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Prenatal Diagnosis and Pregnancy Management of MMC

Open spina bifida (myelomeningocele) is a specific kind of neural tube defect (NTD) resulting from a trouble of closure of the caudal region of the neural tube early in embryogenesis. The diagnosis and management of open spina bifida has changed significantly over the past century. Significant advances in the prevention, diagnosis and treatment of open spina bifida have been made over the last years. The most significant strategy for the prevention of open spina bifida has been with folic acid supplementation. Although progress in the field of myelomeningocele diagnosis and treatment has revolutionised the medical treatment of open spina bifida, the postnatal treatment of myelomeningocele evolved significantly and is now complicated by issues surrounding prenatal diagnosis, including availability, economic feasibility, and selection for invasive fetal surgery and management of pregnancy.


INTRODUCTION
Congenital anomalies (CA) are a real public health problem due to their prevalence of approximately 14% of live births worldwide [1,2] and it's the leading cause of infant mortality in the world (more than 25%). Major or severe CA concerns 3% of all births and 20% of all the CA. Among these major anomalies, 25% are cardiac, 20% of limb anomalies and 15% of the central nervous system [3]. Spina bifida is the most common CA of the central nervous system. Its most common form is myelomeningocele (MMC).
Open spina bifida (myelomeningocele) is a devastating congenital defect of the central nervous system, a specific type of neural tube defect resulting from a failure of closure of the caudal region of the neural tube early in embryogenesis. MMC is characterized by protrusion of the meninges and spinal cord through open vertebral arches leading to lifelong paralysis.
In utero as well as after birth MMC is not a lethal disease but a severe progressive disease with damage to the central and peripheral nervous systems responsible of severe handicaps.
In addition, MMC patients are often limited by various degrees of mental retardation, bowel and bladder dysfunction, and orthopedic disabilities. While the etiology of MMC remains poorly understood, primary failure of either neural tube or mesenchymal closure at the caudal neuropore in the embryonic period results in exposure of the developing spinal cord to the uterine environment [4].
Without protective tissue coverage, secondary destruction of the exposed neural tissue by trauma or amniotic fluid may occur throughout gestation.
The diagnosis and management of open spina bifida has evolved dramatically over the past century. Over the past years, improvements in prenatal diagnosis and advancements have been made in fetal therapy, with the publication of a randomized-controlled trial demonstrating benefit of fetal surgical repair of myelomeningocele [5]. Although progress in the field of myelomeningocele diagnosis and treatment has revolutionized the medical treatment of open spina bifida.
Until 15 years ago, treatment of MMC consisted of surgical closure of the spinal canal at birth and lifelong supportive care. Since that time the clinical experience with midgestational human repair has been shown to improve neurologic function and reduce morbidity from hydrocephalus.

Prenatal diagnosis
Advances in prenatal diagnosis now permit diagnosis of spina bifida as early as the first trimester, and extensive research into the etiology of neural tube defects has elucidated both genetic and micronutrient causes.
The use of maternal serum alpha-fetoprotein levels as a primary modality for screening for open/closed spinal dysraphism should be practiced especially in a pregnant patient with a pre-pregnancy body mass index (BMI) greater than or equal to 35 or greater, or in the presence of geographical access or clinical access factors that affect the implementation of timely and good quality ultrasound screening at 18-22 weeks' gestation.
In the context of maternal serum aneuploidy screening, maternal serum alpha-fetoprotein levels can be used as a secondary screening tool in the second trimester [8].
Maternal serum alpha-fetal protein is a sensitive screening tool for NTDs, with a screening sensitivity of about 80-85% when the screen positive cut-off is set at 2.5 multiples of the median [6][7]. With improving detection rates of NTD by ultrasound, the role of routine MSAFP screening has been challenged, and is useful for early diagnosis.
The Ultrasound Screening has consistently been identified as a sensitive tool for the detection of NTDs, and is considered the gold standard for the prenatal diagnosis of NTDs. Recent studies have reported detection rates by ultrasound, ranging from 96-100%. With advances in ultrasound technology, however, the need for amniocentesis for this purpose has become obsolete [9, 10]. First-trimester examination of the posterior fossa has also been further refined with the use of three-dimensional ultrasound. Cisterna magna width and measurements of the brainstem compared with brainstem-occipital bone distance have been identified as potential first-trimester screening signs for open spina bifida [13].
Abnormal development of the neural tube leads to the development of a Chiari II malformation resulting from herniation of the cerebellar vermis, fourth ventricle, and medulla oblongata through the foramen magnum into the upper cervical canal. The classic cerebellar and cranial findings seen on ultrasound associated with the Chiari II malformation were described by Nicolaides et al. [14] in 1986 as the banana sign and lemon sign. The sonographic cerebellar signs associated with open spina bifida have been found to be the most reliable diagnostic signs. Despite nearly 100% of neonates born with an open myelomeningocele having evidence of hydrocephalus at the time of birth, but only 70% will develop hydrocephalus during fetal life [14,15]. The use of three-dimensional ultrasound may be more accurate for the localisation of lesion level compared with two-dimensional ultrasound, but a discrepancy exists with the clinical significance of the improved accuracy, which is generally in the region of one spinal level compared with postnatal findings [16,17].
The fetal MRI has become an important adjunct tool for perinatologists and paediatric neurosurgeons to aid in counselling and surgical planning for fetuses diagnosed with spina bifida on ultrasound by its ability to characterise accurately the level of myelomeningocele within one to two vertebral levels in 89% of cases using MRI. Compared with ultrasound, MRI seems to be equally accurate for the prediction of the highest affected vertebral [25,26].

Management of Pregnancy in the Presence of MMC
Following the detection of an isolated open/closed spinal dysraphism, families should be offered a choice of obstetrical management options following the results of diagnostic and and genetic screening tests. The offer of these options should include information about prenatal repair of myelomeningocele and its prognosis, postnatal surgical repair of myelomeningocele and its prognosis, and termination of pregnancy (not allowed in Islamic countries) and conducting an autopsy [8].
Caesarean section is the most common mode of delivery in the fetus with myelomeningocele, regardless of presentation (cephalic or Breech); however, cesarean delivery is obligatory in cases of breech presentation. The performance of a vaginal delivery with intrapartum fetal heart rate monitoring may be considered in certain cases of MMC in cephalic presentation, in the absence of macrocephaly (depending on the gestational age) and in the presence of a small MMC sac.
Management of the delivery of a fetus with multiple and complex anomalies (including neural tube defect) should be determined on the basis of on an individualized foundations by the multidisciplinary team of care providers at the center where the delivery is to take place, based on the differential diagnosis, identified congenital anomalies, results of prenatal screening results, prenatal care requirements, anticipated neonatal morbidity or mortality, results of family consultation and family requests.
Many Investigations are improving prenatal therapy for open spina bifida repair. Currently, minimally invasive surgical techniques using fetoscopy have proven to be inferior to open fetal surgery; however, with advancing technology, some of the technical fetoscopic approach may improve over time [18].
The more promising treatment and exciting area of innovation has been with a non-traditional approach using engineered tissues held in a flexible patch, sponge or hydro-gel matrix to create a watertight protective seal over the defect using a single fetoscopic port or a percutaneous approach with an amniocentesis needle [19,20].

CONCLUSION
Several risk factors have been studied in association with spina bifida; the strongest established risk factor for an NTD is a family history. Several studies have estimated that women with a history of a child with an NTD carry a 3-8% risk of and NTD, including spina bifida.
Also Folic acid and genes related to folate metabolism have been identified to play a strong role in neural tube development. Folic acid deficiency has been associated with a two-to eight-fold increased risk of NTDs [21]. Several gene variants involved in the folate metabolism pathway have been identified in association with abnormal neural tube closure in human beings [22]. Of recent discovery has been the complicated interaction between maternal and embryonic genes and the role of regulators of neural tube closure that are not involved in folate metabolism [21][22][23].
Many studies showed a significant benefit of 4 mg of folic-acid supplementation in the preconceptional period to prevent NTD recurrence [24].
The increase in the number of births of children with SB should make the medical community aware of the importance of a global and multidisciplinary care of this pathology, which requires experienced centers from the neonatal period to adulthood to allow the best possible life for these people. The increase in the number of diagnosed cases should allow to alert the public authorities to the need for national prevention campaigns and the need to raise awareness among doctors, especially general practitioners and obstetrician-gynecologists who are in the front line of prevention.