www.AJOG.

org Obstetrics
Research
livery rates, the diagnosis,
management, and clinical
implications of placenta ac- creta
has become more significant.
Pregnancies following
conservative management of
placenta accreta have a
higher rate of maternal
complications than pregnancies
without such history.
nvestigators should attempt to
deter- mine the optimal imaging
modality for diagnosing placenta
accreta and
how to determine the depth of myo-
metrial penetration !accreta"increta"
percreta# accurately.
f
Safety of macrolides during pregnancy
$ueiyu Joshua %in, &', &P() Allen A. &itchell, &') *ai-Ping +au,
Ph') ,arol %oui-, .c') .onia (ern/nde0-'1a0, &', 'rP(
OBJECTIVE: Prior studies have reported increased risks of
congenital heart defects (CHD) and pyloric stenosis (PS) after prenatal
exposure to macrolide antibiotics !e sought to assess the
association bet"een maternal use of erythromycin and
nonerythromycin macrolides and the risks of CHD and PS
STUD DESI!": #mong participants in the Slone $pidemiology
Center %irth Defects Study from &''( through )**+, "e identified
(&-) infants "ith CHD and .-/ "ith PS as cases, and 0'/) infants
"ithout any malformation as controls !e estimated odds ratios
(12s) and '/3 confidence intervals (C4s) associated "ith use of
erythromycin or nonerythromycin macrolides in each trimester us5
ing conditional logistic regression and ad6usting for risk factors for
CHD and PS, fever, specific types of infections, and their associated
treatments
#ESU$TS: During the first trimester, *(3 and *.3 of control "omen
had used erythromycin and nonerythromycin macrolides,
respectively Compared to non5use during pregnancy, first5trimester
exposure to erythromycin "as not associated "ith an increased risk
of CHD (12,
&-7 '/3 C4, *0 8)0) or PS (12, *'7 '/3 C4, *-8-*) 9he
corre5 sponding 12s for nonerythromycin macrolides "ere *. ('/3
C4, *( 8
&-) for CHD and &. ('/3 C4, *0 8 (0) for PS !e found no as5
sociation bet"een third5trimester exposure to erythromycin or
nonerythromycin macrolides and the risk of PS Hypothesis
generation analyses did not identify appreciable associations
bet"een maternal use of macrolides and other common specific
birth defects CO"C$USIO": !e found no meaningful associations
bet"een the risks of CHD, PS, and other common malformations in
relation to use of mac5 rolides in pregnancy
Cite this article as: ;in <=, >itchell ##, ?au !5P, et al Safety of macrolides during pregnancy #m = 1bstet @ynecol )*&-7)*+:))&e&5+
BACKGROUND AND
OBJECTIVE Although
macrolide antibiotics are
commonly prescribed during
preg- nancy, their safety profile
is yet to be determined, not
only with regard to the
hypothesi0ed ris-s of
congenital heart defects !,('#
and pyloric steno- sis !P.# but
also with regard to the range
of other specific ma2or birth de-
fects. *e therefore sought to
test the hypotheses that the
ris-s of ,(' and
P. are elevated among infants or
fe- tuses e3posed to erythromycin
and"or nonerythromycin
macrolides during pregnancy
and, in e3ploratory analy- ses, to
identify possible associations
with other specific defects. 4he
analy- ses used data from the
.lone 5pidemi- ology ,enter
6irth 'efects .tudy !6'.#, an
ongoing program of case-
control surveillance of
medications in relation to birth
defects.
MATERIALS AND
METHODS
4he 6'. was established in
789: and since that time has
interviewed moth- ers of
malformed infants ascertained
through review of admissions
and dis- charges at ma2or
referral hospitals and clinics in
the greater metropolitan areas of
6oston, Philadelphia, 4oronto,
and .an 'iego and through
statewide birth defects registries
in ;ew +or- .tate !since <==>#
and &assachusetts !since
788?#. 6eginning in 788<, the
6'. en-
Arom the Department of $pidemiology, Harvard School of
Public Health (Drs ;in, ?au, and HernBndeC5DDaC), and Slone
$pidemiology Center at %oston Eniversity (Drs >itchell and
;ouik), %oston, >#, and the Department of Pharmacy,
Fational Eniversity of Singapore, Singapore (Dr ?au)
Supported by grant number 2*& HD*(0/'/5*( from the
Eunice Kennedy Shriver Fational
4nstitute of Child Health and Human Development
Participating hospitals and other ackno"ledgments are listed in
the full5length article at #=1@org 9he authors report no
conflict of interest
Presented as an abstract at the )0th 4nternational Conference
on Pharmacoepidemiology and
9herapeutic 2isk >anagement, %righton, Enited <ingdom,
#ug &'5)), )*&*
***)5'-.+Gfree H )*&- >osby, 4nc #ll rights reserved http:GGdxdoiorgG&*&*&0G6a6og)*&)&)*)-
rolled a sample of mothers of
nonmal- formed infants as
controls.
,ases consisted of >7@< infants
and fe- tuses with a diagnosis of
,(' and 9@A infants with P..
*e e3cluded from anal- ysis
infants with chromosomal
defects, -nown mendelian
inherited disorders, syndromes,
'iGeorge seBuence !asso-
ciated with <<B deletion#, and
meta- bolic and functional
disorders. ,(' or
P. complicated with other
defects !but
>#2CH )*&- %merican Journal of
Obstetrics & !ynecology &&'
Research Obstetrics www.AJOG.org
T%B$E
(aternal e)posure to macrolide antibiotics and ris* of congenital +eart defects or pyloric stenosis
Variable
#ny macrolides
"onmalformed
controls ," I
-./&01 n ,20
Cases of C3D ," I 4'5&0 Cases of 6S ," I 75/0
n ,20 O# ,./2 CI0
a
n ,20 O# ,./2 CI0
a

Fo exposure during pregnancy 00// ('/.) -'(+ ('//) &* (2ef) 0'- ('(-) &* (2ef)

$xposure in first trimester

b
.* (&*) (0 (&&) *' (*08&-) &) (&0) &- (*08)+)

$xposure in second trimester

b
.( (&&) (. (&&) && (*.8&.) . (&*) &- (*/8-*)

$xposure in third trimester

b,c
.& (&*) (. (&&) &* (*08&0) && (&/) &- (*08)')

$rythromycin

Fo exposure during pregnancy 0+)+ ('+)) (*0( ('+() &* (2ef) .&. ('.0) &* (2ef)

$xposure in first trimester

d
)+ (*() &+ (*() &- (*08)0) ( (*/) *' (*-8-*)

$xposure in second trimester

d
). (*() &/ (*() *' (*(8)*) ( (*/) &/ (*(8(+)

$xposure in third trimester

c,d
)* (*-) &/ (*() && (*/8)0) / (*.) &/ (*/8/&)

Fonerythromycin macrolides

Fo exposure during pregnancy 0..- ('.() (*&- ('.&) &* (2ef) .&& ('0.) &* (2ef)

$xposure in first trimester

e
(- (*0) )' (*.) *. (*(8&-) + (&&) &. (*08(0)

$xposure in second trimester

e
(+ (*.) -) (*+) &) (*.8)*) - (*() 8

$xposure in third trimester

c,e
/& (*.) -) (*+) &* (*08&.) . (&*) &/ (*08-+)

CHD, congenital heart defects7 CI, confidence interval7 OR, odds

ratio7 PS, pyloric stenosis7 Ref, reference group
a
12s ad6usted for region of participantsJ residences and calendar year "hen they "ere ascertained7 maternal age,
race, education level7 prepregnancy body mass index7 family history of congenital malformations7 diabetes mellitus7
first5trimester cigarette smoking7 periconceptional folic acid supplement7 multiple pregnancy7 urinary tract, respiratory,
or vaginalGyeast infection, sexually transmitted disease, and other kinds of infection7 andGor febrile events that occurred
in first trimester7
b
12s comparing likely exposure to any macrolide antibiotic in the "indo" of interest "ith no exposure
to any macrolide antibiotic during pregnancy based on previously published algorithm
&(
7
c
$xcluding preterm
deliveries,stillbirths, and terminated abortions did not change estimates materially7
d
12s comparing likely exposure
to erythromycin in the "indo" of interest "ith no exposure to erythromycin during pregnancy based on previously
published algorithm
&(
7
e
12s comparing likely exposure to nonerythromycin macrolides in the "indo" of interest "ith
no exposure to nonerythromycin macrolides during pregnancy based on previously published algorithm
&(
Lin. Safety of macrolides in pregnancy.
Am J Obstet Gynecol 2013.
not as part of an identified
chromo- somal or mendelian
inherited syn- drome# were
included in the general analysis
and studied separately in a
secondary analysis.
Other ma2or defects e3amined
in- cluded the following
categoriesC 7@>? oral clefts,
77@? central nervous system
defects, @=? respiratory system
defects,
7?<A gastrointestinal system
defects,
7=88 genital system defects, 7A77
urinary system defects, 78>?
musculos-eletal system defects,
and @?A others. 4he same
e3clusion criteria described
above ap- plied to these case
groups. Our control group
consisted of :8A< infants without
any malformation.
*ithin : months of the sub2ectDs
deliv- ery, trained study nurses
unaware of study hypotheses
interview mothers of study
sub2ects. 4he >A- to :=-minute
interview is detailed and
structured and includes Bues-
tions on maternal demographic
character- istics, mothersD medical
histories, obstetric
histories, maternal health
behaviors and occupation, and a
detailed history of the use of
medication !including
prescription, over-the-counter,
and vitamin and herbal products#
from < months before the date of
the last menstrual period through
the pregnancy.
RESULT
S
*e found no association between
first- trimester maternal use of
macrolides as a class and the ris-
of ,(' !odds ratio EORF, =.8)
8AG confidence interval E,F,
=.: H7.@# or P. !OR, 7.@) 8AG
,, =.: H
<.?#. Ior erythromycin, the ris-
of ,(' was 7.@ !8AG ,, =.: H
<.:# and for P. it was =.8 !8AG
,, =.@H@.=#. 4he corre- sponding
ORs for nonerythromycin
macrolides were =.9 !8AG ,, =.>
H7.@# for ,(' and 7.9 !8AG ,,
=.: H >.:# for P.. *e also found
no meaningful asso- ciation
between the ris- of P. and e3po-
sure to macrolides overall or to
erythro- mycin or
nonerythromycin macrolides in
the second and third trimesters
!4able#.
53amination of macrolide use
in the first trimester in relation to
ma2or birth defects revealed
largely null findings e3- cept for a
borderline association between
e3posure to macrolides overall
and un- specified genital system
defects.
COMMEN
T
Ior the hypotheses we tested
related to ,(' and P., our
results are consistent with @
recently published large studies.
Ior ,(', an American cohort
study found no association
between the ris- of ,(' overall
and maternal use of eryth-
romycin or nonerythromycin
macro- lides during pregnancy,
nor did a ;or- wegian study find
elevated ris-s of ,(' overall or
atrial"ventricular septal defects
&&& %merican Journal of Obstetrics & !ynecology >#2CH )*&-
www.AJOG.org Obstetrics Research
in infants e3posed to
erythromycin in the first
trimester. 4he ;ational 6irth
'efects Prevention .tudy also
reported null findings for
macrolide antibiotic use overall in
relation to subgroups of ,('.
Ior P., our group had
previously re- ported a lac- of
association with erythro- mycin
use in either early !gestational
wee-s 7-<A# or late !K@<nd
gestational wee-# pregnancy.
Iindings from the current study,
which added data col- lected
from 788? through <==?, indi-
cate that e3posure to
erythromycin or
nonerythromycin macrolides in
either early or late pregnancy is
not associ- ated with an increased
ris- of P.) the
results remained consistent when
we e3cluded the data that had
been re- ported in the prior study.
n addition to ,(' and P., we
e3- amined e3posure to
macrolides in re- lation to other
common malformation groups
and, where numbers allowed,
relatively common specific
congenital malformations) the
results were largely null. 4he
possibility that any macrolide
e3posure in the first trimester
may in- crease the ris- of
unspecified genital system
defects may well be a chance
finding given its identification in
the setting of multiple
comparisons.
n conclusion, we could not
replicate the previously described
associations between
macrolides as a class, and more
specifically erythromycin or
nonerythromycin mac- rolides,
and the ris- of ,(' and"or P.,
nor did we identify meaningful
increases in ris-s for many other
specific ma2or con- genital
malformations.
C$I"IC%$ I(6$IC%TIO"S
Although active surveillance
on the safety of macrolide use
during preg- nancy should be
continued, we find no evidence
supporting ma2or terato- genic
effects of macrolide antibiotics
in human fetuses.
f
6re8ention of preterm birt+ by progestational agents: 9+at are t+e molecular
mec+anisms:
,hristopher ;old, &') &oniBue &aubert, 6.) %auren Anton, Ph') .teven +ellon, Ph') &ichal A.
5lovit0, &'
OBJECTIVE: Clinically, vaginal progesterone (LP) and &.
alpha5hy5 droxyprogesterone caproate (&.P) have been
sho"n to prevent preterm birth (P9%) in high5risk populations
!e hypothesiCe that treatment "ith these agents may prevent
P9% by altering molecular path"ays involved in uterine
contractility or cervical remodeling
STUD DESI!": Esing a mouse model, on embryonic
day ($)&(5$&.
CD5& pregnant mice "ere treated "ith: (&) *& m; of )/
mgGm; of &.P sub5 cutaneously7 ()) *& m; of castor oil
subcutaneously7 (-) *& m; of &* mgGm; of progesterone in
a long5lasting 2eplens (;ilJ Drug Store Products, 4nc, Cedar
2apids, 4#)7 or (() *& m; of the same 2eplens, "ith (
dams per treatment group >ice "ere sacrificed 0 hours
after treatment on $&./ Cervices and uteri "ere collected
for molecular analysis
#ESU$TS: $xposure to LP significantly increased the
expression of defensin & compared to 2eplens (P M *&) on
$&./ Feither LP nor
&.P altered the expression of uterine contraction5
associated pro5 teins, progesterone5mediated regulators
of uterine Nuiescence, mi5 cro2F# involved in uterine
contractility, or path"ays involved in cer5 vical remodeling
4n addition, neither agent had an effect on immune cell
trafficking or collagen content in the cervix
CO"C$USIO": Feither LP nor &.P had any effect on the
studied path"ays kno"n to be involved in uterine
contractility or Nuies5 cence 4n the cervix, neither LP nor
&.P altered path"ays demon5 strated to be involved in
cervical remodeling #dministration of LP "as noted to
increase the expression of the antimicrobial protein
defensin & !hether this molecular change from LP
results in a functional effect and is a key mechanism by
"hich LP prevents P9% reNuires further study
Cite this article as: Fold C, >aubert >, #nton ;, et al Prevention of preterm birth by progestational agents:
"hat are the molecular mechanismsO #m = 1bstet
@ynecol )*&-7)*+:))-e&5.
Arom >aternal and Child Health 2esearch Program, Department of 1bstetrics and @ynecology,
Perelman School of >edicine, Eniversity of Pennsylvania, Philadelphia, P# (Drs Fold, #nton, and
$lovitC and >s >aubert), and the Department of Physiology, ;oma ;inda Eniversity School of >edicine,
;oma ;inda, C# (Dr ?ellon)
9he animal experiments and molecular analysis "ere supported by the >aternal and Child Heath
2esearch Aund, Eniversity of Pennsylvania Cervical cell staining and immune cell analysis "ere
performed by the ;oma ;inda Eniversity School of >edicine #dvanced 4maging and >icroscopy
core facility and supported in part by Fational 4nstitutes of Health HD*/('-&
9he authors report no conflict of interest
Presented orally at the --rd annual meeting of the Society for >aternal5Aetal
>edicine, San Arancisco, C#, Aeb &&5&0, )*&- 9he racing flag logo above
indicates that this article "as rushed to press for the benefit of the scientific
community
***)5'-.+Gfree H )*&- >osby, 4nc #ll rights reserved http:GGdxdoiorgG&*&*&0G6a6og)*&-*&*)*
>#2CH )*&- %merican Journal of Obstetrics
& !ynecology &&5