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GENERAL GYNECOLOGY

Are antibiotics necessary after 48 hours of improvement

in infected/septic abortions? A randomized controlled
trial followed by a cohort study
Ricardo F. Savaris, MD, PhD; Gisele S. de Moraes, BSc; Rafael A. Cristovam, BSc; R. Daniel Braun, MD
OBJECTIVE: We sought to investigate whether oral antibiotics are nec-

RESULTS: Cure was observed in all 56 patients. The institutional review

essary, after 48 hours of clinical improvement, in uncomplicated septic

abortion.

board stopped the treatment arm as it was adding risk with no further
benefit to the patients. An observational cohort with additional 75 cases
was followed up in the no treatment arm and no failure was identified
(probability of an adverse event, 0%; 95% confidence interval,
0 0.03).

STUDY DESIGN: In a randomized double-blind clinical trial, 56 women

with uncomplicated septic abortion were treated with intravenous antibiotics, followed by uterine evacuation. On hospital discharge (day 1),
patients were randomized to receive either oral doxycycline plus metronidazole or placebo, until completing 10 days of treatment. Clinical cure
was defined by the absence of fever (37.7C), reduced vaginal bleeding, and minimal or no pelvic pain.

CONCLUSION: After 48 hours of clinical improvement, antibiotics may

not be necessary.
Key words: antibiotics, doxycycline, metronidazole, septic abortion

Cite this article as: Savaris RF, Moraes GS, Cristovam RA, et al. Are antibiotics necessary after 48 hours of improvement in infected/septic abortions? A
randomized controlled trial followed by a cohort study. Am J Obstet Gynecol 2011;204:301.e1-5.

n the developing world, an estimated

5 million women are admitted to the
hospital for treatment of complications
from induced abortions each year. This
is an average of 5.7 per 1000 women per
year in all developing regions, excluding
China.1 In Brazil, abortion is illegal, and
From Departamento e Servio de
Ginecologia e Obstetrcia, Universidade
Federal do Rio Grande do SulHospital de
Clnicas de Porto Alegre, Porto Alegre, Brazil
(Dr Savaris, Ms Cristovam, and Ms Moraes),
and the Department of Obstetrics and
Gynecology, Indiana University School of
Medicine (emeritus), Indianapolis, IN (Dr
Braun).
Received Aug. 7, 2010; revised Sept. 17,
2010; accepted Nov. 2, 2010.
Reprints: Ricardo F. Savaris, MD, PhD,
Departamento e Servio de Ginecologia e
Obstetrcia, Universidade Federal do Rio
Grande do SulHospital de Clnicas de Porto
Alegre, Rua Ramiro Barcelos 2350/1125 Porto
Alegre, 90035-903 Brazil.
rsavaris@hcpa.ufrgs.br.
Supported by Fundao de Incentivo a
Pesquisa e Eventos, Hospital de Clnicas de
Porto Alegre, Grant no. 05-452.
0002-9378/$36.00
2011 Mosby, Inc. All rights reserved.
doi: 10.1016/j.ajog.2010.11.017

because of this, the complications of this

procedure represents the third leading
cause of maternal mortality and accounts for 12% of the maternal mortality
rate. Brazils abortion rate is high at 40.8
per 1000 women, and approximately
31% of pregnancies end in an induced
abortion.2
Patients with established infection, as
indicated by fever (arbitrarily defined as
38C), pelvic peritonitis, or tachycardia, should be hospitalized for parenteral
antibiotic therapy and prompt uterine
evacuation.3 Bacteremia, which is more
common in septic abortion than in other
pelvic infections, may result in septic
shock and adult respiratory distress syndrome. The management of severe sepsis
requires eradication of the infection, and
supportive care for the cardiovascular system and other involved organ systems.3
The Brazilian Ministry of Health recommends the use of intravenous clindamycin plus gentamicin for 7-10 days, in
cases of uncomplicated septic abortions.4 Similarly, the World Health Organization (WHO) advises that broadspectrum intravenous antibiotic therapy
should be followed by oral doxycycline
(200 mg/d) for 10-14 days.5 This regimen is similar to that recommended for

pelvic inflammatory disease by the Centers for Disease Control and Prevention
(CDC).6
Contrary to prolonged treatment with
oral antibiotics, French and Smaill7 demonstrated that it is unnecessary to continue antibiotic therapy in postcesarean
section endometritis once the patient is
afebrile for 48 hours. It could be safe and
less expensive to utilize this regimen in
cases of uncomplicated septic abortion.
There is no evidence thus far to show that
this shorter regimen is safe in such cases.
The objective of this is study was to
investigate the need for oral antibiotics
after 48 hours of clinical improvement,
in patients with uncomplicated septic
abortion who have undergone uterine
evacuation and received a minimum of
48 hours of intravenous antibiotics.

M ATERIALS AND M ETHODS

Participants
Patients admitted to Hospital de Clnicas
de Porto Alegre, with a diagnosis of uncomplicated septic abortion, according
to the WHO, were eligible for the study.
The WHO defines the condition as abortion with the presence of one of the following signs or symptoms: chills or

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Research

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Outcome
At 48-72 hours after hospital discharge,
patients were contacted by telephone to
determine their clinical condition. After
finishing the outpatient treatment (day
10), patients were seen by one of the investigators (G.S.M., R.A.C.). Adherence
to the study protocol was evaluated by
examining the medication packets. At
this visit, a standard interview was utilized to identify the presence or absence
of the primary outcome (clinical cure).
Clinical cure was defined as the absence
of fever (37.8C), reduced vaginal
bleeding, and minimal or no pelvic
pain. Clinical failure was defined as hospital readmission, presence of fever
(37.8C) after hospital discharge, no
reduction of vaginal bleeding, persistence of pelvic pain, or the need to use
additional medication (antibiotics or
pain medication) whether prescribed or
not.

FIGURE

Flowchart of patients through trial

Sample size
Sample size for equivalence was calculated according to Blackwelder,9 using
the formula:
n
Savaris. Antibiotics in infected/septic abortions. Am J Obstet Gynecol 2011.

sweats, fever (37.8C), foul-smelling

vaginal discharge, abdominal rebound
tenderness, hypotension (arterial systolic pressure 90 mm Hg), history of
intrauterine manipulation with nonsterile probes, malaise, or pus coming from
cervix or mixed with blood in the vagina.5 We also used the additional criteria of leukocytosis (14,000 leukocytes/
mL) as suggested by Lurie et al.8
Patients were treated with intravenous
clindamycin 2700 mg, plus gentamicin
240 mg per day and immediate uterine
evacuation (day 1). Patients received intravenous antibiotics in the hospital until 48 hours of clinical improvement was
noted. Clinical improvement was defined as: no fever, normal leukogram,
and a reduction in vaginal bleeding and
pelvic pain.
Patients who used antibiotics within 1
week prior to hospitalization, who were
301.e2

not willing to participate, with a diagnosis of tubo-ovarian abscess, or with

known allergy to doxycycline or metronidazole were excluded.

Intervention
Before hospital discharge, patients were
invited to participate in the study (day
1). Those meeting study criteria and providing consent were randomized to receive either oral doxycycline 100 mg
twice daily plus metronidazole 250 mg
twice a day, or an identical placebo, until
completion of 10 days of treatment (day
10). Medications were prepared by the
pharmacy of the Hospital de Clnicas de
Porto Alegre, in identical coded blister
packets and capsules to assure double
blinding. Patients were instructed not to
use drugs for pain or fever. They were
instructed to return to the hospital if they
experienced pain or fever.

American Journal of Obstetrics & Gynecology APRIL 2011

Z Z2 PS1 PS PT1 PT
PS PT d2
where n the sample size for each treatment group; Z the standard normal
variate corresponding to the significance level, ie, an error of 0.02 2.326;
Z the standard normal variate corresponding to the tail probability of size ,
ie, error of 0.1 1.2816; and d the
difference between the conventional (PS)
and short (PT) treatment effects that is
considered to be clinically meaningful,
herein 10%. In antiinfective studies, a
d of 10% was chosen as recommended by
the US Food and Drug Administration.10 Based on our local experience,
and hospital electronic records, rate of
cures with long antibiotic protocol is
near 99%. The estimated rate of clinical
cure with placebo treatment was 97%.
These figures yield a minimum of 79 patients in each group (conventional and
short treatment).
Interim analysis was planned a priori
and calculated according to Fang,11 con-

General Gynecology

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sidering 2 stages of analysis. The adjusted
critical Z value (derived from adjusted
for 0.05, and of 0.1) was considered
in a scenario where the rate of cure for
the standard intervention is 100% and
for the placebo is 80% (chosen arbitrarily) for possible early stopping. If a
higher rate of cure in the placebo and in
the antibiotic group was observed, eg,
100%, the use of antibiotics would give
no additional benefit for the patients,
and the study should be stopped. These
figures suggested that the first interim
analysis should be with 27 patients per
group, in each stage, yielding a total of
108 patients, ie, 27 2 groups 2 stages.
If the study was stopped due to a high
rate of cure in the placebo arm (eg,
100%), an observational cohort would
be carried out until reaching at least the
initial sample size calculated for the placebo arm.

Observational cohort
In the observational cohort, the same inclusion and exclusion criteria, followup, and outcome assessment used in the
randomized clinical trial were applied.

Research

TABLE 1

Baseline characteristics of study population during randomization

Randomization

Characteristic

Placebo
(n 28)

Doxycycline plus
metronidazole
(n 28)

Age, y (mean SD)

28.2 7.7

25.9 6.2

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

Ethnicity, n

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

Caucasian

16

15

Afro-Brazilian

12

13

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

Days admitted at hospital (mean SD)

3.2 1.1

3.0 0.9

Days of intravenous antimicrobial (mean SD)

2.6 0.8

3.0 1.0

History of intrauterine manipulation with

nonsterile probes, n

Foul-smelling vaginal discharge, n

Pus in cervix, n

Abdominal rebound tenderness, n

11

14

Warm extremities, thready pulse, and

tachycardia, na

Cyanosis and/or paleness, n

Tachypnea (30 respiratory movements/min), n

14

12

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

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

Leukocytosis (14,000 leukocytes/mL), n

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

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

Arterial hypotension (systolic arterial pressure

90 mm Hg), n

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

Randomization
After signing the informed consent,
treatment allocation was dispensed according to a computer-generated randomization list, grouped in blocks of 4.
The allocation list was concealed until
interventions were assigned and coded.
The treatment assignment was then
communicated, via telephone, from a
central location. All study personnel and
participants were blinded to treatment
assignment for the duration of the study.
Treatment was given by one of the authors (G.S.M. or R.A.C.).
Statistical methods and ethical issues
Fisher exact test and descriptive analysis
were used for statistical analysis. The
outcome was analyzed using rates of cure
in intention to treat and per protocol
with 95% confidence intervals (CIs). For
0 events, ie, 100% of cure, the method of
Hanley and Lippman-Hand12 of probability for 95% CI was used. The following
formula was applied: (3/n), where n
number of cases in the group with 0
events. Adherence included exposure to

Oliguria, n

16

18

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

Fever (37.8C), n

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

Some patients had 1 characteristic.

a

Tachycardia defined as 110 beats/min.

Savaris. Antibiotics in infected/septic abortions. Am J Obstet Gynecol 2011.

treatment, availability of measurements,

and absence of protocol violations. The
study protocol followed the CONSORT
guidelines.13 It was approved by the ethics committee of Hospital de Clnicas de
Porto Alegre (number 05-452), and is
registered at ClinicalTrials.gov, number
NCT00353743. In Brazil, Data and Safety
Monitoring Committees (DSMCs) are
usually not appointed in studies, unless
there is pharmaceutical company involvement. This function is performed by the
local institutional review board instead.
Furthermore, little literature on DSMCs
has been published, and guidelines for
managing or serving on such committees
are almost nonexistent. No guide or textbook about DSMC functions has been
written to date, although one such text is in
production.14

R ESULTS
From May 2006 through November
2007, 60 patients with a diagnosis of septic abortion were admitted to Hospital
de Clnicas de Porto Alegre. Of these, 56
were eligible for the study and were randomized. The Figure depicts details of
the randomization. In November 2007,
the first interim analysis was conducted
on 56 patients. There were no clinical
failures in either arm (absolute risk difference, 0; 95% CI, 0.0 0.1). Characteristics of the sample before randomization are in Table 1. A woman from the
placebo group, who returned the medication without taking it, constituted the
only protocol violation. She had a clinical cure. There were no serious adverse
events experienced by any patient after
hospital discharge. Furthermore, 28 pa-

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TABLE 2

Characteristics of study population during observational study

Characteristic

Observational
(n 75)

Age, y (mean SD)

27 6.19

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

Ethnicity, n

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

Caucasian

54

Afro-Brazilian

21

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

Days admitted at hospital (mean SD)

3.2 2.3

Days of intravenous antimicrobial (mean SD)

3.2 2.3

History of intrauterine manipulation with nonsterile probes, n

Foul-smelling vaginal discharge, n

Pus in cervix, n

Abdominal rebound tenderness, n

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

Leukocytosis (14,000 leukocytes/mL), n

52

..............................................................................................................................................................................................................................................
a

Warm extremities, thready pulse, and tachycardia, n

Cyanosis and/or paleness, n

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

Tachypnea (30 respiratory movements/min), n

Arterial hypotension (systolic arterial pressure 90 mm Hg), n

Oliguria, n

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

Fever (37.8C), n

30

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

Some patients had 1 characteristic.

a

Tachycardia defined as 110 beats/min.

Savaris. Antibiotics in infected/septic abortions. Am J Obstet Gynecol 2011.

tients in each arm, with a 0 event, yielded

a probability of failure up to 10% with a
95% CI, which was in accordance to the
initial d.
From December 2007 through June
2010, 75 consecutive patients with uncomplicated septic abortion, using the
same inclusion criteria, were discharged
without medication, and were reviewed
10 days later. There were no losses to
follow-up. All additional observational
cases had clinical cures. According to
the method of Hanley and LippmanHand,12 the probability of an adverse
event is 3% (95% CI, 0 0.03). Characteristics of the observational cohort after the trial suspension are in Table 2. No
serious adverse events were seen in this
group.

C OMMENT
All (100%) of the 103 patients with
uncomplicated infected/septic abortion
treated with intravenous antibiotics fol301.e4

lowed by uterine evacuation had clinical

cure, using a short treatment protocol.
The strengths of the study are few. It is
a randomized, double-blind study reflecting a clinical practice, with an adequate randomization method, an excellent follow-up, a priori specified interim
analysis, which is important to evaluate
initial suppositions about rate of cure.
Sample size can be increased or reduced
after the first interim analysis. Special attention was given to the sample size calculation to give enough power in an
equivalence trial. The reasoning of an
equivalence trial is different from the superiority trials. Instead of rejecting the
null hypothesis, where the percentage of
both treatments is equal, researches want
to prove that it is true. Due to the intrinsic properties of the formula proposed
by Blackwelder,9 treatment with high
rate of cure (ie, 99%) in both arms would
require a smaller sample size, if the d is
10%. That was the case in this study.
With a sample size of 56 patients, consid-

American Journal of Obstetrics & Gynecology APRIL 2011

ering a 99% rate of cure in both arms, an

error of 0.2, and a power of 90%, 26
patients would be necessary in each arm
to have statistical power. With these parameters we were able to state that we are
90% sure that there is no difference
10% between both groups, with a 97%
CI. However, a 10% difference should be
considered too high, and this is a weakness of the study. To reduce this 10% difference, we faced another problem. The
institutional review board determined
that it would be unethical to continue
using standard treatment. Thus, the alternative to increase sample size would
be an observational cohort in the short
treatment group. Thus, from November
2007 through June 2010, an additional
75 cases of uncomplicated infected/septic abortion who received no treatment
after hospital discharge were followed up
in the same manner as the initial 56 patients from the clinical trial. No clinical
failures were observed in these patients,
which was reassuring. Therefore, using
these results from the short treatment
protocol, we are able to state that in 95%
of the cases, we expected to find a rate of
cure of between 97-100%, and that
seems to be an adequate CI.
The implications of the study can be
quite important in terms of reducing
time of hospital stay and antibiotics. The
Brazilian Health Ministry recommendation for infected abortion is 7-10 days of
intravenous, broad-spectrum antibiotics,4 while the WHO recommendation
for infected abortion5 is similar to the
CDCs recommendation for pelvic inflammatory disease, where treatment
would last up to 14 days.6
The mechanisms that might explain
these outcomes could be the same as those
found in the study reported in the Cochrane systematic review on endometritis
after delivery.7 The removal of infected tissue would be enough to reduce the period
of antibiotic use. Endometrial culture was
not performed because of the polymicrobial nature of these infections, as demonstrated by other authors.15-17 For that reason, we believe that the rates of cure found
in our study are comparable to those published by French and Smaill,7 in cases of
postpartum endometritis after caesarean
section or vaginal birth.

www.AJOG.org
To our knowledge, this is the first report pertaining to the non-use of antibiotics, after hospital discharge, in patients
with uncomplicated septic abortion.
Hence we are unable to draw any comparison with other studies. Since the
point of entry into the study was at hospital discharge, the average stay in hospital for both groups was 3 days. In light of
our results, we have stopped giving antibiotics to patients with uncomplicated
septic abortion after 48 hours of clinical
improvement.
This trial questions the need for long
periods of treatment with oral antibiotics after clinical improvement in patients
with uncomplicated septic abortion. It
should be used as a reference for further
research.
f
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