BMC Pregnancy and Childbirth BioMed Central

BMC
2002,Pregnancy and Childbirth
2 x
Research article
Drug therapy and adverse drug reactions to terbutaline in obstetric
patients: a prospective cohort study in hospitalized women
Dulce Mara Hernndez-Hernndez*1, Mara Josefa E Vargas-Rivera2,
Alejandro A Nava-Ocampo2, Jos Antonio Palma-Aguirre2 and
Hctor Sumano-Lpez3

Address: 1Unit of Medical Research in Oncologic Diseases, Area de Epidemiologia, Hospital de Oncologa, Centro Medico Nacional "Siglo XXI",
Institute Mexicano del Seguro Social, Mexico City, Mexico, 2Unit of Medical Research in Pharmacology, Hospital de Especialidades, CMN "Siglo
XXI", IMSS, Mexico City, Mexico and 3Department of Pharmacology, Facultad de Medicina, Universidad Nacional Autnoma de Mxico, Mexico
City, Mexico
E-mail: Dulce Hernndez-Hernndez* - [email protected]; Mara Vargas-Rivera - [email protected]; Alejandro A Nava-
Ocampo - [email protected]; Jos Palma-Aguirre - [email protected]; Hctor Sumano-Lpez - [email protected]
*Corresponding author

Published: 5 April 2002 Received: 15 July 2001

Accepted: 5 April 2002
BMC Pregnancy and Childbirth 2002, 2:3
This article is available from: http://www.biomedcentral.com/1471-2393/2/3
2002 Hernndez-Hernndez et al; licensee BioMed Central Ltd. Verbatim copying and redistribution of this article are permitted in any medium for any
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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.

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Background ery records. Patients were questioned daily, in relation to

The ADR's are considered as a major public health prob- the presence or not, of symptoms relating to drug admin-
lem [1]. Being the fourth cause of general deaths [2], the istration. Nurses trained for purpose of the study collected
ADR's are costly and represent a significant rate of hospital data and an Obstetrician confirmed clinical information.
admissions [3,4]. Furthermore, the number of drugs avail-
able for prescription in the clinical setting is increasing Causality assessment
every day. It is therefore important to acquire, interpret For identifying any ADR, the Kramer's algorithm was used
and report all ADR's identified with any drug [2]. Further- [1214]. This system was previously translated into Span-
more, pharmacovigilance in special populations, e.g. ish and successfully used in pediatric patients [15]. Briefly,
pregnancy women, could be useful to identify unexpected the algorithm contains 56 questions grouped in six deci-
responses probably expressing unusual pharmacokinetic sion-making axes, and it evaluates previous experiences
profiles as a result of their particular physiological state with any drug, potential etiologies of the ADR, a tempo-
[5,6]. rary relationship between drug administration and the
presence of the ADR, the possibility of an overdoses, and
Multiple methods have been used for pharmacovigilance, any re-challenge with the suspected drug. Each axe is grad-
and despite spontaneous reporting is the simplest one, it ed and a total score is obtained to classify the reaction as
has been of low efficacy in Mexican medical practice [7]. improbable (<0), possible (0,+1,+2,+3), probable (+4,+5)
Furthermore, in Latin-America only a limited number of and definitive (+6,+7). For patients receiving more than
drug utilization studies done in order to report any ADR one drug, each drug was evaluated by means of the algo-
during clinical practice are available. In Mexico, the pop- rithm. Any possibility of drugs interaction was evaluated
ulation is growing at a yearly rate of 1.85, representing ap- by means of the Drug interaction program (The Medical
proximately more than 2 millions of newborns every year Letter, Inc., New Rochelle, NY, USA). An ADR was posi-
[8]. The IMSS, one of the two social health systems avail- tively qualified if two or all the evaluators qualified a sus-
able in Mexico, is responsible to attend approximately pected ADR as either probable or definitive. The file of
60% of the Mexican citizens and also a considerable rate each patient was reviewed independently by three of the
of deliveries [9], resulting into a major source of informa- authors trained to use the algorithm (AA Nava-Ocampo,
tion on drugs utilization. The present study was per- JA Palma-Aguirre and H Sumano-Lpez). Inter-observer
formed in order to identify any ADR to tocolytic drugs in agreement among the three evaluators in relation to the
a prospective cohort of hospitalised pregnant women re- scores given to every potential ADR was computed by
quiring medical attention at the IMSS. means of a Kappa analysis at a p < 0.05 level [16,17]. Fi-
nally, severity of each ADR was scored according to Capel-
Materials and Methods l and Laporte into mortal, severe (any life-threatening
After approval by the National Research Committee of the reaction), moderate (any reaction requiring hospitaliza-
IMSS, the study was performed at the Gynecology and Ob- tion or requiring urgent atention), or mild [18].
stetric units of two secondary-care general hospitals. Selec-
tion of these hospitals was based on their similar Statistical analysis
characteristics of medical care while they had a different Data from all patients were summarized by using descrip-
geographic distribution, one at the north and other at the tive statistics. Patients were further goruped into patients
south of Mexico City. A minimal sample size of 148 pa- suffering or not any ADR. Except for vitamins, all drugs re-
tients was estimated using previous studies on ADR's with ceived by patients were presented as only one active prin-
an expected frequency of 2.5% and a significant level of ciple. We therefore counted all drugs daily received by
5% [10,11]. During the study period, 207 women in la- each patient and obtained a mean value. Results were then
bor, premature labor, threatened abortion or suffering any summarized and a final mean value and SD of number of
obstetrical related disease referred to any of the two hos- drugs/day patient-1 was obtained. The unpaired Student
pitals over a 4-month period were included into the co- t test was used to compare age and drugs/day patient-1
hort, and data were obtained during their hospital stay. between patients suffering or not an ADR. The dose of
terbutaline was also compared between the two groups by
Data collection means of the unpaired Student t test. The Fishers' exact
General information including age (yr.), level of educa- chi-square test was used to evaluate differences in diagno-
tion (according to the basic Mexican scholar system, pa- sis and type of drug used for uterine activity inhibition
tients were grouped into 6 and >6 years of scholar level), (terbutaline, indometacine, or none) between groups. The
diagnosis (cesarean section, labor, premature labor, significant level for all statistical analyses was fixed at a p
threatened abortion, or post-cesarean complications), < 0.05. When used, the parametric 95% confidence inter-
and hospital stay (days) were obtained. Drugs and dose val for the difference was computed.
administrated were obtained from the medical and nurs-

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Software In relation to the ADR's, agreeement among the reviewers

Data were collected in a predesigned Microsoft Excel 97 for classification of each ADR was satisfactory (Kappa >
form. For statistical anaylsis, we used the Epi-lnfo 6 v. 0.92). Of the 207 patients included in the cohort, 28 pre-
6.04d (The Center for Disease Control and Prevention, At- sented any suspected ADR, being 25 positively classified
lanta, Georgia, USA). (12.1%, 95%CI 8.1 to 17.5%). Grouping patients with di-
agnosis of threatened abortion, premature labor or under
Results labor (n= 114), 24 ADR's were related to terbutaline, ac-
Demographic data were summarized in Table 1. Patients counting for a rate of 21.1 ADR's per 100 obstetric pa-
were young people, most of them have the basic educa- tients.
tion level, and patients undergoing cesarean section was
the the major clinical condition. Patients suffering an ADR were slightly but significantly
older than those wihout any ADR (Table 2). They also
Table 1: Characteristics of the population were attended mainly for premature labor, have a lower
n = 207 hospital stay, and they were mainly receiving terbutaline.
However, the dose of terbutaline was similar between the
two groups. The tocolytic therapy with terbutaline inhib-
AGE (years)* 27.2 5.2 ited uterine motility in women with with and without any
SCOLARITY ADR in a similar rate, 70 and 76% (x2 0.07; p = 0.8), re-
6 yr 36(17.4) spectively. Of the 24 patients suffering an ADR to terbuta-
>6 yr 171 (82.6)
line, tremor was present in all patients, dizziness in seven,
DIAGNOSTICS
Threatened abortion 27(13.1)
confusion in six, depression in five, adynamia in three, as-
Premature labor 48 (23.2) tenia in other three and headache also in three patients,
Labor 39(18.8) and loss of equilibrium in one, irritability in one, and pal-
Cesarean section 75 (36.2) pitations and aggressiveness in another patient. The only
Post-cesarean complications 18(8.7) patient suffering an ADR to indomethacin referred ab-
HOSPITAL STAY (days)* 3.1 0.7 dominal discomform. All ADR's were classified as minor
reactions, and according with the obstetricians did not
merit to prolong the hospital stay, any additional treat-
* data expressed as mean sd
ment or drug discontinuation, and no fetal complications
was reported by the patient or at the maternal records dur-
ing 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
>3 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 515 515

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Discussion not an ADR. Although efficacy was not our goal, the uter-
Kramer et al., created an algorithm to identify and qualify ine inhibitor effects of terbutaline resulted in a high rate
any ADR without any drug assay [1214]. However, some of patients. The study was performed during a period of 4
problems have emerged with its use. It needs to be trans- months and we did not observe any patient re-entering
lated and adapted for using in different countries, as it into the hospital because of the presence of a new episode
happened to us. The algorithm is extensive, and therefore of uterine activity. Whether the patients underwent anoth-
time-consuming. It requires multiple specific information er period of uterine activity and received medical care in
that was collected due to the prospective nature of the another hospital or successfully completed the pregnancy
present study. Some data, however, could not be available period, cannot be clarified in our study. Also, the fetal and
in the clinical file for a retrospective evaluation. maternal long-term morbidity was unknown. Obstetri-
cian service is the main request of medical care in Mexican
Despite the Council of the International Organization of hospitals, and births have been 31.2% of total hospital
Medical Sciences has provided definitions and basic re- discharges, being 53.9% of total births registered in 1997
quirements for the proper use of ADR terminology [19], a attended at the IMSS [9]. A careful selection of pregnant
diagnosis is often difficult to establish due to the presence women in order to avoid a dangerous impact to both or
of clinical conditions or prescription of two or more either the mother and the fetus due to the production of
drugs. Casuality assessment for ADR's is therefore often palpitations counterbalancing the benefits between its use
difficult in the clinical setting [20]. Comparisons among for managing a threatened abortion or a premature labor
the reported ADR's frequencies are also problematic due and costs of minor ADR's, must be mandatory. Further-
to the differences observed among the studies, including more, the small range of current options to be used as to-
the population (e.g. pediatric, adults or old patients), gen- colytics should stimulate this area in order to identify
der, set of the study (e.g. emergency rooms or hospitalized drugs with lesser production of side effects. In fact, terbu-
patients), and method of measurement (e.g. therapeutic taline could not only be undangerous for the fetus but to
drug monitoring, spontaneous reports) [4,10,11,2128] . promote neonatal respiration and metabolic adaptation
The frequency of 12.1% of ADR's reported in the current after elective cesarean section and to reduce the number of
study was lower than the 33.3% reported for all admis- fetal heart abnormalities [33,34].
sions at an Indian hospital [29], and than 28.2% reported
at a Universitary hospital [11]. However, it resulted higher In relation to indomethacin, this drug has proved safety
than 2.4 to 3.7% of ADR's observed in other studies for and efficacy to inhibit uterine contractions of premature
hospitalized patients [4,10]. Differences could be ex- labor [35,36]. Uterine contractility at term and preterm re-
plained by the fact that obstetric patients do receive a less- sults from an activation of myometrium through several
er amount or less agressive theraphy than patients process varying from mechanical stimulation to a com-
attended e.g. at internal medical wards. plex cascade of endocrine processes [37]. Prostaglandinds
are important regulators of the labor process [38], and
We studied women patients requiring hospital attention therefore its manipulation has resulted into a direct effect
for non-accidental causes, and despite a high incidence of favoring or inhibiting uterine activity [39,40]. However, it
ADR's was identified in patients receiving terbutaline for is well known the adverse effects of all nonsteroidal anti-
premature labor and threatened abortion, mortality was inflamatory drugs administered at the third trimester of
not present. Terbutaline is worldwide formerly approved pregnancy [4143], including constriction of the ductus
for the treatment of asthma. As it was recently reviewed by arteriosus, persistent fetal circulation, impairment of renal
Lam et al. [30], in the United States the off-label utility of function and bleeding. Furthermore, brain maldevelop-
terbutaline as a tocolytic agent has been known by clini- ment and neurobehaviour deviations have been experi-
cians for more than 20 years, estimating that at least mentally demonstrated after neonatal exposure to
260,000 women are yearly receiving terbutaline during indomethacin [44]. Therefore, despite our results seem
pregnancy, being the most popular prescribed -mimetic likely to favour indomethacin administration because it
for tocolysis in the USA. In Mexico, it is also extensively was better tolerated than terbutaline for tocolysis, the se-
used in the obstetric wards provably favored by the fact rious adverse effects potentially produced in the fetus by
that other therapuetic options as ritodrine did never arrive indomethacin make this drug a greatly dangerous option
to our country. In fact, ritodrine was removed from the for preterm labor management.
marked in the United States [30].
Additionally, incidence of preterm birth is greatly in-
Terbutaline is clearly an effective inhibitor of uterine activ- creased among the socially disadvantaged women, proba-
ity [31,32], and its ADR's are abated with discontinuing bly explained by two major factors [45]. First, the presence
treatment only. In our study, no differences in dose of of chronic and acute social stressors which in turn are
terbutaline were detected between patients suffering or translated into organc responses. Second, the presence of

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a gene-environment interaction based on a highly preva- 11. Caranasos GJ, Stewart RB, Cluff LE: Drug-induced illness leading
to hospitalization. JAMA 1974, 228:713-717
lence mutation in the gene for methylentetrahydrofolate 12. Kramer MS, Leventhal JM, Hutchinson TA, Feinstein AR: An algo-
reductase. Even more, maternal education level could de- rithm for the operational assessment of adverse drug reac-
crease infant mortality rate by preventing preterm births tions. I. Background, description, and instructions for use.
JAMA 1979, 242:623-632
[46], without affecting fetal growth [47]. In the present 13. Hutchinson TA, Leventhal JM, Kramer MS, Karch FE, Lipman AG,
study, most patients have the basic education level, and Feinstein AR: An algorithm for the operational assessment of
therefore if any effect was present this would be protector. adverse drug reactions. II. Demonstration of reproducibility
and validity. JAMA 1979, 242:633-638
Finally, there is a need for a simple, efficient and low-cost 14. Leventhal JM, Hutchinson TA, Kramer MS, Feinstein AR: An algo-
of ADR's reporting system covering a wide range of the rithm for the operational assessment of adverse drug reac-
tions. III. Results of tests among clinicians. JAMA 1979,
population receiving any drug. The spontaneous reports 242:1991-1994
probably satisfy these conditions and participation of 15. Vargas-Rivera J, Hernndez HDM, Sumano LH, Palma AA, Bondani
nurses in the design of strategies of recognizing any ADR GA, Ponce MH: Reacciones adversas a los medicamentos en
pacientes peditricos en dos hospitales de segundo nivel. Rev
is undoubtedly necessary [48,49]. Med IMSS 1996, 34:421-427
16. Elwood MJ: Critical appraisal od epidemiological studies and
clinical trials. New York, Oxford University Press 1998, 104-108
In conclusion, terbutaline was responsible of a high rate 17. Landis JR, Koch GG: The measurement of observer agreement
of mild ADR's in women receiving this drug as a tocolytic for categorical data. Biometrics 1977, 33:159-174
agent. However, the lack of well recognized options 18. Capell D, Laporte JR: Spontaneous notification of adverse drug
reactions (in Spanish). In: Phncipios de epidemiologa de los medica-
makes terbutaline the major tocolytic drug currently avail- mentos 1993, 147-170
able. 19. Venulet J, Bankowski Z: Harmonising adverse drug reaction ter-
minology: the role of the Council for International Organiza-
tions of Medical Sciences. Drug Saf 1998, 19:165-172
Competing interests 20. Meyboom RH, Hekster YA, Egberts AC, Gribnau FW, Edwards IR:
None declared Causal or casual? The role of causality assessment in phar-
macovigilance. Drug Saf 1997, 17:374-389
21. Mariani L, Minora T, Ventresca GP: Drug surveillance and ad-
Acknowledgements verse reactions to drugs. The literature and importance of
All the authors dedicate the paper to the memory of the Pharmacist Mara historical data (in Italian). Clin Ter 1996, 147:653-672
Josefa E. Vargas-Rivera "Pepita", who devoted the last years of her wonder- 22. Mariani L: Pharmacovigilance: education and continuing up-
ful existency to promote the studies of pharmacovigilance at the IMSS. In dating. The role of university institutes (in Italian). Clin Ter
fact, the present study was proposed by her and it could not be completed 1998, 149:219-225
without her participation. Dr. A. A. Nava-Ocampo thanks the grant re- 23. Thurmann PA, Schmitt K: Detection and evaluation of adverse
ceived, as a member, from the Sistema Nacional de Investigadores. The drug effects (in German). Med Klin 2000, 95:4-8
helpful and patient assistance of Mr. Victor Manuel Vzquez for preparing 24. Martin RM, Biswas PN, Freemantle SN, Pearce GL, Mann RD: Age
the manuscript in English language is also thanked. Support in any form was and sex distribution of suspected adverse drug reactions to
not received from any pharmaceutical company. newly marketed drugs in general practice in England: analy-
sis of 48 cohort studies. Br J Clin Pharmacol 1998, 46:505-511
25. Ciorciaro C, Hartmann K, Kuhn M: Differences in the relative in-
References cidence of adverse drug reactions in relation to age? An eval-
1. Olsson S: The role of the WHO program on International uation of the spontaneous reporting system of SANZ (Swiss
Drug Monitoring in coordinating wolrdwide drug safety ef- Drug Monitoring Center) (in German). Schweiz Med Wochenschr
forts. Drug Saf 1998, 19:1-10 1998, 128:254-258
2. Lazarou J, Pomeranz BH, Corey PN: Incidence of adverse drug re- 26. Muoz MJ, Ayani I, Rodriguez-Sasiain JM, Gutirrez G, Aguirre C: Ad-
actions in hospitalized patients: a meta-analysis of prospec- verse drug reaction surveillance in pediatric and adult pa-
tive studies. JAMA 1998, 279:1200-1205 tients in an emergency room (in Spanish). Med Clin (Barc) 1998,
3. Detournay B, Fagnani F, Ouyanne P, Haramburu F, Begaud B, Welsch 111:92-98
M, Imbs JL: Cost of hospitalizations related to side-effects 27. Tran C, Knowles SR, Liu BA, Shear NH: Gender differences in ad-
drugs (in French). Thrapie 2000, 55:137-139 verse drug reactions. J Clin Pharmacol 1998, 38:1003-1009
4. Classen DC, Pestotnik SL, Evans RS, Lloyd JF, Burke JP: Adverse 28. Classen DC, Pestotnik SL, Evans RS, Burke JP: Computerized sur-
drug events in hospitalized patients. Excess lenght of stay, veillance of adverse drug events in hospital patients. JAMA
extra costs, aand attributable mortality. JAMA 1997, 277:301- 1991, 266:2847-2851
306 29. Uppal R, Jhaj R, Malhotra S: Adverse drug reactions among inpa-
5. Walson PD: Therapeutic drug monitoring in special popula- tients in a north Indian referral hospital. Natl Med J India 2000,
tions. Clin Chem 1998, 44:415-419 13:16-18
6. Ghandour FZ, Knauss TC, Hricik DE: Immunosuppressive drugs 30. Lam F, Elliott J, Jones JS, Katz M, Knuppel RA, Morrison J, Newman R,
in pregnancy. Adv Ren Replace Ther 1998, 5:31-37 Phelan J, Willcourt R: Clinical issues surrounding the use of
7. Becerril-Martnez MC, Daz-Martnez A, Bondani-Guasti A: Intro- terbutaline sulfate for preterm labor. Obstet Gynecol Surv 1998,
duccin a la farmacovigilancia. Mxico DF, Secretara de Salud, 53(suppl):S85-S95
1995, 13-14 31. Perry KG Jr, Morrison JC, Rust OA, Sullivan CA, Martin RW, Naef
8. Instituto Nacional de Estadstica, Geografa e Informtica: XII Censo RW 3rd: Incidence of adverse cardiopulmonary effects with
General de Poblacin y Vivienda 2000: Sntesis de Resulta- low-dose continuous terbutaline infusion. Am J Obstet Gynecol
dos. IAEGI: Estados Unidos Mexicanos [http://www.inegi.gob.mx] 1995, 173:1273-1277
9. Secretara de Salud, Direccin General de Estadstica e Informtica 32. Gyetvai K, Hannah ME, Hodnett ED, Ohisson A: Tocolytics for pre-
del Sistema Nacional de Salud, Sistema Sectorial de Informacin en term labor: a systematic review. Obstet Gynecol 1999, 94:869-
Salud: Principales servicios de hospitalizacin por institucin 877
de salud. Bol Inform Estad 1997, 1:25-43 33. Kulier R, Hofmeyr GJ: Tocolytics for suspected intrapartum fe-
10. Brennan TA, Leape LL, Laird NM, Hebert L, Localio AR, Lawthers tal distress. Cochrane Database Syst Rev 2000, 2:CD000035
AG, Newhouse JP, Weiler PC, Hiatt HH: Incidence of adverse 34. Eisler G, Hjertberg R, Lagercrantz H: Randomised controlled trial
events and negligence in hospitalized patients. Results of the of effect of terbutaline before elective caesarean section on
Harvard Medical Practice Study I. N Eng J Med 1991, 324:370-
376

Page 5 of 6
(page number not for citation purposes)
BMC Pregnancy and Childbirth 2002, 2 http://www.biomedcentral.com/1471-2393/2/3

postnatal respiration and glucose homeostasis. Arch Dis Child

Fetal Neonatal Ed 1999, 80:F88-F92
35. Katz Z, Lancet M, Yemini M, Mogilner BM, Feigl A, Ben-Hur H:
Treatment of premature labor contractions with combined
ritodrine and indomethacine. Int J Gynaecol Obstet 1983, 21:337-
342
36. Morales WJ, Smith SG, Angel JL, O'Brien WF, Knuppel RA: Efficacy
and safety of indomethacin versus ritodrine in the manage-
ment of preterm labor: a randomized study. Obstet Gynecol
1989, 74:567-572
37. Challis JR, Lye SJ, Gibb W, Whittle W, Patel F, Alfaidy N: Under-
standing preterm labor. Ann N Y Acad Sci 2001, 943:225-234
38. Zakar T, Hertelendy F: Regulation of prostaglandins synthesis in
the human uterus. J Matern Fetal Med 2001, 10:223-235
39. Frohn WE, Simmons S, Carlan SJ: Prostaglandin E2 gel versus mi-
soprostol for cervical ripening in patients with premature
rupture of membranes after 34 weeks. Obstet Gynecol 2002,
99:206-210
40. Scott JE, Grigsby PL, Hirst JJ, Jenkin G: Inhibition of prostaglandin
synthesis and its effect on uterine activity during established
premature labor in sheep. J Soc Gynecol Investig 2001, 8:266-276
41. Ostensen M, Ramsey-Goldman R: Treatment of inflammatory
rheumatic disorders in pregnancy: what are the safest treat-
ment options? Drug Saf 1998, 19:389-410
42. Weintraub Z, Solovechick M, Reichman B, Rotschild A, Waisman D,
Davkin O, Lusky A, Bental Y: Effect of maternal tocolysis on the
incidence of severe periventricular/intraventricular haemor-
rhage in very low birthweight infants. Arch Dis Child Fetal Neona-
tal Ed 2001, 85:F13-F17
43. Cuzzolin L, Dal-Cere M, Fanos V: NSAID-induced nephrotoxicity
from the fetus to the child. Drug 2001, 24:9-18
44. Benesova O, Tejkalova H, Kristofikova Z, Husek P, Nedvidkova J,
Yamamotova A: Brain maldevelopment and neurobehavioural
deviations in adult rats treated neonatally with indometh-
acin. Eur Neuropsychopharmacol 2001, 11:367-373
45. 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: Socio-
economic disparities in preterm birth: causal pathaways and
mechanisms. Pediatr Perinatal Epidemiol 2001, 15(suppl 2):104-123
46. Scott-Wright AO, Wrona RM, Flanagan TM: Predictors of infant
mortality among college-educated black and white women,
Davidson County, Tennessee, 19901994. J Natl Med Assoc
1998, 90:477-483
47. Zeitlin JA, Ancel PY, Saurel-Cubizolles MJ, Papiernik E: Are risk fac-
tors the same for small for gestational age versus other pre-
term births? Am J Obstet Gynecol 2001, 185:208-215
48. Arnold GJ: Clinical recognition of adverse drug reactions: ob-
stacles and opportunities for the nursing profession. J Nurs
Care Qual 1998, 13:45-55
49. Morrison-Griffiths S, Pirmohamed M, Walley T: Reporting of ad-
verse drug reactions: practice in the UK. Nurs Times 1998,
94:52-54

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