Postnatal closure of membranous ventricular septal defects in Sprague-Dawley rat pups after maternal exposure with trimethadione.
BACKGROUND
Congenital membranous ventricular septal defects (VSD) have been shown to close during postnatal development in rats [Solomon et al., Teratology 55:185-194, 1997]. Although they may differ in size, spontaneous and treatment-related VSD are histologically similar; however, the postnatal fate of treatment-induced VSD is not known. The objective of this study was to determine if treatment-induced VSD persist throughout postnatal development.


METHODS
Groups of 40 female rats were given oral doses of trimethadione (TMD) at 400 mg/kg/day (200 b.i.d.) or 600 mg/kg/day (300 b.i.d.) on Gestation Days (GD) 9 and 10. Twenty dams in each group were designated for Cesarean section and 20 were allowed to deliver and rear their offspring to Postnatal Day (PND) 21. The integrity of the ventricular septum was evaluated in fetuses (GD 21) and pups (PND 21).


RESULTS
The incidence of membranous VSD was 0.6, 7.6, and 49.8% per litter in the Control, 400, and 600 mg/kg groups, respectively, on GD 21. Both the incidence and severity of VSD increased with dose. The VSD at 400 mg/kg were small in size and initially detected by the presence of blood flowing through the defect from the closed right ventricle. In the 600 mg/kg dose group, the VSD, although still membranous, were larger and more readily detected without the need to examine the blood flow. At 600 mg/kg, not only were the VSD larger than those in the Control or the 400 mg/kg group, 10.1% per litter of the affected fetuses had other vessel anomalies associated with the VSD, which were incompatible with pup survival. On PND 21, VSD was noted in 0.3, 0, and 6.4% per litter evaluated in the Control, 400, and 600 mg/kg groups, respectively. This demonstrates that the small, isolated treatment-related VSD can resolve postnatally; however, the closure of the larger or more severe VSD may be prolonged or may not occur at all. Although TMD exposure reduced group mean fetal weights at both dose levels, there was no difference between the mean weight of fetuses with VSD and those fetuses without VSD in the same group.


CONCLUSIONS
Treatment-induced VSD close postnatally, and appears to be a delay in cardiac development not associated with fetal weight. The timing of closure and survivability during closure is dependent on the severity of the VSD. Further characterization of the two sizes of VSD may provide diagnostic clarity; however, the current data support the smaller VSD as a variation with no significant impact on viability and growth, and the more severe VSD to be a malformation.
Pfizer Global Research and Development, Groton, Connecticut 06340, USA. tammye_l_fleeman@groton.pfizer.com
Tammye L
TL
Fleeman
Gregg D
GD
Cappon
Mark E
ME
Hurtt
D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects* / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006345:Heart Septal Defects, Ventricular / Q000139:chemically induced*; D006352:Heart Ventricles / Q000187:drug effects / Q000196:embryology*; D018811:Maternal Exposure; D051381:Rats; D017207:Rats, Sprague-Dawley; D012075:Remission, Spontaneous; D013997:Time Factors; D014293:Trimethadione / Q000009:adverse effects* / Q000633:toxicity*
D000927:Anticonvulsants; D014293:Trimethadione