Keywords: meningomyelocele - mortality - folic acid
Palavras-chave: meningomielocele - mortalidade - ácido fólico
Myelomeningocele (MMC), or spina bifida cystica, is the most common neural tube defect,
developing between days 21 and 28 after fertilization[1 ],[2 ]. The lack of a protective lining exposes the neural tissue to gradual destruction
due to the deleterious effects of amniotic fluid over the neural plate[3 ].
The prevalence of MMC varies according to the geographic, racial, and ethnic characteristics
of the population being studied, and may differ greatly between different regions
of the same continent or country[4 ],[5 ]. In Brazil, the prevalence of Chiari II malformation (CMII) is estimated to range
be-tween 1.4 and 1.5 per 10,000 births[6 ],[7 ]. The cause of MMC is multifactorial, but folic acid (FA) deficiency is the main
risk factor. Chromosomal and genetic abnormalities, maternal hyperthermia during the
early stages of pregnancy, use of antiepileptic drugs (e.g. , valproic acid), diabetes mellitus, and obesity may also be involved[8 ].
Around 14% of the children born with MMC die before the age of five years, and the
mortality rate of children with brain stem dysfunction may exceed 35%[9 ]. The most frequent causes of death in patients with MMC include CMII-related complications;
urinary tract, pulmonary, and cerebrospinal fluid infections; as well as ventricular
shunt malfunction[10 ]. In Brazil, fortification of wheat and maize flour and their derivatives with FA
became mandatory after 2002.
In 2006, Bol et al.[11 ] reported significantly improved first-year survival after implementation of mandatory
folic acid fortification (FAF), compared with the survival rate of children with MMC
born before fortification. A significant decline in perinatal and infant mortality
was also shown by Sayed et al.[12 ] in 2008. In 2010, Blencowe et al.[2 ] conducted a systematic review of the literature and estimated that FAF reduces the
incidence of neural tube defect by 46% and expected neonatal deaths by 13%.
The aim of this study was to evaluate the impact of FAF on the mortality rate of patients
with MMC who underwent surgery at a pediatric hospital in Rio de Janeiro, Brazil.
METHODS
We performed a retrospective study of a cohort of 383 children diagnosed with MMC
who were surgically repaired from January 1990 to December 2013. There were 39 deaths,
and our focus was on the children who died after hospital dis-charge, which accounted
for 23 out of the 39 (58.97%) deaths.
This study was approved by the institution's Committee of Ethics in Research.
The relationship of mortality to the following variables were evaluated: age, cause
of death, risk factors, postoperative complications, and gender. Data were analyzed
using Epi Info, ver. 7.1.4.0 software (Centers for Disease Control and Prevention,
Atlanta, USA). Results with p values < 0.05 were considered significant. The period
of implementation of flour fortification was calculated according to the model used
by Orioli et al.[6 ], and consisted of the sum of the 18 months elapsed from the time of publication
of the decree, the three-month period for the implementation of fortified flours,
and the nine months of gestation.
RESULTS
Demographics
Of the 21,310 live births between 1994 and 2013 at the Insitituo Fernandes Figueira,
10,894 (51.1%) were boys and 10,299 (48.3%) were girls (male/female ratio of 1.05:1).
Gender-related information was not found for 0.5% (n = 117) of the children. Analysis
of the 330 cases of MMC showed that the proportion of female children with MMC was
56.6% (n = 187) and that of male children with MMC was 43.3% (n = 143, p = 0.0038).
The frequency of MMC before mandatory flour fortification was 1.34% (n = 172), while
the incidence after implementation of FAF was 1.81% (n = 158), which was a significant
in-crease in the incidence rate (p = 0.0055).
Surgical technique
For all 383 MMC cases, the initial treatment was correction of the MMC according to
the usual 5-layer technique. Among the 23 patients who died after hospital discharge,
five patients also underwent simultaneous placement of a ventriculoperitoneal shunt.
Surgical complications
There were 28 surgical complications; the most common were infections of cerebrospinal
fluid and shunt hardware (78.5%, n = 22), as well as ventriculoperitoneal shunt mal-function.
The complications and incidence rates are shown in [Table 1 ].
Table 1
Complications of surgical treatment.
Variable
N
%
Surgical procedure
6
21.4
Wound Infection
3
10.7
Intracranial hypertension*
3
10.7
Ventriculoperitoneal shunt (VPS)
22
78.5
CNS Infection
8
28.5
VPS Infection
7
25
VPS Malfunction**
6
21.4
VPS Shortening***
1
3.5
CNS: central nervous system; VPS: ventriculoperitoneal shunt;
*Intracranial hypertension occurred in three children not derived at MMC correction;
**Three children have resultant intracranial hypertension;
***Resulting in intracranial hypertension
Risk factors and causes of death
Neurogenic bladder, recurrent urinary tract infections, lower-limb paralysis; recurrent
respiratory infections, chronic constipation, chronic renal failure, hydronephrosis,
apneic crises, and gastroesophageal reflux disease were risk factors for mortality.
The most common causes of death were central nervous system (CNS) infections, occurring
in eight of the 23 (34.7%) fatalities after hospital discharge. Respiratory infections
and sepsis of urinary tract origin were the second most common cause of death, each
being a major contributing factor in 21.7% (n = 5) of the 23 deaths. Respiratory tract
infections were also an aggravating factor in eight cases. All the cases of urinary
sepsis had kidney failure. Intracranial hypertension and CMII were major contributing
factors in two of 23 (8.69%) patients. Chiari II malformation was also present and
associated with death in four other cases. The cause of death of one patient was septic
gastroenteritis complicated by kidney failure.
Nine of 23 (39.1%) children died in the first year of life, five between the ages
of two and three years, and four between the ages of one and two years. Five children
died between the ages of three and 11 years ([Figure ]). The highest number of deaths after hospital discharge occurred in female children,
60.8% (n = 14), but this rate was not significant (p = 0.981).
Figure Distribution of deaths by age group.
At a given moment, five live births presenting with signs and symptoms of CMII were
identified, and accounted for 21.7% of the 23 children analyzed.
Correlation of deaths with hospital discharge and FAF
Of the 383 operated children, the total number of deaths was 39 (10.1%). The deaths
were classified as occurring before hospital discharge (BHD) or after hospital discharge
(AHD). The BHD group, composed of 16 of the 383 (4.1%) cases of MMC, included the
children who died at younger than 30 days and those who, despite surviving the first
month of life, were not discharged. The AHD group included 23 of 383 (6.0%) children
who died after hospital discharge. The mean survival period was 2.8 years, ranging
from two months to 11 years.
The mortality rates before and after fortification of the BHD group and AHD and group
were compared. Before forti-fication there were 11 BHD deaths and 20 AHD deaths. After
fortification, five BHD patients and three AHD patients died. The total number of
deaths was 31 before and eight after mandatory fortification. The reduction in total
number of deaths after mandatory fortification was significant (p = 0.00919) and the
reduction in the number of AHD deaths after fortification was significant (p = 0.0088),
but not the number of BHD deaths (p = 0.568). The results are shown in [Table 2 ].
Table 2
Deaths before and after mandatory flour fortification.
Variable
DBF n (%)
DAF n (%)
pc
Fisher exact
Total
31 (13.7)
8 (5)
0.00919
0.00569
BHD
11 (4.8)
5 (3.1)
0.568
0.450
AHD
20 (8.8)
3 (1.8)
0.0088
0.0040
DBF: Deaths before fortification; DAF: Deaths after fortification.
Of the 23 children who died AHD, the highest prevalence was observed in the lumbosacral
region, followed by thoracolumbar. The locations and frequencies are presented in
[Table 3 ].
Table 3
MMC frequency according the site of the defect.
Site
n
%
Lumbosacral
9
39.1
Thoracolumbar
8
34.8
Lumbar
5
21.7
Thoracic
1
4.3
DISCUSSION
There have been few studies related to late mortality in patients with MMC, particularly
regarding etiology and age ranges.
The decrease in the incidence of MMC at our institution before and after mandatory
FAF was not significant. There are several possible explanations for this finding:
a) FAF of flour alone was not sufficient for promoting a significant decrease in MMC
rates, because the FA concentration in Brazilian flours is 1.5 mg/kg, which is lower
than the FA con-centration adopted by other Latin American countries, such as Argentina
and Chile where the FA concentration is higher and where they have experienced a significant
decrease in neural tube defects and MMC[6 ],[7 ],[13 ]; b) the Brazilian public health system nowadays provides easier and faster access
to prenatal diagnostic tools, thereby increasing the frequency of early MMC diagnosis
and directing these cases to reference centers such as the Insitituo Fernandes Figueira;
c) our institution is a tertiary reference center for a low-income population, which
is much more frequently affected by neural tube defects; d) Brazil is a multiracial
country with an ethnic profile different from other Latin-American countries[7 ]. Moreover, in some countries, the prevalence of MMC was not substantially reduced
by FAF of flours, and in some countries the prevalence has even increased[14 ]. These findings might be a result of heterogeneous supplementation policies and
lack of flour fortification. Also, educational and social interventions regarding
folic acid supplementation are needed[14 ].
In our series, of the 383 live births with MMC, 23 (6%) died after hospital discharge;
most of the deaths occurred before five years of age (n = 20), corresponding to 86.9%
of the total number of AHD deaths. Analysis of deaths by age range showed that 39.1%
(n = 9) of the children died during the first year of life. Ten deaths occurred from
the ages of one to four, as follows: four (17.3%) between one and two years, five
(21.7%) between two and three years, and one (4.3%) between three and four years.
The remaining four deaths occurred at the ages of seven (n = 1), nine (n = 1), and
11 years (n = 2). The highest death rates occurred in the lowest age ranges.
A Brazilian study of 36 cases of MMC found a mortality rate of 16.6% (n = 6), with
all the deaths occurring before two years of age[15 ]. Another study followed 84 patients after dis-charge, and most of the deaths (74%)
occurred during the first month of life[16 ]. Another case series reported that most deaths occurred between the neonatal period
and preschool age[9 ],[17 ],[18 ]. Mortality rates in MMC do not stabilize as the patients be-come older. An analysis
of long-term studies showed that 240 (71.2%) of 337 reported deaths occurred in patients
up to 16 years of age[9 ],[16 ],[17 ],[18 ]. The main cause of death in patients older than 16 years was unrecognized ventriculoperitoneal
shunt dysfunction[18 ],[19 ]. A cohort study that followed patients for more than 40 years found that there were
56% of patients who survived to around 20 years of age, but the mortality rate continued
to increase with age, and the last evaluation showed that there were 33.3% of patients
of the initially observed population who were still alive[9 ],[20 ]. These results are very different from those presented by Talamonti et al., who
reported only five deaths among 202 patients followed over 25 years[21 ].
The total number of deaths in our study was 39 (10.1%). During the period before FAF
(January 1990 - December 2005), there were 225 cases of MMC, with a mortality rate
of 13.7% (n = 31). Considering only the cases in which AHD deaths occurred, the mortality
rate was 8.8% (n = 20). After implementation of FAF, there were 158 cases of MMC,
and the total death rate for this period was 5.0% (n = 8). There were five neonatal
deaths (3.1%) during the same period. These data show a significant reduction in the
total number of deaths during the years after FAF implementation. However, regarding
neonatal mortality, that is, the live births not discharged from the hospital, the
mortality rate was not significantly reduced after FAF. This result differs from the
findings of others on the protective role of FAF against neonatal mortality[2 ],[11 ],[12 ]. There was a significant decrease in AHD deaths 1.8% (n = 3) after implementation
of mandatory FAF versus 8.8% (n = 20) before implementation. A series of 304 children
with MMC, who were born in Ireland before FA supplementation, showed that only 33%
of the children survived to their first birthday, and just over 27% survived to the
age of five years[22 ]. However, after mandatory FAF, there was a significant increase in the survival
rate of children with MMC, leading to the hypothesis that FA, in addition to preventing
MMC, might also play an important role in reducing the severity of MMC among live
births[1 ], as well as malformations in other organs or systems[23 ] and the resulting neonatal mortality[24 ].
The most common cause of death detected in our study was CNS infections, particularly
those related to the cerebrospinal fluid (34.7%), followed by urinary sepsis and respiratory
infections (21.7%). Cerebrospinal fluid infections were mostly caused by shunt infections
and these are regarded as a highly significant predictor of mortality[25 ]. Children with shunts are at high risk of cerebrospinal fluid infection, ranging
from 5.5% to 25% of cases[26 ], and shunts are thought to be the cause of death in 33% to 50% of children with
MMC[15 ],[16 ].
Urinary tract infections resulting from neurogenic bladder and vesicoureteral reflux,
in some cases, have led to urinary sepsis, kidney failure, and ultimately death[27 ].
Chiari II malformation was the third most common cause of death, acting either as
a determining or contributory factor. The signs and symptoms of this malformation
are protean and may be transient, making it difficult to estimate its real prevalence
among neonates and infants. It is assumed that, at some time, 6% to 32% of individuals
with MMC will have neurological manifestations related to CMII[28 ]. The mortality is higher and may be the main cause of death among neonates with
CMII, affecting more than 40% of MMC patients[18 ],[29 ],[30 ].
Discontinuing the follow-up of patients with MMC has a dramatic impact on the number
of deaths[21 ],[22 ]. The most common cause of discontinuation is the lack of multidisciplinary centers
for spina bifida treatment. Since most families have a low income and live on the
outskirts of large cities, regular follow-ups are reduced or even neglected, since
most patients have severe limitations in ambulation and need special requirements
for transportation, which is not always available[31 ].
In conclusion, the mortality rate of patients with MMC after they were discharged
from the hospital was 6%. Most children died before their first birthday. The most
common causes of death were CNS infections, respiratory infections, and urinary sepsis.
Symptomatic CMII was the most common comorbidity factor. The mortality rate after
hospital dis-charge decreased after implementation of mandatory flour fortification
with folic acid.
