+terine

in2e4ti3n 3r 1leeding. E=5+lsi3n 32 the 2et+s and 5la4enta may limit the

+nt36ard 43nse8+en4es 32 3ng3ing maternal in2e4ti3n. -t is entirely

53ssi1le that inhi1iti3n 32 la13r in this setting n3t 3nly is li7ely t3 1e

+ns+44ess2+l at 5r3l3nging 5regnan4y#: 1+t als3 may a4t+ally harm the

m3ther 1y all36ing 1l33d l3ss t3 43ntin+e 3r in2e4ti3n t3 remain

+n4he47ed.

C"rret Clii!al Tools a) Maagemet

Alth3+gh 1asi4 and translati3nal resear4h have 5r3vided s3me

+nderstanding 32 the 4a+sal 5ath6ays +nderlying 5reterm 1irth, there aren3 ade8+ate 4lini4al t33ls t3 disting+ish am3ng the 43ntri1+ti3ns 32 these

5ath6ays in any given 5atient. The treatment 32 a4+te 5reterm la13r as a

means 32 5reventing 5reterm 1irth is anal3g3+s t3 the treatment 32 a4+te

my34ardial in2ar4ti3n as a means 32 5reventing 43r3nary artery disease.

3th 43r3nary artery disease and 5reterm 1irth are 43mm3n yet 43m5le=

43nditi3ns that have heter3gene3+s 4a+ses antedating 4lini4ally a55arent



http://www.nejm.org/action/showImage?doi=10.1056%2FNEJMra050435&iid=t01











disease 1y 6ee7s, m3nths, 3r even years.*" Certainly, a55li4ati3n 32 an

eviden4ed)1ased thera5e+ti4 a55r3a4h t3 a4+te my34ardial in2ar4ti3n has

1een a 63rth6hile e223rt.* Yet n3 5ra4titi3ner e=5e4ts that the treatment 32

a4+te my34ardial in2ar4ti3n 6ill 5revent 43r3nary artery disease. Fi7e6ise,

as 5revi3+sly n3ted, treatment 32 a4+te 5reterm la13r als3 has s3me1ene2it 6ith res5e4t t3 the 5erinatal 3+t43me 1+t 6ill 5r31a1ly d3 little t3

5revent 5reterm 1irth. H36ever, as 6ith 4ardi3vas4+lar disease, e223rts t3

5revent 5remat+rity sh3+ld als3 234+s 3n 5rimary and se43ndary

5reventi3n.

+st as ma<3r e223rts have 1een made t3 identi2y asym5t3mati4 ad+lts 6h3

are at ris7 23r 43r3nary artery disease 1y s4reening 23r ris7 2a4t3rs e.g.,

hy5erli5idemia and hy5ertensi3nB, s+1stantial 63r7 has 1een d3ne t3

identi2y asym5t3mati4 63men early in 5regnan4y 6h3 are at high ris7 23r

5reterm 1irth. Several 4lini4al ris7)s43ring systems have 1een 5r353sed,*!)*/ 1+t +n23rt+nately, s+4h systems a55ear t3 1e 533r 5redi4t3rs 32 5reterm

1irth. S4reening 23r and treatment 32 asym5t3mati4 1a4teri+ria 4an red+4e

the 2re8+en4y 32 5reterm 1irth 3r l36 1irth 6eight 1y a55r3=imately

&"9.*#,** Systemi4 1i34hemi4al mar7ers, genital tra4t mar7ers e.g., 2etal

2i1r3ne4tinB, +ltras3n3gra5hi4 meas+rement 32 the 4ervi=, and identi2i4ati3n

32 asym5t3mati4 43ntra4ti3ns 6ith the +se 32 a h3me +terine)a4tivity

m3nit3r have all 1een e=amined as 5redi4t3rs 32 5reterm 1irth.*#,*:):

The a55li4ati3n 32 s3me 3r all 32 these s4reening strategies t3 the general

31stetri4al 535+lati3n has n3t 1een re43mmended 23r several reas3ns.>irst, any individ+al test has 533r 53sitive 5redi4tive val+e 23r s+1se8+ent

5reterm 1irth. Se43nd, there are n3 e22e4tive, eviden4ed)1ased 5reventive

strategies t3 322er 63men 6h3 have 53sitive res+lts 3n s4reening. The

administrati3n 32 1r3ad)s5e4tr+m anti1i3ti4s has n3t 5revented 5reterm

1irth am3ng 63men 6h3 have 1a4terial vagin3sis:! 3r 53sitive res+lts 3n a

test 23r 2etal 2i1r3ne4tin.:% Un23rt+nately, eviden4e)1ased 5reventive

strategies al3ng these lines are 4+rrently +navaila1le 23r 63men 6h3 have

53sitive res+lts 3n tests 32 mar7ers that have 1een identi2ied t3 date.

There are eviden4ed)1ased 5reventive strategies 23r 63men 6ith a hist3ry

32 5reterm 1irth. Alth3+gh 43ntr3versial, data s+ggest that am3ng 63men

6h3 have had a 5revi3+s 5reterm 1irth, s4reening 23r and treating 1a4terial

vagin3sis red+4e the ris7 32 re4+rren4e 32 5reterm 1irth.:(,:&Data 2r3m

meta)analyses and a m+lti4enter, rand3mi;ed 4lini4al trial s+ggest that

6ee7ly administrati3n 32 # al5ha)hydr3=y5r3gester3ne 4a5r3ate in

63men 6ith a 5revi3+s 5reterm 1irth red+4es the ris7 32 re4+rren4e 1y





















%%9.:/,:# H36ever, the ma<3rity 32 5reterm 1irths in the United States d3

n3t 344+r in 63men 6ith a hist3ry 32 5reterm 1irth. Petrini et al. 5r3<e4ted

that the administrati3n 32 # al5ha)hydr3=y5r3gester3ne 4a5r3ate in

eligi1le 63men in the United States might l36er the 3verall 2re8+en4y 32

5reterm 1irth 1y a m3dest, th3+gh signi2i4ant, 5er4entage, as 43m5ared6ith an +ntreated 535+lati3n !.9 vs. .*9, PJ".""B.:* The e22e4t 32

the +se 32 # al5ha)hydr3=y5r3gester3ne 4a5r3ate, h36ever, sh3+ld n3t

1e +nderestimated. -2 the 535+lati3n 32 U.S. 63men 6ith 5revi3+s 5reterm

1irth 6ere +niversally and s+44ess2+lly treated 6ith # al5ha)

hydr3=y5r3gester3ne 4a5r3ate, li2etime medi4al 43sts 23r their 322s5ring

might 1e red+4ed 1y m3re than ! 1illi3n ann+ally.::

The +se 32 5r3gestati3nal agents t3 5revent 5reterm 1irth am3ng 63men

6ith ris7 2a4t3rs 3ther than 5revi3+s 5reterm 1irth is an area 32 a4tive

resear4h interest. -n this iss+e 32 the Journal, t63 st+dies re53rt 3n the +se32 5r3gestins t3 5revent 5reterm 1irth am3ng high)ris7 63men. >3nse4a et

al."" re53rt that daily administrati3n 32 vaginal 5r3gester3ne red+4ed 1y

m3re than ("9 the 2re8+en4y 32 1irth 1e23re %( 6ee7s 32 gestati3n am3ng

asym5t3mati4 63men 6ith a sh3rt 4ervi= as seen 3n +ltras3n3gra5hy.

H36ever, the st+dy 1y R3+se et al." d3es n3t sh36 a red+4ti3n in the

2re8+en4y 32 5reterm 1irth 6ith the 5r35hyla4ti4 administrati3n 32

intram+s4+lar # al5ha)hydr3=y5r3gester3ne 4a5r3ate in 63men 5regnant

6ith t6ins. These st+dies di22er greatly 6ith res5e4t t3 the ris7 2a4t3r 3n

6hi4h in4l+si3n 6as 1ased, the 5r3gestati3nal agent +sed, the r3+te 32administrati3n, and the gestati3nal age.

Alth3+gh the +se 32 5r3gestati3nal agents t3 5revent 5reterm 1irth am3ng

high)ris7 63men is 5r3mising, the res+lts 32 these t63 trials highlight the

ga5s in 3+r 4+rrent 7n36ledge 32 the 1i3l3gi4 43ntri1+ti3n 32 vari3+s ris7

2a4t3rs t3 5reterm 1irth. Unans6ered 8+esti3ns regarding the 53ssi1le

me4hanisms 32 a4ti3n 32 the vari3+s 5r3gestins in 5reventing 5reterm 1irth

have led t3 +n4ertainty 6ith res5e4t t3 4h3i4e 32 agent, r3+te 32

administrati3n, d3se regimen, and 4lini4al indi4ati3n. Clearly, 2+rther

resear4h 3n 5r3gestati3nal agents is needed, sin4e the 53tential is

immense 23r 13th 4lini4al 1ene2it and advan4ement 32 3+r +nderstanding 32

the 1i3l3gy 32 5reterm 1irth.

Therapy De!isios

The treatment 32 63men 6h3 have a4+te 5reterm la13r has 1een the 234+s

23r 5reventi3n 32 5reterm 1irth. Alth3+gh s+4h a strategy has n3t red+4ed

the 2re8+en4y 32 5reterm 1irths in the United States, it is still im53rtant t3













+se availa1le eviden4e t3 g+ide the treatment 32 63men 6ith 5reterm

la13r. A44+rate estimati3n 32 gestati3nal age and 4lini4al and la13rat3ry

eval+ati3n 32 5ath3l3gi4 4a+ses 32 5reterm la13r are vital 1e23re em1ar7ing

3n a 5lan 23r t343lysis.

>3r the sele4ti3n 32 a t343lyti4 agent, the literat+re des4ri1ing the 1alan4e1et6een sa2ety and e22i4a4y is 2ra+ght 6ith design 2la6s 1+t 322ers s3me

g+idan4e. -n s+m, as 43m5ared 6ith )adrenergi4?re4e5t3r ag3nists,

ni2edi5ine 63+ld seem t3 1e a reas3na1le 4h3i4e 23r initial t343lysis, given

the 3ral r3+te 32 administrati3n, l36 2re8+en4y 32 side e22e4ts, and e22i4a4y

in red+4ing ne3natal 43m5li4ati3ns. Ni2edi5ine 4an 1e +sed at any

gestati3nal age 6hen la13r)inhi1iti3n thera5y is 1eing 43nsidered.

>3r 5regnan4ies 32 less than %! 6ee7s gestati3n, a reas3na1le alternative

t3 ni2edi5ine is ind3metha4in 3r 3ther CL inhi1it3rs. These agents have

1een sh36n t3 1e m3re e22e4tive than the )adrenergi4?re4e5t3r ag3nistsin 43m5arative st+dies. -nd3metha4in sh3+ld 1e av3ided in 63men 6ith a

5latelet dys2+n4ti3n 3r 1leeding dis3rder, he5ati4 3r renal dys2+n4ti3n,

gastr3intestinal +l4erative disease, 3r asthma in 63men 6ith

hy5ersensitivity t3 as5irinB. @e generally av3id the +se 32 these agents in

gestati3ns 32 m3re than %! 6ee7s t3 av3id in +ter3 4l3s+re 3r narr36ing 3r

ne3natal 5aten4y 32 the d+4t+s arteri3s+s.

The +se 32 )adrenergi4?re4e5t3r ag3nists is an alternative t3 thera5y 6ith

ni2edi5ine and ind3metha4in. The side)e22e4t 5r32ile 32 this 4lass 32 dr+gs is

less 2av3ra1le than that 32 ni2edi5ine, 1+t their e22e4tiveness in st355ing43ntra4ti3ns a55ears t3 1e similar.

-n Preterm Birth: Causes, Consequences, and Prevention, the -nstit+te 32

Medi4ine 4ites 4riti4al ga5s in 3+r 7n36ledge regarding the identi2i4ati3n

and treatment 32 63men at high ris7 23r 5reterm la13r$ it als3 targets this

area 23r 2+t+re resear4h."! T3 1e res53nsive t3 this need, st+dies 32 ne6

t343lyti4 dr+gs 3r dr+g 4lasses and e223rts t3 35timi;e the +se 32 4+rrently

availa1le dr+gs m+st 1e in23rmed 1y a 2+ller +nderstanding 32 the 1i3l3gy

32 5reterm 5art+riti3n.

N3 53tential 43n2li4t 32 interest relevant t3 this arti4le 6as re53rted.

SO%RCE INFORMATION

>r3m the De5artment 32 1stetri4s, Gyne43l3gy, and Re5r3d+4tive S4ien4es, University

32 Pitts1+rgh S4h33l 32 Medi4ine, Pitts1+rgh.

Address re5rint re8+ests t3 Dr. Simhan at %"" Hal7et St., Pitts1+rgh, PA &!%, 3r

at hsimhanOmail.magee.ed+.


mailto:[email protected]




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