1. Intrauterine Exposure to Opioids and Pregnancy Outcomes
– a Prospective Motherisk Cohort Study
Xiaoyun Lu1,2, Tom Leibson1, Pina Bozzo1, Gideon Koren1,2
The safety of opioids as therapeutic
analgesics in pregnancy is a controversial topic.
Although the safety profiles of non-opioids
medication are thoroughly documented,
sometimes it is not practical to prescribe non-
opioid analgesics due to the insufficiency in pain
relief. With increasing numbers of pregnant
women in need of effective analgesics, it is
essential to inquire whether maternal treatment
with opioids is associated with an increased rate of
congenital malformations or pregnancy or
neonatal adverse events.
Introduction
Motherisk Program is a teratogen
Information Service located in Toronto, Canada. The
Motherisk database was searched for women who
contacted our service during their pregnancy or while
they were planning their pregnancy regarding safety of
therapeutic use of medications. Several months after
delivery the women were contacted to complete a 20-
30min pregnancy outcome questionnaire.
Women without history of drug abuse or
exposure to known teratogens were included in the
study. The pregnancies were divided into three groups:
 women who used opioid-containing medications for
pain or cough during any stage of their pregnancy;
 women who used non-opioid analgesics for
management of pain or cough
 women who did not use an analgesic during their
pregnancy.
These three groups were then compared
for pregnancy outcomes.
Methods
In our cohort study, the
therapeutic use of opioids during pregnancy
did not elevate the rate of congenital
malformations above the baseline risk. A
significant decrease in birth weight was
observed with exposure to opioids beyond
the 1st trimester of pregnancy. For women
who use opioids chronically, it may be of
clinical value to re-examine the necessity of
opioids prior to the 2nd and 3rd trimester.
However, further investigation with a larger
cohort is required to examine these
associations.
Conclusion
In this cohort study, the use of
opioids-containing medications during
pregnancy failed to show significant
association with increased malformation rate
and any increased incidence of adverse
pregnancy and neonatal events.
However, maternal exposure to
opioids during 2nd and 3rd trimesters was
reported to have an influence on birth weight.
During the 2nd and the 3rd trimesters, the fetus
grows sufficiently in length and weight. As well
the central nervous system continues to
develop. Our result may indicate that the
exposure to opioids in the later stages of
pregnancy may influence the proper process of
fetal growth, including the weight gain.
Although the impairment may not cause
stillbirth or fetal death, it may be worth
monitoring the usage of opioids in late
pregnancy.
LIMITATIONS
 The sample size is relatively small, therefore
the results are not powerful enough, and also
limits further analysis of individual opioids
 As a lot of data was collected at the follow-
up calls, which were made at least 4-6 months
after the expected delivery date, recall bias
may had an effect on the answers we received.
Discussion
1Motherisk Program, the Division of Clinical Pharmacology & Toxicology, the Hospital for Sick Children, Toronto, ON,
Canada; 2Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON, Canada
Figure 1. After the initially collection of the pregnancy
outcomes for the three groups, the unqualified
subjects were ruled out according to the inclusion and
exclusion. The remaining subjects’ data were used for
further analysis.
Results
Following intrauterine exposure to opioid-containing
medication, there was no significant increase in the rate of major or
minor malformations, miscarriages, stillbirths, prematurity
(<37weeks), low birth weight (<2.5kg), admission to NICU and/or SCN
and neonatal death (see Table below).
When examining the timing of opioid cessation in the
opioid group, a decrease in birth weight is observed (p=0.019) in
pregnancies that continued opioid use after first trimester (Figure 2).
Pregnancy Outcomes
Interested
Outcome
Opioids
Exposure
Non-Opioids
Exposure
No-Exposure
Control
p-value
Malformations
[N(%)] 6 (5.00%) 5 (5.38%) 4 (3.45%) 0.8192
Miscarriages [N(%)] 3 (2.50%) 2 (2.15%) 7 (6.03%) 0.2322
Stillbirth [N(%)] 2 (1.67%) 0 (0.00%) 0 (0.00%) 0.1792
Prematurity [N(%)] 10 (8.33%) 4 (4.30%) 8 (6.90%) 0.4692
Average Birth
Weight(kg) 3.342 3.308 3.378 0.6631
Low Birth Weight
[N(%)] 7 (5.83%) 4 (4.30%) 4 (3.45%) 0.5292
NICU Admission
[N(%)] 7 (5.83%) 4 (4.30%) 6 (5.17%) 0.8662
SCN Admission
[N(%)] 9 (7.50%) 1 (1.08%) 5 (4.31%) 0.0792
Significance level α = 0.05
1 One-way ANOVA; 2 Pearson χ2 Tests
3.554
(n=28)
3.328
(n=29)
3.256
(n=54)
3.378
(n=109)
3.308
(n=89)
2.6
2.8
3.0
3.2
3.4
3.6
3.8
1st 2nd 3rd No Exposure Non-opioids
Exposure
Birthweight(kg)
Trimester Opioids was stopped
Figure 2. Average Birth Weight Linked to
the Timing of Medication Cessation
Obtained Follow-up of Pregnancy Outcomes (2008-13)
• Opioid Exposure – 130
• Non-opioid Exposure – 97
• No Exposure Control – 121
Excluded cases with
missing data in exposure
(n=3)
Excluded mothers with
pre-existing or gestational
diabetes mellitus in
pregnancy (n=15)
Excluded mothers with
age below 20 or above
45 (n=2)
Excluded pregnancy
outcome of twins (n=8)
Analyzed Pregnancy Outcomes
• Opioid Exposure – 120
• Non-opioid Exposure – 93
• No Exposure Control – 116
Codeine
N=73 (60.8%)
Multiple
N=12 (10.0%)
Fentanyl
N=1 (0.8%)
Morphine
N=4 (3.3%)
Hydrocodone
N=7 (5.8%)
Oxycodone
N=23 (19.2%)
Figure 2. Classification of
Opioids usage during
pregnancy. Multiple refers
to the group of women who
exposed to two or three of
those five kinds of opioids
during pregnancy.
Results cont’d
Subject Selection
Classification of Opioids