**9. Conclusion**

According to the study of Van Landingham et al. in 2009, the mother's age is not associated with CH, unlike the study by Sipek et al. for the period 1961–2000 in the Czech Republic which found that a mother's age over 37 years was significantly associated with CH [4, 6]. Hydrocephalus is significantly associated with a mother's age above 40 years and third-degree consanguinity, and it is 18 times higher compared to women above 40 years of age without consanguinity

In regard to maternal disease, it is known that mothers suffering from diabetes mellitus have a significantly higher risk for giving birth to a child with congenital malformations, especially

Hydrocephalus is often divided by genetic specialists into a syndromic and non-syndromic form, depending on the presence of associated malformations [21, 22]. Some authors prefer to differentiate hydrocephalus in which the phenotype is characterized mainly with brain malformations and hydrocephalus which is associated with significant physical anomalies and clinical symptoms [23]. In cases with a specific clinical syndrome or genetic changes, hydrocephalus is best to be defined as hydrocephalus associated with the corresponding syndrome. Some enzyme mutations result in defective neuron connections with the extracellular matrix, abnormal formation of the limiting glial membrane, and disturbances in the neuronal migration [24, 25]. As a result, characteristic brain malformation develops—loss of cerebral gyrification, abnormal white matter of the hemispheres as well as brainstem anomalies (flat pons, enlarged tectum, and curved medulla oblongata), often associated with an aqueductal stenosis and cerebellar cysts. These findings often cannot be found by the prenatal examination, especially in cases of significant ventriculomegaly, making the MRI study essential [26]. In our study, the risk increases almost five times for the association of FHLO and polygyria when the mother's age is above 35 years (OR = 4.894; CI: 1.094–13.94). The association of FHLO and agenesis of the cerebellar vermis is significantly associated with previous abortions (OR = 3.483; CI: 1.099– 1.040) and the effect of risk factors (OR = 3.463; CI: 0.977–12.274). Ventriculomegaly is significantly associated with agenesis of corpus callosum, as well as O(+) blood group of the mother, when compared to other blood groups (OR = 3.614; CI: 1.044–12.510). Hydrocephalus may be associated with other brain malformations such as holoprosencephaly, rhombencephalosynapsis, Aicardi syndrome, agenesis of corpus callosum, and periventricular heterotopia [27–31]. Some cytogenetic malformations are associated with hydrocephalus, including trisomy 13, 18, 21, and triploidy [32]. The trisomies in our study were 27 (24.1%) and their occurrence is significantly

associated with a mother's age above 38 years (OR = 13.689; CI: 3.952–52.122).

being spina bifida, followed by myelomeningocele, encephalocele, and meningocele.

NTD-associated hydrocephalus has a multifactor genesis. Experiments with animals have found that the intrauterine leak age of cerebrospinal fluid causes the Arnold-Chiari type II malformation, which causes an obstruction of the cerebrospinal fluid flow [33, 34]. Genetic mutations responsible for planar cell polarity such as Fuzzy (FUZ), VANGL1, and CELSR1 add to the development of NTDs [35–37]. Other mutations of genes with a relation to planar cell polarity (CELSR2 and MPDZ) may cause hydrocephalus regardless of the presence of NTDs [38, 39]. The specific pathogenetic mechanism is not completely clear, but it is accepted that a disjunction of the ependymal cilia is present [40]. The neural tube defects in our study were 33 (29.4%), with the most common

(OR = 18.500; CI: 1.146–298.547).

86 Congenital Anomalies - From the Embryo to the Neonate

cardiovascular and neural tube defects [4, 19, 20].

Congenital hydrocephalus with a lethal outcome is the result of a significant number of risk factors and is often associated with other malformations. Therefore, it is important to perform a prenatal ultrasound study in pregnancies with risk factors to diagnose possible CH or other malformations. Currently, the prenatal ultrasound is able to visualize ventriculomegaly and should be directed toward the search of other associated malformations, and when they are suspected, an MRI study and genetic testing must follow. In cases of medical abortion, stillbirth, or neonatal death, a fetopathological study must be carried out which enriches our knowledge of malformations, complements and completes the ultrasound examination, modifies genetic counseling, and determines the behavior to be followed when taking responsibility for a subsequent pregnancy. It is also important to further study the associated risk factors and the fetopathological changes in CH in order to increase the success of the ultrasound prenatal diagnosis.
