The natural history of neural tube defects in the setting

Journal of Obstetrics and Gynaecology

ISSN: 0144-3615 (Print) 1364-6893 (Online) Journal homepage: http://www.tandfonline.com/loi/ijog20

The natural history of neural tube defects in the setting of an Irish tertiary referral foetal medicine unit B. Anglim, T. Mandiwanza, J. Miletin, M. Turner & M. M. Kennelly To cite this article: B. Anglim, T. Mandiwanza, J. Miletin, M. Turner & M. M. Kennelly (2015): The natural history of neural tube defects in the setting of an Irish tertiary referral foetal medicine unit, Journal of Obstetrics and Gynaecology To link to this article: http://dx.doi.org/10.3109/01443615.2015.1030597

Published online: 27 Jul 2015.

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Date: 23 November 2015, At: 08:09

Journal of Obstetrics and Gynaecology, 2015; Early Online: 1–5 © 2015 Informa UK, Ltd. ISSN 0144-3615 print/ISSN 1364-6893 online DOI: 10.3109/01443615.2015.1030597

ORIGINAL ARTICLE

The natural history of neural tube defects in the setting of an Irish tertiary referral foetal medicine unit B. Anglim1, T. Mandiwanza2, J. Miletin3, M. Turner4 & M. M. Kennelly5 1Coombe Women and Infants University Hospital, 2Department Paediatrics, Neurosurgery, Temple Street Children’s University Hospital, 3Department Paediatrics, Coombe Women and Infants University Hospital, 4UCD Centre for Human Reproduction, Ultrasound and Fetal Medi-

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cine Centre, and 5UCD Centre for Human Reproduction, Dublin, Ireland

Neural tube defects (NTDs) carry a heavy burden for affected individuals and their family. Physical and neurological outcome measures may help in counselling couples. The aim of this audit was to review all cases of NTDs seen at a tertiary referral foetal medicine unit. Cases were identified from obstetric, neonatal and neurosurgical records. Thirty-six cases of NTDs were identified. Of the 36, 25% (n  9, one trisomy 18) opted for termination of pregnancy abroad. Of the remaining 27, 19% (n  5) died in the antepartum period. 81% (n  22) were liveborn with four neonatal deaths (one trisomy 18). Of 15 cases, 14 had neurosurgical repair within a median time of 3 days and 9 of these also had a ventriculoperitoneal shunt inserted. Antenatal ultrasound accurately diagnosed lesion level in the majority of cases. The survival rate for babies diagnosed with non-lethal neural tubes defects is high when multidisciplinary care is initiated early. Keywords: Antenatal diagnosis, neural tube defects, neurological outcome, postnatal repair of spina bifida Abbreviations: NTD, Neural tube defects; SB, Spina Bifida; TSH, Temple Street Children’s University Hospital; SCBU, Special Baby Care Unit; MMC, myelomeningocele; MC, meningocele

Introduction Neural tube defects (NTDs) have a pan-European incidence of 9.36 per 10,000 births. However, rates in Ireland are higher at 1.04 per 1,000 births (EUROCAT registry 2008–2011). NTDs can be divided into myelomeningocele (MMC), meningocele (MC), encephalocele and anencephaly. The aim of this population-based study was to report our experience of spina bifida over a three and a half-year period within a tertiary referral foetal medicine unit in a country where termination of pregnancy is not available. We report on management decisions in this group. We report the correlation between antenatal ultrasound parameters and postnatal lesion size, level and ventriculomegaly requiring ventriculoperitoneal shunting. We report on antenatal, labour and perinatal outcomes. These outcome measures may help counselling women with affected pregnancies and may aid them in decision-making.

Methods A systematic review of all high-risk pregnancies referred to foetal medicine centre with NTDs from February 2010 to July 2013 was undertaken. The hospital has an annual delivery rate of approximately 8500 births, and is one of three main tertiary referral centres in Ireland that receives referrals from a stable population base of up to 4.5 million. Screening for anomalies at the 18–22-week scan is a part of the standardised practice at the referral centre and part of routine antenatal care. A search of the foetal medicine database was carried out in order to include all NTDs, with or without concurrent anomalies. All cases were seen by a foetal medicine sub-specialist, where a detailed targeted anatomical survey was performed for soft markers and extracranial abnormalities. Antenatal information was obtained from ViewPoint ultrasound reports and patient charts. Postnatal information was obtained from imaging reports, patient charts and multidisciplinary letters. Surgical findings and postoperative course were retrieved from records at Temple Street Children’s University Hospital (TSH) the Irish Centre for Paediatric Neurosurgery since 2008. The ultrasound report included information on the size and level of lesion, as well as the presence of ventriculomegaly, Arnold– Chiari II malformation, talipes and other structural abnormalities. Any change in ventricular size throughout the gestation was noted. Foetal karyotyping was an integral part of the investigation and counselling in all cases. Once lesion level was approximated, likely functional outcome was discussed with the parents in the presence of the obstetrician, a paediatric neurosurgeon and spina bifida clinical nurse specialist. Amniocentesis was carried out where permission was granted by the parents. The mode of delivery, birth weight and delivery complications such as postpartum haemorrhage, difficulty with delivery of the head, angle extension and return to theatre were documented. After delivery, initial examination was performed by a neonatologist, and any neonatal admission to the Special Baby Care Unit (SCBU) was noted, prior to discharge. Transfer to TSH usually occurred within a day.

Results Thirty-six cases of NTDs were identified during this period. They included MMC (n  26), MC (n  2), encephalocele (n  2) and anencephaly (n  6). The mean gestational age at diagnosis was 22 weeks (range: 12–31 weeks). Ten cases were referred from other hospitals. Table I profiles the clinical and ultrasound details of this group.

Correspondence: Breffini Anglim, MB, BCh, BAO, Coombe Women and Infants University Hospital, Cork Street, Dublin 8, Ireland. E-mail: breffini.anglim@ gmail.com

MMC

MMC MMC MMC

MMC

MMC Meningocele MMC MMC Meningocele MMC

MMC MMC MMC

MMC MMC Encephalocele encephalocele

MMC MMC MMC

MMC

MMC MMC MMC MMC

MMC

MMC

2 3 4

5

6 7 8 9 10 11

12 13 14

15 16 17 18

19 20 21

22

23 24 25 26

27

28

Defect type

1

Case No.

27  2

24  6

20  4 31  6 22  0 21  2

21  2

21  5 30  1 20  1

21  3 27  2 20  5 16  5

14  4 18  4 19  6

22  3 24  3 26  3 31  0 27  6 22  1

22  3

31  4 22  5 22  5

21  5

GA at diagnosis

20

 10

31 22 13 15

15

 10 20 55

 10 20  10 15

 10 14 40

 10 11 24 20  10 32

12

 10 41 15

26

Max Vp (mm)

Table I. Diagnosis and management of Spina Bifida.

Not done

Not done

Not done Normal Normal Normal

Normal

Not done Normal Normal

Not done Normal Normal Normal

Normal Normal Normal

Normal Not done Normal Normal Not done Not done

Normal

Normal Not done Not done

Normal

Karyotype

TOP TOP 34w, SVD, NND 34w, SVD, IUD TOP TOP TOP 26w, SVD, IUD 26w, SVD, IUD TOP

38w, SVD TOP 39w, SVD 35w, ELCS

39w, SVD 41w, EMCS 35w, EMCS

37w, SVD 39w, SVD 38w, SVD 38w, SVD 39w, ventouse 38w, EMCS

38w, ELCS

39w, EMCS 39w, ELCS 38w, EMCS

38w, EMCS

GA & Mode of delivery

Hypoglycaemia Hypoglycaemia nil

Fever 37.7C  2

CSF leak, hypoglycaemia

Hypoglycaemia

CSF leak, hypoglycaemia

Complications prior to transfer

L4-S3

LS

S1-S4 LS LS Sacral

LS

Sacral L2-S1 T5-T7

Low sacral L4-S3 Occipital Cervical

L5-S4 L5-S1 LS

S1-S3 L1/L2 LS LS L4-S4 L2-S3

Low LS

LS L4-S2 S1-S3

L2-S4

Antenatal ultrasound defect level

Occipital

Sacral

LS (MRI) LS (MRI) LS (MRI)

Sacral (MRI) L1-L2 (MRI) Sacral (MRI) L3-S (MRI) L2 (MRI) Lumbar (MRI)

L4-S (MRI)

S2-S4 (MRI) L2-S (MRI) L3-S (MRI)

L3-S (MRI)

Size of lesion postnatally

NO

11

NO 3

No Day 30 Day 5

No No Day 6 No No Yes- day 26

Day 4

No Day 7 Day 9

Day 8

Ventriculo Peritoneal shunt

3

9 4 2

1 NO 3 2 3/12 3

1

1 3 1

2

Time to repair


Developed hydrocephalus

No CSF leak Wound breakdown, 1 shunt revision CSF leak, shunt infection, 1 shunt revision, meningitis No No 1 shunt revision No No Wound breakdown, CSF leak, shunt infection, 6 shunt revisions, meningitis No No Wound breakdown, CSF leak, 1 shunt revision No

Wound breakdown, CSF leak

Surgical complications

(Continued)

Physiotherapy, Occupational therapy

Physiotherapy. Occupational therapy

physiotherapy

Occupational therapy

Occupational therapy, physiotherapy Too young to assess

Occupational therapy, physiotherapy, Ponseti cast Occupational therapy

Additional therapies

2 B. Anglim et al.

S1-S4 T18 Not done

Not done Not done Not done

Not done Not done

11 n/a

n/a n/a n/a

n/a n/a

40w, SVD, NND TOP 38, SVD, NND TOP 35, SVD, IUD 38, SVD, NND TOP 39, SVD, IUD Anencephaly Anencephaly Anencephaly

Anencephaly Anencephaly

32 33 34

35 36

16  2 18  0

MMC Anencephaly 30 31

15  2 21  2 12  6

MMC

21  6 12  6

T18  10

There were a total of 9 (25%) terminations of pregnancy (one confirmed trisomy 18 and 2 cases of anencephaly). Of those that continued, 65% of babies (13/20 – excluding anencephaly) had ventriculomegaly, ranging from mild (n  2), moderate (n  3) to severe (n  8). The maximum lateral ventricle diameter was 55 mm. There were fourteen babies with Arnold–Chiari II malformation. 64% (n  14) of the ventriculomegaly patients had Arnold–Chiari malformation and 93% (n  13) of the cases with Arnold–Chiari malformation had ventriculomegaly. There were five (5/22) cases of talipes. Of those that continued, 81% (22/27) were liveborn, (five intrauterine deaths), with four neonatal deaths (one trisomy 18). Of the remaining 18, 78% (n  14) delivered at term. 53% (14/27) of those that continued were delivered by caesarean section. 55% (n  6) of caesarean sections were emergency cases. There was one case of breech presentation in labour, one mother who presented in labour with a history of two previous caesarean sections, one case of cord prolapse and three cases of non-reassuring cardiotocograph on a background of previous caesarean deliveries. There were no intraoperative complications with blood loss being average and no angle extensions or need for cephalocentesis at the time of delivery of the foetal head. 47% (13/27) were delivered by spontaneous/assisted vaginal delivery. The median birth weight was 3220 (1550–4850) g. The majority of lesions were in the lumbar and sacral regions. There were no undiagnosed associated abnormalities. In 8 of the fourteen cases which had a postnatal MRI, lesion level was correctly diagnosed. In the other 6 cases lesion level was correct to within 1–2 vertebrae. In two of these cases the lesion was larger/higher on MRI than determined on antenatal ultrasound. Nineteen cases had ventriculomegaly, ranging from mild (n  2), moderate (n  4) to severe (n  13). The maximum lateral ventricle diameter was 55 mm. The median change in lateral ventricle diameter from initial ultrasound diagnosis to delivery was 5 mm, ranging from 1 mm to 40 mm. A total of fourteen cases underwent repair, with the median time to repair of 3 days (1 day to 3 months). Of these, 57% (n  8) of cases also had a ventriculoperitoneal shunt inserted. The median interval to shunt insertion was 8 days, ranging from 4 days to 30 days. 43% (6/14) of those repaired had postoperative complications. Postoperative complications included wound infection, cerebrospinal fluid leak, meningitis and shunt infection, and shunt revision due to blockage. Postnatal function was difficult to assess, as many of our patients were less than 6 months of age at last assessment. Outcome information on surviving neonates was obtained from paediatric neurodevelopmental clinic records. However, the older survivors were managed with a multidisciplinary approach including physiotherapy, occupational therapy and clinical nurse specialists.

Discussion

29

33  1

Karyotype Defect type Case No.

Table I. (Continued)

GA at diagnosis

Max Vp (mm)

GA & Mode of delivery

Complications prior to transfer

Antenatal ultrasound defect level

Size of lesion postnatally

Time to repair


Ventriculo Peritoneal shunt

Surgical complications

Additional therapies

Natural history of neural tube defects 3

Our study shows that the majority (75%) of couples with a diagnosis of neural tube defect continued with their pregnancy. In those women who had a termination of pregnancy, there were 5 cases with lumbosacral lesions and 2 cases with sacral lesions. Of these, there were 4 cases with severe ventriculomegaly, 2 with moderate ventriculomegaly and 2 with no ventriculomegaly. Lesion level and size varied, with some confined to the sacrum or lumbar vertebrae, and others combining both. Two cases of anencephaly had a termination of pregnancy. Of the three cases diagnosed with aneuploidy, only one chose to interrupt their pregnancy. Previous articles have reviewed antenatal diagnosis of NTDs, repair techniques and prognosis (Coniglio et al. 2008;


4 B. Anglim et al. Cochrane et al. 1996; Adzick 2012; Arslan et al. 2011). There are limited articles which have connected antenatal ultrasound findings with outcome, postnatal surgical and MRI findings, and followed up the natural history of these children in order to establish the effectiveness of antenatal counselling. Our results show it is possible to determine the level of the last intact vertebral level by antenatal ultrasound, allowing foetuses to be broadly categorised into functional groups. On ultrasound reports, the last intact vertebrae were documented in 66%. This was confirmed in the perinatal period in all cases which went for repair. MRI was more accurate than motor level determined at birth, with all of our antenatal ultrasound estimations being correct to within 1–2 vertebrae when compared with MRI findings. Functional outcomes relating to degree of ambulation, urinary and bowel continence and school performance were discussed, however patterns are identifiable based on the level of neural involvement. One study showed that antenatal ultrasound diagnosis is more accurate than motor level determined at birth (Coniglio et al. 2008; Cochrane et al. 1996). An intact vertebral level of L4 and above has been broadly used to suggest a reduced incidence of wheelchair dependency, with previous studies showing full ambulatory function in cases confined to the sacral involvement only (Hoffer et al. 1973). The strength of our study is that it looks at the natural history of NTDs, from antenatal ultrasound diagnosis, postnatal MRI, to timing for repair and the multidisciplinary input needed in these children from an early age. The relatively small sample size and limited follow-up of 2 years in these children is a potential weakness. In our study 57% of cases underwent ventriculoperitoneal shunt insertion, with the median interval to shunt insertion being 8 days, none of which were done at the time of primary lesion repair. Of those who did not require shunt insertion, the majority of lesions were small, ranging in size from 1 to 3 vertebrae, with one case involving 5 vertebrae. These lesions were lower or smaller in size, than those which required shunt insertion. Most patients remain shunt dependent, requiring long-term management of shunt dysfunction, such as mechanical obstruction, excessive cerebrospinal fluid drainage and infection (Elgamal 2012). Tethering occurs as a result of adhesion formation between the spinal cord and surrounding tissues. This causes tension on the neural axis and worsening of neurological function (Adzick 2012). There is debate on the appropriate mode of delivery for children with MMC. In our study 13 (87%) delivered at term, with 53% of these being delivered by caesarean section and 47% by spontaneous/assisted vaginal delivered. Both groups showed no difference in perinatal or neurological outcome, allowing for lesion level and size. There were no cases requiring cephalocentesis. There was one case of breech presentation in labour, one mother who presented in labour with a history of two previous caesarean sections, one case of cord prolapse and three cases of non-re-assuring cardiotocograph on a background of previous caesarean deliveries. Previous studies have shown that there is no difference in outcome when delivery was by caesarean section compared with trial of labour (Lewis et al. 2004). A similar study looking at 208 children showed a comparable ambulatory function in those delivered by vaginal delivery and caesarean section (Cochrane et al. 1991). Closure is recommended in the first 48 h of life to reduce neurological morbidity and infection. The key to successful operative outcome is infection-free closure, with primary wound healing being shown to have significant impact on neurological outcome, by preserving functioning neural tissue (Ghozlan and Eisa 2007).

In our study we report that 14 children underwent repair, with 57% (8) of cases requiring ventriculoperitoneal shunt insertion. The median interval to shunt insertion was 8 days, ranging from 4 days to 30 days, with a 43% (6/14) rate of postoperative complications. Shunt placement may be required in approximately 81% of neonates (Rintoul et al. 2002). A study of 166 children showed that early (24–48 h) separate surgery (repair followed by shunt insertion) had a lower rate of shunt infection (3.44%) than either simultaneous repair and shunt insertion (12.3% in early surgery and 33.3% in late surgery) or late surgery (14.9%) (Arslan et al. 2011). Foetal surgical repair is a further option, which is becoming more common in the larger paediatric units. None of our cases had foetal surgery as an option for treatment. The Management of Myelomeningocele Study (MOMS) compared foetal surgery at 19–25 weeks’ gestation to postnatal repair. The ventriculoperitoneal shunt rate at one year of age was reduced (40% vs 82%). Ambulatory function was improved in the foetal repair group. The incidence of hindbrain herniation was reversed in the foetal surgery group. However, the rate of preterm spontaneous rupture of membranes was increased in the foetal repair group, at 46% versus 8%. There was also a higher rate of preterm delivery in the foetal repair group, 79% versus 15%, with 13% of the foetal surgery group born before 30 weeks’ gestation. There were no cases of hysterotomy rupture, however, notable thinning of the uterine wound was evident in one-quarter of cases. A follow-up of this patient population, MOMS 2, shall further evaluate the trial patients at 5–9 years of age (Adzick et al. 2011). Postnatal function in our group of children was difficult to assess, as many of our patients were less than 6 months of age, however the older survivors were managed with a multidisciplinary approach including physiotherapy, occupational therapy and clinical nurse specialists. One study examined the longterm outcome of 101 children born with MMC. The follow-up was a minimum of 8.6 years, with a mortality rate of 18%. It highlighted the high percentage of those with good ambulation (53%), urine (75%) and stool (86%) continence, with a total of 58% attending normal school (Steinbok et al. 1992). There have been many improvements since this study, and the possibility of a higher functioning, socially acceptable lifestyle is becoming more realistic with early, more advanced surgical techniques and foetal surgery. This research has outlined the natural history of NTDs. It is important to understand the reality of this condition, as it requires ongoing multidisciplinary input throughout children’s lives, and extending into adulthood. The involvement of multidisciplinary support has resulted in significant improvements in functional outcome for those affected with this condition. However, it must be understood that the life expectancy of a substantial number of these patients will be reduced and they will require care extending into adult life (Thompson 2009). Most deaths occur as a result of renal and cardiac failure and respiratory complications associated with MMC (McDonnell and McCann 2000). Kyphoscoliosis occurs in up to 90% of patients, and may be congenital or acquired (Nelson et al. 1988; Elgamal 2012). Neurogenic bowel and bladder have a long-term impact, requiring intermittent bladder catherisation or lower urinary tract reconstruction, and a bowel regimen to manage constipation (Clayton et al. 2011). Functional outcome can be determined antenatally with the use of foetal ultrasound. It is imperative to counsel the parents accordingly, with a combination of obstetricians, neonatologists, paediatric neurosurgeons and clinical nurse specialists, clearly outlining the possible challenges that they may face. It must be clearly outlined that long-term multidisciplinary input will be an

Natural history of neural tube defects 5 integral part of these children’s lives, and that life-long therapy is likely.

Acknowledgements This study describes original work and has not been submitted for consideration by any other journal. All authors have approved the manuscript and its submission. All authors have contributed substantially to obtaining and analysing data obtained for this study. All authors have had input both drafting and revision of the article and final approval of the version published.


Declaration of interest: There are no potential conflicts of interest for each author. The authors report no declarations of interest.

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