{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T09:20:42Z","timestamp":1769160042630,"version":"3.49.0"},"reference-count":191,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2003,3,31]],"date-time":"2003-03-31T00:00:00Z","timestamp":1049068800000},"content-version":"vor","delay-in-days":58,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Birth Defects Research Pt B"],"published-print":{"date-parts":[[2003,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p><jats:bold>BACKGROUND:<\/jats:bold> Nonsteroidal anti\u2010inflammatory drugs (NSAIDs) are among the most commonly prescribed to pregnant women. Some case\u2010control studies have linked the NSAIDs aspirin and indomethacin with a risk of congenital abnormalities and low birthweight. High doses of aspirin produce developmental toxicity in rats (e.g., gastroschisis\/umbilical hernia, diaphragmatic hernia [DH]) when administered during sensitive windows of development. Unlike other NSAIDs, aspirin irreversibly inhibits cyclooxygenases (COXs) 1 and 2. Hence, the developmental toxicity seen in rats after exposure to aspirin may be due to the irreversible inhibition of COX\u20101 and\/or COX\u20102. If so, other NSAIDs, which act through a reversible inhibition of COX, may produce a weak developmental toxicity signal or no developmental toxicity signal when tested in preclinical models. To investigate this relationship, a comprehensive analysis of the NSAID developmental toxicity literature was undertaken to determine whether NSAIDs other than aspirin induce developmental anomalies similar to those elicited by aspirin. <jats:bold>METHODS:<\/jats:bold> Developmental toxicity studies were identified through literature searches of PubMed and TOXNET, and pregnancy outcome data were extracted and tabulated. By using a set of defined criteria, each study was evaluated for quality and assigned to one of five tiers. The relation between certain malformations and NSAID treatment was analyzed for the best studies (tiers 1\u20134) by using concurrent control data (Mantel\u2013Haenszel and permutation tests) and by combining the concurrent control data with historical control data (\u03c7<jats:sup>2<\/jats:sup> test and permutation tests). <jats:bold>RESULTS:<\/jats:bold> A qualitative analysis of these data led to a focus on three types of malformations: DH, ventricular septal defects (VSDs), and midline defects (MDs). In rats, the incidences of VSD and MD were increased among fetuses treated with NSAIDs when compared with the concurrent controls. The extent of the increase was attenuated when the data from the aspirin studies were excluded from the analysis. There were no qualifying (i.e., tiers 1\u20134) aspirin studies conducted in rabbits, but the incidences of the three defects were increased over control incidences among non\u2010aspirin NSAID\u2010treated animals. Statistical analysis of these data was subsequently conducted. When tiers 1\u20134 were combined and compared with concurrent controls plus the most appropriate historical control database, the strongest associations were between NSAID treatment and VSD in rats, VSD in rabbits, and MD in rabbits. There also was some suggestion of an association between NSAID treatment and DH in rabbits. <jats:bold>CONCLUSIONS:<\/jats:bold> This analysis of the non\u2010clinical NSAID literature demonstrated a possible association between exposure to NSAIDs and developmental anomalies. The anomalies were similar for aspirin and for other NSAIDs, but effects occurred at a much lower incidence with non\u2010aspirin NSAIDs than previously reported with aspirin. Such a finding is consistent with the concept that reversible inhibition of COX\u20101 and\/or COX\u20102 by other NSAIDs would produce weaker developmental toxicity signals than aspirin. However, there were limitations of the evaluated studies: (1) there were very few robust International Conference on Harmonization\u2013compliant studies conducted with NSAIDs in the published literature; (2) many of the studies were conducted at doses well below the maximum tolerated dose (MTD), where effects are rarely seen; and (3) numerous studies were conducted above the MTD, where reduced numbers of fetuses hampered detection of low\u2010incidence findings. Although weak associations were observed, these limitations prevented us from definitively determining the presence or absence of a developmental toxicity signal from the existing body of NSAID data. Further exploration of this hypothesis will require assessing the potential association in animal models by using dose levels centered around the MTD. <jats:italic>Birth Defects Research (Part B)<\/jats:italic> 68:5\u201326, 2003. \u00a9 2003 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/bdrb.10005","type":"journal-article","created":{"date-parts":[[2003,4,2]],"date-time":"2003-04-02T17:37:20Z","timestamp":1049305040000},"page":"5-26","source":"Crossref","is-referenced-by-count":50,"title":["Analysis of the nonsteroidal anti\u2010inflammatory drug literature for potential developmental toxicity in rats and rabbits"],"prefix":"10.1002","volume":"68","author":[{"given":"Jon C.","family":"Cook","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catherine F.","family":"Jacobson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feng","family":"Gao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melissa S.","family":"Tassinari","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark E.","family":"Hurtt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John M.","family":"DeSesso","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2003,3,31]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/0041-008X(69)90032-5"},{"key":"e_1_2_7_3_1","first-page":"658","article-title":"[Toxicologic studies on the effect of azapropazone on reproduction in the rat]","volume":"23","author":"Adrian RW","year":"1973","journal-title":"Arzneimittelforschung"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1185\/03007997609109278"},{"key":"e_1_2_7_5_1","volume-title":"Categorical data analysis","author":"Agresti A","year":"1990"},{"key":"e_1_2_7_6_1","first-page":"451","article-title":"Teratogenicity study of oxepinac in mice and rabbits","volume":"28","author":"Arauchi T","year":"1978","journal-title":"Arzneimittelforschung"},{"key":"e_1_2_7_7_1","first-page":"23","article-title":"Experimental production of malformations due to acetyl salicylate and phenyl salicylate in rats","volume":"12","author":"Baba T","year":"1966","journal-title":"Osaka City Med J"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/0041-008X(77)90140-5"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00315569"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/newbio236211a0"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdrb.10008"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdrb.10004"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0773.1974.tb00730.x"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420300304"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(94)92633-6"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/0041-008X(71)90227-4"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/0300-483X(81)90052-4"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420010205"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/0272-0590(88)90104-2"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1080\/15287398209530252"},{"key":"e_1_2_7_21_1","first-page":"111","volume-title":"Handbook of developmental toxicology","author":"DeSesso JM","year":"1997"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(64)92875-2"},{"key":"e_1_2_7_23_1","first-page":"195","article-title":"Effects of oral administration of tiaprofenic acid (RU 15060) on reproduction in the mouse. 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