{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T17:33:48Z","timestamp":1787592828025,"version":"build-2736575974"},"reference-count":36,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2006,10,30]],"date-time":"2006-10-30T00:00:00Z","timestamp":1162166400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Anat. Rec."],"published-print":{"date-parts":[[2006,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Valproic acid, a drug commonly used to treat seizures and other psychiatric disorders, causes neural tube defects (NTDs) in exposed fetuses at a rate 20 times higher than in the general population. Failure of the neural tube to close during development results in exencephaly or anencephaly, as well as spina bifida. In mice, nonspecific activation of the maternal immune system can reduce fetal abnormalities caused by diverse etiologies, including diabetes\u2010induced NTDs. We hypothesized that nonspecific activation of the maternal immune system with interferon\u2010\u03b3 (IFN\u2010\u03b3) and granulocyte\u2010macrophage colony\u2010stimulating factor (GM\u2010CSF) could reduce valproic acid (VA)\u2010induced defects as well. Female CD\u20101 mice were given immune stimulant prebreeding: either IFN\u2010\u03b3 or GM\u2010CSF. Approximately half of the control and immune\u2010stimulated pregnant females were then exposed to 500 mg\/kg VA on the morning of gestational day 8. The incidence of developmental defects was determined on gestational day 17 from at least eight litters in each of the following treatment groups: control, VA only, IFN\u2010\u03b3 only, IFN\u2010\u03b3 + VA, GM\u2010CSF only, and GM\u2010CSF + VA. The incidence of NTDs was 18% in fetuses exposed to VA alone, compared to 3.7% and 2.9% in fetuses exposed to IFN\u2010\u03b3 + VA, or GM\u2010CSF + VA respectively. Ocular defects were also significantly reduced from 28.0% in VA exposed groups to 9.8% in IFN\u2010\u03b3 + VA and 12.5% in GM\u2010CSF + VA groups. The mechanisms by which maternal immune stimulation prevents birth defects remain unclear, but may involve maternal or fetal production of cytokines or growth factors which protect the fetus from the dysregulatory effects of teratogens. Anat Rec Part A, 2006. \u00a9 2006 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/ar.a.20397","type":"journal-article","created":{"date-parts":[[2006,10,30]],"date-time":"2006-10-30T15:20:36Z","timestamp":1162221636000},"page":"1303-1309","source":"Crossref","is-referenced-by-count":21,"title":["Valproic acid\u2010induced fetal malformations are reduced by maternal immune stimulation with granulocyte\u2010macrophage colony\u2010stimulating factor or interferon\u2010\u03b3"],"prefix":"10.1002","volume":"288A","author":[{"given":"Terry C.","family":"Hrubec","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingjin","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keying","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn M.","family":"Salafia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven D.","family":"Holladay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2006,10,30]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3940(00)01457-9"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0890-6238(99)00038-6"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0890-6238(99)00064-7"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-003-1100-1"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-9926(200004)61:4<305::AID-TERA10>3.0.CO;2-8"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.1980.tb06014.x"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2005.07.008"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8628(19991119)87:2<143::AID-AJMG6>3.0.CO;2-J"},{"key":"e_1_2_6_10_1","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1093\/jn\/126.1.67","article-title":"Methionine reduces the valproic acid induced spina bifida rate in mice without altering valproic acid kinetics","volume":"126","author":"Ehlers K","year":"1996","journal-title":"J Nutr"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1286-0115(04)97999-4"},{"key":"e_1_2_6_12_1","first-page":"253","article-title":"Prepregnancy care and prevention of birth defects","volume":"20","author":"Eskes TKAB","year":"1992","journal-title":"J Perinat Med"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.280.5372.2107"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1520-6866(1998)18:2<49::AID-TCM1>3.0.CO;2-D"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/1096-9926(200012)62:6<413::AID-TERA8>3.0.CO;2-B"},{"key":"e_1_2_6_16_1","article-title":"Reduction of teratogen induced birth defects in mice: role of maternal immune stimulation","author":"Hrubec TC","year":"2006","journal-title":"Curr Topics Toxicol"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdrb.20062"},{"key":"e_1_2_6_18_1","first-page":"223","article-title":"Valproic acid use in psychiatry: issues in treating women of reproductive age","volume":"23","author":"Kennedy D","year":"1998","journal-title":"J Psycho Neurosci"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420450605"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.2307\/3001469"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.20176"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(91)90193-Y"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.172.5.1325"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1741-4520.2003.tb01024.x"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.20082"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1567-5769(03)00200-5"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.10137"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/1096-9926(200012)62:6<420::AID-TERA9>3.0.CO;2-8"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1567-5769(02)00094-2"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1567-5769(03)00093-6"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.10128"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.10045"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1007\/s001250050727"},{"key":"e_1_2_6_34_1","first-page":"1","volume-title":"The problem with multiple comparisons: unpublished manuscript in the collected works of John W. 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