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Caffeine is a methylxanthine class of compounds that can cross the placenta to substantially amniotic fluid, umbilical cord blood, plasma and urine. In pregnant women, caffeine half-life increased from 3.5 hours to 16 hours (European Food and Safety Authority, 2015). The pharmacokinetic changes occur due to an increased number of steroid hormones (estrogen and progesterone) during pregnancy. Steroid hormones (estrogen and progesterone) was acting as a competitive inhibitor of microsomal enzyme oxidase. When this enzyme is inhibited can cause a decrease in the amount of drug eliminated. This causes the longer the half-life of caffeine and caffeine also increases bioavailability, so that caffeine is in the plasma for a long time and the accumulation of substantial caffeine are potentially disrupt the fetus and placenta (Lee, 2009;European Food and Safety Authority, 2015).
The use of caffeine as inducer compounds based on studies in animals during pregnancy, caffeine can cause skeletal abnormalities in the mice fetus (Nishimura & Nakai, 1960;Santoso, 2004). The use of propolis in this study was based on the role of propolis can accelerate osteogenesis (Bereket et al., 2014), significantly increase the number of osteoblasts (Sartika et al., 2013), and affect bone metabolism (Elwakkad et al., 2008). The use of milk in this study was based on the knowledge that milk is a source of calcium and phosphorus which is very good for the growth of bones and teeth. In addition, milk is safe for consumption by pregnant women and is an antidote to the toxic substances that can harm pregnant women by chelating these harmful substances. Experiment D1 between propolis with caffeine was done because the content based on propolis chrysin can reduce the maximum concentration of caffeine in plasma (Jeong et al., 2016), thus being a protective agent for the negative effects caused by caffeine. Later experiments D2 between milk and caffeine was done because milk is an antidote to neutralize the negative effects caused by caffeine.
Caffeine dose used in this study was 75 mg/kg BW, it is based on previous research that says that mice are more sensitive and malformations occurred in mice induced by caffeine at a dose of 75 mg/kg BW (Anderson et al., 2005). Propolis dose used in this study were taken from 1/5 of the LD 50 in mice. Propolis LD 50 in mice is 7340 mg/kgBW (Burdock, 1998), so we get 1/5 of the LD 50 dose is 1400 mg/kgBW. The use of propolis dose of 1400 mg/kgBW as the positive group based on the research conducted by Burdock in 1998 stated that the NOAEL (No Adverse Effect Level) of the mice were given a dose of 1400 mg propolis/kgBW for 90 days. And the milk dose used in this study was 200 ml by human daily consumption patterns in general.
Experimental animals used in this study were female white mice at the age of approximately two months, had a body weight of 20-30 grams (Kementerian Kesehatan RI, 1979) and had never given birth. White mice were used as experimental animals because they have a short gestation period (Almahdy, 2012), the high number of fetuses (Almahdy, 2012), simple handling, the price is relatively cheap and easy to obtain. In addition, in some research, mice are more susceptible to teratogens than other experimental animals (Dillasamola et al., 2016).
Before being treated, mice were acclimatized for ten days to get the animals in the experimental conditions and avoid stress during treatment. Acclimatization for 10 days was also aimed to observe the estrous cycle.  (Dillasamola et al., 2016).
Giving the test preparation carried out for ten days beginning on the 6th day and ending on the 15th day because at this time the fetus is during the period of organogenesis (Harbinson, 2001). In this organogenesis period, the fetus is very vulnerable to teratogenic compounds and at this time the embryo organ began to take shape such as the eye, brain, heart, skeleton, urogenital (Harbinson, 2001). This period is referred to as the critical period of pregnancy (Harbinson, 2001). On day 1 until the 5th of gestation, mice were not given the test preparation because at the moment there are totipotency properties in the fetus that can repair damaged tissue. On day 16 and onwards, teratogen compound did not cause morphological defects but resulted in dysfunctional disorders that can not be detected immediately after birth (Lu, 1995).
Observation of the increase in parent body weight during gestation to see the state of the parent of nutrition and health in general. In this case, the weighing is done   (Table 1).
The increase in mice body weight, seen in the 6th to 8th gestation, yet an increase in mice body weight is large enough. The increase in mice body weight is likely to increase at day 11 to 17 of pregnancy. The increase is due Evaluation of Propolis and Milk Administration Pharm Sci Res, Vol 5 No 1, 2018 to the development of mice fetal and increased volume of amniotic fluid, placenta, and amniotic membranes (Guyton, 1990). The number of fetus also affect the increase in body weight of mice parent, generally, the greater the increase of total fetus, the greater increase in body weight of the mother (Figure 1).
To see the effect of the test preparation to the fetal mice, then on day 17 of pregnancy performed laparotomy is spending parent fetus from the uterus. This is done because the mice gave birth spontaneously, tend to eat the defective, dead and nearly die offspring so that it can affect the results of the calculation data. Besides, laparotomy was conducted to observe whether or not the resorption site that is the red or brownish-yellow blob on the former site of fetus implantation of the uterus (Wilson & Fraser, 1973).
Hemorrhage happen spontaneously due to platelet dysfunction. Hemorrhage is a discharge of blood from the cardiovascular system is accompanied by accumulation of tissue (Wilson & Fraser, 1973). A foreign substance in the network can change the osmotic pressure. Osmotic imbalance can be caused due to an interruption of pressure and viscosity of the liquid in different parts of the fetus such as the blood plasma and capillary extra space (Wilson & Fraser, 1973). This osmotic imbalance was caused by the concentration of methylxanthine in high fetal blood vessels. Methylxanthine high concentration can inhibit enzymes that hydrolyze cAMP phosphodiesterase, thereby increasing the amount of cAMP (Beck & Urbano, 1991). The increase in cAMP causes blood vessels to dilate (Katzung, 2004). It could also be the cause of hemorrhage. In pregnancy frequent hemorrhage shock. Hemorrhage shock can also be diagnosed with changes in body temperature. Hyperthermia is a failure condition regulation of body temperature (thermoregulation) due to the inability of the body to release heat or excessive heat production by the body to release heat at a normal rate. Therefore, the possibility of hyperthermia can lead to hemorrhage.
Growth inhibition occurs when a teratogen agents affecting cell proliferation, cell interaction, and a reduction in the rate of biosynthesis-related barriers to the synthesis of nucleic acids, proteins or mucopolysaccharides (Wilson & Fraser, 1973). Teratogen compounds with low dose capable of causing the death of some cells and can also cause cell turnover because of fetal cells have high regeneration ability. If one or a group of cells damaged by the interruption of toxic agents, the surrounding normal cells will divide and replace cells that are damaged. Substitution of damaged fetal cells will be maintained during the period of organogenesis in order to form a normal morphology. If that fails or does not reach the target in organogenesis phase, it will cause fetal malformations.
Fetal growth restriction may be caused by disruption of cell division, so that the synthesis of nucleic acids and proteins are disturbed. Fetal growth proliferation by mitosis and cell proliferation rate is a function of the speed of growth (Herbold, 1985). Giving caffeine during organogenesis is potentially causing delayed embryonic development because caffeine can decrease the activity of DNA polymerase enzyme, induces mitotic cells before DNA replication perfect ending, as well as inhibiting the enzyme phosphodiesterase (Beck & Urbano, 1991). Therefore it can be restricted growth fetuses.
From the results of fetuses with alizarin red soaking dosing 1 and 2, bone disorders are not found. Such as those disorders found in the positive group of caffeine. In normal fetuses the skull, ribs, and coccyx normal. All observed after the fetus is immersed in a solution of alizarin red -KOH 1% that causes the fetus becomes transparent and the bone becomes dark red so that shape of bones can be observed. In the administration of caffeine at the dose of 75 mg/kg, it was found that the ribs were not fused, abnormalities of the fetal skull, and no tail. These is caused by caffeine, due to reduced amount of calcium, thus deficiency of calcium ( Figure  2, 3, 4). The absence of bone abnormalities in the first dose group fetus given caffeine is because propolis. Propolis contains flavonoids chrysin to lower the concentration of caffeine in plasma in vivo. Later in the dose group 2 fetus given milk and caffeine are also no bone disorders found, because milk may act as antidotes simultaneously nourish the fetus with calcium contained in milk, so that calcium deficiency caused by caffeine is not the case. On the caffeine positive group, fetus has a skeleton with a perfect ossification. This is due to internal factors, the hormone that may maintain bone mass. A study stated that the hormone is one of the factors that influence whether or not the bones strong. Hormones are natural