Combined malformations

Azathioprine can be administered both orally and intravenously. It is well absorbed orally and after its rapid conversion to 6-mercaptopurine it is inactivated by xanthine oxidase which converts 6-mercaptopurine to 6-thiouric acid. This final metabolite is then excreted in the urine. In combination with the xanthine oxidase inhibitor allopurinol dose adjustments of azathioprine are needed. Renal disease also raises 6-mercaptopurine concentrations and can make dose adjustments necessary. Azathioprine is still used in organ transplantation programs and for the management of several autoimmune diseases. Its adverse effects include nausea, vomiting, diarrhea and, more seriously, bone marrow suppression and hepatotoxicity. Azathioprine is not thought to cause fetal malformation. 

The prenatal developmental toxicity study design includes sacrifice of the rodent or rabbit dam one day prior to expected delivery, in order to ensure that malformed fetuses are not lost to maternal cannibalism. .. Nevertheless, even the prenatal developmental toxicity study does not allow the researcher to distinguish the source or cause of prenatal mortality. Intrauterine deaths may be the result of malformations that are incompatible with continuing viability... The contribution of malformed fetuses to overall effect on litter viability can be appropriately analysed by combining the litter incidence of conceptuses that are malformed, resorbed (early and late), and dead (full term but nonviable at caesarean section) and performing appropriate statistical analyses of group values (13). 

Studies of reproductive and teratogenic effects of OPPs on humans are few. Gordon et al. (1981) found stronger correlations of cleft lip and palate malformations for insecticides and/or herbicides than for all other agrichemicals combined. The post mortem examination of women s ovaries following acute intoxication revealed adverse ovarian effects from parathion and both infertility and menstrual disturbances were observed in female applicators of OPPs. Also, women from fruit growing areas exposed to OPPs experienced earlier menopause, infertility and other functional irregularities—e.g., in the liver and nervous system and in bile production. 

A combination of 150 mg/kg caffeine administered by injection to pregnant rats in conjunction with a single dose of 9,756 mg/kg DEHP on day 12 of gestation caused a 5-fold increase in the number of dead and resorbed fetuses and nearly a 4-fold increase in the malformed survivors as compared to the effects of DEHP alone (Ritter et al. 1987). The mean fetal weight was also depressed. The addition of the caffeine to the treatment using equimolar quantities of 2-ethylhexanol and 2-ethylhexanoic acid at doses half of the molar quantity used for DEHP resulted in 2-30-fold increases in the dead and malformed fetuses and malformed survivors, but only minor decreases in the fetal weights. 

Calcium and magnesium are very abundant in soils, and soils deficient in Ca are rare, calcium status is maintained when lime is added to correct acidity. Plant cells contain relatively large concentrations of Ca, but most of it is bound in the cell-wall as the pectate (about 60%) or sequestered in different organelles (Clarkson, 1984). Ca affects the permeability of the cytoplasmic membrane and its deficiency leads to malformation of the growing parts of the plant. Hewitt and Smith (1975) have discussed the early experiments on the morphological effects of Ca deficiency. Calcium is often found in combination with organic acids, for example oxalic acid, a soluble, toxic metabolic by-product is converted to insoluble calcium oxalate. 

Thus, acute, subacute, or chronic impairment of spinal blood supply can result from a deficient arterial supply and from venous circulatory problems (Mull and Thron 2004). Spinal vascular malformations like spinal dural arteriovenous (AV) fistulas and AV malformations (AVM) of the perimedullary fistula type are the typical disorders associated with venous congestion of the spinal cord. On the other hand, AVM of the glomerular type are seldom combined with a venous outflow disorder. 

An infant exposed to cocaine in utero had a combination of facial, ear, eye, and vertebral anomalies, accompanied by cardiac, central nervous system, and other malformations (261). 

A third embryonic hemoglobin, termed Hb-Portland 1, has recently been described (Cl, C2, H6, T8, W17). The protein was first discovered in a malformed newborn with a complex autosomal chromosomal mosaicism. However, it is probably also present for some 0.5 to 5% in newborn infants with a D, trisomy and in very small amounts (0.1-0.2%) in normal newborns. Hb-Portland 1 does not contain a chains but is composed of one pair of y chains and one pair of chains which have been termed C chains. The C chain is probably a normal embryonic hemoglobin chain. Hb-Portland 1 does react with free a chains to form Hb-F or aayz and a aafa component (T8). It seems, therefore, that the chain can combine with the a chain, but the afiSnity of the a chain for the C chain is apparently lower than for either the e chain or y chain. Embryonic hemoglobins have also been found in several mammalian species, such as the pig, cattle, and sheep (K13, K15). 

Teratogenic activity has been attributed to doxylamine, a constituent of many combinations with vitamin B6 and antispasmodic agents, and used in the treatment of hyperemesis gravidarum. However, extensive studies and reviews have suggested that the incidence of malformations is not higher in children whose mothers have taken formulations containing antihistamines as a group, and in particular the combination of doxylamine/pyridoxine with or without dicycloverine (100-102). 

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