David Armstrong Ma

FRCPC Alan Br Thomson

MD John K Marshall

PhD FRCPC Frcp Facg

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Omeprazole for refractory
gastroesophageal reflux disease
during pregnancy and lactation
John K Marshall MD FRCPC, Alan BR Thomson MD PhD FRCPC FRCP FACG, David Armstrong MA MRCP(UK) FRCPC
Symptomatic gastroesophageal reflux disease (GERD)complicates 30% to 80% of all pregnancies. It is a com-
mon reason for physician consultation during pregnancy (1),
but, in the majority of patients, reflux symptoms resolve rap-
idly after delivery (2). For many patients, lifestyle modifica-
tion measures are effective, and oral antacids or alginates can
be administered without significant risk to the developing
fetus (3). Although few rigorous trials of antireflux therapies
in pregnancy have been performed for ethical reasons, the
available evidence supports the use of H2 receptor antago-
nists (H2RA) or sucralfate in selected patients (1,3-7). In
nonpregnant patients, proton pump inhibitors (PPIs) are sig-
nificantly more effective than either prokinetic agents such
as cisapride or H2RAs, particularly for refractory GERD.
There are, however, few data on their safety and efficacy dur-
ing pregnancy and lactation. We report a patient who re-
quired therapy with oral omeprazole during the third
trimester of pregnancy and postpartum without any apparent
adverse effect, and present data on the excretion of omepra-
zole in breast milk.
CASE PRESENTATION
A 41-year-old primipara was referred to the gastroenterology
service at 19 weeks of gestation because of worsening symp-
toms of gastroesophageal reflux refractory to treatment with
an H2RA and a prokinetic agent. She first developed inter-
Can J Gastroenterol Vol 12 No 3 April 1998 225
JK Marshall, ABR Thomson, D Armstrong. Omeprazole for re-
fractory gastroesophageal reflux disease during pregnancy and
lactation. Can J Gastroenterol 1998;12(3):225-227. Sympto-
matic gastroesophageal reflux is a common complication of preg-
nancy and lactation. However, the safety of many effective
medical therapies, including oral proton pump inhibitors, has not
been well defined. The administration of oral omeprazole to a 41-
year-old female during the third trimester of pregnancy, after rani-
tidine and cisapride failed to control her refractory gastroesophag-
eal reflux, is reported. No adverse fetal effects were apparent, and
the patient elected to continue omeprazole therapy (20 mg/day)
while breastfeeding. Peak omeprazole concentrations in breast milk
(58 nM, 3 h after ingestion) were less than 7% of the peak serum
concentration (950 nM at 4 h), indicating minimal secretion. Al-
though omeprazole is a potentially useful therapy for refractory
gastroesophageal reflux during pregnancy and lactation, further
data are needed to define better its safety and efficacy.
Key Words: Gastroesophageal reflux disease, Lactation, Omepra-
zole, Pregnancy, Proton pump inhibitors
L’oméprazole pour le reflux gastro-œsophagien
réfractaire durant la grossesse et l’allaitement
RÉSUMÉ : Le reflux gastro-œsophagien symptomatique est une compli-
cation pendant la grossesse et l’allaitement. Or, l’innocuité de nombreuses
thérapeutiques efficaces, y compris celle des inhibiteurs de la pompe à
protons, n’a pas encore été clairement définie. On dresse ici le bilan d’un
traitement oral à l’oméprazole chez une parturiente de 41 ans, au troisième
trimestre de la grossesse, après l’échec de traitements à la ranitidine et au
cisapride pour un reflux gastro-œsophagien réfractaire. Aucun effet
indésirable n’a semblé affecter le fœtus et la patiente a choisi de continuer
son traitement à l’oméprazole (20 mg/jour) pendant l’allaitement. Les
concentrations de pointe d’oméprazole dans le lait maternel (58 nM,
3 heures après son administration) équivalaient à moins de 7 % des
concentrations plasmatiques de pointe (950 nM après 4 heures),
représentant une sécrétion minime dans le lait. L’oméprazole pourrait se
révéler utile dans le traitement du reflux gastro-œsophagien réfractaire
durant la grossesse et l’allaitement, mais il faudra accumuler d’autres
données pour avoir une idée plus précise de son innocuité et de son
efficacité.
Division of Gastroenterology, McMaster University, Hamilton, Ontario; and Division of Gastroenterology, University of Alberta,
Edmonton, Alberta
Correspondence: Dr David Armstrong, Division of Gastroenterology (HSC-4W8), McMaster University Medical Centre, 1200 Main Street
West, Hamilton, Ontario L8N 3Z5. Telephone 905-521-2100 ext 3495, fax 905- 521-4958, e-mail armstro@fhs.csu.mcmaster.ca
Received for publication December 8, 1997. Accepted March 13, 1998
BRIEF COMMUNICATION
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mittent nocturnal heartburn at the age of 26 years following
an open cholecystectomy for cholelithiasis. There was no
other medical history of note. Over the following 15 years,
her symptoms were intermittent, requiring only occasional
short courses of oral ranitidine. A gastroscopy at age 32 was un-
remarkable, and a barium meal revealed only a hiatus hernia.
Eight weeks after conception, the patient developed noc-
turnal heartburn, which became severe by the 12th gesta-
tional week. A four-week course of oral ranitidine (150 mg
every night) and a subsequent two-week course of cisapride
(10 mg three times daily) produced no symptomatic relief.
Gastroscopy, performed at 20 weeks because of worsening
symptoms and frequent vomiting, revealed grade 2 esophagi-
tis (8) and bile staining of the gastric mucosa. At 23 weeks,
combination therapy with ranitidine (150 mg bid) and cisa-
pride (10 mg four times daily) was initiated because of refrac-
tory heartburn and nausea. However, her symptoms
progressed and became intolerable by the 29th week, with
continuous heartburn and nausea, and intractable vomiting.
Monotherapy with omeprazole (20 mg once daily) was then
prescribed and produced significant symptomatic improve-
ment, with only mild intermittent residual heartburn, mini-
mal nausea and no vomiting. At 35 weeks’ gestation, she
was admitted to the obstetrical service for management of
pregnancy-induced hypertension. In the 36th week, a
healthy male child was delivered, requiring outlet forceps for
fetal bradycardia. Apgar scores were 6 and 9 at 1 and 5 mins,
respectively.
Postpartum, the patient elected to breastfeed her infant
despite persistent severe reflux symptoms that necessitated
ongoing administration of omeprazole (20 mg once daily).
As a precaution, the patient fed the child just before taking
her omeprazole dose at 08:00 h, then refrained from nursing
for 4 h before expressing and discarding her breast milk at
midday. The patient chose to wean her child at three
months. Twelve months later she continues to take omepra-
zole as maintenance therapy, and both she and her child re-
main well.
Three weeks following the delivery, the patient con-
sented to provide serial timed samples of blood and expressed
breast milk for analysis. Baseline samples were collected at
08:00, then the remaining samples were collected at 30 min
intervals over 4 h following ingestion of a single 20 mg tablet
of omeprazole. Blood samples were centrifuged immediately,
and the separated serum stored at –40°C along with the milk
samples before shipment for laboratory analysis. Omeprazole
concentrations in maternal serum and breast milk were
determined with high performance liquid chromatography
with a detection threshold of 10 nM (9). The maternal serum
concentration of omeprazole was negligible until 90 mins after
ingestion and reached 950 nM at 240 mins (Figure 1). The
breast milk concentration of omeprazole began to rise
90 mins after ingestion but peaked after 180 mins at 58 nM,
which was less than 7% of the highest serum level.
DISCUSSION
We report the successful use of omeprazole for treatment of
refractory GERD during the third trimester of pregnancy and
during lactation, without evidence of adverse effect to
mother or child. Omeprazole was highly effective in a pa-
tient refractory to ranitidine and cisapride, both alone and in
combination.
Considerable evidence supports the use of intravenous
omeprazole before emergency caesarean section as prophy-
laxis against acid aspiration (10,11). However, support for
the safety of PPIs earlier in pregnancy remains largely anec-
dotal. The predominant concerns about the safety of PPIs in
women of childbearing age relate to the possibility that ther-
apy may affect the fetus, either directly by placental transfer
of the PPI or indirectly because of the rise in maternal serum
gastrin that accompanies reduced acid secretion. In the post-
partum period, an additional concern is that omeprazole ex-
creted in breast milk might be absorbed and produce
significant inhibition of acid secretion in the infant.
Animal studies suggest that placental transfer may expose
the fetus to plasma omeprazole levels of approximately one
half those detected in the mother (12). However, it is not
known whether omeprazole is teratogenic. Tsirigotis et al
(13) reported two consecutive pregnancies resulting from in
vitro fertilization in a woman who was taking oral omepra-
zole covertly at the time of each implantation. The first preg-
nancy was terminated when an ultrasound revealed
anencephaly, and the second was terminated for severe tali-
pes. Although the authors of that study urged caution in pre-
scribing omeprazole in early pregnancy, several other case
reports have documented ingestion of a PPI during the first
trimester with no apparent adverse fetal effects (14-17).
Similarly, no complications have been reported following
the administration of omeprazole in the third trimester (15-
18), as was the case in our patient.
Although the potential long term trophic effects of gas-
trin are unknown, maternal and fetal serum gastrin levels are
normally elevated during pregnancy (19,20), and there have
been no reports of untoward sequelae among children born
to mothers with the Zollinger-Ellison syndrome (15). Fur-
thermore, maternal gastrin may not cross the placenta (21).
Before receiving omeprazole, our patient received raniti-
226 Can J Gastroenterol Vol 12 No 3 April 1998
Marshall et al
Figure 1) Omeprazole concentrations in maternal serum and breast
milk up to 4 h after ingestion of a 20 mg tablet
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dine and cisapride without apparent ill effect, but also with-
out any benefit. Relatively good evidence exists to support
the safety of H2RA agents during pregnancy (1,3,4,6,7).
However, significant placental transfer of cisapride has been
demonstrated in animal models, and cisapride is excreted in
human breast milk (22,23). Only a handful of case reports
support the use of prokinetics such as cisapride and domperi-
done during pregnancy (24,25).
The concentration of omeprazole in breast milk has not,
to our knowledge, been reported previously. Because breast
milk has a slightly lower pH than that of plasma, it might be
anticipated that weak bases such as omeprazole would
achieve higher concentration in breast milk. However,
because omeprazole is highly protein-bound in plasma, it
could be argued that only a small fraction is available for dif-
fusion and that the actual concentration in breast milk is low
(12). In support of the latter hypothesis, we demonstrated a
peak concentration of omeprazole in expressed breast milk of
58 nM, 3 h after ingestion of a 20 mg tablet. This was less
than one-10th the mother’s peak plasma level. If a 5 kg in-
fant were to consume 200 mL of breast milk per day, our data
suggest that the maximum daily omeprazole ingestion would
be 4.0 µg. This intake, equivalent to 0.80 µg/kg (omeprazole
molecular weight 345.438), would be less than 1% of the
usual adult dose of 200 to 400 µg/kg. Furthermore, omepra-
zole is unstable in an acid environment, with a half-life of
less than 10 mins at pH values below 4 (26). In the absence
of the enteric coating used in oral formulations of omepra-
zole, the acid contents of the newborn infant’s stomach
would inactivate the small amount of omeprazole present in
breast milk (27). Thus, it is expected that the omeprazole re-
ceived by a breastfed infant would have a negligible effect on
acid secretion.
CONCLUSIONS
This case report documents the successful use of oral ome-
prazole for refractory GERD during pregnancy and the ab-
sence of complications attributable to therapy with
omeprazole, ranitidine and cisapride. It also demonstrates
that there is minimal excretion of omeprazole in human
breast milk during lactation. Because symptomatic GERD is
a common and disabling complication of pregnancy, further
studies are needed to assess the safety and efficacy profiles of
PPIs in the management of GERD that has not responded to
lifestyle modification, H2RAs and/or prokinetics.
ACKNOWLEDGEMENTS: The authors thank Dr B Brennan for
her kind cooperation in allowing them to report this case, Mrs
Cindy James for her invaluable help in collecting the samples and
Dr Monika Keelan for her assistance in performing the omeprazole
measurements.
Can J Gastroenterol Vol 12 No 3 April 1998 227
Omeprazole in pregnancy and lactation
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Omeprazole for refractory gastroesophageal reflux disease during pregnancy and lactation

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Omeprazole for refractory gastroesophageal reflux disease during pregnancy and lactation

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