Obstetrics

www.AJOG.org

livery rates, the diagnosis, management,

and clinical implications of placenta accreta has become more significant.
Pregnancies following conservative
management of placenta accreta have a

higher rate of maternal complications

than pregnancies without such history.
Investigators should attempt to determine the optimal imaging modality
for diagnosing placenta accreta and

Research

how to determine the depth of myometrial penetration (accreta/increta/

percreta) accurately.
f

Safety of macrolides during pregnancy

Kueiyu Joshua Lin, MD, MPH; Allen A. Mitchell, MD; Wai-Ping Yau, PhD;
Carol Louik, ScD; Sonia Hernndez-Daz, MD, DrPH

OBJECTIVE: Prior studies have reported increased risks of congenital

RESULTS: During the first trimester, 0.4% and 0.7% of control women

heart defects (CHD) and pyloric stenosis (PS) after prenatal exposure to
macrolide antibiotics. We sought to assess the association between
maternal use of erythromycin and nonerythromycin macrolides and the
risks of CHD and PS.
STUDY DESIGN: Among participants in the Slone Epidemiology
Center Birth Defects Study from 1994 through 2008, we identified
4132 infants with CHD and 735 with PS as cases, and 6952 infants
without any malformation as controls. We estimated odds ratios
(ORs) and 95% confidence intervals (CIs) associated with use of
erythromycin or nonerythromycin macrolides in each trimester using conditional logistic regression and adjusting for risk factors for
CHD and PS, fever, specific types of infections, and their associated
treatments.

had used erythromycin and nonerythromycin macrolides, respectively.

Compared to non-use during pregnancy, first-trimester exposure to
erythromycin was not associated with an increased risk of CHD (OR,
1.3; 95% CI, 0.6 2.6) or PS (OR, 0.9; 95% CI, 0.33.0). The corresponding ORs for nonerythromycin macrolides were 0.7 (95% CI, 0.4
1.3) for CHD and 1.7 (95% CI, 0.6 4.6) for PS. We found no association between third-trimester exposure to erythromycin or
nonerythromycin macrolides and the risk of PS. Hypothesis generation
analyses did not identify appreciable associations between maternal
use of macrolides and other common specific birth defects.
CONCLUSION: We found no meaningful associations between the risks
of CHD, PS, and other common malformations in relation to use of macrolides in pregnancy.

Cite this article as: Lin KJ, Mitchell AA, Yau W-P, et al. Safety of macrolides during pregnancy. Am J Obstet Gynecol 2013;208:221.e1-8.

B ACKGROUND AND O BJECTIVE

Although macrolide antibiotics are
commonly prescribed during pregnancy, their safety profile is yet to be
determined, not only with regard to
the hypothesized risks of congenital
heart defects (CHD) and pyloric stenosis (PS) but also with regard to the
range of other specific major birth defects. We therefore sought to test the
hypotheses that the risks of CHD and

PS are elevated among infants or fetuses exposed to erythromycin and/or

nonerythromycin macrolides during
pregnancy and, in exploratory analyses, to identify possible associations
with other specific defects. The analyses used data from the Slone Epidemiology Center Birth Defects Study
(BDS), an ongoing program of casecontrol surveillance of medications in
relation to birth defects.

From the Department of Epidemiology, Harvard School of Public Health (Drs Lin, Yau, and
Hernndez-Daz), and Slone Epidemiology Center at Boston University (Drs Mitchell and Louik),
Boston, MA, and the Department of Pharmacy, National University of Singapore, Singapore (Dr
Yau).
Supported by grant number R01 HD046595-04 from the Eunice Kennedy Shriver National
Institute of Child Health and Human Development.
Participating hospitals and other acknowledgments are listed in the full-length article at AJOG.org.
The authors report no conflict of interest.
Presented as an abstract at the 26th International Conference on Pharmacoepidemiology and
Therapeutic Risk Management, Brighton, United Kingdom, Aug. 19-22, 2010.
0002-9378/free 2013 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2012.12.023

M ATERIALS AND M ETHODS

The BDS was established in 1976 and
since that time has interviewed mothers of malformed infants ascertained
through review of admissions and discharges at major referral hospitals and
clinics in the greater metropolitan areas
of Boston, Philadelphia, Toronto, and
San Diego and through statewide birth
defects registries in New York State
(since 2004) and Massachusetts (since
1998). Beginning in 1992, the BDS enrolled a sample of mothers of nonmalformed infants as controls.
Cases consisted of 4132 infants and fetuses with a diagnosis of CHD and 735
infants with PS. We excluded from analysis infants with chromosomal defects,
known mendelian inherited disorders,
syndromes, DiGeorge sequence (associated with 22q deletion), and metabolic and functional disorders. CHD or
PS complicated with other defects (but

MARCH 2013 American Journal of Obstetrics & Gynecology

221

Research

Obstetrics

www.AJOG.org

TABLE

Maternal exposure to macrolide antibiotics and risk of congenital heart defects or pyloric stenosis

Variable

Nonmalformed
controls (N 6952),
n (%)

Cases of CHD (N 4132)

n (%)

Cases of PS (N 735)

OR (95% CI)a

n (%)

OR (95% CI)a

Any macrolides

.......................................................................................................................................................................................................................................................................................................................................................................

No exposure during pregnancy

6655 (95.7)

3948 (95.5)

Exposure in first trimester

70 (1.0)

46 (1.1)

0.9 (0.61.3)

1.0 (Ref)

693 (94.3)
12 (1.6)

1.3 (0.62.8)

1.0 (Ref)

Exposure in second trimester

74 (1.1)

47 (1.1)

1.1 (0.71.7)

7 (1.0)

1.3 (0.53.0)

Exposure in third trimester

71 (1.0)

47 (1.1)

1.0 (0.61.6)

11 (1.5)

1.3 (0.62.9)

.......................................................................................................................................................................................................................................................................................................................................................................
b
.......................................................................................................................................................................................................................................................................................................................................................................
b
.......................................................................................................................................................................................................................................................................................................................................................................
b,c
................................................................................................................................................................................................................................................................................................................................................................................

Erythromycin

.......................................................................................................................................................................................................................................................................................................................................................................

No exposure during pregnancy

6828 (98.2)

4064 (98.4)

1.0 (Ref)

717 (97.6)

1.0 (Ref)

Exposure in first trimester

28 (0.4)

18 (0.4)

1.3 (0.62.6)

4 (0.5)

0.9 (0.33.0)

Exposure in second trimester

27 (0.4)

15 (0.4)

0.9 (0.42.0)

4 (0.5)

1.5 (0.44.8)

Exposure in third trimester

20 (0.3)

15 (0.4)

1.1 (0.52.6)

5 (0.7)

1.5 (0.55.1)

.......................................................................................................................................................................................................................................................................................................................................................................
d
.......................................................................................................................................................................................................................................................................................................................................................................
d
.......................................................................................................................................................................................................................................................................................................................................................................
c,d
................................................................................................................................................................................................................................................................................................................................................................................

Nonerythromycin macrolides

.......................................................................................................................................................................................................................................................................................................................................................................

No exposure during pregnancy

6773 (97.4)

4013 (97.1)

1.0 (Ref)

711 (96.7)

1.0 (Ref)

Exposure in first trimester

43 (0.6)

29 (0.7)

0.7 (0.41.3)

8 (1.1)

1.7 (0.64.6)

Exposure in second trimester

48 (0.7)

32 (0.8)

1.2 (0.72.0)

3 (0.4)

Exposure in third trimester

51 (0.7)

32 (0.8)

1.0 (0.61.7)

7 (1.0)

1.5 (0.63.8)

.......................................................................................................................................................................................................................................................................................................................................................................
e
.......................................................................................................................................................................................................................................................................................................................................................................
e
.......................................................................................................................................................................................................................................................................................................................................................................
c,e
................................................................................................................................................................................................................................................................................................................................................................................

CHD, congenital heart defects; CI, confidence interval; OR, odds ratio; PS, pyloric stenosis; Ref, reference group.
a

ORs adjusted for region of participants residences and calendar year when they were ascertained; maternal age, race, education level; prepregnancy body mass index; family history of congenital
malformations; diabetes mellitus; first-trimester cigarette smoking; periconceptional folic acid supplement; multiple pregnancy; urinary tract, respiratory, or vaginal/yeast infection, sexually transmitted
disease, and other kinds of infection; and/or febrile events that occurred in first trimester; b ORs comparing likely exposure to any macrolide antibiotic in the window of interest with no exposure to any
macrolide antibiotic during pregnancy based on previously published algorithm14; c Excluding preterm deliveries,stillbirths, and terminated abortions did not change estimates materially; d ORs
comparing likely exposure to erythromycin in the window of interest with no exposure to erythromycin during pregnancy based on previously published algorithm14; e ORs comparing likely exposure
to nonerythromycin macrolides in the window of interest with no exposure to nonerythromycin macrolides during pregnancy based on previously published algorithm.14

Lin. Safety of macrolides in pregnancy. Am J Obstet Gynecol 2013.

not as part of an identified chromosomal or mendelian inherited syndrome) were included in the general
analysis and studied separately in a
secondary analysis.
Other major defects examined included the following categories: 1348
oral clefts, 1138 central nervous system
defects, 308 respiratory system defects,
1825 gastrointestinal system defects,
1099 genital system defects, 1511 urinary
system defects, 1948 musculoskeletal
system defects, and 385 others. The same
exclusion criteria described above applied to these case groups. Our control
group consisted of 6952 infants without
any malformation.
Within 6 months of the subjects delivery, trained study nurses unaware of study
hypotheses interview mothers of study
subjects. The 45- to 60-minute interview is
detailed and structured and includes questions on maternal demographic characteristics, mothers medical histories, obstetric
222

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 2 months before the date
of the last menstrual period through the
pregnancy.

sure to macrolides overall or to erythromycin or nonerythromycin macrolides

in the second and third trimesters
(Table).
Examination of macrolide use in the
first trimester in relation to major birth
defects revealed largely null findings except for a borderline association between
exposure to macrolides overall and unspecified genital system defects.

R ESULTS
We found no association between firsttrimester maternal use of macrolides as a
class and the risk of CHD (odds ratio
[OR], 0.9; 95% confidence interval [CI],
0.6 1.3) or PS (OR, 1.3; 95% CI, 0.6
2.8). For erythromycin, the risk of CHD
was 1.3 (95% CI, 0.6 2.6) and for PS it
was 0.9 (95% CI, 0.33.0). The corresponding ORs for nonerythromycin
macrolides were 0.7 (95% CI, 0.4 1.3)
for CHD and 1.7 (95% CI, 0.6 4.6) for
PS. We also found no meaningful association between the risk of PS and expo-

American Journal of Obstetrics & Gynecology MARCH 2013

C OMMENT
For the hypotheses we tested related to
CHD and PS, our results are consistent
with 3 recently published large studies.
For CHD, an American cohort study
found no association between the risk of
CHD overall and maternal use of erythromycin or nonerythromycin macrolides during pregnancy, nor did a Norwegian study find elevated risks of CHD
overall or atrial/ventricular septal defects

Obstetrics

www.AJOG.org
in infants exposed to erythromycin in
the first trimester. The National Birth
Defects Prevention Study also reported
null findings for macrolide antibiotic use
overall in relation to subgroups of CHD.
For PS, our group had previously reported a lack of association with erythromycin use in either early (gestational
weeks 1-25) or late (32nd gestational
week) pregnancy. Findings from the
current study, which added data collected from 1998 through 2008, indicate that exposure to erythromycin or
nonerythromycin macrolides in either
early or late pregnancy is not associated with an increased risk of PS; the

results remained consistent when we

excluded the data that had been reported in the prior study.
In addition to CHD and PS, we examined exposure to macrolides in relation to other common malformation
groups and, where numbers allowed,
relatively common specific congenital
malformations; the results were largely
null. The possibility that any macrolide
exposure in the first trimester may increase the risk of unspecified genital
system defects may well be a chance
finding given its identification in the
setting of multiple comparisons.
In conclusion, we could not replicate the
previously described associations between

Research

macrolides as a class, and more specifically

erythromycin or nonerythromycin macrolides, and the risk of CHD and/or PS, nor
did we identify meaningful increases in
risks for many other specific major congenital malformations.

CLINICAL IMPLICATIONS

Although active surveillance on the

safety of macrolide use during pregnancy should be continued, we find
no evidence supporting major teratogenic effects of macrolide antibiotics
in human fetuses.
f

Prevention of preterm birth by progestational

agents: what are the molecular mechanisms?
Christopher Nold, MD; Monique Maubert, BS; Lauren Anton, PhD; Steven Yellon, PhD; Michal A. Elovitz, MD
OBJECTIVE: Clinically, vaginal progesterone (VP) and 17 alpha-hy-

droxyprogesterone caproate (17P) have been shown to prevent preterm

birth (PTB) in high-risk populations. We hypothesize that treatment with
these agents may prevent PTB by altering molecular pathways involved
in uterine contractility or cervical remodeling.
STUDY DESIGN: Using a mouse model, on embryonic day (E)14-E17
CD-1 pregnant mice were treated with: (1) 0.1 mL of 25 mg/mL of 17P subcutaneously; (2) 0.1 mL of castor oil subcutaneously; (3) 0.1 mL of 10
mg/mL of progesterone in a long-lasting Replens (Lil Drug Store Products,
Inc., Cedar Rapids, IA); or (4) 0.1 mL of the same Replens, with 4 dams per
treatment group. Mice were sacrificed 6 hours after treatment on E17.5.
Cervices and uteri were collected for molecular analysis.
RESULTS: Exposure to VP significantly increased the expression of
defensin 1 compared to Replens (P .01) on E17.5. Neither VP nor

17P altered the expression of uterine contraction-associated proteins, progesterone-mediated regulators of uterine quiescence, microRNA involved in uterine contractility, or pathways involved in cervical remodeling. In addition, neither agent had an effect on immune
cell trafficking or collagen content in the cervix.
CONCLUSION: Neither VP nor 17P had any effect on the studied
pathways known to be involved in uterine contractility or quiescence. In the cervix, neither VP nor 17P altered pathways demonstrated to be involved in cervical remodeling. Administration of VP
was noted to increase the expression of the antimicrobial protein
defensin 1. Whether this molecular change from VP results in a
functional effect and is a key mechanism by which VP prevents PTB
requires further study.

Cite this article as: Nold C, Maubert M, Anton L, et al. Prevention of preterm birth by progestational agents: what are the molecular mechanisms? Am J Obstet
Gynecol 2013;208:223.e1-7.

From Maternal and Child Health Research Program, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania,
Philadelphia, PA (Drs Nold, Anton, and Elovitz and Ms Maubert), and the Department of Physiology, Loma Linda University School of Medicine, Loma Linda,
CA (Dr Yellon).
The animal experiments and molecular analysis were supported by the Maternal and Child Heath Research Fund, University of Pennsylvania. Cervical cell
staining and immune cell analysis were performed by the Loma Linda University School of Medicine Advanced Imaging and Microscopy core facility and
supported in part by National Institutes of Health HD054931.
The authors report no conflict of interest.
Presented orally at the 33rd annual meeting of the Society for Maternal-Fetal Medicine, San Francisco, CA, Feb. 11-16, 2013.
The racing flag logo above indicates that this article was rushed to press for the benefit of the scientific community.
0002-9378/free 2013 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2013.01.020

MARCH 2013 American Journal of Obstetrics & Gynecology

223