CONGENITAL ANOMALIES: OCCURRENCE AND POTENTIAL RISK FACTORS

Background/Aim: Congenital malformations still represent one of the most
 important causes of prenatal and infant death. The study goal was to analyze
 occurrence and outcomes of different types of congenital anomalies from the
 tertiary referral center during a ten-year period. Moreover, study aimed at
 examining potential predictors of congenital anomalies based on patients?
 characteristics and medical history data. Methods: Study included all
 pregnant women directed to Clinic of Obstetrics and Gynecology Clinical
 Center of Serbia due to prenatally diagnosed congenital fetal anomalies
 during past ten years. Upon admission to our clinic a detailed general
 medical and obstetrical history were taken from every patient. All women
 underwent genetic testing. Ultrasonography and magnetic resonance were
 diagnostic methods for fetal malformations confirmation. Results: Study
 included 773 pregnant women aged from 18 to 46 years. Out of registered nine
 different groups of fetal anomalies/malformations, the most common were
 malformations of the central nervous system, while majority of fetuses had
 combined multiple anomalies. Genetic cause for congenital anomalies was
 present in 25.2% of pregnancies. Medical pregnancy abortion was performed in
 71.8% of cases. Only 10.2% of pregnancies ended in term. The best outcome
 for children was obtained in case of gastrointestinal anomalies (52%
 live-born). Contrary only one child with neck and thorax malformations could
 be saved. According to logistic regression the most important predictor of
 having a child with combined multiple anomalies was mother?s age, while
 predictor of central nervous system anomalies was gestational diabetes. The
 significant predictor of genetic anomalies was mother?s age. Conclusion: In
 our sample neurological congenital anomalies were the most common, although
 abnormalities of all organ systems were registered. Majority of pregnancies
 had to be discontinued due to combined multiple anomalies caused by genetic
 disorders. Older mother?s age and diabetes can imply on the increased risk
 for fetal malformations.


INTRODUCTION
Congenital anomalies or malformations of the fetus are disorders of the structure, behavior, function and metabolism that arose before birth 1 .They result from disturbed development and growth during the embryonic and fetal intrauterine period.Etiology can be chromosomal and genetic, infectious, medicamentous, multifactorial, etc 2 .
According to the literature data the incidence of fetal anomalies is 1.5% per year.
The incidence of anomalies in pregnancies ending in spontaneous abortion is 3.3%, with intrauterine fetal death is 13%, while 0.4% of fetal anomalies are diagnosed after birth 3,4 .
Infant mortality rate from congenital malformations in a period of 15 years prior to our study (1993 to 2007) in Serbia was 1.8 (confidence interval 1.5-2.1)out of which 45.1% was caused by genetic disorders 5 .
Whether the developmental anomalies occurred during organogenesis (malformation) or after their initial normal organ formation (disruption and deformation) the timely diagnosis of fetal anomalies allows medical practitioners to make an appropriate decision on the further pregnancy management 2,6 .It is necessary to detect and discontinue pregnancy with fetal anomalies incompatible with life in time, or to begin the appropriate treatment of diagnosed malformation as soon as possible to enable not only survival, but also good quality of life for the child 7 .
Although recently much has been done to improve malformation early diagnosis and treatment, there is still a debate about all risk factors causing congenital anomalies.
Therefore, the study goal was to analyze occurrence and outcomes of different types of congenital anomalies from the tertiary referral center during a ten-year period.Moreover, study aimed at examining potential predictors of congenital anomalies based on patients' characteristics and medical history data.

METHODS
Study included all consecutive pregnant women directed to Clinic of Obstetrics and Ultrasonography was the main diagnostic method for assessing fetal malformations.
All examinations were performed by three obstetrics and gynecology specialists and perinatology US experts (study authors).Moreover, in some cases magnetic resonance (MR) imaging of the fetus was also done using the Siemens 1.5 Tesla Symphony apparatus.
The final diagnose as well as the decision for anomaly treatment or pregnancy termination was done in accordance with neonatologists and pediatric surgeons, members of the Congenital Anomalies/malformations Consilium of our clinic.
In case of minor fetal anomalies, which could be surgically corrected after birth, it was decided to continue the pregnancy and these patients were regularly checked-up throughout the second and third pregnancy trimester according to the high-risk pregnancy guidelines.The main positive pregnancy outcome assessed in the study was having liveborn children.
Contrary, if the anomaly was of genetic origin, surgically uncorrectable or incompatible with life, pregnancy was terminated after the parents signed the informed consent.We noted the method of pregnancy termination for every patient (curettage in the first or early second trimester, instillation or feticide) as well as the way of abortion/delivery (Caesarean Section or vaginal delivery with or without prostaglandins PGM15 or PGE2, Folly catheter or Syntocinone induction/stimulation).
We noted the week of obtaining the final diagnosis of congenital anomaly as well as the week of pregnancy termination in each case.For final malformation verification all fetuses that were not live-born were sent to autopsy and histopathological examinations.
Live-born children were assessed by neonatologist after birth.All malformations were grouped according to the affected organ system and divided on those with and without genetic cause.
All obtained data were statistically analyzed using methods of descriptive (number, percent, mean, standard deviation) and analytical statistics and applying the SPSS 20 software.Significance of differences between categories of assessed parameters was examined by χ 2 test.Correlations of fetal anomaly type and pregnancy outcome with patients' characteristics and medical history data were tested using pearman correlation.
Finally, we applied multiple logistic regression to investigate the predictors of occurrence of different types of congenital anomalies based on patients' characteristics and medical history data.Moreover, we performed binary logistic regression to investigate the predictors genetic anomalies based on patients' characteristics and medical history data.

RESULTS
Study included 773 pregnant women aged from 18 to 46 years.Data regarding patients' age, previous parity and the gestational week when the malformation was diagnosed are presented on the Table 1.Majority of women did not have any hereditary or chronic illnesses as well as pregnancy complication in previous and investigated pregnancy (Table 2).
Significantly more women had low risk on screening test, both Double and Triple.
However, Triple test seemed to be more reliable in our population for congenital malformation prediction as almost 40% of pregnancies were adequately recognized as in risk.Ultrasound and magnetic resonance as diagnostic tool for congenital malformations were very reliable as 74.3% of malformations were appropriately prenatally detected (Table 3).These imaging methods had the best results for assessment of central nervous system anomalies.Still, in some cases no anomalies were visualized or only IUGR and abnormality in amniotic fluid volume was registered.
Nine different groups of fetal anomalies/malformations (according to organ system) were confirmed on the examinations upon pregnancy termination (Table 3).The most common once were malformations of the central nervous system, while majority of fetuses had combined multiple anomalies.Genetic cause for congenital anomalies was present in Differences found in congenital anomalies rates in different countries and studies could be based on actual variations among assessed populations or due to different anomalies definitions or study methods 7,15 .Additionally, inclusion of stillbirths, prenatally diagnosed cases and pregnancy terminations increase significantly the overall prevalence of children with congenital anomalies.Moreover, in less developed countries there are no registries of children with malformations or the data are poorly documented and insufficient 13,16 .Consequently, epidemiologists are often reluctant to present the total prevalence of congenital anomalies in certain countries and populations 9 .Nevertheless, congenital malformations, taken collectively, are fairly common, and account for a disproportionate share of adverse perinatal outcomes.Therefore, in the year 1979 a network of population-based registries EUROCAT (European Surveillance of Congenital Anomalies) was made in order to conduct epidemiological surveillance of congenital anomalies in Europe 4 .Clinicians and researchers are encouraged to use data from this and other reliable population-based registries, while all countries should take participation in active registration and reporting of congenital anomalies 3 .

of pregnancies (
Congenital malformations still represent one of the most important causes of prenatal as well as infant death12,17.Mortality is considerably increased in cases of multiple malformations.Etiological factors of congenital anomalies are unknown in over 50% of cases.In most of the cases, the causes are complex and multifactorial8,18. However, the most common known causes are genetic (chromosomal anomalies and gene mutations and rearrangements) and environmental factors (viruses, bacteria, drugs, radiation, mother's disease)5,19.The most common chromosomal anomalies encountered in literature as the basis for fetal malformations are numerical (Down, Tarner, Edwards and Clinefelter's syndromes) and structural aberrations (Cri du chat, Prader-Willi and Angelman syndromes)20.Numerous studies aimed at identification of potential predictors for congenital anomalies.However, findings are inconsistent2,6,14.While some data imply that RhD immunization and diabetes mellitus are associated with increased occurrence of malformations, other studies did not confirm the correlation of any chronic or gestational illness with higher risk of fetal congenital anomalies21.Actually, the only consistent predictor of congenital malformations is maternal age.This might be explained by the well documented association of older maternal age and majority of genetic disorders especially trisomies of autosomal chromosomes15,20.However, the widespread prenatal screening and termination of pregnancy in case of fetal malformations seems to have canceled out the effect of maternal age and resulted in relatively stable live-born children rates in European countries7-9.
In our study of prenatally diagnosed congenital malformations in the population from central Serbia the most common single organ system anomalies were registered on the central nervous system, while numerous children also had multiple combined anomalies.
Majority of these multiple anomalies were due to genetic syndromes (mostly Down syndrome).In our sample only 12.9% of children were live-born.This was the first study in Serbian population that made prediction models for congenital anomalies based on patients' characteristics and medical history data.According to logistic regression the most important predictors of having a child with combined multiple anomalies were mother's age, while gestational diabetes was associated with central nervous system anomalies.The significant predictor of genetic anomalies was mother's age.

CONCLUSION
In our sample from central Serbian referral tertiary clinic congenital anomalies of central nervous system were the most common single system anomalies, although malformations of all organ systems were registered.
Table )out of which Down's syndrome was the most common.When genetic abnormalities were analyzed we registered eight deletions, five duplications, six inversions, four translocations and 14 single gene polymorphysms.When aneuploidies were evaluated Sindrom Turner was registerd in eight case, Patau in eight cases, Edvards in 15 cases, Klinefelter in seven cases, triple X in three cases, trisomies of chromosomes 8, 18 and 20 in one case each, mosaic in six cases, while in one case multiple trisomies were registered.In patients with gestational diabetes mellitus we registered anomalies of the CNS in six cases, KVS in two cases, GIT in two cases (omphalocela), while in one patient fetus had urogenital (kidney) anomalies.In four patients with gestational diabetes mellitus we registered multiple fetal anomalies out of which in two cases fetuses had combined cystic neck higroma with abdominal tumefakts and in remaining two cases cystic neck higroma was combined with mediastinal tumors and generalised fetal hydrops.Pregnancy outcomes are presented on Table4.Medical pregnancy abortion was performed in 71.8% of cases.Only 10.2% of pregnancies ended in term.Significantly more pregnancies were ended during the second trimester.In 63 women Caesarean Section had to be performed due to obstetrical indications.
Having live-born children with congenital anomalies correlated positively with having all previous children live-born, gestational week of malformation diagnosis and the findings of U MR, while it correlated negatively with patient's age, findings of Double and Triple tests, genetic abnormalities as well as the pregnancy termination time and type.So it can be seen that having healthy previous pregnancies and performing regular pregnancy check-ups that could allow early diagnosis of any gestational complications is the best way to ensure that even children with congenital anomalies can be live-born if their malformations are correctable.Conversely, genetic anomalies are the major cause of both spontaneous as well as medically induced pregnancy terminations.Major anomalies, which significantly affect the development and quality of life of a human individual, are present in 2-3% of newborn children, while another 2-3% of malformations are diagnosed by the age of five10,11.They are one of the main causes of childhood deaths (up to 20-25% of cases).Contrary, minor anomalies (skin lesions, small ears or a narrow gap between the eyebrows) occur in about 15% of newborns, they do not affect health, but their presence can indicate at the same time the existence of some major malformations1,12.Furthermore, frequency and structure of different types of congenital anomalies depend on the investigated population.Specific studies have registered the predominance of different congenital anomalies, however, based on all available literature data the most common ones are usually neurologic, cardiac, gastrointestinal and musculoskeletal malformations.Abnormalities on all other organ systems are less often reported13,14.

Table 1 .
Majority of pregnancies had to be discontinued due to combined multiple anomalies caused by genetic disorders.Older mother's age and diabetes can imply on the high risk for fetal malformations.Regular pregnancy check-ups can allow early diagnosis of any gestational complications and ensure that even children with congenital anomalies can be live-born if their malformations are correctable.Construction and regular updating of a detailed (including all patients data) congenital anomalies registry in Serbia is necessary and might help both clinitians and further investigations regarding this issue.Descriptive general data of investigated patients

Table 2 .
Frequency of investigated parameters in examined patients

Table 3 .
US/MR and final findings of fetal congenital anomalies/malformations

Table 5 .
Correlations of fetal anomaly type and pregnancy outcome with patients' characteristics and medical history data