Genetic counseling for teratogenic risk due to exposure to medications 89 pregnancies conceived during oral contraceptive use.код для вставкиСкачать
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: email@example.com 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.