Drug therapy and adverse drug reactions to terbutaline in obstetric patients: a prospective cohort study in hospitalized women

1471-2393-2-3 1471-2393 Research article Drug therapy and adverse drug reactions to terbutaline in obstetric patients: a prospective cohort study in hospitalized women Hernández-Hernández María Dulce dulcema@servidor.unam.mx Vargas-Rivera Josefa E María dulcema@servidor.unam.mx Nava-Ocampo A Alejandro navaocampo_aa@yahoo.com Palma-Aguirre Antonio José palmaguirre@hotmail.com Sumano-López Héctor palmaguirre@hotmail.com

Unit of Medical Research in Oncologic Diseases, Area de Epidemiologia, Hospital de Oncología, Centro Medico Nacional "Siglo XXI", Institute Mexicano del Seguro Social, Mexico City, Mexico

Unit of Medical Research in Pharmacology, Hospital de Especialidades, CMN "Siglo XXI", IMSS, Mexico City, Mexico

Department of Pharmacology, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico

BMC Pregnancy and Childbirth 1471-2393 2002 2 1 3 http://www.biomedcentral.com/1471-2393/2/3 10.1186/1471-2393-2-3 11934352 15 7 2001 05 4 2002 05 4 2002 2002 Hernández-Hernández et al; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.

Abstract

Background

Adverse drug reactions (ADR's) could be expected more frequently in pregnant women. This study was performed in order to identify ADR's to tocolytic drugs in hospitalised pregnant women.

Methods

A prospective cohort study was performed in two General Hospitals of the Instituto Mexicano del Seguro Social (IMSS) in Mexico City. Two hundred and seven women undergoing labor, premature labor, threatened abortion or suffering any obstetric related disease were included. Drug prescription and signs and symptoms of any potential ADR were registered daily during the hospital stay. Any potential ADR to tocolytic drugs was evaluated and classified by three of the authors using the Kramer's algorithm.

Results

Of the 207 patients, an ADR was positively classified in 25 cases (12.1%, CI95% 8.1 to 17.5%). All ADR's were classified as minor reactions. Grouping patients with diagnosis of threatened abortion, premature labor or under labor (n= 114), 24 ADR's were related to terbutaline, accounting for a rate of 21.1 ADR's per 100 obstetric patients. Obstetric patients suffering an ADR were older than obstetric patients without any ADR. However, the former received less drugs/day × patient^-1 and had a shorter hospital stay (p < 0.05) whereas the dose of terbutaline was similar between the two groups. Terbutaline inhibited uterine motility in women with and without any ADR at a similar rate, 70 and 76% respectively (x² = 0.07; p = 0.8).

Conclusion

Terbutaline, used as a tocolytic drug, was related to a high frequency of minor ADRs and to a high rate of effcicacy.

Background

The ADR's are considered as a major public health problem 1. Being the fourth cause of general deaths 2, the ADR's are costly and represent a significant rate of hospital admissions 34. Furthermore, the number of drugs available for prescription in the clinical setting is increasing every day. It is therefore important to acquire, interpret and report all ADR's identified with any drug 2. Furthermore, pharmacovigilance in special populations, e.g. pregnancy women, could be useful to identify unexpected responses probably expressing unusual pharmacokinetic profiles as a result of their particular physiological state 56.

Multiple methods have been used for pharmacovigilance, and despite spontaneous reporting is the simplest one, it has been of low efficacy in Mexican medical practice 7. Furthermore, in Latin-America only a limited number of drug utilization studies done in order to report any ADR during clinical practice are available. In Mexico, the population is growing at a yearly rate of 1.85, representing approximately more than 2 millions of newborns every year 8. The IMSS, one of the two social health systems available in Mexico, is responsible to attend approximately 60% of the Mexican citizens and also a considerable rate of deliveries 9, resulting into a major source of information on drugs utilization. The present study was performed in order to identify any ADR to tocolytic drugs in a prospective cohort of hospitalised pregnant women requiring medical attention at the IMSS.

Materials and Methods

After approval by the National Research Committee of the IMSS, the study was performed at the Gynecology and Obstetric units of two secondary-care general hospitals. Selection of these hospitals was based on their similar characteristics of medical care while they had a different geographic distribution, one at the north and other at the south of Mexico City. A minimal sample size of 148 patients was estimated using previous studies on ADR's with an expected frequency of ≥ 2.5% and a significant level of 5% 1011. During the study period, 207 women in labor, premature labor, threatened abortion or suffering any obstetrical related disease referred to any of the two hospitals over a 4-month period were included into the cohort, and data were obtained during their hospital stay.

Data collection

General information including age (yr.), level of education (according to the basic Mexican scholar system, patients were grouped into ≤ 6 and >6 years of scholar level), diagnosis (cesarean section, labor, premature labor, threatened abortion, or post-cesarean complications), and hospital stay (days) were obtained. Drugs and dose administrated were obtained from the medical and nursery records. Patients were questioned daily, in relation to the presence or not, of symptoms relating to drug administration. Nurses trained for purpose of the study collected data and an Obstetrician confirmed clinical information.

Causality assessment

For identifying any ADR, the Kramer's algorithm was used 121314. This system was previously translated into Spanish and successfully used in pediatric patients 15. Briefly, the algorithm contains 56 questions grouped in six decision-making axes, and it evaluates previous experiences with any drug, potential etiologies of the ADR, a temporary relationship between drug administration and the presence of the ADR, the possibility of an overdoses, and any re-challenge with the suspected drug. Each axe is graded and a total score is obtained to classify the reaction as improbable (<0), possible (0,+1,+2,+3), probable (+4,+5) and definitive (+6,+7). For patients receiving more than one drug, each drug was evaluated by means of the algorithm. Any possibility of drugs interaction was evaluated by means of the Drug interaction program (The Medical Letter, Inc., New Rochelle, NY, USA). An ADR was positively qualified if two or all the evaluators qualified a suspected ADR as either probable or definitive. The file of each patient was reviewed independently by three of the authors trained to use the algorithm (AA Nava-Ocampo, JA Palma-Aguirre and H Sumano-López). Inter-observer agreement among the three evaluators in relation to the scores given to every potential ADR was computed by means of a Kappa analysis at a p < 0.05 level 1617. Finally, severity of each ADR was scored according to Capellá and Laporte into mortal, severe (any life-threatening reaction), moderate (any reaction requiring hospitalization or requiring urgent atention), or mild 18.

Statistical analysis

Data from all patients were summarized by using descriptive statistics. Patients were further goruped into patients suffering or not any ADR. Except for vitamins, all drugs received by patients were presented as only one active principle. We therefore counted all drugs daily received by each patient and obtained a mean value. Results were then summarized and a final mean value and SD of number of drugs/day × patient^-1 was obtained. The unpaired Student t test was used to compare age and drugs/day × patient^-1 between patients suffering or not an ADR. The dose of terbutaline was also compared between the two groups by means of the unpaired Student t test. The Fishers' exact chi-square test was used to evaluate differences in diagnosis and type of drug used for uterine activity inhibition (terbutaline, indometacine, or none) between groups. The significant level for all statistical analyses was fixed at a p < 0.05. When used, the parametric 95% confidence interval for the difference was computed.

Software

Data were collected in a predesigned Microsoft^® Excel 97 form. For statistical anaylsis, we used the Epi-lnfo^® 6 v. 6.04d (The Center for Disease Control and Prevention, Atlanta, Georgia, USA).

Results

Demographic data were summarized in Table 1. Patients were young people, most of them have the basic education level, and patients undergoing cesarean section was the the major clinical condition.

Table 1

Characteristics of the population

n = 207

AGE (years)^*

27.2 ± 5.2

SCOLARITY

≤ 6 yr

36(17.4)

>6 yr

171 (82.6)

DIAGNOSTICS

Threatened abortion

27(13.1)

Premature labor

48 (23.2)

Labor

39(18.8)

Cesarean section

75 (36.2)

Post-cesarean complications

18(8.7)

HOSPITAL STAY (days)^*

3.1 ± 0.7

^* data expressed as mean ± sd

In relation to the ADR's, agreeement among the reviewers for classification of each ADR was satisfactory (Kappa > 0.92). Of the 207 patients included in the cohort, 28 presented any suspected ADR, being 25 positively classified (12.1%, 95%CI 8.1 to 17.5%). Grouping patients with diagnosis of threatened abortion, premature labor or under labor (n= 114), 24 ADR's were related to terbutaline, accounting for a rate of 21.1 ADR's per 100 obstetric patients.

Patients suffering an ADR were slightly but significantly older than those wihout any ADR (Table 2). They also were attended mainly for premature labor, have a lower hospital stay, and they were mainly receiving terbutaline. However, the dose of terbutaline was similar between the two groups. The tocolytic therapy with terbutaline inhibited uterine motility in women with with and without any ADR in a similar rate, 70 and 76% (x² 0.07; p = 0.8), respectively. Of the 24 patients suffering an ADR to terbutaline, tremor was present in all patients, dizziness in seven, confusion in six, depression in five, adynamia in three, astenia in other three and headache also in three patients, and loss of equilibrium in one, irritability in one, and palpitations and aggressiveness in another patient. The only patient suffering an ADR to indomethacin referred abdominal discomform. All ADR's were classified as minor reactions, and according with the obstetricians did not merit to prolong the hospital stay, any additional treatment or drug discontinuation, and no fetal complications was reported by the patient or at the maternal records during the hospital stay.

Table 2

Characteristics of patients with diagnosis of threatened abortion, premature labor or labor in relation to the presence or not of any ADR.

With ADR (n = 25)

Without ADR (n = 89)

Significant level

Age (yr., mean ± SD)

28.8 ± 5.9

25.6 ± 6.0

p = 0.02

DIAGNOSIS

Threatened abortion

4(16%)

23 (25.8%)

Premature labor

20 (80%)

28(31.5%)

<0.001

Labor

1 (4%)

38 (42.7%)

HOSPITAL STAY (days)

≤ 3

20 (80%)

45 (50.6%)

p= 0.016

5 (20%)

44 (49.4%)

DRUGS/DAY × PATIENT^-1

Mean ± SD

3.3 ± 1.3

4.4 ± 2.2

p = 0.02

UTERINE INHIBITOR

a) Terbutaline

24 (96%)

19(21.3%)

b) Indomethacin

1 (4%)

35 (40.4%)

p < 0.001

c) None

34 (38.3%)

TERBUTALINE DOSE (mg/day)

)

Mean ± SD

13.0 ± 3.5

14.5 ± 2.2

p > 0.05

Range

5–15

Discussion

Kramer et al., created an algorithm to identify and qualify any ADR without any drug assay 121314. However, some problems have emerged with its use. It needs to be translated and adapted for using in different countries, as it happened to us. The algorithm is extensive, and therefore time-consuming. It requires multiple specific information that was collected due to the prospective nature of the present study. Some data, however, could not be available in the clinical file for a retrospective evaluation.

Despite the Council of the International Organization of Medical Sciences has provided definitions and basic requirements for the proper use of ADR terminology 19, a diagnosis is often difficult to establish due to the presence of clinical conditions or prescription of two or more drugs. Casuality assessment for ADR's is therefore often difficult in the clinical setting 20. Comparisons among the reported ADR's frequencies are also problematic due to the differences observed among the studies, including the population (e.g. pediatric, adults or old patients), gender, set of the study (e.g. emergency rooms or hospitalized patients), and method of measurement (e.g. therapeutic drug monitoring, spontaneous reports) 410112122232425262728 . The frequency of 12.1% of ADR's reported in the current study was lower than the 33.3% reported for all admissions at an Indian hospital 29, and than 28.2% reported at a Universitary hospital 11. However, it resulted higher than 2.4 to 3.7% of ADR's observed in other studies for hospitalized patients 410. Differences could be explained by the fact that obstetric patients do receive a lesser amount or less agressive theraphy than patients attended e.g. at internal medical wards.

We studied women patients requiring hospital attention for non-accidental causes, and despite a high incidence of ADR's was identified in patients receiving terbutaline for premature labor and threatened abortion, mortality was not present. Terbutaline is worldwide formerly approved for the treatment of asthma. As it was recently reviewed by Lam et al. 30, in the United States the off-label utility of terbutaline as a tocolytic agent has been known by clinicians for more than 20 years, estimating that at least 260,000 women are yearly receiving terbutaline during pregnancy, being the most popular prescribed β-mimetic for tocolysis in the USA. In Mexico, it is also extensively used in the obstetric wards provably favored by the fact that other therapuetic options as ritodrine did never arrive to our country. In fact, ritodrine was removed from the marked in the United States 30.

Terbutaline is clearly an effective inhibitor of uterine activity 3132, and its ADR's are abated with discontinuing treatment only. In our study, no differences in dose of terbutaline were detected between patients suffering or not an ADR. Although efficacy was not our goal, the uterine inhibitor effects of terbutaline resulted in a high rate of patients. The study was performed during a period of 4 months and we did not observe any patient re-entering into the hospital because of the presence of a new episode of uterine activity. Whether the patients underwent another period of uterine activity and received medical care in another hospital or successfully completed the pregnancy period, cannot be clarified in our study. Also, the fetal and maternal long-term morbidity was unknown. Obstetrician service is the main request of medical care in Mexican hospitals, and births have been 31.2% of total hospital discharges, being 53.9% of total births registered in 1997 attended at the IMSS 9. A careful selection of pregnant women in order to avoid a dangerous impact to both or either the mother and the fetus due to the production of palpitations counterbalancing the benefits between its use for managing a threatened abortion or a premature labor and costs of minor ADR's, must be mandatory. Furthermore, the small range of current options to be used as tocolytics should stimulate this area in order to identify drugs with lesser production of side effects. In fact, terbutaline could not only be undangerous for the fetus but to promote neonatal respiration and metabolic adaptation after elective cesarean section and to reduce the number of fetal heart abnormalities 3334.

In relation to indomethacin, this drug has proved safety and efficacy to inhibit uterine contractions of premature labor 3536. Uterine contractility at term and preterm results from an activation of myometrium through several process varying from mechanical stimulation to a complex cascade of endocrine processes 37. Prostaglandinds are important regulators of the labor process 38, and therefore its manipulation has resulted into a direct effect favoring or inhibiting uterine activity 3940. However, it is well known the adverse effects of all nonsteroidal anti-inflamatory drugs administered at the third trimester of pregnancy 414243, including constriction of the ductus arteriosus, persistent fetal circulation, impairment of renal function and bleeding. Furthermore, brain maldevelopment and neurobehaviour deviations have been experimentally demonstrated after neonatal exposure to indomethacin 44. Therefore, despite our results seem likely to favour indomethacin administration because it was better tolerated than terbutaline for tocolysis, the serious adverse effects potentially produced in the fetus by indomethacin make this drug a greatly dangerous option for preterm labor management.

Additionally, incidence of preterm birth is greatly increased among the socially disadvantaged women, probably explained by two major factors 45. First, the presence of chronic and acute social stressors which in turn are translated into organc responses. Second, the presence of a gene-environment interaction based on a highly prevalence mutation in the gene for methylentetrahydrofolate reductase. Even more, maternal education level could decrease infant mortality rate by preventing preterm births 46, without affecting fetal growth 47. In the present study, most patients have the basic education level, and therefore if any effect was present this would be protector. Finally, there is a need for a simple, efficient and low-cost of ADR's reporting system covering a wide range of the population receiving any drug. The spontaneous reports probably satisfy these conditions and participation of nurses in the design of strategies of recognizing any ADR is undoubtedly necessary 4849.

In conclusion, terbutaline was responsible of a high rate of mild ADR's in women receiving this drug as a tocolytic agent. However, the lack of well recognized options makes terbutaline the major tocolytic drug currently available.

Competing interests

None declared

Acknowledgements

All the authors dedicate the paper to the memory of the Pharmacist María Josefa E. Vargas-Rivera "Pepita", who devoted the last years of her wonderful existency to promote the studies of pharmacovigilance at the IMSS. In fact, the present study was proposed by her and it could not be completed without her participation. Dr. A. A. Nava-Ocampo thanks the grant received, as a member, from the Sistema Nacional de Investigadores. The helpful and patient assistance of Mr. Victor Manuel Vázquez for preparing the manuscript in English language is also thanked. Support in any form was not received from any pharmaceutical company.

The role of the WHO program on International Drug Monitoring in coordinating wolrdwide drug safety efforts. Olsson S Drug Saf 1998 19 1 10 9673854 Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. Lazarou J Pomeranz BH Corey PN JAMA 1998 279 1200 1205 10.1001/jama.279.15.1200 9555760 Cost of hospitalizations related to side-effects drugs (<it>in French</it>). Detournay B Fagnani F Ouyanne P Haramburu F Begaud B Welsch M Imbs JL Thérapie 2000 55 137 139 10860015 Adverse drug events in hospitalized patients. Excess lenght of stay, extra costs, aand attributable mortality. Classen DC Pestotnik SL Evans RS Lloyd JF Burke JP JAMA 1997 277 301 306 10.1001/jama.277.4.301 9002492 Therapeutic drug monitoring in special populations. Walson PD Clin Chem 1998 44 415 419 9474053 Immunosuppressive drugs in pregnancy. Ghandour FZ Knauss TC Hricik DE Adv Ren Replace Ther 1998 5 31 37 9477213 Introducción a la farmacovigilancia. Becerril-Marténez MC Díaz-Marténez A Bondani-Guasti A México DF, Secretaría de Salud, 1995 13 14 XII Censo General de Población y Vivienda 2000: Síntesis de Resultados. Instituto Nacional de Estadística, Geografía e Informática IAEGI: Estados Unidos Mexicanos http://www.inegi.gob.mx Principales servicios de hospitalización por institución de salud. Secretaría de Salud, Dirección General de Estadística e Informática del Sistema Nacional de Salud, Sistema Sectorial de Información en Salud Bol Inform Estad 1997 1 25 43 Incidence of adverse events and negligence in hospitalized patients. Results of the Harvard Medical Practice Study I. Brennan TA Leape LL Laird NM Hebert L Localio AR Lawthers AG Newhouse JP Weiler PC Hiatt HH N Eng J Med 1991 324 370 376 1987460 Drug-induced illness leading to hospitalization. Caranasos GJ Stewart RB Cluff LE JAMA 1974 228 713 717 10.1001/jama.228.6.713 4406257 An algorithm for the operational assessment of adverse drug reactions. I. Background, description, and instructions for use. Kramer MS Leventhal JM Hutchinson TA Feinstein AR JAMA 1979 242 623 632 10.1001/jama.242.7.623 449002 An algorithm for the operational assessment of adverse drug reactions. II. Demonstration of reproducibility and validity. Hutchinson TA Leventhal JM Kramer MS Karch FE Lipman AG Feinstein AR JAMA 1979 242 633 638 10.1001/jama.242.7.633 449003 An algorithm for the operational assessment of adverse drug reactions. III. Results of tests among clinicians. Leventhal JM Hutchinson TA Kramer MS Feinstein AR JAMA 1979 242 1991 1994 10.1001/jama.242.18.1991 480646 Reacciones adversas a los medicamentos en pacientes pediátricos en dos hospitales de segundo nivel. Vargas-Rivera J Hernández HDM Sumano LH Palma AA Bondani GA Ponce MH Rev Med IMSS 1996 34 421 427 Critical appraisal od epidemiological studies and clinical trials. Elwood MJ New York, Oxford University Press 1998 104 108 The measurement of observer agreement for categorical data. Landis JR Koch GG Biometrics 1977 33 159 174 843571 Spontaneous notification of adverse drug reactions (<it>in Spanish</it>). Capellá D Laporte JR In: Phncipios de epidemiología de los medicamentos Barcelona, Ediciones científicas y técnicas SA Laporte JR, Tognoni G 1993 147 170 Harmonising adverse drug reaction terminology: the role of the Council for International Organizations of Medical Sciences. Venulet J Bankowski Z Drug Saf 1998 19 165 172 9747664 Causal or casual? The role of causality assessment in pharmacovigilance. Meyboom RH Hekster YA Egberts AC Gribnau FW Edwards IR Drug Saf 1997 17 374 389 9429837 Drug surveillance and adverse reactions to drugs. The literature and importance of historical data (<it>in Italian</it>). Mariani L Minora T Ventresca GP Clin Ter 1996 147 653 672 9296925 Pharmacovigilance: education and continuing updating. The role of university institutes (<it>in Italian</it>). Mariani L Clin Ter 1998 149 219 225 9842106 Detection and evaluation of adverse drug effects (<it>in German</it>). Thurmann PA Schmitt K Med Klin 2000 95 4 8 10851841 Age and sex distribution of suspected adverse drug reactions to newly marketed drugs in general practice in England: analysis of 48 cohort studies. Martin RM Biswas PN Freemantle SN Pearce GL Mann RD Br J Clin Pharmacol 1998 46 505 511 10.1046/j.1365-2125.1998.00817.x 9833605 Differences in the relative incidence of adverse drug reactions in relation to age? An evaluation of the spontaneous reporting system of SANZ (Swiss Drug Monitoring Center) (<it>in German</it>). Ciorciaro C Hartmann K Kuhn M Schweiz Med Wochenschr 1998 128 254 258 9540150 Adverse drug reaction surveillance in pediatric and adult patients in an emergency room (<it>in Spanish</it>). Muñoz MJ Ayani I Rodriguez-Sasiain JM Gutiérrez G Aguirre C Med Clin (Barc) 1998 111 92 98 9706601 Gender differences in adverse drug reactions. Tran C Knowles SR Liu BA Shear NH J Clin Pharmacol 1998 38 1003 1009 9824780 Computerized surveillance of adverse drug events in hospital patients. Classen DC Pestotnik SL Evans RS Burke JP JAMA 1991 266 2847 2851 10.1001/jama.266.20.2847 1942452 Adverse drug reactions among inpatients in a north Indian referral hospital. Uppal R Jhaj R Malhotra S Natl Med J India 2000 13 16 18 10743370 Clinical issues surrounding the use of terbutaline sulfate for preterm labor. Lam F Elliott J Jones JS Katz M Knuppel RA Morrison J Newman R Phelan J Willcourt R Obstet Gynecol Surv 1998 53 suppl S85 S95 10.1097/00006254-199811002-00001 9812326 Incidence of adverse cardiopulmonary effects with low-dose continuous terbutaline infusion. Perry KG Jr Morrison JC Rust OA Sullivan CA Martin RW Naef RW 3rd Am J Obstet Gynecol 1995 173 1273 1277 10.1016/0002-9378(95)91369-6 7485336 Tocolytics for preterm labor: a systematic review. Gyetvai K Hannah ME Hodnett ED Ohisson A Obstet Gynecol 1999 94 869 877 10.1016/S0029-7844(99)00329-4 10546776 Tocolytics for suspected intrapartum fetal distress. Kulier R Hofmeyr GJ Cochrane Database Syst Rev 2000 2 CD000035 10796094 Randomised controlled trial of effect of terbutaline before elective caesarean section on postnatal respiration and glucose homeostasis. Eisler G Hjertberg R Lagercrantz H Arch Dis Child Fetal Neonatal Ed 1999 80 F88 F92 10325782 Treatment of premature labor contractions with combined ritodrine and indomethacine. Katz Z Lancet M Yemini M Mogilner BM Feigl A Ben-Hur H Int J Gynaecol Obstet 1983 21 337 342 10.1016/0020-7292(83)90026-7 6141090 Efficacy and safety of indomethacin versus ritodrine in the management of preterm labor: a randomized study. Morales WJ Smith SG Angel JL O'Brien WF Knuppel RA Obstet Gynecol 1989 74 567 572 2677863 Understanding preterm labor. Challis JR Lye SJ Gibb W Whittle W Patel F Alfaidy N Ann N Y Acad Sci 2001 943 225 234 11594542 Regulation of prostaglandins synthesis in the human uterus. Zakar T Hertelendy F J Matern Fetal Med 2001 10 223 235 11531147 Prostaglandin E2 gel versus misoprostol for cervical ripening in patients with premature rupture of membranes after 34 weeks. Frohn WE Simmons S Carlan SJ Obstet Gynecol 2002 99 206 210 10.1016/S0029-7844(01)01677-5 11814498 Inhibition of prostaglandin synthesis and its effect on uterine activity during established premature labor in sheep. Scott JE Grigsby PL Hirst JJ Jenkin G J Soc Gynecol Investig 2001 8 266 276 10.1016/S1071-5576(01)00124-1 11677146 Treatment of inflammatory rheumatic disorders in pregnancy: what are the safest treatment options? Ostensen M Ramsey-Goldman R Drug Saf 1998 19 389 410 9825952 Effect of maternal tocolysis on the incidence of severe periventricular/intraventricular haemorrhage in very low birthweight infants. Weintraub Z Solovechick M Reichman B Rotschild A Waisman D Davkin O Lusky A Bental Y Arch Dis Child Fetal Neonatal Ed 2001 85 F13 F17 10.1136/fn.85.1.F13 11420315 NSAID-induced nephrotoxicity from the fetus to the child. Cuzzolin L Dal-Cere M Fanos V Drug 2001 24 9 18 Brain maldevelopment and neurobehavioural deviations in adult rats treated neonatally with indomethacin. Benesova O Tejkalova H Kristofikova Z Husek P Nedvidkova J Yamamotova A Eur Neuropsychopharmacol 2001 11 367 373 10.1016/S0924-977X(01)00102-X 11597823 Socio-economic disparities in preterm birth: causal pathaways and mechanisms. Kramer MS Goulet L Lydon J Seguin L McNamara H Dassa C Platt RW Chen MF Gauthier H Genest J Kahn S Libman M Rozen R Masse A Miner L Asselin G Benjamin A Klein J Koren G Pediatr Perinatal Epidemiol 2001 15 suppl 2 104 123 10.1046/j.1365-3016.2001.00012.x Predictors of infant mortality among college-educated black and white women, Davidson County, Tennessee, 1990–1994. Scott-Wright AO Wrona RM Flanagan TM J Natl Med Assoc 1998 90 477 483 9727291 Are risk factors the same for small for gestational age versus other preterm births? Zeitlin JA Ancel PY Saurel-Cubizolles MJ Papiernik E Am J Obstet Gynecol 2001 185 208 215 10.1067/mob.2001.114869 11483930 Clinical recognition of adverse drug reactions: obstacles and opportunities for the nursing profession. Arnold GJ J Nurs Care Qual 1998 13 45 55 9842175 Reporting of adverse drug reactions: practice in the UK. Morrison-Griffiths S Pirmohamed M Walley T Nurs Times 1998 94 52 54 9735778

Pre-publication history

The pre-publication history for this paper can be accessed here:

http://www.biomedcentral.com/1471-2393/2/3/prepub