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A total of 113 cases of fetal hydrocephalus with a lethal outcome (FHLO) from the Embryo-Fetopathologic Clinic at the Center for Maternity and Neonatology, Tunis, Tunisia and Obstetrics and Gynecology Clinic at St. George EAD University Hospital, Plovdiv, Bulgaria were studied, 86 of which had syndrome malformations: neural tube defects (NTDs)—29.2%, chromosomal abnormalities—23.9%, skeletal dysplasias—9.8%, VACTERL association—5.3%, Dandy-Walker malformation—3.4%, Other—14.2%. Risk factors for FHLO are miscarriages (odds ratio (OR): 19.500; confidence interval (CI): 4.020-94.594), stillbirths (OR: 10.897; CI: 1.169-10.564) and previous birth of a malformative child (OR = 5.385; CI: 1.385–18.896). FHLO is significantly associated with a maternal age over 40 years and third degree consanguinity of the fetus (OR = 18.500; CI: 1.146–298.547). The trisomies in our study were 27 (23.9%) and are significantly associated with an age above 38 years and FHLO (OR = 13.689; CI: 3.952–52.122). In medical abortion, stillbirth, or neonatal death, a fetopathological study enriches our knowledge of malformations, complements and completes the ultrasound examination, modifies genetic counseling, and determines the medical behavior in subsequent pregnancies. Also, associated risk factors and fetopathological changes in FHLO must be studied to increase the ultrasound prenatal diagnosis success.
Department of Anatomy, Histology and Embryology, Medical University of Plovdiv, Bulgaria
Borislav Kitov
Department of Neurosurgery, Medical University of Plovdiv, Bulgaria
Denis Milkov
Medical Faculty, Medical University of Plovdiv, Bulgaria
Aida Masmoudi
University of Tunis—El Manar, Faculty of Medicine of Tunis, Center of Maternity and Neonatology of Tunis, Tunisia
*Address all correspondence to: tanyakitova@yahoo.com
1. Introduction
Congenital hydrocephalus (CH) is a severe malformation which is often associated with other abnormalities. The prenatally diagnosed serious birth defects, especially those associated with a high risk of premature death, stillbirth, or neonatal death, are often referred to as “lethal,” as it is assumed that their potential treatment will be unsuccessful, which is the basis for the decision for the interruption of pregnancy due to medical reasons [1, 2]. Depending on the clinical criteria used in the definition of the disease, its incidence varies from 1 to 32 per 10,000 live births [3]. An increase in the prenatal diagnosis of CH has been observed, whereas the incidence of stillbirths remains stable. The interruption of pregnancy due to medical reasons reduces by almost a half the rate of hydrocephalus in live births. Currently, prenatal ultrasound is able to visualize ventriculomegaly, which can be caused by a number of reasons. Knowledge of the risk factors associated with CH may increase the chances of an early prenatal ultrasound diagnosis. Animal experiments have found that a wide range of environmental factors can cause hydrocephalus. They include alcohol consumption, X-rays, infections, eating disorders, and exposure to chemicals during pregnancy [4]. It has been established that one gene (L1 of Xq28 encoded for L1CAM) is connected with CH in humans. Although X-linked CH has a frequency of about 2–7% of all cases, L1CAM is found in about 15% of sporadic cases [5]. L1CAM mutations are closely related to stenosis of the cerebral aqueduct, the major pathology causing hydrocephalus in these cases. Sipek et al., in their study of CH for the period 1961–2000 in the Czech Republic, found that a mother’s age of over 37 years was statistically significantly related to CH, unlike the study by Van Landingham et al. [4, 6].
To study the prenatally ultrasound diagnosed ventriculomegaly by fetopathological autopsy in fetuses, which ended in interruption of pregnancy due to medical reasons, stillbirth, or neonatal death, by searching associated with the congenital hydrocephalus isolated or syndromic malformations as well as the eventual risk factors for their occurrence.
A total of 113 fetuses with CH were studied whose outcome was lethal. One hundred and three of them were received over a period of 3 years (2006–2009) and autopsied at the Embryo-Fetopathologic Clinic at the Center for Maternity and Neonatology, Tunis, Tunisia, out of a total of 21,316 births. Ten of the cases were from the Obstetrics and Gynecology Clinic at St. George EAD University Hospital, Plovdiv, Bulgaria, during the year 2016 out of a total of 2104 deliveries. The incidence of fetal hydrocephalus with a lethal outcome (FHLO) in both centers is almost identical—4.8 and 4.9 per 1000 births.
The fetuses are the result of interruption of pregnancy due to medical reasons, spontaneous abortions, and stillbirths. The maternal and fetal data were collected from the obstetric history, and a classical autopsy was performed immediately following the expulsion of the fetus, after authorization for macroscopic and microscopic examination. The autopsy includes observation, biometry of the fetus, and in situ examination of the body cavities. The examination of the brain was performed 6 months later, after conservation with 10% formalin. It began with biometrics, measurement of the biparietal and frontal-occipital diameters, and study of the relationship between ocular distance and eyelid length. After opening the cranial cavity, the meninx, brainstem, cerebellum, cerebral hemispheres, gyrification, and morphology were observed. The biometry of the brain—weight and bitemporal and fronto-occipital diameters of the encephalon, and weight and transverse diameter of the cerebellum—was also studied. The ventricular system was examined by horizontal or vertical hemispheric slices until the central part of the lateral ventricle was opened. The presence, shape, and thickness of corpus callosum were examined. With a linear meter, the ventricular width in the central part was measured. At a width of more than 10 mm, ventricular dilatation was diagnosed as hydrocephalus and at a diameter of over 15 mm—major hydrocephalus. In each study, material was taken for histological examination of the cerebral cortex, cerebellum, brainstem, choroid plexus, and cerebral meninx. SPSS version 19 was used for the interpretation of the data. A descriptive analysis and χ2-analysis were used.
Age structure of the mothers: The age range of mothers carrying fetuses with FHLO was 21–43 years. Under 26 years of age were 24 mothers (22%), 27–35 were 64 (58%) and 36–50 years of age were 21 mothers (19.3%). The average age of the mothers was 29.5 ± 0.72.
Number of previous pregnancies of the mothers: Most of the mothers carrying FHLO had one previous pregnancy (38.1%), followed by mothers with two previous pregnancies (19.5%). The average number of previous pregnancies is 2.50 ± 1.808, with a range of 1 to 5 pregnancies. There were no data for previous pregnancies for only 2.7% of the mothers.
Number of previous births of the mothers: In the studied group, most of the mothers had one previous birth (36.6%), followed by mothers without previous births (31.3%). The average number of births is 1.24 ± 1.23, with a range of 0–5.
Blood group of the mothers: Data were collected for the mothers’ blood groups, but unfortunately there is no information for about 21% of the mothers carrying a fetus with FHLO of the studied group. It is noteworthy that most of the mothers were of blood group O(+) – 36 (32.0%), followed by А(+) – 23 (over 20.0%).
Consanguinity: In our study, 27.4% of the marriages were consanguineous, with those of first degree being 15.4%, those of second degree 8.3%, and of third 3.7%.
In the present study, 80 of the pregnancies (70.7%) were without risk factors, and only 33 (29.3%) were under the influence of such. The risk factors were grouped into three categories: obstetric risk factors from past events, risk factors due to diseases of the mother, and exogenous risk factors.
Obstetric risk factors. This group includes spontaneous abortions—13 (11.5%), voluntary abortions—1 (0.9%), birth of a child with malformations—11 (9.8%), stillbirths—2 (1.8%), multifetal pregnancy—2 (1.8%), and multi-year sterility—4 (3.5%).
Endogenous risk factors. The risk factors from the mother include maternal age, hypertension—1 (0.9%), diabetes mellitus—2 (1.8%), bronchial asthma—2 (1.8%), thalassemia—2 (1.8%), and epilepsy—3 (2.7%).
Exogenous risk factors. Exogenous risk factors for the pregnancy include pregnancies carried in geographical areas near mines and underground mineral water deposits and consanguineous marriages. In our study, the pregnancies from geographic regions with mining and underwater mineral water deposits were 5 (4.4%). Supplementation with folic acid is mandatory in Tunisia and Bulgaria. There were no women without folic acid supplementation.
The term of pregnancy termination is presented in Figure 1. Most interrupted pregnancies are between the 20th and 24th gestational weeks. Six pregnancies were carried to birth.
Figure 1.
Term of pregnancy termination.
Motives for pregnancy termination. Interruption of pregnancy due to medical reasons was performed in 87 cases (77%); spontaneous abortions were 13 (11.5%), and there was 1 voluntary abortion (0.9%). There were 2 live births (1.8%) and 2 stillbirths (1.8%). In eight of the cases (7%), there is no information on the motive for pregnancy interruption (Figure 2).
Distribution of lethal hydrocephalus by gender (sex ratio). The genders were equally affected, but the mean weight of male fetuses (842.17 ± 115.2) was less than that of female fetuses (892.06 ± 101.1), without the difference being statistically significant (u = 0.51, p > 0.05).
Age of the fetus. The average pregnancy term in the entire study is 24 ± 0.45 gestational weeks. The fetal expulsion in two-thirds of the cases occurred before the 24th gestational week, with the smallest fetus being 13 gestational weeks (Figure 1).
Fetus weight. The average weight of the fetuses is 865.99 ± 809.8 g with a range of 23–3800 g. It is worth noting that 50 fetuses (44.2%) weigh less than the corresponding gestational age.
Hypoplasia Incorrect lobulation Hypoplasia and Incorrect lobulation Situs inversus Liver agenesis Total
21/18.6 16/14.2 6/5.3
2/1.8 1/0.9 46/40.7
Table 1.
Hydrocephalus-related abnormalities of the head, extremities, and respiratory system.
The cardiovascular system abnormalities are a total of 32 and are from all groups. The digestive system abnormalities are 56 and are broken down into groups: mesenteric (affecting the small intestine and colon), parenchymal (affecting the liver and spleen), anal imperforation (affecting the terminal part of the intestines), gall bladder agenesis, and situs inversus. The parenchymal and mesenteric abnormalities are evenly distributed. The gender abnormalities are present in both male and female fetuses with a ratio of female to male of 8:7. Hermaphroditism was established in four (3.5%) fetuses. The fatal hydrocephalus-associated anomalies of the cardiovascular, digestive, excretory, and genital systems are presented in Table 2.
Systems
Types of anomalies
Anomalies
N/%
Anomalies of the cardiovascular system
Position Organomegaly
Dextroradia Cardiomegaly
1/0.9 2/1.8
Defects
Atrial septal defect (ASD) Ventricular septal defect (VSD) Both together Tetralogy of Fallot Minor form of AV channel of the heart AV channel of the heart
Hydrocephalus-related abnormalities of cardiovascular, digestive, excretory, and genital systems.
Association of hydrocephalus with other brain abnormalities. In 85 fetuses (76%), hydrocephalus was associated with other brain abnormalities: polygyria—12 (10.7%); lissencephaly—2 (1.8%); agenesis of corpus callosum—18 (16%); agenesis of the cerebellar vermis—19 (16.9%); diastamatomyelia—1 (0.9%); stenosis of the Sylvian aqueduct—5 (4.4%); holoprosencephaly—1 (0.9%) and cyst of the choroid plexus—2 (1.8%) (Table 3, Figure 4). The relations between the prenatal and postnatal diagnosis of hydrocephalus-associated brain abnormalities are shown in Figure 3.
Brain associations
Number of cases
%
Polygyria
12
10.6
Lissencephaly
2
1.8
Agenesis of corpus callosum
18
15.9
Agenesis of cerebellar vermis
19
16.8
Cerebellar hypoplasia
25
22.1
Diastematomyelia
1
0.9
Aqueductal stenosis (stenosis of the aqueduct of Sylvius)
5
4.4
Holoprosencephaly
1
0.9
Choroid plexus cysts
2
1.8
Total
85
75.2
Table 3.
Distribution of associated brain abnormalities with lethal hydrocephalus.
Figure 3.
Relations between the prenatal and postnatal diagnosis of hydrocephalus-associated brain abnormalities. Abbreviations: CC, corpus callosum; CV, cerebeller vermis; H, hypoplasia.
Figure 4.
(A) Polygria (inferior view of the brain); (B) Agenesis of corpus callosum (medical view of hemisphere); (C) Extracted brain and spinal cord from the skull and vertebral canal. Split of the cord. Diastematomyelia; (D) Thorac-lumbar spina bifidia; (E) Occipital meningo-encephalocele; (F) Rachischisis; (G) Wedging of the cerebellar tonsils through the foramen magnum. Arnold-Chiari malformation; (H) Cystic dilatation of IVth ventricle, elevating of the tentorium, cerebellar hypoplasia. Dandy-Walker malformation; (I) Ventriculomegaly-ultrasound examination; (J) Ventriculomegaly (horizontal section of the right hemisphere); (K) Holoprosencephaly. Fetal MRI; (L) Holoprosencephaly. Fetal autopsy (White-black arrow—hemisphere, white arrow—brain stem, dotted arrow—cerebellum).
The hydrocephalus-associated syndromes and malformations are presented in Table 4.
Types of anomalies
Anomalies
N/%
Neural tube defects
Spina bifida Myelomeningocelе Encephalocele Meningocele Rachischisis Total
Distribution of syndromes and malformations associated with lethal hydrocephalus.
Most are neural tube defects followed by trisomies and skeletal dysplasias. The VACTERL association has been established in six fetuses (5.3%), four of which were male and two female, and the Dandy-Walker malformation in four fetuses (3.5%) (Figure 4).
The Meckel-Gruber syndrome, which is a ciliopathy, was established six times (5.4%). A karyotype study was performed on 23 fetuses (20.5%)—one by fluorescent in situ hybridization (FISH) and the rest by chromosome study. A magnetic resonance tomography (MRI) was performed in three cases.
The degree of hydrocephalus according to the fetopathological study is major hydrocephalus (hydrancephaly; >15 mm)—15 cases (13.3%) and ventriculomegaly (>10 mm)—77 cases (69%). Obstructive hydrocephalus as a result of intraventricular hemorrhage was found in 20 fetuses (17.7%) (Table 5, Figure 4).
According to the degree of hydrocephalus
Number of cases
%
Major hydrocephalus (hydranencephaly)
15
13.3%
Ventriculomegaly
78
69.0%
Hydrocephaly due to intraventricular hemorrhage
20
17.7%
Total
113
100.0%
Table 5.
Distribution of data on the extent and origin of hydrocephalus.
The assessment of the significance of spontaneous abortions, abortions due to medical reasons, stillbirth, and a previous child with malformations as risk factors for the occurrence of hydrocephalus was accomplished by means of a χ2-analysis (Table 6).
Indicators
Groups
Without risk factors
Risk factors
Total
χ2
Fisher Р
OR (CI)
N
%
N
%
N
%
Miscarriage
No
78
78
22
22
100
100.0
21.816
0.000
19.500
There are
2
15.4
11
84.6
13
100.0
(4.020–94.594)
Total
80
70.8
33
29.2
11
100.0
Abortion
No
78
81.3
18
18.8
96
100.0
33.727
0.000
32.500
There are
2
11.8
15
88.2
17
100.0
(6.817–154.954)
Total
80
70.8
33
29.2
113
100.0
Stillbirth
No
79
73.1
29
29.6
108
100.0
6.529
0.011
10.897
There are
1
20
4
80
5
100.0
(1.169–10.564)
total
80
70.8
33
29.2
113
100.0
Baby with malformation
No
76
75.4
26
25.5
102
100.0
6.988
0.008
5.385
There are
4
36.4
7
63.6
11
100.0
(1.385–18.896)
Total
80
70.8
33
29.2
113
100.0
Table 6.
Risk factors and lethal hydrocephalus.
Abbreviations: No, number; CI, confidence intervals; OR, odds ratio; χ2, chi-square; P, sig.
The proportion of spontaneous abortion is almost four times higher, and the abortion due to medical reasons is more than four times higher, when compared to other risk factors for FHLO. Hydrocephalus is almost three times more likely to develop in cases of previous stillbirths in the obstetric history and more than two times more likely to occur in the presence of a pre-term birth of a child with a malformation, compared to the studied risk factors. The assessment of the significance of the different degrees of consanguinity in the presence of a child with malformations, epileptic mother, as well as the mother’s age is shown in Table 7.
Indicators
Groups
No malformation
Baby with malformation
Total
χ2
Fisher Р
OR (CI)
N
%
N
%
N
%
Consanguinity
No
74
96.1
3
3.9
77
100.0
9.768
0.002
7.309 (1.806–29.584)
There are
27
77.1
8
22.9
35
100.0
Total
101
90.2
11
9.8
112
100.0
Indicators
Groups
Without epilepsy
Epilepsy
Total
χ2
Р
OR (CI)
N
%
N
%
N
%
Consanguinity first degree
No
77
96.1
3
3.9
77
100.0
25.742
0.000
24.667 (5.189–117.247)
There are
7
50.0
7
50.0
14
100.0
Total
84
89.0
10
11.0
94
100.0
Indicators
Groups
Without risk factors
Risk factors
Total
χ2
Р
OR (CI)
N
%
N
%
N
%
Consanguinity second degree
No
71
93.4
5
6.6
76
100.0
4.014
0.045
75.680 (0.872–36.997)
There are
5
71.4
2
28.6
7
100.0
Total
76
91.6
7
8.4
83
100.0
Maternal age
Others
81
95.3
4
4.7
85
100.0
4.247
0.039
4.203 (0.977–18.601)
27–35 years
19
82.6
4
17.4
23
100.0
Total
100
92.6
8
7.4
108
100.0
Indicators
Groups
Under 40 years of age
Over 40 years
Total
χ2
Р
OR (CI)
N
%
N
%
N
%
Consanguinity third degree
No
74
97.4
2
2.6
76
100.0
7.447
0.006
18.500 (1.146–298.547)
There are
2
66.7
1
33.3
3
100.0
Total
76
96.2
3
3.8
79
100.0
Table 7.
Consanguinity, risk factors, and lethal hydrocephalus.
Abbreviations: No, number; CI, confidence intervals; OR, odds ratio; χ2, chi-square; P, sig.
The incidence of FHLO is nearly six times higher when it is the result of a consanguineous marriage with a history of a previous pregnancy with a malformation, relative to the presence of hydrocephalus of a non-consanguineous marriage with no such a history. Almost 13 times higher is the incidence of FHLO in cases of maternal epilepsy with a consanguineous marriage of first degree (first cousins), when compared to the proportion of FHLO in a fetus carried by an epileptic mother but not from such a marriage. Over four times higher is the proportion of FHLO in cases of consanguinity of second degree, when compared to hydrocephalus influenced by the other studied maternal risk factors. Almost four times higher is the proportion of FHLO with a maternal age between 27 and 35 years compared to other ages, with maternal risk factors present. The rate of hydrocephalus when the maternal age is over 40 years and with consanguinity of third degree is 13 times greater than women over 40 years of age without the risk factor consanguinity. The assessment of the degree of risk of consanguinity, the presence of spontaneous abortion, and the mother’s blood group is presented in Table 8.
Indicators.
Groups
Another group
А+
Total
χ2
Р
OR (CI)
N
%
N
%
N
%
Consanguinity first degree
No
63
81.8
14
18.2
77
100.0
4.206
0.04
3.375 (1.010–11.279)
First
8
57.1
6
42.9
14
100.0
Total
71
78.0
20
22.0
91
100.0
Indicators
Groups
Another group
O+
Total
χ2
Р
OR (CI)
N
%
N
%
N
%
Miscarriage
No
74
74.0
26
26.0
100
4.315
0.038
3.321
There are
6
46.2
7
53.8
13
(1.022–10.789)
Total
80
70.8
33
29.2
113
Table 8.
Blood groups, risk factors, and lethal hydrocephalus.
Abbreviations: No, number; CI, confidence intervals; OR, odds ratio; χ2, chi-square; P, sig.
When the mother is from the A(+) blood group and has a consanguineous marriage (giving second-degree consanguinity in the fetus), FHLO has a two times higher incidence than in cases without consanguinity. Around two times higher is the incidence of FHLO, carried by mothers with O(+) blood group and a history of a previous spontaneous abortion, compared to the occurrence when there is no such history. The degree of significance of the mother’s age for the incidence of polygyria and abortions, obstetric and other risk factors, as well as the blood group for the occurrence of agenesis of the cerebellar vermis are shown in Table 9.
Indicators
Groups
Without polygyria
Polygyria
Total
χ2
Р
OR (CI)
N
%
N
%
N
%
Maternal age
≤35
82
92.1
7
7.9
89
100.0
4.894
0.027
4.894 (1.094–13.94)
≥35
15
75.0
5
25.0
20
100.0
Total
97
89.1
12
11.0
109
100.0
Indicators
Groups
Without agenesis of cerebellar vermis
Agenesis of cerebellar vermis
Total
χ2
Р
OR (CI)
N
%
N
%
N
%
Abortion
No
83
86.5
13
13.5
96
100.0
4.886
0.027
3.483 (1.099–1.040)
There are
11
64.7
6
35.3
17
100.0
Total
94
83.2
19
16.8
113
100.0
Obstetric risk factors
No
71
87.7
10
12.3
81
100.0
4.432
0.035
2.905
There are
22
71.0
9
29.0
31
100.0
(1.048–8.052)
Total
93
83.0
19
17.0
112
100.0
Risk factors
No
47
90.4
5
9.6
52
100.0
3.898
0.046
3.463
There are
19
73.1
7
26.9
26
100.0
(0.977–12.274)
total
66
84.6
12
15.4
78
100.0
А+ blood group
No
78
86.7
12
13.3
90
100.0
3.830
0.050
2.844
There are
16
69.6
7
30.4
23
100.0
(0.969–8.342)
Total
94
83.2
19
16.8
113
100.0
Table 9.
Brain abnormalities, risk factors, and lethal hydrocephalus.
Abbreviations: No, number; CI, confidence intervals; OR, odds ratio; χ2, chi-square; P, sig.
The association of FHLO and polygyria is more than three times higher in cases where the mother is over 35 years of age, when compared to cases with a mother’s age less than 35 years. More than 2.5 times higher is the incidence of FHLO associated with agenesis of the cerebellar vermis in cases of a mother with a previous abortion, when compared to cases without a previous abortion. In the present study, the incidence of the association FHLO and agenesis of the cerebellar vermis is more than two times higher when exposed to the obstetric risk factors. Almost three times higher is the incidence of the association of FHLO and agenesis of the cerebellum in cases in which the mother’s blood group is A(+), when compared to other maternal blood groups. The assessment of the importance of the maternal age for the association of hydrocephalus with trisomies, as well as the mother’s blood group for the association of hydrocephalus and agenesis of corpus callosum is presented in Table 10.
Indicators
Groups
Without trisomy
Trisomy
Total
χ2
Р
OR (CI)
N
%
N
%
N
%
Maternal age
≤38
88
90.7
9
9.3
97
100.0
20.518
0.000
13.689 (3.952–52.122)
≥38
5
41.7
7
58.3
12
100.0
total
93
85.3
16
14.7
109
100.0
Indicators
Groups
Without agenesis of corpus callosum
Agenesis of corpus callosum
Total
χ2
Р
OR (CI)
N
%
N
%
N
%
O+ blood group
No
53
86.9
8
13.1
61
100.0
4.441
0.035
3.614 (1.044–12.510)
There are
11
64.7
6
35.3
17
100.0
Total
64
82.1
14
17.9
78
100.0
Table 10.
Risk factors, trisomy, agenesis of corpus callosum, and lethal hydrocephalus.
Abbreviations: No, number; CI, confidence intervals; OR, odds ratio; χ2, chi-square; P, sig.
The rate of FTLO associated with trisomy is more than six times higher when the mother’s age is over 38 years of age, than in younger than 38-year-old mothers. Almost three times higher is the share of the association of FHLO with agenesis of corpus callosum in the fetus in cases of O(+) maternal blood group.
Currently, prenatal ultrasound is able to visualize ventriculomegaly. Knowledge of the risk factors associated with CH may increase the success of the prenatal ultrasound study. It has been established that a wide range of factors can cause hydrocephalus in animal experiments including alcohol consumption [7], X-ray [8], infections, food disorders, exposure to chemicals [9] and medications taken during pregnancy [10].
Our study is similar to those of Fernell et al., Stoll et al., and Porto et al. which showed that CH was significantly associated with previous abortions, stillbirth, and birth of a child with a malformation [11, 12, 13]. Our findings show that the risk of FHLO is increased in cases of previous spontaneous abortions (odds ratio (OR) = 19.500, confidence interval (CI): 4.020–94.594), stillbirth (OR = 10.897; CI: 1.169–10.564), and births of a child with a malformation (OR = 5.385; CI: 1.385–18.896). Pregnancy complications, such as an increase in the amniotic fluid over 1500 ml (polyhydramnios) or a reduction below 500 ml (oligohydramnios), are also considered as potential risk factors for CH [12, 13].
The role of consanguinity is also known for the occurrence of congenital malformations such as hydrocephalus, postaxial polydactyly of the hands, and defects of the lips and palate [13, 14]. In our study, FHLO is significantly associated with a maternal age over 40 years and third-degree consanguinity of the fetus (OR = 18.500; CI: 1.146–298.547). FHLO, previous pregnancies with malformations, and consanguinity are also significantly associated (OR = 7.309; CI: 1.806–29.584). FHLO with agenesis of the cerebellar vermis is significantly associated with the effect of obstetric risk factors (OR = 2.905; CI: 1.048–8.052).
Almost all studies have documented a slightly higher percentage of male fetuses in cases of CH in live births and stillbirths as well as in fetopathologic autopsies [15, 16, 17, 18]. Van Landingham et al. did not find a difference in the genders of the children with hydrocephalus compared to the general population [4].
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 (OR = 18.500; CI: 1.146–298.547).
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 cardiovascular and neural tube defects [4, 19, 20].
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, 28, 29, 30, 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).
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, 36, 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 being spina bifida, followed by myelomeningocele, encephalocele, and meningocele.
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.
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Written By
Tanya Kitova, Borislav Kitov, Denis Milkov and Aida Masmoudi
Submitted: 23 May 2017Reviewed: 25 October 2017Published: 20 December 2017
Open access peer-reviewed chapter
