Pre &amp; Perinatal care characteristics and management of children with myelomeningocele after 25 years of folate fortification of staple foods in Costa Rica

doi:10.21203/rs.3.rs-2632067/v1

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Pre & Perinatal care characteristics and management of children with myelomeningocele after 25 years of folate fortification of staple foods in Costa Rica

https://doi.org/10.21203/rs.3.rs-2632067/v1

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published 02 May, 2023

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Purpose

To describe the clinical characteristics of pre and perinatal care of children born with myelomeningocele in Costa Rica from 2004 to 2022 after the introduction of mandatory four staple food fortification policy, describing the clinical features of this cohort including the size of the meningomyelocele, neurological level, presence of symptomatic Chiari II at birth, kyphosis and the severity of hydrocephalus requiring cerebrospinal fluid (CSF) shunting.

Methods

We performed a retrospective review of the clinical records of patients with myelomeningocele at the spina bifida clinic from the National Children´s Hospital of Costa Rica who were born after the introduction of the four staple food folic acid fortification.

Pre and perinatal care data pertaining to the number of obstetric ultrasound studies, the trimester in which they were performed and the detection of myelomeningocele and associated hydrocephalus, gestational age and route of delivery, neurological level, myelomeningocele defect size, associated kyphosis and symptomatic Chiari II malformation at birth, time periods of myelomeningocele repair and eventual CSF shunting were examined.

Results

A total of 215 patients born between 2004 and 2022 were eligible for analysis with a follow up ranging from 1 to 19 years (median follow up: 7.9 years). Among 99.1% of the mothers of patients who had prenatal consultations, 95.8% had an average of 3.8 obstetric ultrasound studies which led to a 59% prenatal detection rate of myelomeningocele.

This cohort had a slight male predominance (54.8%). Among these newborns, 7.5% had the myelomeningocele lesion repaired in less than 8 hours, 12.2% from 8-12 hrs., 66.5% 12-24 hrs. and 12.7% from 24-48 hrs. and 1% later than 48 hrs.

Regarding the myelomeningocele anatomic and functional characteristics, defect size was measured as less than 3 cm in 7% of cases, 3 to 5 cm in 50% of cases, 5 to 7 cm in 42% of cases and greater than 7 cm in 1% of cases. 13% of the cases had paraplegia due to a thoracic level, 9.3% had a high lumbar level, 58% had a middle lumbar level, 13% a lower lumbar level and 5.6% only sacral compromise.

Postnatal closure was performed in less than 8 hrs. in 7.4% of cases, 8 to12 hrs. in 12.1% of cases, 12 to24 hrs. in 65.8% of cases, and 24 to48 hrs. in 12.5% of cases. Kyphotic deformities were observed in 3 patients who had very large defects and only 6 patients had symptomatic Chiari II malformation at birth. 79% of the cohort required CSF VP shunting with a mean time for insertion of 10 days after spinal defect closure.

Conclusions

This study describes a four staple folate fortified population of live born patients with myelomeningocele lesions whose neurological level, defect size, and associated deformities such as spinal kyphosis and symptomatic Chiari II at birth, suggest that folate fortification could have diminished the severity of this congenital disease.

Folic acid

food fortification

neural tube defects

myelomeningocele

Chiari malformation

prenatal diagnosis.

Neural tube defects (NTDs) (including anencephaly, iniencephaly, encephalocele, craniorachischisis and myelomeningocele) represent severe congenital diseases that affect pregnancies worldwide leading to stillbirth and perinatal mortality especially in low- and middle-income countries[1]. While anencephaly, iniencephaly and craniorachischisis are usually fatal a few hours after birth, myelomeningocele (MMC) is the most severe congenital defect compatible with life even if left untreated[2–6].

While some high-income countries in the European union have chosen to detect and terminate these pregnancies[7–10], middle- and low-income countries suffer the economic, social, and healthcare challenges of MMC and its associated lifelong complications (hydrocephalus, neurogenic bladder, scoliosis, soft tissue ulcers, cognitive deficits)[6].

The British Research Council Study published in 1991 the unequivocal evidence that folic acid prevents a large percentage of these congenital anomalies[4], which was later confirmed by several observational studies[2, 5, 6].

Mandatory folic acid fortification is effective, safe and cost effective in reducing the number of folate sensible cases of anencephaly and MMC and their associated stillbirth, neonatal, infant and under five mortality rates[11–14]. Additionally, it has been suggested that folic acid decreases the severity of spina bifida as pre and post fortification cohorts show a decrease in the number of cases of upper-level lesions (cervical and thoracic). This reduction in severity reflects on the quality of life by increasing the chance of independent mobility with greater access to daily living activities, healthcare and education[15, 16]

Costa Rica, a country located in Central America, has a population of 5,195,735 inhabitants (2022) and has a universal government-based health system where 99% of deliveries are conducted by skilled healthcare personnel (World Bank)[17, 18]. After setting up a national registry for congenital malformations, conducting nutritional survey and blood folate level studies; mandatory folate fortification of food staples was implemented in 1997 on the basis that such policy would have a broad reach, would not imply changes in the nutritional habits, producing effective measurable results in a short time period at a very low cost.

While it has been reported previously the significant decline in the prevalence of NTD in Costa Rica from 11.7 to 5.4 per 10,000 live births after the sequential fortification of wheat, maize, rice and dairy products[19–22], we conducted a retrospective observational cohort study of the prenatal care, detection rates, perinatal features and management of those children who were born with MMC under this four component folate fortification policy over a 18 year period.

Data were collected through retrospective chart review of medical records at the multidisciplinary spina bifida clinic at the National Children’s Hospital of Costa Rica. Individuals were included if they were live born in Costa Rica from 2004 to 2022, when the four staple food fortification policy (wheat and maize flour, rice and dairy products) had been gradually established and adjusted for adequate dosage (1997–2003), had sufficient documentation of maternal prenatal care including number of obstetric ultrasound studies, the trimester when these had been performed, the detection of MMC and associated hydrocephalus, as well as data describing delivery route and gestational age at birth.

The patient’s neurological level was documented by physical examination of the functional active movements of the lower limbs, measurement of the diameter of the MMC defect as recorded in the charts, the presence of associated congenital malformations such as spinal kyphosis and symptomatic Chiari II malformation at birth that required surgical management such as cerebrospinal fluid (CSF) shunts insertion and suboccipital decompression. Finally, time to closure of the MMC after birth and time to insertion of CSF shunts were documented.

Individuals were excluded from our analysis if they had been conceived in countries where folate fortification is different from the Costa Rica standards, had insufficient documentation regarding the prenatal and perinatal care or had a diagnosis of spina bifida occulta, lipomyelomeningocele, fatty filum terminale or anorectal associated congenital spine malformations.

A descriptive comparative frequency analysis between MMC defect size, CSF shunt insertion, symptomatic Chiari II and kyphosis between the different functional levels was performed with the estimation of the Fisher’s exact chi-square test by contingency tables and 0.05 was set as significance level. All the estimates were calculated using Jamovi statistical software (Version 2.3, 2022).

After a retrospective review of 418 charts from eligible patients followed at the spina bifida clinic with the diagnosis of MMC who were live born in or after 2004, complete data was available for 215 patients with an age range of 1 to 19 years and an average of 7.9 years of follow up.

Prenatal care was followed in 99.1% of the patients’ mothers. 1 mother reported chronic valproic acid intake due to epilepsy and another mother reported that the pregnancy was achieved by IVFT.

Obstetric ultrasound studies were performed in 95.8% of the patient’s mothers with an average of 3.8 studies, and this led to a 59% prenatal detection rate. Average prenatal week of detection was 26 weeks. Delivery was conducted at an average of 38.4 weeks, with 67%% by vaginal route whilst 36% were cesarean sections.

After delivery, there were 118 (54.8%) males and 97 females (45.12%). The neurological level was determined as the most caudal complete sensory and motor functional level at postnatal examination. For functional purposes, all defects that extended into the low thoracic segments that led to paraplegia were considered under a single category, thoracic. We only detected one case of a cervical MMC within this series. 13% of the cases led to paraplegia due to a thoracic level, 9.3% had a high lumbar level, 58.6% had a middle lumbar level with 80% of these patients having a L3 level, 13.5% had a lower lumbar level and 5.6% had only sphincter compromise due to lower sacral compromise respectively. See Table and Fig. 1.

The MMC defect was repaired in 7.5% of these newborns in less than 8 hours, 12.2% from 8–12 hrs., 66.5% 12–24 hrs. and 12.7% from 24–48 hrs. and 1%, later than 48 hrs. See Fig. 2.

MMC defect size as measured at time of closure at its maximum diameter, as less than 3 cm in 15.7% of cases, 3 to 5 cm in 50% of cases, 5 to 7 cm in 42% of cases and greater than 7 cm in 1% of cases.

It is to note that severe associated clinical deformities such as spinal kyphosis were observed in 3 patients (1.4%) with 2 being associated to the extensive thoracic defects greater than 7 cm in size. Symptomatic Chiari II malformation at birth defined as stridor, swallowing abnormalities and apnea was also observed in 6 patients (2%) in this series.

Hydrocephalus requiring shunt insertion was documented in 79% of the patients, and the timing for insertion was concurrent with the MMC closure in 20 patients. The mean timing of insertion was 10 days with an average of 15 days after birth. Furthermore 19.5% of the patients that required a shunt revision became shunt free with the use of ETV.

The analysis of the characteristics between the MMC functional level and size, demonstrated a significant frequency between smaller lesions and caudal functional levels. Defects with sizes larger than 5 cm were present in 82.8% (24/29) of the thoracic level and in the 61.9% (13/21) of high lumbar MMC patients, while defects smaller than 5 cm were predominant in 64.8% (81/125) of middle and 72.5% (29/40) of low lumbar/sacral level MMC patients respectively (P < 0.01).

Shunt requirement comparison between functional levels evidenced that higher lesions not only correlate with larger size but also with clinically significant hydrocephalus, as 86.2% (25/29) of thoracic cases required shunting in contrast with 57.5% (23/40) of low lumbar/sacral MMC patients (P < 0.05). These findings can also attest to the severity of the disease manifested by the presence of the symptomatic Chiari II malformation, reported in 10.3% (3/29) of thoracic, 4.8% (1/21) of high lumbar, 1.6% (2/125) of middle lumbar and none in patients with low lumbar or sacral level MMC (P < 0.05). Additionally, the presence of kyphosis as another severity marker was evaluated, and it was only documented in three of the thoracic cases (10.3%) without presence in any of other functional levels categories (P < 0.01). See Table 2.

Table 1

Distribution of neurological levels in patients with myelomeningocele in Costa Rica post-fortification (N = 215).

Modified from ref. 22
Functional level	Active movement of lower extremities	Anatomical medullary segments	Percentage
Thoracic	Flaccid lower extremities	T1-T12	13%
High lumbar	Hip flexors present	L1-L2	9.3%
Middle lumbar	Knee extensors present	L3-L4	58.6%
Lower lumbar	Ankle dorsiflexion present	L5-S1	13.5%
Sacral	Ankle plantar flexion present	S2-S5	5.6%

Table 2

Clinical findings representing severity and frequency relationship to myelomeningocele functional level location
Characteristics		Functional Level								p value
Characteristics		Thoracic,N = 29		High Lumbar,N = 21		Middle Lumbar,N = 125		Low Lumbar/Sacral,N = 40
Defect size	≤ 5 cm	5	(17.2%)	8	(38.1%)	81	(64.8%)	29	(72.5%)	< 0.01*
Defect size	> 5 cm	24	(82.8%)	13	(61.9%)	44	(35.2%)	11	(27.5%)
Shunt Requirement		25	(86.2%)	19	(90.5%)	101	(80.8%)	23	(57.5%)	< 0.05*
Symptomatic Chiari II		3	(10.3%)	1	(4.8%)	2	(1.6%)	0	(0.0%)	0.05*
Kyphosis		3	(10.3%)	0	(0.0%)	0	(0.0%)	0	(0.0%)	< 0.01*
*Fisher's exact test

The National Children's Hospital in San Jose, Costa Rica treats every single live born patient with a NTD within the country’s territory and the public universal healthcare system guarantees that all children will benefit from free medical care throughout their childhood. The spina bifida clinic opened its doors in 1993 and has closely followed this population from the pre folate to the full four component fortification policy to this day. All these circumstances provide a very accurate depiction of the incidence, clinical characteristics, and management of this group of patients.

Additionally, in Costa Rica there is no legal termination of affected pregnancies and even if this is a possibility, it is often not a choice for pregnant women due to cultural and religious beliefs[23]. This adds validity to our findings, as we consider that the studied population reflects most patients born with spina bifida under current folate fortification policies.

Fetal structural abnormalities have been described in up to 3% of all pregnancies and prenatal ultrasound remains one of the most reliable screening methods[23, 24][24]During the first trimester detection rates have been quoted close to 51% and this rate may increase to 90% in the second trimester[25–29] The identification of the lemon & banana signs along with ventriculomegaly are suggestive of MMC, however detection may be challenging during the first trimester[26–28]. In our cohort, 52% of cases OF MMC were detected during the second semester and 53% during the third semester respectively which underlines that early detection is still challenging within our healthcare system, however it opens the possibility of reaching early second semester evaluation that could allow prenatal MMC repair.

Literature has cited a hypothetical benefit of a cesarean delivery in reducing infant morbidity and mortality among MMC patients, quoting decreased trauma to the spinal defect, less probability of infection due to exposure of vaginal flora and improved access to surgical closure following the cesarean section[30–33]. In our series, despite having a 36% of the patients delivered vaginally, there were no recorded incidents of wound infection and as the cohort shows, 85% of the patient underwent prompt surgical closure within 24 hours after vaginal or cesarean delivery.

Several authors have described a positive impact of folate fortification on the functional level of patients with MMC, which indirectly improves morbidity and mortality[16, 34, 35]. Our results are consistent with previous studies as 77% of our patients have lesions at or below L3 which allows them to walk with the use of orthoses (independent ambulation)[36]

Given this tendency, there is also an increased frequency matching severity, as 67% of the MMC lesions were lesser than 5 cm of diameter, therefore allowing a feasible closure without the use of flaps or releasing incisions. This potentially shows a significant impact of folic acid in the decrease of anatomical level (caudalization of MMC) and reduction of diameter which along with almost nonexistent kyphosis (only 3 patients − 1.4%), facilitates not only the closure of the defect, but can also prevent the occurrence of this orthopedic problem that has been reported in 12 to 20%[37, 38]

The presence of symptomatic Chiari II malformation at birth in only 6 patients (2.7%), two of whom had lesions above L3 and which were larger than 5 cm of diameter could also be attributable to the protective effect of folate in the rest of this cohort, as Pollack, Protzenko and McDowell have reported 4.5, 12 and 21% rates of symptomatic Chiari II at birth requiring surgical management respectively[39–42]

It is to note that all three of our patients that underwent perinatal VP shunting followed by suboccipital decompression due to symptomatic Chiari II malformation (apnea, stridor and swallowing abnormalities), had a poor outcome, requiring tracheostomy and PEG, however they remain alive at follow up. This bad outcome has also been reported in other series[39, 40, 43] probably due to intrinsic brainstem anomalies as described by McLone[44].

In contrast to other studies, where there has been a reduction in the number of cases which require VP shunting[45, 46], our cohort shows that 78% of the patients underwent a shunt insertion which is also consistent with traditional series[29, 47, 48]. Of patients requiring a CSF shunt, 12% underwent the procedure at the time of spine repair due to the presence of overt hydrocephalus and a surgical timing less than 8 hours after delivery.

It is to note that the very low incidence of symptomatic Chiari II malformation at birth plus the significant percentage of ambulatory patients and the near absence of kyphosis in our cohort could suggest a protective effect from folic acid in live born MMC patients, which overlaps with the potential therapeutic objectives of prenatal MMC repair, warranting further studies and analysis of[49–54].

A major strength of our study is the analysis of representative data obtained from the only spina bifida clinic that manages every single case of live born myelomeningocele in Costa Rica, where there is a free universal healthcare system, and mandatory food fortification policy with four different staple foods are fortified with adequate folic acid dosage.

Limitations of this study are the lack of control data from the same population before the staple food folate fortification policy was introduced to conduct as pre- and post-fortification effectiveness analysis for severity.

In conclusion, mandatory four staple food fortification effectively and safely decreases the prevalence of NTD. A universal healthcare system that enforces a good prenatal care provides an early possibility of detection of NTD cases which optimizes their obstetric care. Additionally, a centralized spina bifida care institution provides a uniform approach to multidisciplinary evaluation and treatment with prompt clinical and surgical management of patients with MMC and associated hydrocephalus.

This preventive and curative approach not only prevents the saturation of health services with cases that otherwise can be prevented through folate fortification, but also optimizes the use of resources and personnel to other healthcare needs.

Ethics approval and consent to participate.

Article was submitted for approval to the IRB of the National Children´s Hospital of Costa Rica. Due to the retrospective longitudinal observational nature of the study where the information was de-identified, the study poses minimal risk to participants and safeguards are in place to protect their privacy and confidentiality, therefore a waiver was issued and no informed consent was required from the participants.

Consent for publication

There are no tables or figures in this article that require consent from second parties.

Availability of data and material

Pertinent information/databases to this study are kept passworded/encrypted and stored in the Onedrive online servers of the Caja Costarricense de Seguro Social (Costa Rica) and may be available upon pertinent request.

Disclosures

The authors declare that there are no financial or non- financial relationships to disclose

Competing interests

The authors declare there are no competing interests to disclose.

Funding

The authors declare that no funding was required for the present study.

Authors' contributions

AC, ALJC and PAAQ collected clinical data.

AC wrote the manuscript main text and prepared figures 1-2

RW prepared tables 1 and 2 and provided statistical analysis of the results.

All authors reviewed the manuscript.

Acknowledgements

The authors would like to thank Vijaya Kancherla at the Center for Spina Bifida Prevention & Department of Epidemiology, Emory University, USA and Adriana Benavides from Instituto Costarricense de Investigacion y enseñanza en nutrición y salud (INCIENSA) Costa Rica for proofreading and providing technical suggestions for this paper.

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published 02 May, 2023

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Pre & Perinatal care characteristics and management of children with myelomeningocele after 25 years of folate fortification of staple foods in Costa Rica

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