Diapositive 1 - WorldPharma 2010

First-trimester exposure to
tramadol:
A prospective comparative study
A . G O U R A U D , M . N . B E Y E N S , M . B O Y E R , P . C A R L I E R ,
M . A . T H O M P S O N , T . V I A L
A N D T H E N E T W O R K O F F R E N C H P H A R M A C O V I G I L A N C E C E N T R E S

Tramadol during pregnancy: what is known?
• Tramadol is a synthetic analogue of codeine use to treat
moderate to severe pain.
• Animal teratogenicity studies were negative in all tested
species whatever the dose
• In pregnant women:
◦ Shown to be safe when used during labor.
◦ No documented studies on the safety of tramadol in early pregnancy
Other analgesics such as codeine or propoxyphene should be
preferred during the first trimester of pregnancy.
• Is tramadol a potentially safe alternative in case of
propoxyphene withdrawal ?

A French collaborative study
• Prospective comparative study using data collected by
participating French pharmacovigilance centers.
• Objectives:
◦ Primary objective:
To evaluate the rate of (major or minor) congenital malformations
following exposure to tramadol during early pregnancy.
◦ Secondary objectives:
To evaluate the rate of spontaneous or voluntary abortions
To describe the characteristics of neonates

Method
● Inclusion criteria
◦ Exposure to tramadol during embryogenesis (weeks 4 to 12 after LMP)
◦ Only pure prospective cases with data collected before week 22, i.e
before the level II US.
● Data collection was performed by phone or mail
◦ At the time of request for risk evaluation.
◦ Within 2-3 months after the expected date of delivery.
● Control group:
Healthy women counseled after a non-teratogenic exposure.
● Data collected from 1997 to 2009

Matching
1 exposed woman 2 control women
Age ± 2 years
Matched for:
Gestational age at time of first request ± 1 week
Nearest calendar date

Maternal baseline characteristics
Exposed
N= 146
Controls
N = 292
p value
Maternal age
(years: mean ±SD)
Gestational age
(weeks after LMP)
31.1 ± 5.5 30.8 ± 5.1 0.7
9.5 ± 4.5 9.7 ± 4.5 0.7
Previous history of
spontaneous abortion
19.4%
(/108)
15.6%
(/263)
0.4
Gestity
(mean ±SD)
1.71 ± 1.77 1.33± 1.32 0.023
Parity
(mean ±SD) 1.24± 1.37 0.98± 1.02 0.049

Characteristics of exposure
Indications or purpose :
Low back pain: 34.3%
Post-operative pain: 15.7%
Not stated: 31.1%
Others: 18.9% including
• 4 Suicidal attempts
• 1 Maternal addiction
Mean daily dose (n=79) :
188 ±171 mg
Tramadol-only exposure:
17%
50
45
40
35
30
25
20
15
10
5
0
Treatment duration (n=119)
45.6%
21.4%
20.4%
12.6%
Exposure between 0 and 7
weeks : 77.5%
single dose
2-7 days
7-30 days
>30 days

Outcome:
Elective or medical abortion
Exposed
Elective abortion: 9.6% (14)
Medical abortion: 2.7% (4)
p=0.01
Control
Elective abortion: 3.4% (10)
Medical abortion: 0.7% (2)
Statistically more abortions in exposed group than in control group.
Medical abortion:
‣ Exposed group (4):
• 3 because of fetal anomalies
-2 Down’s syndrome
- 1 polyskeletal malformation
• 1 because of severe maternal disease
‣ Control group (2): 2 Down’s syndrome

Spontaneous abortion
Exposed: 21 (14.4%)
Control: 10 (3.4%)
p

Live births
Exposed
Control
Live birth
108 (74%)
3 sets of twins
267 (91%)
5 sets of twins
Malformations
(major and minor)
5/104 (4.8%)
Major: 2
Minor: 3
15/261 (5.7%)
Major: 4
Minor: 11
RR= 0.84
(IC 95% : 0.31-2.24)
Gestational age
(weeks after LMP)
39 ± 2.4 39 ± 2.9 p=1
Prematurity rate
(

Major congenital malformation
(chromosomal anomalies excluded)
Malformation
Hydronephrosis
Tramadol
exposure
Up to 9 weeks
after LMP
Other risk
factor or drug
exposure
during
embryogenesis
Paternal exposure
to methotrexate
Camptodactily and
skeletal anomalies
Up to 19 weeks
after LMP
Maternal low
dose methotrexate
therapy (RA) until
19 weeks
Medical abortion

Neonatal outcome: withdrawal syndrome
• Neonatal withdrawal symptoms were reported in two neonates
exposed during the whole pregnancy
◦ A premature female (2,110 g) delivered at 36 weeks from a tramadoladdicted
mother (daily dose of tramadol ≥300mg) experienced :
transient neonatal hypoglycemia at H2
an episode of seizure at H48 and myoclonic movements during 48h (normal
EEG)
◦ A full-term male (3,490g) delivered at 39 weeks from a mother treated
for headache with a maternally reported daily dose of 50mg, experienced
irritability and hyperexitability during his first days of life.
• First description in 1997 (Meyer et al.). Since then at least 2
others published reports involving premature newborns in 2
cases and with a mean maternal daily dose of >350mg.

Conclusion
Main limitation : relatively small size sample
Main results :
• Exposure to tramadol does not appear to be associated with an
increased risk of MCM, low birthweight or prematurity.
• Short exposure appears as a safe alternative to propoxyphene for the
management of severe pain during the early stage of pregnancy.
• High daily dose and/or exposure throughout pregnancy should be
taken into account owing to the risk of neonatal withdrawal symptoms.