Clinical & Experimental Allergy Reviews, 12, 31–36

© 2012 Blackwell Publishing Ltd

REVIEW

Treatment of allergic rhinitis during pregnancy

Kodo Sato
Department of Gynecology, Meirikai Chuo General Hospital, Tokyo, Japan

Summary
Clinical & Many women suffer from allergic rhinitis (AR). The disease is often pre-existing and
Experimental sometimes coincidental during pregnancy, and can worsen, improve, or stay the same
during pregnancy. Besides ameliorating the detrimental effects of AR on the patient’s
Allergy Reviews quality of life, correct treatment is important for controlling concomitant asthma. If possi-
ble, it is important to highlight the risks of not taking such medications at a pre-concep-
tion visit. Although most medications for AR readily cross the placenta, there are several
choices of treatment for controlling the symptoms during pregnancy. The choices may be
varied depending on the disease course and symptoms, and inhaled corticosteroids are
Correspondence: considered to be the first-line medical treatment. In addition, either a first-generation
Kodo Sato
antihistamine, such as chlorpheniramine, or a second-generation antihistamine, such as
Department of Gynecology, Meirikai
Chuo General Hospital, cetirizine or loratadine, can be prescribed as the second-line medical treatment. As an
3-2-11 Higashi Jyujo, Kita-ku, alternative, intranasal cromolyn can be prescribed safely. Some of the leukotriene receptor
Tokyo 114-0001, Japan. antagonists and nasal decongestant sprays can only be prescribed when other methods
are no longer valid and strict benefits can be expected. It is considered safe to continue
Conflicts of interest: The author has immunotherapy during pregnancy.
received travel assistance and an
honorarium for a talk from Nippon Keywords allergic rhinitis, antihistamine, corticosteroid, decongestant, immunotherapy,
Boehringer Ingelheim, Co., Ltd. leukotriene receptor antagonist, pregnancy, prescription, teratogenicity

risk communications concerning medical treatments

Introduction
during pregnancy.
Numerous pregnant women suffer from allergic rhinitis The purpose of this review is to summarize the recent
(AR). The disease is often pre-existing and sometimes data regarding the risks associated with drugs pre-
coincidental during pregnancy [1], and may worsen, scribed for AR. I will also discuss the drug safety infor-
improve, or stay the same during pregnancy [2]. Besides mation service for pregnant women in Japan.
ameliorating the detrimental effects of AR on the
patient’s quality of life (QOL), correct treatment is
General principles of prescription in pregnancy
important for controlling concomitant asthma [3].
Discussions with pregnant women about their treat- It can be difficult and stressful for clinicians to prescribe
ment are particularly important for compliance and drugs for pregnant women, especially because of the
concordance by eliminating unnecessary anxiety. The lack of evidence-based information. In particular, data
primary concerns of pregnant women are focused on on the long-term effects of drug exposure during the
the risks of taking medications. Consequently, it is fetal period are almost completely lacking. For example,
important to discuss these issues thoroughly, and to there is reasonably sufficient data for the teratogenicity
highlight the risks of not taking the medication before of first-generation antihistamines, but data regarding
prescription as well as the potential hazards of the med- their effects on postnatal physical and psychological
ication for the fetus. When the disease is pre-existing, development and learning ability are few. Recently, the
adequate discussions are required before conception. intrauterine environment has been proposed to have a
Even if the patient is not planning to become pregnant, permanent impact on the determination of the funda-
such discussions are required because of the high mental processes of life, such as hypertension [4]. We
chance of unexpected pregnancy. Health care providers still have very limited knowledge about the long-term
are therefore requested to train their skills for proper effects of drug exposure during the fetal period.
32 K. Sato

With these points in mind, no treatment and non- ter of pregnancy, fetal malformations do not tend to be
specific measures should be evaluated and discussed caused by drugs, but fetotoxicity, such as increased
thoroughly before starting medical treatment. For AR, fetal and infant mortality, impaired physiological func-
avoiding known irritants or triggers, such as pollen, tion, alterations to growth, increased preterm or post-
dust mites, pets, and smoking, is important. An external term birth, and perinatal symptoms of drug intoxication
nasal dilator or humidification are also among the pos- or withdrawal, may be caused by drugs. Even after the
sible non-specific measures. second trimester, abnormal morphologies of fetal
If no treatment and non-specific measures are not organs may be caused by drugs through breakdown of
effective, and the patient’s QOL is highly impaired and normally developed organs. This mechanism is known
limited, there is no need to hesitate before prescribing as disruption, and may be caused by drugs that can
drugs for AR. However, it is preferable to avoid newly damage the fetal vascular system. Thus, the susceptibil-
developed drugs, such as leukotriene receptor antago- ity of a fetus to an agent and the subsequent outcome
nists, because of the lack of available human data. of exposure to the agent vary with the developmental
The drug effects on a fetus can be divided into sev- stage at which the exposure occurs, meaning that the
eral types which relate to the exposure time during timing of exposure is another important factor for con-
pregnancy (Fig. 1) [5]. First, until about 2 weeks after sideration when prescribing drugs for pregnant women.
conception (i.e., until about 4 weeks of pregnancy, For example, drugs with teratogenic effects on the fetus
since pregnancy weeks are calculated using the first should preferably be avoided during the first trimester.
day of the last menstrual period as week 0 of preg- When prescribing drugs during pregnancy, one
nancy), exposure to a teratogen produces an all-or- should keep in mind that almost all drugs are able to
none effect. This means that a conceptus usually either pass through the placenta, with the exception of those
does not survive or survives without anomalies even with molecular weights of > 1,000 g/mol, such as insu-
when detrimental effects occur, and as a result, no fetal lin and heparin. As shown in Table 1, the molecular
malformation can be caused by exposure to drugs dur- weights of all the drugs mentioned in this review are
ing this period. After 4 weeks of pregnancy, organogen- below 1,000 g/mol [6]. This means that the drugs pre-
esis of the main fetal organs, such as the neural tube, scribed for the mother’s benefit may be delivered to the
heart, limbs and so on, starts and continues until about fetus without any direct benefit.
7 weeks of pregnancy. During this critical period, tera- Besides the placental passage of drugs, the route of
togenic drugs may cause malformations of the organs administration, i.e. systemic or topical, is sometimes
developing at the time of drug exposure. For a few important, because any drug can adversely affect fetal
weeks after this period, the palate and external genitalia development by passing through the placenta from the
still continue to differentiate. Corticosteroids during this maternal blood circulation. In other words, the maternal
period may cause cleft palate. After the second trimes- blood concentrations of a drug are important. Topical

May be able Delivery

Fertilization
to survive
outside of
the uterus
Sensitivity to
teratogens

Fetotoxicity

Gestational age 1 2 3 4 5 6 7 8 9 10 11
(month)
Gestational 0w0d 4w0d 8w0d 12w0d 16w0d 20w0d 24w0d 28w0d 32w0d 36w0d 40w0d
age (week/day)
3w6d 7w6d 11w6 15w6d 19w6d 23w6d 27w6d 31w6d 35w6d 39w6d 43w6d
d
Gestational age 0-27 29-50 51-84 85-112 113-delivery
(days)
Trimester First trimester Second trimester Third trimester

Effects Not Sensitive to Fetotoxicity/Fetal period

of sensitive/ teratogens
drugs All-or-none /Organogenesis
on
fetus

Fig. 1. Pregnancy and fetal development and the effects of drug exposure.

© 2012 Blackwell Publishing Ltd, Clinical & Experimental Allergy Reviews, 12 : 31–36
 AR treatment during pregnancy 33

Table 1. Molecular weights of the drugs described in this review, the former case, the maximum benefits and minimal
taken from [6] risks are required, while in the latter case, possible
Drugs Molecular weight (g/mol) harmful effects of drugs on the fetus should be com-
pared with the 2–3% background risk of malformations.
Corticosteroids
Betamethasone 392
Dexamethasone 392 Drug safety information service for pregnant women in
Prednisolone 360 Japan
Prednisone 358
Budesonide 431 In April 1988, a pioneering clinic was opened at Toran-
Fluticasone 445 omon Hospital, located in the centre of Tokyo, for
First-generation antihistamines
counselling of patients who had been exposed to drugs
Diphenhydramine 255 during pregnancy. The majority of the attending women
Chlorpheniramine 275 visited the clinic with excessive anxiety relating to the
Clemastine 344 teratogenic effects of drug exposure while they were
Promethazine 284 unaware of their pregnancy. The clinic was operated by
Hydroxyzine 375 the Department of Obstetrics and Gynecology and
Dimenhydrinate 470 Department of Pharmacology. Several trained obstetri-
Second-generation antihistamines cians and pharmacists were engaged in the project.
Cetirizine 462 The mothers were usually referred to the clinic by
Desloratadine 311 attending physicians or visited directly. Initially, they
Fexofenadine 502 were asked to fill out questionnaires regarding the
Loratadine 383 name, dose, and duration of medications as well as
Leukotriene receptor antagonists
their history of past and current pregnancy. The obste-
Pranlukast 981 tricians and pharmacists reviewed evidence-based
Montelukast 586 reports, case reports, expert opinions, and animal stud-
Zafirlukast 576 ies. The staff tried to establish a database for the risks
of individual drugs, and tried to classify the teratogenic
Decongestants
risks into six grades (0–5). The drugs with epidemiolog-
Pseudoephedrine 165
Phenylephrine 167
ical studies showing no increase in the incidence of
Naphazoline 247 malformations and no animal studies indicating fetal
Oxymetazoline 260 damage were classified into grade 0. On the other hand,
when a drug was reported to significantly increase the
incidence of fetal malformations in epidemiological
administration of a drug with low absorption to the studies, the drug risk per se was classified as 5. The
affected site can maintain a significantly lower mater- data were updated and accumulated with every new
nal blood concentration than systemic administration. It consultation. The risks concerning gestational age of
is therefore important to select agents that are poorly drug exposure were also classified into six grades (0–5).
absorbed into the maternal circulation, when the same When the drug was taken during the period of 28–
benefit can be expected. Fortunately for pregnant 50 days after the first day of the last menstrual period,
women, the affected sites in AR are the nasal mucosa representing the critical period for major malforma-
and surrounding paranasal sinuses where drugs can be tions, the gestational age-related risk was assigned as 5.
delivered topically. And the risk was assigned as 0 for 0–27 days, repre-
Dose is another important point for consideration, as senting the period of all-or-none effect. In addition, the
there is a dose-response relationship between the dose risks were assigned as 3 for 51–84 days, 2 for 85–
of a drug and its teratogenicity or fetotoxicity. In gen- 112 days, and 1 for 113 days to delivery, since the
eral, the lowest effective dose of a single agent for the potential risk for malformation was reduced as preg-
shortest necessary period is recommended. nancy progressed after the critical period for major
Owing to differences in the regulations among coun- malformations.
tries, it is advisable to conform to the resident country’s By multiplying the two risk numbers assigned as 0–5,
regulations. In Japan, measures for prescription during scores of 0–25 could be obtained. These scores were
pregnancy are written on the drug information sheets assigned as the overall risk scores. Risk communications
provided by each manufacturer. between the staff and the mothers were carried out on
The contents of risk communications should differ a face-to-face basis for the overall risk. When the
for drugs before prescription and drugs already pre- overall risk score was above 20, the mother was
scribed to women who are unaware of pregnancy. In informed about the possibility of increased incidence of

© 2012 Blackwell Publishing Ltd, Clinical & Experimental Allergy Reviews, 12 : 31–36
34 K. Sato

malformations. In all cases, the baseline incidence of Japan Drug Information Institute in Pregnancy,
malformations without drug exposure, the possible National Center for Child Health and Development, was
harmful effects on the fetus by the mother’s illness per established in October 2005 as a national center for
se, and the benefits of the drugs were described in the information delivery, and 18 hospitals have been regis-
same setting. tered as cooperative hospitals to date.
Up to March 2007, i.e. for 20 years, a total of 8,982 Besides the national centre, a training system was
women visited the clinic [7]. Table 2 shows the top 20 started for Board Certified Pharmacists in Pharmaco-
categories of consulted drugs and the numbers of cases. therapy during Pregnancy and Lactation and Board Cer-
As consultations for anti-epileptic drugs, which are tified Pharmacy Specialists in Pharmacotherapy during
known to be teratogens, were rather rare and not Pregnancy and Lactation by the Japan Society of Hos-
among the top 20 categories, they are not shown in pital Pharmacists in 2008.
Table 2. Therefore, on suspicion, the attending physi- According to our experience, thorough discussions
cians had to explain about the risks and benefits of and complete risk communications before prescription
anti-epileptic drugs in advance of prescription, so that are essential for successful pharmacological interven-
pregnant women felt secure about taking these drugs. tion.
In contrast to anti-epileptic drugs, the drugs potentially
prescribed for AR, such as anti-allergic agents, anti-
Corticosteroids
histamines, and corticosteroids, were among the top 20
consulted drugs. It was suggested that women visited Synthetic corticosteroids administered to mothers are
the clinic not because of the risk of drug exposure per known to be teratogenic in animals and humans. In
se but instead because of inadequate or insufficient humans, the odds ratio in case-control studies examin-
information from their attending physicians. Conse- ing oral clefts was reported to be significant (3.35; 95%
quently, adequate and thorough information and dis- CI: 1.97, 5.69) [8]. Betamethasone and dexamethasone
cussions before prescription are particularly important cross the placenta to the fetus, and are prescribed for
for pregnant women. the fetus through the mother to reduce the incidence of
This pioneering clinic pointed out the needs and neonatal respiratory distress syndrome and intracranial
importance of such a service and encouraged the estab- haemorrhage and, as a result, to increase the survival
lishment of a system for information delivery. The of premature infants [9]. Besides the positive actions for
the fetus, many adverse effects other than teratogenic-
ity, such as intrauterine growth restriction, altered fetal
Table 2. Top 20 categories of consulted drugs at Toranomon Hospital brain development [10], and altered cortisol response to
clinic for pregnancy and drugs from April 1988 to March 2007 [7] a stressor [11], have been reported. For systemic treat-
Top 20 categories of drugs No. of cases ment of the mother, prednisolone or prednisone is rec-
ommended because the placenta can oxidize these
1 Non-steroidal anti-inflammatory drugs 4,743
2 Agents for gastrointestinal ulcers 2,986
drugs to inactive forms [12] and reduce their adverse
3 OTC – agents for coryza 2,857 effects on the fetus.
4 Anti-psychotic agents, anti-depressants 2,742 For AR, inhaled corticosteroids such as budesonide,
5 Hypnotics, sedatives 2,680 fluticasone, and beclomethasone are known to be extre-
6 Antibiotics 2,534 mely effective because of their expected high concen-
7 Anti-allergic agents* 1,634 trations at receptor sites in the nasal mucosa, with
8 Kampo 1,434 minimal absorption into the systemic blood flow [13].
9 Antiemetics, antinauseants 1,343 All drugs can affect the fetus through the maternal
10 Antitussives 1,230 blood and placenta. Thus, minimal absorption into the
11 Anti-histamines* 1,203
maternal systemic blood flow means minimal effects on
12 Vitamins 1,128
the fetus. As a result, no adverse effects of inhaled cor-
13 Anti-inflammatory enzyme preparations 1,112
14 Bronchodilators 1,073
ticosteroids on the fetus were reported for congenital
15 Anti-diarrhoeal agents 1,039 malformations and development [14, 15].
16 Quinolones 1,010 Based on their high efficacy and safety, inhaled corti-
17 Digestive enzyme preparations 999 costeroids are thought to be the first-line choice for the
18 Expectorants and mucolytics 929 treatment of AR in pregnancy.
19 Antitussives and expectorants 824
20 Corticosteroids* 798
Antihistamines
Adapted from Drugs and Pregnancy, 2nd edn. Tokyo: JIHO, 2010: 43
–6 (in Japanese) with permission. Two types of antihistamines are prescribed for AR,
*Those might be prescribed for allergic rhinitis. OTC, over-the-counter. referred to as first-generation and second-generation

© 2012 Blackwell Publishing Ltd, Clinical & Experimental Allergy Reviews, 12 : 31–36
 AR treatment during pregnancy 35

antihistamines. The first-generation antihistamines second-generation antihistamines for working pregnant

include diphenhydramine, chlorpheniramine, clemastine, women to avoid the side-effect of drowsiness.
promethazine, hydroxyzine, and dimenhydrinate. Pro- When prescribing an oral antihistamine, the provider
methazine was reported to have some possible terato- is recommended to choose chlorpheniramine as a first-
genic effects in humans [16], but the findings were not generation antihistamine, or cetirizine or loratadine as
conclusive. The other first-generation antihistamines are a second-generation antihistamine, because these drugs
suggested to be safe as far as teratogenicity is con- are classified as FDA pregnancy category B [2].
cerned. However, their long-term effects on the psycho-
logical and physical development of newborns have
Leukotriene receptor antagonists
been poorly studied.
The second-generation antihistamines were developed Pranlukast, montelukast, and zafirlukast are among the
to be unable to cross the blood–brain barrier to reduce leukotriene receptor antagonists. For AR in non-preg-
the side-effects of the first-generation antihistamines nant women, leukotriene receptor antagonists are
on the central nervous system, such as sedation and another treatment choice. However, it is preferable to
drowsiness. Cetirizine, desloratadine, fexofenadine, and avoid leukotriene receptor antagonists during preg-
loratadine are among the second-generation antihista- nancy, because of the little available experience and
mines. Desloratadine is a major metabolite of lorata- data for human pregnancy and their effects on the fetus.
dine. No teratogenic effects have been reported for In particular, pranlukast should be avoided because of
cetirizine and loratadine/desloratadine, while no human the lack of human data. The molecular weights of these
data are available for fexofenadine [17]. drugs are higher than those of antihistamines, but are
For the treatment of nasal symptoms caused by AR, still below 1,000 g/mol, and they have long elimination
first-generation or second-generation antihistamines half-lives. Fetal exposure through the placenta should
need to be administered systemically. This means that be expected, although it is not known whether the drugs
antihistamines work through the maternal blood flow in this class cross the human placenta.
reaching the nasal sites. Therefore, all of the antihista-
mines have the possibility of crossing the placenta and
Decongestants
reaching the fetal blood. The molecular weights of the
first-generation antihistamines were far below 1,000 g/ Sympathomimetic vasoconstrictors may be prescribed
mol, and some of them were reported to cross the pla- for the short-term relief of nasal congestion in AR.
centa [18]. The molecular weights of the second-genera- Pseudoephedrine and phenylephrine are commonly used
tion antihistamines are similar to or slightly higher oral decongestants. Although teratogenicity of oral
than those of the first-generation antihistamines, but sympathomimetic vasoconstrictors is not suspected in
still low enough that passage to the fetus should be humans [20], they are teratogenic in animals and may
expected. No human data for placental passage are cause constriction of the uterine vessels, thereby reduc-
available for the second-generation antihistamines. ing the uterine blood flow. Therefore, it is preferable to
Human data start to be accumulated from the first avoid oral decongestants during pregnancy.
marketing of a drug even if only case reports have been Naphazoline and oxymetazoline are used topically in
published [19]. This means that the evidence of safety long-acting nasal decongestant sprays. It is reasonable
for individual drugs depends upon their marketing his- to expect that the topical use of decongestants is safer
tory. The first-generation antihistamines have more than oral use. However, the use of nasal decongestant
than 50 years of marketing history, while the second- sprays should be limited to patients for whom inhaled
generation antihistamines have around 20 years. Some corticosteroids and antihistamines are ineffective. Topi-
of the antihistamines were marketed as over-the-coun- cal vasoconstrictors should not be used continuously
ter medications with expected wide exposure to preg- because they can induce pharmacological rhinitis.
nant women. Many women with AR are considered to
purchase antihistamines without the intervention of a
Other medical treatments
physician or pharmacist.
For pregnant women who cannot obtain sufficient Intranasal cromolyn is not absorbed through the muco-
benefits from inhaled corticosteroids as the first-line sal surface and is thought to have excellent safety. It
treatment, which antihistamines should be recom- was previously considered to be a first-line therapy for
mended as the second-line treatment, first-generation AR. However, inhaled corticosteroids have recently been
or second-generation antihistamines? Some clinicians considered to have similar safety but more efficacy than
prefer to choose the first-generation antihistamine intranasal cromolyn. For patients who are not candi-
chlorpheniramine for pregnant women because it has dates for corticosteroids, intranasal cromolyn is a good
been extensively studied. Other clinicians may prescribe alternative.

© 2012 Blackwell Publishing Ltd, Clinical & Experimental Allergy Reviews, 12 : 31–36
36 K. Sato

Allergen-specific immunotherapy is clinically useful 7 Hayashi M. Clinic for counseling and evaluation of drug-
for improving the symptoms of AR by inducing a state exposed pregnant women. In: Hayashi M, Sato K, Kitagawa H,
of immunological tolerance. Although it is considered eds. Drugs and Pregnancy 2nd edn. Tokyo: JIHO, 2010:43–6
safe to continue immunotherapy during pregnancy, (in Japanese).
8 Park-Wyllie L, Mazzotta P, Pastuszak A et al. Birth defects
increasing the dose or starting immunotherapy during
after maternal exposure to corticosteroids: prospective cohort
pregnancy is not recommended because systemic reac- study and meta-analysis of epidemiological studies. Teratology
tions may occur [3]. 2000; 62:385–92.
9 Wapner RJ, Sorokin Y, Thom EA et al. Single versus weekly
Conclusions courses of antenatal corticosteroids. Am J Obstet Gynecol
2006; 195:633–42.
Although AR is not a life-threatening disease, it may 10 Michael AE, Papageorghiou AT. Potential significance of
have detrimental effects on the patient’s QOL. In addi- physiological and pharmacological glucocorticoids in early
tion, correct treatment of AR is important for control- pregnancy. Hum Reprod Update 2008; 14:497–517.
ling concomitant asthma. Inhaled corticosteroids, 11 Ashwood PJ, Crowther CA, Willson KJ et al. Neonatal adrenal
antihistamines, leukotriene receptor antagonists, nasal function after repeat dose prenatal corticosteroids: a random-
ized controlled trial. Am J Obstet Gynecol 2006; 194:861–7.
decongestant sprays, intranasal cromolyn, and immuno-
12 Burton PJ, Waddell BJ. Dual function of 11b-hydroxysteroid
therapy have not been associated with increased inci- dehydrogenase in placenta: modulating placental glucocorti-
dences of human malformations. However, the long- coid passage and local steroid action. Biol Reprod 1999;
term physical, psychological, and developmental effects 60:234–40.
on children have not been well studied. Inhaled corti- 13 Jackson LD, Polygenis D, McIvor RA et al. Comparative effi-
costeroids are recommended as a first-line therapy dur- cacy and safety of inhaled corticosteroids in asthma. Can J
ing pregnancy because of their therapeutic Clin Pharmacol 1999; 6:26–37.
effectiveness, low absorption into the maternal circula- 14 Kallen B, Rydhstroem H, Aberg A. Congenital malformations
tion, lack of reported adverse effects, and long market- after the use of inhaled budesonide in early pregnancy. Obstet
ing history. Gynecol 1999; 93:392–5.
15 Wilson TT, Waters L, Patterson CC et al. Neurodevelopmental
and respiratory follow-up results at 7 years for children from
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© 2012 Blackwell Publishing Ltd, Clinical & Experimental Allergy Reviews, 12 : 31–36