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Genetic counseling for teratogenic risk due to exposure to medications 89 pregnancies conceived during oral contraceptive use.

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RESEARCH LETTER
Genetic Counseling for Teratogenic Risk Due To
Exposure to Medications: 89 Pregnancies Conceived
During Oral Contraceptive Use
Serena Belli,1* Silvia Mazzola,2 Roberto Luongo,3 Luca Barcella,4 Brunilda Alushi,3,5 Alessia Favaro,1
and Matteo Bertelli3
1
Ambulatorio di Consulenza Genetica APSS Provincia Autonoma di Trento, Trento, Italy
2
Department of Mother and Child, Biology and Genetics, Section of Biology and Genetics, University of Verona, Verona, Italy
3
Laboratory of Medical Genetics, Pharmacogenetics Unit, MAGI-onlus, Riva del Garda, Trento, Italy
Clinical Research Center for Rare Diseases Aldo e Cele Dacco, Mario Negri Institute for Pharmacological Research, Bergamo, Italy
4
5
Research Center for Experimental Medicine (CeRMS), University of Turin, Turin, Italy
Received 4 January 2008; Accepted 17 October 2008
TO THE EDITOR:
Congenital malformations are relatively frequent (2% of the general
population) but only a small proportion of them can be ascribed to
medication exposure during pregnancy [Polifka and Friedman,
2002]. Nevertheless, for the purposes of accurate prenatal diagnosis,
monitoring and research, is it important to offer teratology counseling to patients exposed to drugs [Hancock et al., 2007]. There are
approximately 20 medications currently on the market that have
been universally acknowledged as teratogenic (Table I) [Webster
and Freeman, 2001]. At the current state of the art, exposure of early
embryos to oral contraceptives is not considered teratogenic
[Bracken, 1990].
Oral contraceptive use may be continuous (estrogen and progesterone or progesterone alone) or emergency (levonorgestrel is
the only drug authorized in Italy). Like all drugs, oral contraceptives
have a therapeutic failure rate, which means that a number of
women on oral contraceptives conceive each year and request
genetic counseling about teratogenic effects.
During the period 1998–2006 at our genetics clinic we received
89 requests for counseling regarding teratogenic risk due to oral
contraceptives. We obtained medical histories and records of the
drugs taken. This was followed by diagnostic tests to assess maternal
and fetal status (prenatal ultrasonography, screening for fetal
aneuploidy, invasive prenatal diagnosis for karyotype when indicated, routine blood chemistry, gynecological examination). All
women then received genetic and gynecological counseling to
provide them with clear and complete information on the tests
outcome and fetal health. Women were thus able to decide whether
or not to proceed with the pregnancy, and were subsequently
referred to specific clinics. Women who proceeded with the pregnancy were offered two further sessions of genetic and pediatric
counseling when their babies were 3 and 6 months old. All clinical
data were stored electronically and consent was requested in order
Ó 2009 Wiley-Liss, Inc.
How to Cite this Article:
Belli S, Mazzola S, Luongo R, Barcella L,
Alushi B, Favaro A, Bertelli M. 2009. Genetic
counseling for teratogenic risk due to
exposure to medications: 89 pregnancies
conceived during oral contraceptive use
Am J Med Genet Part A 149A:1555–1557.
to be used for research purposes; signed informed consent forms
were stored confidentially as required by law.
The most widely used pill was an estrogen-progestogen contraceptive (55 cases), followed by emergency contraception
(25 cases) and a progestogen pill (9 cases). Besides oral contraceptives, 24 women were taking other drugs which included
nonsteroidal anti-inflamitory drugs (NSAIDs) (11 cases), antibiotics (8 cases), cortisone (4 cases), benzodiazepine (4 cases), gastric
protonic-pump inhibitors (3 cases), antihistamines (2 cases),
antiepileptics (1 case), acyclovir (1 case), methadone (1 case),
paroxetine (1 case), and allopurinol (1 case) (Table II).
Miscarriage occurred in two cases exposed to oral contraceptives
alone. Twelve women opted for pregnancy interruption; amongst
them two were exposed to oral contraceptives alone, three to
contraceptives and drugs known as teratogenic agents (Table II,
*Correspondence to:
Serena Belli, Ambulatorio di Consulenza Genetica, Dipartimento Materno
Infantile, APSS Provincia Autonoma di Trento, Via Petrarca 138100
Trento, Italy. E-mail: serena.belli@apss.tn.it
Published online 5 June 2009 in Wiley InterScience
(www.interscience.wiley.com)
DOI 10.1002/ajmg.a.32608
1555
1556
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
TABLE I. Therapeutic Drugs Recognized as Being Teratogenic to
Humans [From Webster and Freeman, 2001, Modified]
Anticonvulsants
Hydantoin
Primidone
Oxazolidine-2,4-diones, (trimethadione, paramethadione)
Valproic acid
Carbamazepine
Anticancer agents
Busulfan
Cyclophosphamide
Chlorambucil
Mechlorethamine
Aminopterin
Methotrexate
Cytarabine
Androgenic hormones
For example, danazol
Antithyroid drugs
For example, propylythiouracil
Aminoglycoside antibiotics
For example, streptomycin
Coumarin anticoagulants
For example, warfarin
Retinoic acids
For example, isotretinoin
ACE inhibitors
For example, captopril
Tetracyclines
For example, tetracycline
Other drugs
Diethystilbistrol
Thalidomide
Penicillamine
Lithium
patients number 2, 22, 42), and the remaining to contraceptives plus
other drugs (Table II, patients number 16, 18, 26, 58, 70, 80, 84). In
these women the decision to terminate pregnancy may have been
influenced by the fact that the teratogenic risk of drugs’ combination was difficult to assess. There was also a case of intrauterine fetal
death at the 4th month of pregnancy (Table II, patient number 81),
leading to delivery induction. The mother has been taking NSAIDs.
Two studies have shown a link between the use of NSAIDs during
pregnancy and miscarriage [Nielsen et al., 2001; Li et al., 2003].
By contrast, a meta-analysis of aspirin during pregnancy and a
case-control study did not confirm this findings [Kozer et al., 2003;
Keim and Klebanoff, 2006].
One delivery was premature (at the 7th month). The mother had
severe allergy and asthma and has been taking inhaled cortisone and
oral antihistamines, and has also undergone a 15-day course of
antibiotics and NSAIDs for lung infection (Table II, patient number
8). It is possible that maternal pathology and the complex mixture
of drugs taken were the cause of prematurity, though a cause-effect
relationship is difficult to pinpoint, partly due to a lack of knowl-
TABLE II. Concurrent Exposures and Length of Exposure
(d, Days; w, Weeks)
Patient
number
2
7
8
16
18
22
23
26
29
41
42
50
54
56
58
63
67
70
71
74
80
81
83
84
Other drugs taken and duration of
(post-conceptional) exposure
Tetracycline (2w), NSAIDs (3d)
Topical cortisone (2w), NSAIDs (2w)
Antibiotic (2w), NSAIDs (2w), antihistamines (4w),
inhaled cortisone (4w)
NSAIDs (4d)
Gastric proton-pump inhibitors (4w)
Carbamazepine (6w), benzodiazepine (6w)
Benzodiazepine (4w)
NSAIDs (2w), spiramicin (2w)
Gastric proton-pump inhibitors (8w)
Antibiotic (1w)
Tetracycline (2w), metadone (4w)
Gastric proton-pump inhibitors (4w)
Benzodiazepine (4w)
Paroxetine (4w)
NSAIDs (5d)
Antihistamines (8w)
NSAIDs (2w)
Acyclovir (1w), benzodiazepine (2w)
Topical cortisone (6d)
Antibiotic (1w)
Antibiotic (1w), NSAIDs (4d), cortisone (4d)
NSAIDs (2w)
Antibiotic (6d), NSAIDs (1w)
Allopurinol (2w), NSAIDs (3d)
edge about molecular interactions between drugs, mother and
fetus.
All other women had normal pregnancies. There were three
caesarean deliveries and one case of twins (healthy boy and girl). All
babies were in good health and without malformations, except for
one case presenting a mild auricular alteration. In the latter the
mother had been taking the antidepressant paroxetine for several
months. It seems unlikely that this mild malformation was due to
the combination of drugs [Louik et al., 2007]. Postnatal examination of all babies at 3 and 6 months of age showed no malformations,
and neuromotor development was normal in all cases.
This study confirms an absence of teratogenic risk for pregnancies occurring during oral contraceptive use. Teratology counseling
was useful to reassure the mothers about the low risk (in the case of
oral contraceptive use alone), since only 12 women chose to
terminate pregnancy. This represents a good result, since conception was the result of failed contraception. Counseling was also
useful to optimize the timing of ultrasonographic monitoring,
indicating the target organs to examine (which differs in relation
to the combination of drugs taken) and suggesting in some cases
other diagnostic tests. Finally, we wish to underline the utility of
follow-up at birth and, if possible, also subsequently. Only by
checking neonatal health can subtle morphological or developmental variations potentially due to drugs be detected. In our opinion,
BELLI ET AL.
follow-up should be systematic for all centers involved in teratology
counseling because only careful and regular evaluation of this
activity can confirm its efficacy.
REFERENCES
Bracken MB. 1990. Oral contraception and congenital malformations in
offspring: A review and meta-analysis of the prospective studies. Obstet
Gynecol 76:552–557.
1557
outcomes: Meta-analysis. Birth Defects Res B Dev Reprod Toxicol
68:70–84.
Li DK, Liu L, Odouli R. 2003. Exposure to non-steroidal anti-inflammatory
drugs during pregnancy and risk of miscarriage: Population based cohort
study. Br Med J 327:368.
Louik C, Lin AE, Werler MM, Hernandez-Diaz S, Mitchell AA. 2007. Firsttrimester use of selective serotonin-reuptake inhibitors and the risk of
birth defects. N Engl J Med 356:2675–2683.
Hancock RL, Koren G, Einarson A, Ungar WJ. 2007. The effectiveness of
Teratology Information Services (TIS). Reprod Toxicol 23:125–132.
Nielsen GL, Sorensen HT, Larsen H, Pedersen L. 2001. Risk of adverse
birth outcome and miscarriage in pregnant users of non-steroidal
anti-inflammatory drugs: Population based observational study and
case-control study. Br Med J 322:266–270.
Keim SA, Klebanoff MA. 2006. Aspirin use and miscarriage risk. Epidemiology 17:435–439.
Polifka JE, Friedman JM. 2002. Medical genetics: 1. Clinical teratology in
the age of genomics. Can Med Assoc J 167:265–273.
Kozer E, Costei AM, Boskovic R, Nulman I, Nikfar S, Koren G. 2003.
Effects of aspirin consumption during pregnancy on pregnancy
Webster WS, Freeman JA. 2001. Is this drug safe in pregnancy? Reprod
Toxicol 15:619–629.
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