Reproductive Toxicology 28 (2009) 100–104
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Reproductive Toxicology
journal homepage: www.elsevier.com/locate/reprotox
Senna treatment in pregnant women and congenital abnormalities in their
offspring—A population-based case–control study
Nándor Ács a , Ferenc Bánhidy a , Erzsébet H. Puhó b , Andrew E. Czeizel b,∗
a
b
Second Department of Obstetrics and Gynecology, Semmelweis University, School of Medicine, Budapest, Hungary
Foundation for the Community Control of Hereditary Diseases, Budapest, Hungary
a r t i c l e
i n f o
Article history:
Received 17 July 2008
Received in revised form 2 February 2009
Accepted 13 February 2009
Available online 24 February 2009
Keywords:
Senna
Congenital abnormalities
Birth outcomes
Population-based case–control study
a b s t r a c t
Previously, the possible teratogenic effect of frequently used laxative drug, senna has not been checked in
case–control epidemiological study. Objective of the study was the comparison of cases with congenital
abnormalities (CAs) and their matched controls without CAs in the population-based large data set of the
Hungarian Case–Control Surveillance System of Congenital Abnormalities. Of 22,843 cases with CA, 506
(2.2%) had mothers with senna treatment, while of 38,151 control newborn infants without CA, 937 (2.5%)
were born to mothers with senna treatment (adjusted OR with 95% CI: 1.0, 0.9–1.1), and of 834 malformed
controls with Down syndrome, 26 (3.1%) had mothers with the use of senna (OR with 95% CI: 0.7, 0.5–1.1).
The range of senna doses was between 10 mg and 30 mg, but most pregnant women used 20 mg daily. The
mothers with senna treatment showed the characteristics of pregnant women with constipation (elder
with larger proportion of primiparae). There was no higher risk for 23 different CA groups after the senna
treatment during the second and/or third gestational month of 260 mothers, i.e. in the critical period of
most major CAs, compared with their 500 matched controls. Gestational age at delivery was somewhat
longer (0.2 week) and the rate of preterm birth was lower (6.6% vs. 9.2%) in newborn infants without CA
born to mothers with senna treatment compared with babies born to mothers without senna treatment.
In conclusion, senna treatment did not associate with a higher risk of CAs in the offspring of pregnant
women with constipation.
© 2009 Elsevier Inc. All rights reserved.
1. Introduction
Among maternal diseases during pregnancy, constipation is one
of the most frequent pathological conditions which affects 11–38%
of pregnant women [1,2]. However, some clinical reports mentioned the complaints of constipation in over half of pregnant
women [3]. The recommended first line therapy of constipation
includes diet with increased intake of bran and wheat fibre, in
addition of fluid intakes, regular defecation and increased exercise. The second line of therapy comprises of osmotic laxatives
such as magnesium hydrochloride and lactulose. The third line of
therapy is based on stimulant medications, mainly senna [4–6].
About 80% of Hungarian pregnant women with severe constipation were treated by senna [7]. Nevertheless, as far as we know
the possible association between senna treatment (ST) in pregnant
women and birth outcomes, particularly structural birth defects,
i.e. congenital abnormalities (CAs) in their newborn babies has
∗ Corresponding author. Tel.: +36 1 3944 712; fax: +36 1 3944 712.
E-mail address: czeizel@interware.hu (A.E. Czeizel).
0890-6238/$ – see front matter © 2009 Elsevier Inc. All rights reserved.
doi:10.1016/j.reprotox.2009.02.005
not been evaluated in population-based epidemiological studies
[8].
The anthraquinone group of laxatives includes senna, cascara
and aloes and senna is one of the strongest classes of stimulant laxatives. Senna contains two stereoisomers: sennosides A and B. These
compounds do not appear to be absorbed in the small intestine
but are broken by colonic bacteria of large bowel to monoanthrone,
a glycone structure, the active compound which exerts a laxative
action [9]. Basically senna preparations stimulate colonic motility
and may interfere with water and sodium reabsorption. Senna compounds usually work within 8–12 h and occasionally take 24 h to
produce a stool evacuation.
Senne glycosides are absorbed only in minimal amount by
the intestine and excreted in the bile (thereby may alter the
small intestine function). Thus the pharmacokinetics of senna
compounds does not suggest a teratogenic potential, however,
the prolonged use of senna may cause fluid and electrolyte
disturbances mainly potassium loss. Thus the objective of our
study was to evaluate the total (birth + fetal) prevalence of different CAs in offspring of mothers who were treated by senna
during pregnancy and compared with control newborns without CA in the population-based large data set of the Hungarian
N. Ács et al. / Reproductive Toxicology 28 (2009) 100–104
Case–Control Surveillance of Congenital Abnormalities (HCCSCA)
[10].
2. Materials and method
The protocol of the HCCSCA was described in details previously [10,11].
2.1. Selection of cases and malformed controls for the HCCSCA
Cases with CA were selected from the data set of the Hungarian Congenital
Abnormality Registry (HCAR), 1980–1996 [12] for the HCCSCA. Notification of CAs
is compulsory for physicians from the birth until the end of first postnatal year to
the HCAR in Hungary. Pathologists sent a copy of the autopsy report to the HCAR if
defects were identified in stillbirths and infant deaths. The total (birth + fetal) prevalence of cases with CA diagnosed from the second trimester of pregnancy through
the age of one year was 35 per 1000 informative offspring (live-born infants, stillborn
fetuses and electively terminated malformed fetuses) in the HCAR, 1980–1996, and
about 90% of major CAs were recorded in the HCAR during the 17 years of the study
period [13]. However, there were three exclusion criteria of cases with CAs from the
HCAR for the data set of the HCCSCA: (i) cases (33%) reported after three months of
birth or pregnancy termination, (ii) three mild CAs (congenital dysplasia of hip and
inguinal hernia, large hemangioma), and (iii) CA-syndromes caused by major gene
mutations or chromosomal aberrations with preconceptional origin were excluded.
Malformed controls affected with Down syndrome and notified to the HCAR
within the first three postnatal month or less than three month after elective termination of pregnancy were also selected from the HCAR for the data set of the
HCCSCA.
101
The fourth through ninth months of gestation, i.e. pregnancy after the organforming
period.
Birth weight and gestational age were medically recorded in the discharge summary of mothers after delivery. The rate of low birth weight (less than 2500 g)
and preterm birth (less than 37th gestational week) was also calculated and
evaluated.
2.4. Statistical analysis
Statistical analyses were performed using the software package SAS version 8.02
(SAS Institute Ins., Cary, North Caroline, USA). First, the occurrences of senna treatment during the study pregnancy were compared between the study groups and
crude odds ratios (OR) with 95% confidence interval (CI) were calculated. Second,
frequency tables were made for the main maternal variables to describe the study
groups of mothers with senna treatment and of mothers without senna treatment
as reference. Third, the prevalence of pregnancy complications, acute and chronic
maternal diseases, other drug treatments and pregnancy supplements used during the study pregnancy were compared between case and control mothers with
senna treatment, and crude OR with 95% CI were evaluated. Fourth, the prevalence
of senna treatment was evaluated according to gestational period in 23 different CA
groups (including at least three cases born to mothers with senna treatment during
pregnancy) in the second and/or third gestational months and these prevalences
were compared with the frequency of senna treatment in their all matched control
pairs, and adjusted OR with 95% CI were evaluated in a conditional logistic regression model. Finally the occurrence of senna treatment in the mothers of cases with
different CAs and of malformed controls with Down syndrome was compared in
unconditional logistic regression model.
2.2. Control identification for the HCCSCA
Appropriate controls were identified from the National Birth Registry of the Central Statistical Office for the HCCSCA. Controls were defined as newborn infants
without CA. In general two controls were matched to every case according to sex,
birth week in the year when the case was born, and district of parents’ residence.
2.3. Maternal and exposure data were obtained from three sources
2.3.1. Prospective medically recorded data
An explanatory letter was mailed to mothers immediately after the selection of
cases (including malformed controls) and controls and they were asked to send us
the prenatal care logbook and other medical records for three weeks. Prenatal care was
mandatory for pregnant women in Hungary (if somebody did not visit prenatal care
clinic, she did not receive a maternity grant and leave), thus nearly 100% of pregnant
women visited prenatal care clinics, an average seven times in their pregnancies.
The role of licensed obstetricians is to record all pregnancy complications, maternal
diseases and related drug prescriptions in the prenatal care logbook.
2.3.2. Retrospective self-reported maternal information
A structured questionnaire with a list of medicinal products (drugs and pregnancy
supplements) and diseases, plus a printed informed consent form were also mailed
to the mothers. To standardize the answers, mothers were asked to read the enclosed
lists of medicinal products (including senna) and diseases as a memory aid before
they filled in the questionnaire.
The mean ± S.D. time elapsed between the birth or pregnancy termination and
the return of the “information package” (questionnaire, logbook, discharge summary, and informed consent form) was 3.5 ± 1.2, 5.2 ± 2.9 and 3.8 ± 2.0 months in
the case, control and malformed control groups, respectively.
2.3.3. Complementary data collection
Regional nurses were asked to visit all non-respondent case and malformed
control mothers, in addition 200 non-respondent control mothers. Regional nurses
helped mothers to fill in the same questionnaire used in the HCCSCA. Regional nurses
did not visit all non-respondent control mothers because the committee on ethics
considered this follow-up to be disturbing to the parents of all healthy children [14].
Overall, the necessary information was available on 96.3% of cases (84.4% from
reply to the mailing, 11.9% from the nurse visit), 83.0% of the controls (82.6% from
reply, 0.4% from visit) and 96.0% of malformed controls (86.0% from reply and 10.0%
from visit).
In Hungary senna was available in the tablet: Tisasen A + B (ICN Magyarország)
containing 10 mg for oral treatment, but only short-term (maximum two weeks)
treatment was recommended for patients with severe constipation with the contraindication in pregnant women [15].
The gestational age was calculated from the first day of the last menstrual period.
Three time intervals were considered: (i) first month of gestation because it is before
the organogenesis. The first two weeks are before conception while the third and
fourth weeks comprise the pre- and implantation period of zygotes and blastocysts
including omnipotent stem cells. Thus CAs cannot be induced by environmental
agents in the first month of gestation and it explains the “all-or-nothing effect” rule,
i.e. total loss or normal further development. (ii) The second and third months of
gestation. This is the most sensitive, the so-called critical period for major CAs. (iii)
3. Results
The case group consisted of 22,843 malformed newborns or
fetuses (“informative offspring”) with CAs, of whom 506 (2.2%) had
mothers with oral senna treatment. The total number of births in
Hungary was 2,146,574 during the study period between 1980 and
1996. Thus the 38,151 controls without CA represented 1.8% of all
Hungarian births, and among those controls, 937 (2.5%) were born
to mothers treated orally with senna tablets (crude OR with 95% CI:
0.90, 0.81–1.00). Finally of 836 malformed controls, 26 (3.1%) had
mothers with senna treatment during the study pregnancy (crude
OR with 95% CI: 0.71, 0.47–1.05).
Of 506 case and 937 control mothers, 99 (19.6%) and 245 (26.1%)
had medically recorded oral senna treatments in the prenatal logbooks (21 = 7.8; p = 0.005). Most pregnant women took two tablets
(i.e. 20 mg) per day, followed by daily one tablet; however, about
10% of pregnant women used daily three tablets. Of 506 case and
937 controls mothers, only 5 (1.0%) and 11 (1.2%) used alone senna,
thus pregnant women with senna plus other drug treatments were
evaluated together.
The onset and duration of senna treatments in case and control
mothers are shown in Table 1. About one-third of pregnant women
used senna in the first gestational month; we consider them as
chronic user of senna because all continued this treatment in the
second gestational month and most of them until the end of pregnancy. The distribution of gestational months according to the onset
of senna treatment (28 = 2.7; p = 0.95) and the mean duration of
this treatment (t = 0.5; p = 0.59) did not show significant difference
between case and control mothers.
The birth data of controls are summarized here, because CAs may
have a more drastic effect for these variables than senna itself. The
mean gestational age at delivery was somewhat (0.2 week) longer
(t = 2.9; p = 0.004) while the mean births weight was larger (48 g)
(t = 2.8; p = 0.004) in controls born to mothers with senna treatment
during the study pregnancy compared with controls born mothers without senna treatment. These differences were in agreement
with the somewhat lower rate of low birth weight newborns (4.6%
vs. 5.7%; OR with 95% CI: 0.8, 0.6–1.1) and significantly lower rate
of preterm births (6.6% vs. 9.2%; OR with 95% CI: 0.7, 0.5–0.9) in
the control babies born to mothers with senna treatment during
pregnancy.
102
N. Ács et al. / Reproductive Toxicology 28 (2009) 100–104
Table 1
Onset and duration of senna treatment (ST) during pregnancy of case and control mothers.
Gestational months
Case mothers with ST
Control mothers with ST
Duration
No.
%
Until end of pregnancy
Duration
Mean
S.D.
No.
%
No.
Until end of pregnancy
No.
%
I
II
III
IV
V
VI
VII
VIII
IX
158
41
61
40
46
59
49
41
11
31.2
8.1
12.1
7.9
9.1
11.7
9.7
8.1
2.2
7.7
3.3
3.3
2.7
2.2
1.9
2.1
1.4
1.0
2.7
3.0
2.6
2.2
1.7
1.3
0.9
0.5
–
124
9
15
9
11
15
23
18
11
78.5
22.0
24.6
22.5
23.9
25.4
46.9
43.9
100.0
312
82
106
80
84
92
96
65
20
33.3
8.8
11.3
8.5
9.0
9.8
10.2
6.9
2.1
8.2
3.7
3.4
2.9
2.3
2.3
1.9
1.6
1.0
2.3
3.1
2.8
2.3
1.8
1.4
0.9
0.5
–
273
23
35
27
22
31
36
36
20
87.5
28.0
33.0
33.8
26.2
33.7
37.5
55.4
100.0
Total
506
100.0
4.1
3.3
255
46.4
937
100.0
4.2
3.4
503
53.7
Table 2 shows the basic characteristics of case and control
mothers with senna treatment and without senna treatment as
reference. The mean maternal age was slightly higher in pregnant
women with senna treatment than in pregnant women without
this treatment though the proportion of primiparae was larger.
Thus the mean birth order was lower in mother with senna treatment. The comparison of treated case and control mothers showed
some difference in the distribution of maternal age groups (22 =
6.3; p = 0.04) and birth orders (21 = 4.4; p = 0.04), in addition in
the mean maternal age (t = 1.8; p = 0.06) and birth order (t = 2.3;
p = 0.02). There was no significant difference in the proportion
of marital status of mothers among the study groups, including between treated case and control mothers (21 = 2.5; p = 0.11).
Maternal employment status as an indicator of socioeconomic status showed also some differences because treated mothers were
more frequently among professional and managerial compared
with untreated mothers. The distribution of employment status
showed some difference between treated case and control mothers
(26 = 14.1; p = 0.03). On the other hand, malformed control mothers showed the well-known higher mean maternal age (about 28.5
%
Mean
S.D.
years) and birth order (2.4), but these variables are not shown in
Table 3.
Among pregnancy supplements, the use of folic acid and iron
was higher in mothers with senna treatment, particularly in control mothers. However, there was no significant difference in the
occurrence of folic acid (OR with 95% CI: 0.9, 0.8–1.2) and iron
(OR with 95% CI: 0.9, 0.7–1.1) supplementation between treated
case and control mothers. The use of multivitamins did not show
significant difference among the study groups.
All pregnancy complications showed a somewhat higher prevalence in pregnant women with senna treatment than in pregnant
women without the use of senna. However, only the rate of polyhydramnios was higher in treated case mothers than in treated
control mothers (3.2% vs. 0.9%; OR with 95% CI: 3.8, 1.6–8.9). Among
acute maternal disease, the rate of influenza-common cold (35.4%
vs. 22.4%; OR with 95% CI: 1.9, 1.5–2.4) and acute diseases of digestive system (8.1% vs. 4.6%; OR with 95% CI: 1.8, 1.2–2.8) was higher
in case mother than in control mothers with senna treatment. Constipation was reported by nearly all and hemorrhoids by 11% of
pregnant women with senna treatment, but there was no difference
Table 2
Main variables of case and control mothers with or without senna treatment (ST).
Case mothers
Control mothers
Without ST (N = 22,337)
With ST (N = 506)
Without ST (N = 37,214)
With ST (N = 937)
No.
%
No.
%
No.
%
No.
%
2,461
15,242
3,712
25.5
11.0
68.2
16.6
5.3
45
351
91
25.6
8.9
69.4
18.0
5.1
3,226
26,924
5,619
25.4
8.7
72.3
15.1
4.9
51
678
170
26.1
5.4
72.4
18.1
4.8
Unmarried
10,392
11,945
1.9
No.
1,248
46.5
53.5
1.1
%
5.6
316
190
1.5
No.
21
62.4
37.6
0.8
%
4.2
17,667
19,537
1.7
No.
1,451
47.5
52.5
0.9
%
3.9
532
405
1.6
No.
20
56.8
43.2
0.8
%
2.1
Employment status
Professional
Managerial
Skilled worker
Semiskilled worker
Unskilled worker
Housewife
Others
1,838
4,799
6,186
3,796
1,490
2,108
2,120
8.2
21.5
27.7
17.0
6.7
9.4
9.5
63
169
143
73
13
20
25
12.5
33.4
28.3
14.4
2.6
4.0
4.9
4,207
9,775
11,433
5,678
1,866
2,017
2,258
11.3
26.3
30.7
15.3
5.0
5.4
6.1
146
359
257
105
13
21
36
15.6
38.3
27.4
11.2
1.4
2.2
3.8
Pregnancy supplements
Iron
Folic acid
Multivitamin
14,359
10,971
1,299
64.3
49.1
5.8
385
308
31
76.1
60.9
6.1
26,037
20,174
2,443
70.0
54.2
6.6
737
601
66
78.7
64.1
7.0
Maternal age (year)
–19
20–29
30–
Mean, S.D.
Birth order
1st
2nd or more
Mean, S.D.
N. Ács et al. / Reproductive Toxicology 28 (2009) 100–104
103
Table 3
Results of conditional logistic regression analysis of cases and all matched controls to estimate the association between all senna treatments during the entire pregnancy and
in second and/or third gestational month and different CA groups.
Study groups
Grand total
Entire pregnancy
No.
No.
%
OR
Second and/or third gestational months
Controls
38,151
937
2.5
Reference
Cases with isolated CAs
Neural-tube defects
Cleft lip ± palate
Cleft palate only
Oesophageal atresia/stenosis
Pyloric stenosis, congenital
Intestinal atresia/stenosis
Rectal/anal atresia/stenosis
Renal a/dysgenesis
Obstructive CA of urinary tract
Hypospadias
Undescended testis
Exomphalos/gastroschisis
Hydrocephaly, congenital
Ear CAs
Cardiovascular CAs
CAs of genital organs
Clubfoot
Limb deficiencies
Poly/syndactyly
CAs of skeletal system
Diaphragmatic CAs
Other isolated CAs
Cases with multiple CAs
Total CAs
1,202
1,374
582
217
241
153
220
104
457
3,038
2,051
238
314
354
4,479
123
2,424
548
1,744
211
243
1,177
1,349
22,843
32
31
11
5
8
5
5
2
15
39
48
5
6
6
90
5
62
21
35
5
5
31
34
506
2.7
2.3
1.9
2.3
3.3
3.3
2.3
1.9
3.3
1.3
2.3
2.1
1.9
1.7
2.0
4.1
2.6
3.8
2.0
2.4
2.1
2.6
2.5
2.2
1.8
0.9
0.9
1.1
0.8
1.7
1.7
0.4
2.0
0.5
1.1
1.6
0.4
0.7
0.9
1.4
1.0
1.9
1.0
0.7
0.6
1.3
1.0
1.0
95% CI
1.0–3.0
0.6–1.5
0.4–2.0
0.4–3.5
0.3–1.9
0.5–6.6
0.5–6.0
0.1–2.6
0.6–7.2
0.4–0.8
0.7–1.6
0.5–5.7
0.1–1.2
0.2–1.9
0.7–1.1
0.4–5.3
0.8–1.4
0.9–3.5
0.7–1.5
0.2–2.0
0.2–1.8
0.8–1.9
0.6–1.6
0.9–1.1
No.
%
OR
500
1.3
Reference
21
10
3
5
5
2
4
1
12
23
24
2
5
3
42
2
31
12
21
2
3
14
13
260
1.7
0.7
0.5
2.3
2.1
1.3
1.8
1.0
2.6
0.8
1.2
0.8
1.6
0.8
0.9
1.6
1.3
2.2
1.2
0.9
1.2
1.2
1.0
1.1
1.7
0.6
0.9
3.8
1.2
1.0
1.5
0.4
2.2
0.5
1.1
1.3
1.0
0.6
0.7
–
0.9
2.2
1.1
1.1
0.5
1.3
0.9
1.0
95% CI
0.9–3.3
0.3–1.2
0.2–4.0
0.9–16.6
0.3–4.0
0.1–6.6
0.3–6.2
0.0–5.0
0.5–9.1
0.3–0.9
0.6–1.8
0.2–9.9
0.3–3.9
0.2–2.2
0.5–1.1
–
0.6–1.5
0.9–5.3
0.6–1.9
0.2–6.1
0.1–2.1
0.7–2.4
0.4–1.7
0.8–1.1
OR adjusted for maternal age (<20 year vs. 20–29 year vs. 30 year or more), birth order (first delivery vs. one or more previous deliveries), maternal employment status
(professional-managerial-skilled worker vs. semi-skilled worker-unskilled worker-housewife vs. others), fever related influenza-common cold and acute maternal diseases
of digestive system, in addition some other drug treatments (as a dichotomous variable) as confounders.
in the rate of chronic diseases between treated case and controls
mothers. The use of other drugs did also not show significant differences between case and control mothers with senna treatment.
The main objective of the study was to evaluate cases with different CAs and their all matched controls according the senna treatment
in their mothers during pregnancy after the consideration of confounding factors (Table 3). There was no higher rate of total CAs in
offspring of mothers with senna treatment during the entire pregnancy or in the second and/or third gestational months compared
to control mothers with this treatment. At the evaluation of different CA, neural-tube defects showed a marginal association with
senna treatment during the entire pregnancy. However, at the evaluation of different CAs in 260 cases born to mothers with senna
treatment in the second and/or third gestation months, there was
no higher risk for any CA group compared with 500 controls. The
critical period of neural-tube defects is in the second gestational
month, and this association was not seen after the senna treatment
during this period (OR with 95% CI: 1.2, 0.7–1.8). On the other hand,
the rate of hypospadias was lower in cases born to mothers with
senna treatment during pregnancy, but the critical period of this
CA is in the third and fourth gestational month (OR with 95% CI:
0.6, 0.2–1.1).
We evaluated only medically recorded senna treatment during
the second and/or third gestational months separately as well without association of any CA group.
Finally we made a comparison of senna treatment between case
and malformed control mothers. Senna treatment during the entire
pregnancy or in the second and/or third gestational months did not
show a higher risk for total CA (OR with 95% CI: 0.8, 0.4–1.4) or for
any CA group. (These figures did not show here.).
4. Discussion
The objective of our study was to evaluate the possible association between oral senna treatment during the critical period of
CA groups and the risk for different CAs. Our data did not show
any association between CAs and oral senna treatment during
pregnancy.
At the evaluation of these findings we have to consider the indication of senna treatment, i.e. constipation of pregnant women.
Two groups of constipations can be differentiated. If the onset
of constipation occurred before conception and continued during
pregnancy, these conditions were considered as chronic. However,
there was a new wave of “pregnancy constipation” mainly after the
third gestational month and it may associated with the common
oral iron therapy during pregnancy which may exacerbate constipation, poor oral fluid intake due to nausea and vomiting during
pregnancy, increased transit time due to slower gastrointestinal
movement (explained by higher production of progesterone) and
alteration in diet.
Senna treatment due to constipation was more frequent in elder
primiparae with a higher socioeconomic status as in other studies
[1–3]. In addition it is worth mentioning that our pregnant women
did not follow the recommendation of short-term senna treatment,
but most women used senna during longer period, many of them
during the entire pregnancy. The explanation may be that partly
they had no adverse side effects and getting accustomed to senna,
partly we cannot exclude a selection bias that pregnant women
with chronic use reported more frequently the use of senna.
Pregnant women with constipation and senna treatment had a
longer gestational age at delivery and lower rate of preterm birth
because they had a somewhat higher socioeconomic status [16],
and/or a better preconceptional and/or antenatal care (e.g. a higher
proportion of folic acid supplementation).
The strengths of HCCSCA can be explained by the populationbased large data set including 1,469 pregnant women with senna
treatment in the ethnically homogeneous Hungarian (Caucasian)
people. Additional strengths include the matching of cases to
controls without CAs, in addition malformed controls; available
data for potential confounders, and finally that the diagnosis of
104
N. Ács et al. / Reproductive Toxicology 28 (2009) 100–104
medically reported CAs was checked in the HCAR [12] and later
modified, if necessary, on the basis of recent medical examination
within the HCCSCA [10]. Our study design regarding birth outcomes
were based on medically recorded gestational age at delivery and
birth weight.
However, this data set also has limitations. (i) There was an
active follow-up for all non-respondent case mothers, but for only
200 non-respondent control mothers. (ii) The mean time between
the birth/pregnancy termination and the return of the information
package was 1.7 months longer in the group of case mothers (t = 4.4;
p < 0.001). However, this time difference does not cause recall bias
in long term treatment such as senna [14]. (iii) Only about one-fifth
of case mothers and one-quarter of control mothers had prospectively and medically recorded senna treatment during the study
pregnancy. Thus, we have to consider recall bias, because the birth
of an infant with CA is a serious traumatic event for most mothers who therefore try to find a causal explanation such as diseases
or drug uses during pregnancy for CA of their babies. This does
not occur after the birth of a healthy newborn infant. Thus recall
bias might inflate an increased risk for CAs. Our previous analysis showed that a case–control surveillance of this type may cause
spurious association between drugs and CAs with biased OR up to
a factor of 1.9 [17]. However, we can limit recall bias by four different approaches. First, we differentiated CAs for different specific
groups because teratogens cause specific CA [8] but recall bias is
nearly similar for all CAs. Second we evaluated of the specific critical
period of different CAs [18] because we expect an underreporting
of senna treatment in both the critical and non-critical periods of
CAs in the control group. Third we can exclude recall bias with the
use of only prospectively and medically recorded data as a gold
standard. Finally we compared the occurrence of senna treatment
in case and malformed control mothers because the latter group
also had not recall bias. These approaches did also not show any
association between different CAs and maternal senna treatment.
Previously only the results of one animal investigation were
published: Mengs gave rats and rabbits up to 100 and 20 mg/kg
senna, respectively, during organogenesis and found no evidence
of teratogenicity [19].
In conclusion, our study showed that senna treatment did not
associate with a higher risk for any CA group and adverse birth
outcomes.
Conflict of interest
None.
Acknowledgement
This study was partly sponsored by a generous grant from
Richter Gedeon Pharmaceuticals Ltd., Budapest, Hungary.
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