Fetal Macrocrania: Diagnosis, Delivery and Outcomes

MR Laye1, BC Moore2, MA Kosek3, LK Bufkin4, JC Morrison4 and JA Boﬁll4 1Regional Maternal-Fetal Medicine, Spartanburg Regional Medical Center, Spartanburg, SC, USA; 2Department of Obstetrics and Gynecology, The University of Tennessee College of Medicine Chattanooga, Chattanooga, TN, USA; 3Division of Neonatology, Department of Pediatrics, University of Mississippi Medical Center, Jackson, MS, USA and 4Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson, MS, USA

different entities. Making the distinction is important because use of Objective: To describe fetal macrocrania including prenatal diagnosis, the correct term may yield information about the underlying process delivery considerations and clinical outcomes. causing the clinical finding, and may confer information about Study Design: A retrospective case series was developed by reviewing prognosis and/or management. Macrocrania is defined as an 26 885 ultrasounds performed between 1 March 2003 and 30 June 2007 abnormal increase in the size of the skull, with the facial area being for the prenatal diagnosis of macrocrania. Medical records of each disproportionately small in comparison. In contrast, macrocephaly mother/infant pair were reviewed for demographic information, is excessive size of the whole head, whereas megalencephaly ultrasound findings, obstetric management and outcomes. represents overgrowth of the brain.1 Result: Twenty-three fetuses were diagnosed with macrocrania. Median Macrocrania is a term rarely encountered in obstetrics or gestational age at diagnosis was 31.1 weeks (range 18.3–38.1) and at prenatal diagnosis but is a very common diagnosis in pediatrics 2 delivery was 36.9 weeks (range 30.7–39.9). Fifteen patients (65%) and in radiology, affecting up to 5% of pediatric patients. underwent amniocentesis for karyotype; none were aneuploid but one had Unfortunately, diagnostic criteria are inconsistent. A review of the a duplication on chromosome 7. All the 23 infants were liveborn. Twenty- literature on the topic shows criteria that are both objective and one deliveries were by Cesarean (91%), with thirteen of these by classical subjective. Objective measures are inconsistent from study to study incision (62%). Of the infants, 5 (22%) died shortly after birth, 16 (70%) and include children with a head circumference >95th–98th were stabilized in the neonatal intensive care unit and were discharged percentile for age, disproportionate head size compared with body alive and 2 (8%) were transferred to another center and subsequently length and weight, and rapidly enlarging head circumference on 3,4 died. Eighteen babies required ventriculoperitoneal shunting (78%). serial measurements. The descriptors ‘disproportionate’ and Conclusion: Macrocrania is a diagnosis usually made in children but ‘rapidly enlarging’ are not well defined. A large-appearing head by 4 can also be made prenatally. Fetal macrocrania is usually a result of observation is an example of a subjective measure. ventriculomegaly due to an obstructive process to cerebrospinal fluid flow. In the pediatric population, macrocrania is most commonly due 3 Abdominal delivery is usually required, often necessitating a classical to abnormal fluid collections in the head. These most commonly uterine incision. Targeted ultrasonography, extensive counseling of include abnormalities in the ventricular system of the central parents and delivery at a tertiary care center with availability of nervous system (ventriculomegaly) or external hydrocephalus neurosurgery is recommended. (abnormal fluid collection in the subarachnoid space with normal 2 Journal of Perinatology (2009) 29, 201–204; doi:10.1038/jp.2008.196; cerebral ventricles). When ventriculomegaly is noted, this is most published online 4 December 2008 often due to obstruction in the flow of cerebrospinal fluid, such as is seen with stenosis or atresia of the aqueduct of Sylvius.4 Other Keywords: prenatal diagnosis; ultrasound; anomaly; ventriculomegaly differential diagnostic considerations when macrocrania is encountered include space occupying lesions such as tumors, 2,5 Introduction hemorrhages, large arachnoid cysts and myelomeningoceles. It has long been advocated that children considered to have Terms used to describe a large head are often used interchangeably. macrocrania be evaluated with imaging studies to determine the However, this is incorrect because the different terms represent need for surgical versus nonsurgical management.2,6 Which Correspondence: Dr MR Laye, Regional Maternal-Fetal Medicine, 853 North Church Street, modality to use is the subject of some debate. The classic way to Suite 610, Spartanburg, SC 29303, USA. evaluate children with macrocrania was to use ventriculography E-mail: [email protected] Received 1 June 2008; revised 21 October 2008; accepted 24 October 2008; published online and cerebral angiography. Due to the desire to avoid these invasive 4 December 2008 tests in children, these were limited to only the most severe cases. Fetal macrocrania MR Laye et al 202

The introduction of computed tomography (CT) permitted outpacing the other biometric parameters by greater than or noninvasive evaluation of these cases, allowing those with lesser equal to 4 weeks size. degrees of head enlargement to be included.3 Cranial ultrasound (2) Fetal head size greater than would likely be successfully has since been shown to correlate well with CT, with no significant delivered vaginally as evidenced by a biparietal diameter of abnormality missed using this modality. This, coupled with the greater than or equal to 11 cm (given that a completely dilated desire to avoid ionizing radiation in children, led to cranial cervix is usually 10 cm). ultrasonography being advocated as a first line method of imaging the head in pediatrics.4 CT or magnetic resonance imaging is now used in cases that are unclear, finer discrimination is needed, or Results for imaging the external subarachnoid spaces.6 A total of 26 885 ultrasound studies were reviewed and 23 fetuses Given the frequency of ultrasonography during pregnancy and diagnosed with macrocrania were identified. None were lost to that evaluation of the head and intracranial contents is a part of each follow-up and all deliveries were at our institution. The targeted sonogram, many of the same diagnoses made in children demographics of this cohort are summarized in Table 1. Fifteen with macrocrania should be made in the fetus. The paucity of patients (65%) underwent genetic amniocentesis; none were information in the obstetric literature regarding the prenatal diagnosis aneuploid but one had a duplication on chromosome 7. All the 23 of macrocrania, the associated obstetric management and outcomes is fetuses were liveborn. Continuous variables regarding infant birth striking. Accordingly, we created this retrospective case series at our data are summarized in Table 2. Fifteen infants (65%) were male. tertiary referral center so that we could better counsel patients and referring physicians when a fetus with an abnormally large head is Table 1 Demographic variables of patients diagnosed with macrocrania encountered on ultrasound. Our main interests included Demographic variable Median result (range) demographics of patients whose fetuses were diagnosed with macrocrania, obstetric management and delivery considerations in Maternal age 23 years (15–36) these pregnancies and outcomes including duration of stay in the Gravidity 2 (1–7) neonatal intensive care unit (NICU), need for surgery shortly after Parity 1 (0–4) Gestational age at diagnosis 31.1 weeks (18.3–38.1) delivery and ultimate survival. Gestational age at delivery 36.9 weeks (30.7–39.9)

Methods Table 2 Infant birth data of patients diagnosed with macrocrania The Institutional Review Board of the University of Mississippi Medical Center (UMC), the primary perinatal referral center for the Variable Median result (range) state of Mississippi, approved this retrospective review of deidentiﬁed Birth weight 3308 g (2230–4305) data (IRB File no. 2007–0016). Sonographers, maternal–fetal APGAR at 5 min 9 (2–9) medicine fellows and attending physicians performed all Head circumference 42.5 cm (35.5–59) ultrasounds in the Antenatal Diagnostic Unit at UMC. Ultrasound studies performed during a 52-month period from March 2003 to June 2007 were reviewed and those cases in which the prenatal Table 3 Underlying causes of macrocrania by diagnosis diagnosis of macrocrania was suspected were identiﬁed. This was Diagnosis Number of infants followed by a review of both maternal and neonatal medical (% of all infants) records. Demographic variables, fetal information including diagnoses, obstetric management including amniocentesis and Stenosis/atresia of the aqueduct of Sylvius 10 (43.5) results, timing and mode of delivery and neonatal data including Meningomyelocele 3 (13.0) survival were recorded for each mother/infant pair. VATER anomalad 3 (13.0) Diagnostic criteria were based on those used for children after Communicating hydrocephalus 1 (4.3) birth. However, choosing a particular percentile above which we Hydranencephaly 1 (4.3) Dandy–Walker defect 1 (4.3) could make the diagnosis would have been arbitrary given the Goldenhar syndrome 1 (4.3) discrepancies by different authors in the pediatric literature as Pseudoporencephaly 1 (4.3) described above. Therefore, we considered a fetus to have Intracranial hemorrhage 1 (4.3) macrocrania if either or both of the following were met: Agenesis of corpus callosum and interhemispheric cyst 1 (4.3) (1) A rapidly enlarging head as evidenced by the head Total 23 (B100) measurements (head circumference and biparietal diameter)

Journal of Perinatology Fetal macrocrania MR Laye et al 203

Twenty-one deliveries were by Cesarean (91%), with thirteen of confirmed after delivery by appropriate imaging, consultation and these by classical uterine incision (62%). Of the infants, 5 (22%) autopsy where appropriate. A patient-by-patient summary of died shortly after birth, 16 (70%) were stabilized in the NICU with ultrasound findings, diagnoses (before and after delivery), subsequent discharge and 2 (8%) were transferred to another outcomes and length of NICU stay can be seen in Table 4. center and subsequently died. Median length of stay in the NICU was 21 days (range 3–101). Eighteen babies (78%) required ventriculoperitoneal shunting; the median day of life for this Discussion procedure was day 2 (range 1–20). This case series documents our experience with fetal The underlying causes of the macrocrania encountered on macrocrania, and to our knowledge is the first to specifically prenatal sonography are listed in Table 3. All diagnoses were describe the diagnosis prenatally. Therefore, our data may be

Table 4 Summary of ultrasound ﬁndings, diagnoses, outcomes, and NICU length of stay (LOS) for each patient. The diagnoses in parentheses were made after delivery and were not documented antepartum

Pt no. Ultrasound ﬁndings Diagnoses Outcome NICU LOS (days)

1 Midline falx, no neural tissue above brainstem Hydranencephaly Died 4 2 Dilation of lateral and third ventricles Aqueductal stenosis Survived 21 3 Dilation of lateral and third ventricles Aqueductal stenosis Survived 7 4 Dilation of lateral and third ventricles Aqueductal stenosis (VATER anomalad: Transferred, Died 15 imperforate anus, tracheal stenosis, single kidney, hemivertebrae) 5 Dilation of lateral and third ventricles, posterior fossa cyst, Dandy–Walker malformation, (ear tags, Survived 50 single umbilical artery perimembranous VSD) 6 Dilated lateral and third ventricles, polyhydramnios Aqueductal stenosis, (periauricular skin tags, Survived 20 truncus arteriosus) 7 Dilated lateral and third ventricles Aqueductal stenosis (Goldenhar syndrome: Survived 45 left anotia, right microtia, hypertelorism, cleft palate) 8 Absence of CSP, intrahemishperic cyst, hypertelorism, absent clavicles Agenesis of the corpus callosum, Survived 4 intrahemispheric cyst, (pachygyria) 9 Unilateral absence of brain parenchyma extending to skull table Pseudoporencephaly Survived 22 10 Dilation of lateral and third ventricles Aqueductal stenosis Survived 13 11 Dilated lateral and third ventricles, cleft lip and palate, single umbilical artery, VATER anomalad (imperforate anus, Died 27 hemivertebrae, clenched right hand ambiguous genitalia) 12 Dilated lateral and third ventricles, thoracolumbar ONTD Meningomyelocele Survived 34 13 Dilated lateral and third ventricles Aqueductal stenosis Survived 44 14 Disorganized intracranial tissue, visible clot and fibrin stranding in skull Intracranial hemorrhage Died 4 15 Dilated lateral and third ventricles Aquedutal stenosis Survived 13 16 Dilated lateral and third ventricles, dilated loops of small bowel, ventricular Aqueductal stenosis, jejunal atresia, Died 23 septal defect, polyhydramios (interrupted aortic arch) 17 Dilated lateral and third ventricles, lumbosacral ONTD, talipes Meningomyelocele Survived 31 equinovarus deformity 18 Dilation of lateral and third ventricles, polyhydramnios Aqueductal stenosis Survived 50 19 Dilation of lateral and third ventricles, hypoplastic cerebellum Aqueductal stenosis Survived 21 20 Dilation of lateral and third ventricles, lumbosacral ONTD Meningomyelocele Survived 19 21 Dilated lateral and third ventricles, esophageal atresia, hemivertebrae, VATER anomalad, Died 101 bifid great toe, pulmonary hypoplasia, preaxial polydactyly, (tracheoesophageal fisulta) malformed tibia and fibula on right, ventriculoseptal defect, short ribs 22 Dilated lateral and third ventricles Aqueductal stenosis Survived 22 23 Tetraventricular dilation, polyhydramnios, micrognathia, atriventricular Communicating hydrocephalus, Transferred, died 3 septal defect, hypoplastic left ventricle AV canal defect, (coarctation of aorta, interrupted IVC)

Abbreviations: AV, atrioventricular; IVC, inferior vena cava; NICU, neonatal intensive care unit;ONTD, open neural tube defect; VSD, ventricular septal defect.

Journal of Perinatology Fetal macrocrania MR Laye et al 204 useful in counseling patients and detailing physicians on what to with the VATER anomalad and the infant with hydranencephaly expect once the diagnosis is made. However, our data must be died shortly after birth but all cases with isolated aqueductal viewed in light of what has been reported in infants after birth. stenosis survived. Long-term outcomes for survivors will also Our median gestational age at diagnosis (31.1 weeks) is vary based upon the underlying diagnoses and are a potential somewhat later than expected. However, in our study the most further course of investigation. The pediatric literature reflects that frequent cause of macrocrania was stenosis/atresia of the aqueduct infants do well if the macrocrania is due to external hydrocephalus of Sylvius. This leads to progressive ventriculomegaly and although or mild ventriculomegaly.2,4,6,7 However, when moderate to the diagnosis of ventriculomegaly can be made earlier in gestation, severe ventriculomegaly is noted, especially when associated with the diagnosis of macrocrania is only possible after weeks or months cerebral atrophy, outcomes are poor. Bosnjak et al. reported when the ventriculomegaly has become severe enough to cause only 2 of 20 patients with cerebral atrophy were neurologically marked expansion of the fetal head. normal at presentation and in most cases the initial abnormal The median gestational age at delivery (36.9 weeks) is more a finding persisted at follow-up.6 Babcock et al. reported that reflection of the management of these patients than the natural 19% of term infants and 25% of preterm infants with history of infants with macrocrania. Management of prenatal macrocrania were neurologically or developmentally abnormal patients with suspected fetal macrocrania at the University of on follow-up that ranged from 1 month to 5 years.4 The diagnosis Mississippi includes observation with monthly scans to follow the of macrocrania has also been linked to epilepsy and autistic size of the head and amniocentesis at 37 weeks followed by delivery disorders.8 if lung maturity is documented. This strategy allows for patients In summary, the diagnosis of macrocrania is possible from our fairly rural state to deliver at a tertiary institution. Indeed, prenatally. Fetal macrocrania is usually a result of 70% of infants (16/23) in this series underwent amniocentesis for ventriculomegaly due to an obstructive process to cerebrospinal fetal lung maturity, whereas the other 30% had preterm labor or an fluid flow. Suspicion for macrocrania necessitates a targeted indicated preterm delivery before undergoing the amniocentesis as sonographic evaluation by personnel experienced in prenatal planned. diagnosis to evaluate for the underlying pathology leading to the The underlying diagnoses leading to fetal macrocrania in this macrocrania. This allows extensive counseling of parents, series were similar to that recorded in pediatric populations. Donat arrangements for delivery at a tertiary care center with availability reported in 1981 that hydrocephalus from ventriculomegaly is the of neurosurgery, and evaluation for mode of delivery. Abdominal leading cause of macrocrania in children,3 and the current case delivery is usually required, often necessitating a classical uterine series echoes this finding. Babcock et al. reported in 1988 that in incision. infants with macrocrania, 5 of 11 (45.5%) infants with significantly abnormal findings on cranial sonography had aqueductal stenosis.4 This is very similar to the 43.5% incidence of Acknowledgments aqueductal stenosis reported in this series. No financial support was obtained for this study. We noted a majority of male fetuses diagnosed with macrocrania. Our 65% male predominance is very close that previously reported in children. Medina reported 59 of 88 (67%) References children diagnosed with macrocrania were male,2 whereas Donat reported 53 of 72 (73.6%) children were male.3 This might be 1 Dorland, WA, Newman. Dorland’s Illustrated Medical Dictionary, 29th edn, WB Saunders Company: Philadelphia, PA, 2000, pp 1043–1044, 1073. explained by the high number of diagnoses of aqueductal stenosis, 2 Medina LS, Frawley K, Zurakowski D, Buttros D, DeGrauw AJ, Crone KR. Children with which is known to have an X-linked form. macrocrania: clinical and imaging predictors of disorders requiring surgery. AJNR Am J Ventriculoperitoneal shunting was required in this series in 78% Neuroradiol 2001; 22(3): 564–570. of infants. However, this is much higher than expected, based on 3 Donat JF. Evaluation of macrocrania using computed tomography. Am J Dis Child 1981; pediatric literature. Medina et al. reported in 2001 that only 18% of 135(12): 1118–1121. children with macrocrania required surgical treatment.2 This 4 Babcock DS, Han BK, Dine MS. Sonographic findings in infants with macrocrania. AJR Am J Roentgenol 1988; 150(6): 1359–1365. marked difference is likely due to worse ventriculomegaly in those 5 Park SW, Cho KH, Shin YS, Kim SH, Ahn YH, Cho KG et al. Helmetlike skull deformity infants diagnosed prenatally. Further, some of the infants shunted with a large arachnoid cyst. Surg Neurol 2006; 65(1): 95–98. in this series did not survive and therefore may not have been 6 Bosnjak V, Besenski N, Marusic´-Della Marina B, Kogler A. Cranial ultrasonography included in pediatric investigations. in the evaluation of macrocrania in infancy. Dev Med Child Neurol 1989; 31(1): There were no intrauterine fetal demises. However, our overall 66–75. 7 Parmeggiani A, Posar A, Giovanardi-Rossi P, Andermann F, Zifkin B. Autism, survival rate with prenatally diagnosed macrocrania was only 70%. macrocrania and epilepsy: how are they linked? Brain Dev 2002; 24(5): 296–299. This reflects the diagnoses made underlying the macrocrania and 8 Hamza M, Bodensteiner JB, Noorani PA, Barnes PD. Benign extracerebral fluid will vary from case to case. For example, all three of the infants collections: a cause of macrocrania in infancy. Pediatr Neurol 1987; 3(4): 218–221.

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