This survey of the development of a large number of virtually unselected human embryos from healthy women allowed us to establish more reliable standards of normal development with respect to crown-rump length, body weight, and external form than those usually cited. Remarkable variation was noted with regard to the relation between clinical age and these attributes and thus it is concluded that crown-rump length and body weight are more reliable indicators of the general state of development than clinically established age.Dead embryos occurred with a significantly greater frequency in women with a history of genital bleeding during pregnancy than in those without. Externally m dformed embryos were found with increasing frequency with advancing developmental stage, with the maximum figure of 3.92% at horizons 19-23. Malformations observed included external defects such as exencephaly, cyclopia, myeloschisis, cleft lip, and several limb malformations. It is of considerable interest that the incidence of most of these defects was far higher than that observed in newborn infants.

Acetazolamide and ethoxzolamide incorporated into the diet of pregnant rats at 0.3% or 0.6% level caused localized appendicular malformation typically affecting the distal, postaxial part of the right forelimb. Other malformations and intrauterine death were also more frequent than in the offspring of untreated rats. Treatment on day 10 or 11 of gestation with 1000 mg/kg of acetazolamide injected subcutaneously also produced a high incidence of typical abnormalities but similar treatment on day 9 or 12 failed to do so. The susceptible period of rat embryos to this agent is thus defined as the tenth and eleventh days. Analysis of maternal blood after teratogenic treatment revealed that both acetazolamide and ethoxzolamide produced metabolic acidosis but little change in other electrolytes except potassium, which was sharply reduced. It was not possible to prevent the occurrence of characteristic malformations by supplemental dosing with potassium. The production of litters with acetazolamide‐induced defects was associated with loss of maternal weight after treatment exceeding 10% of pretreatment weight. It has not been possible to produce typical defects using the potent diuretic furosemide. Analysis of embryos from untreated females revealed that carbonic anhydrase does not appear in measurable amounts in the developing rat until the thirteenth day of gestation, making highly unlikely the possibility that the drug's teratogenic action is associated with carbonic anhydrase inhibition in the embryo.

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Two separate experiments were camed out. (1) Alloxan was injected subcutaneously into ICR female mice at 200 mg/kg on day 0 (zero) of gestation. In the animals which became persistently diabetic, 27.5% of the conceptuses underwent resorption or death and 7.2% of surviving fetuses showed gross malformations, including exencephaly, spina bifida and cleft palate. In nondiabetic experimental animals there was no increase in fetal mortality or malformation rate. (2) Wistar rats were treated by alloxan intraperitoneally at 160 mg/kg on the seventh day of gestation.Again, only in cases of persistent diabetes were there raised fetal mortality and high incidence of external and internal malformations (50.0% of survivors abnormal), including cataract, hydronephrosis, microphthalmia, exencephaly and cleft palate. When glucose concentration was determined in the embryo and amniotic fluid on the eleventh and thirteenth days of gestation, it was found to be much higher in the diabetic than in the control or the nondiabetic treated animals. The embryonic glucose level was always slightly lower than that of the maternal blood,