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BMJ 2018;361:k2232 doi: 10.1136/bmj.k2232 (Published 4 June 2018) Page 1 of 5

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CLINICAL UPDATES Fetal microcephaly

Aamod Nawathe subspecialty trainee in fetal maternal medicine 1, Jane Doherty general practitioner 2, Pranav Pandya consultant and lead in fetal medicine 1

1Fetal Maternal Medicine, University College London Medical School, London WC1E 6BT, UK; 2Nexus Health Group, London SE1 6JP

has been defined as circumference smaller than 3 standard What you need to know deviations below the mean.7 8 • Fetal microcephaly can be isolated or be associated with other Making a prenatal diagnosis of microcephaly can be challenging congenital anomalies for several reasons, including uncertain gestational age, lack of • Causes include genetic, chromosomal, infections, exposure to toxins customised charts to account for factors such as ethnicity, and, (such as alcohol), metabolic, intrauterine growth restriction, or a normal 9 variant of course, the absence of a routine third trimester scan.

• The consequences of microcephaly can include neurodevelopmental Prospective observational studies have shown that ultrasound http://www.bmj.com/ delay, cerebral palsy, epilepsy, and problems with eyesight and hearing measurements themselves are subject to intra-observer and • There is no treatment that can reverse the effects of microcephaly in inter-observer variations,10 11 so the diagnosis may not be made utero until after birth. • Advise women diagnosed with primary or infection to wait for at least six months before conception What are the causes of fetal Fetal microcephaly, a small head circumference in utero or at microcephaly? on 29 September 2021 by guest. Protected copyright. birth is a rare but important clinical finding that may occur as Microcephaly may be identified as part of a range of part of a range of conditions or, rarely, as a normal variant. The heterogenous conditions including genetic or chromosomal prevalence of prenatal microcephaly in Europe is 1.53 per 10 disorders, infection, exposure to toxins such as alcohol, 000,1 2.3 per 10 000 in India,2 and about 6 per 10 000 in the 3 metabolic errors, intrauterine growth restriction, or, rarely, a US. Identifying microcephaly is important because the smaller normal variant (see box 1). Fetal microcephaly can be an isolated the fetal head circumference the greater the risk of 4 finding or may be associated with other anomalies. The developmental and intellectual delay. underlying aetiology can be confirmed in just over half of cases, Although there is no treatment available, early diagnosis allows and this figure may increase with advances in genetic testing for timely investigations, as well as allowing parents to receive such as exome sequencing.13 appropriate counselling about long term prognosis. This update discusses the diagnosis and management of fetal microcephaly, and is aimed at obstetricians, midwives, and general practitioners.

Sources and selection criteria

We searched PubMed and the Cochrane Library using the MESH term “microcephaly” and subheadings such as , preconception counselling, prenatal diagnosis, toxoplasmosis, and cytomegalovirus. Our search included randomised controlled trials, systematic and observational reviews and relevant case reports from 1965 to 2017. We excluded non-English articles without reliable translation or other internet sources of uncertain accuracy.

What is fetal microcephaly? Microcephaly is a head circumference significantly smaller than the average for the gestational age (fig 1).6 Fetal microcephaly

Correspondence to: P Pandya [email protected]

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Box 1: Causes of microcephaly (adapted from Pilu et al12) or cytomegalovirus. If clinical infection with Zika virus is suspected then Zika serology testing is offered four weeks after Microcephaly with associated malformations return from an area where is endemic. Screening for BMJ: first published as 10.1136/bmj.k2232 on 4 June 2018. Downloaded from • Chromosomal or genetic maternal infections such as toxoplasmosis or cytomegalovirus – Chromosomal—Trisomy 13, trisomy 18, trisomy 21 by testing for antibodies such as IgG, IgM and the IgG avidity – Single gene defects—Meckel-Gruber , Smith-Lemli-Opitz (which measures the strength of binding of IgG to the virus syndrome, , Nijmegen breakage syndrome, De Lange syndrome antigen) can help in differentiating a recent from an old 25 26 • Environmental infection. – Intrauterine growth restriction Amniocentesis—The woman is usually also offered an – Prenatal infections—Toxoplasmosis, cytomegalovirus, Zika virus, HIV amniocentesis to make a diagnosis of a chromosomal – Prenatal exposure to drugs—Fetal alcohol syndrome, fetal hydantoin abnormality (such as Down’s syndrome), a specific genetic syndrome syndrome (as recommended by a clinical geneticist), and for – Inborn errors of metabolism—Maternal syndrome direct analysis of infectious pathogens if there is a suspicion on • Unknown aetiology maternal serology (such as cytomegalovirus or 25 27 28 Microcephaly without associated malformations Toxoplasma). Further tests to investigate inborn errors of metabolism are needed if an underlying genetic abnormality is • Genetic—Autosomal recessive primary microcephaly, Paine syndrome, 13 Alpers disease suspected as suggested by a retrospective study. • Environmental—Maternal , hypoxia If the microcephaly is “isolated” (no other anomalies seen with • Unknown aetiology no evidence of infection) then offer serial ultrasound scans every four weeks to monitor changes in fetal biometry and intracranial structures. Fetal magnetic resonance imaging (MRI) on the is an adjunct to ultrasound and can provide further information What are the consequences of fetal about brain development.29 microcephaly? Up to 55% of comprises of , and How is fetal microcephaly managed? most neurones are generated by 21 weeks of gestation.14 Fetal During pregnancy microcephaly is therefore likely to be associated with a relatively If drug or alcohol misuse is suspected, involve the safeguarding smaller cerebral cortex with fewer neurones, thus making head team and offer support to reduce or stop alcohol or drug use. circumference a proxy marker of neural growth.14-18 The consequences of microcephaly, as shown by longitudinal Refer women with fetal microcephaly to a tertiary fetal medicine http://www.bmj.com/ observational studies, include neurodevelopmental delay or centre with a multidisciplinary team that includes a fetal impairment in other areas of development such as gross motor, medicine expert, virologist, neonatologist, neuroradiologist, and visual-motor, language, and epilepsy.15 19 Therefore, with a geneticist to counsel depending on the suspected underlying microcephaly are at risk of long term morbidity such as epilepsy aetiology. and developmental delay.20 Furthermore observational studies Microcephaly, either isolated or with other anomalies, is have shown a correlation between the severity of microcephaly associated with significantly increased risk of neurodisability, 4 21

and severity of mental retardation. and, after appropriate counselling by the multidisciplinary team, on 29 September 2021 by guest. Protected copyright. termination of pregnancy may be discussed as an option with How is it diagnosed? the parents. If the parents continue the pregnancy, offer appropriate guidance from the multidisciplinary team, which Figure 2 outlines how specialists might approach investigation may include contacting a specific charity or support group (see and management of fetal microcephaly in a tertiary centre. “Information for patients” box).

History Options for delivery During routine antenatal care note whether the woman has a Discussing options for delivery with parents needs to be tailored history that might increase the risk of fetal microcephaly, such to the underlying cause. Vaginal delivery is usually as drug use, alcohol consumption, known chromosomal or recommended unless there are obstetric contraindications such genetic syndrome, or travel to areas with high prevalence of as placenta praevia.30 Zika virus (such as Brazil) while pregnant or within eight weeks before conception. Most cases of fetal microcephaly are detected What is the prognosis and postnatal by routine ultrasound examination at 18-20 weeks or on a subsequent scan.23 In these circumstances refer women to a fetal follow-up? medicine unit to take a detailed history and for further ultrasound The prognosis for a fetus with microcephaly could range from assessment and appropriate investigations. normal development to a wide range of neurodisability depending on factors such as severity of the microcephaly, and Further investigations the underlying cause (box 1). Ultrasound—A detailed ultrasound scan is the first line A retrospective study found a lack of data on how to counsel investigation to confirm the diagnosis and identify other fetal parents when isolated microcephaly is detected incidentally in 24 anomalies such as ventriculomegaly. Specific ultrasound the third trimester with no other abnormalities.31 Although fetal markers of congenital infection include ventriculomegaly, MRI is offered in the presence of other malformations,29 32 echodense areas suggestive of calcifications, and growth sometimes even a combination of MRI and an ultrasound scan restriction. is not helpful in counselling parents about the prognosis.33 In a Blood tests—When a congenital anomaly is suspected, maternal large retrospective study evaluating 680 cases of postnatal blood is then taken to screen for infections such as toxoplasmosis microcephaly, 29% of cases had an underlying genetic cause.13

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Although the outcomes for patients with non-isolated How patients were involved in the creation of this article microcephaly varied widely, neurodevelopmental delay,

Patient involvement was not possible as we were unable to find a patient who BMJ: first published as 10.1136/bmj.k2232 on 4 June 2018. Downloaded from , and refractory epilepsy were the most was willing to share their experiences due to the sensitive nature of the topic common reasons for referral to specialist paediatric services for further assessment.13 A few studies have tried to investigate the correlation between neurodevelopmental delay and isolated microcephaly but with conflicting results. One study showed Contributors: AN did the literature search and wrote the paper. PP verified and the risk of neurodevelopmental delay to be 10.5% when head revised the paper. He is the guarantor. JD added inputs from a primary care level. circumference is between two and three standard deviations Competing interests: We have read and understood BMJ policy on declaration of below the mean,4 while others showed no significant interests and have no competing interests to declare. 34 35 difference. Provenance and peer review: Commissioned; externally peer reviewed. Although fetal brain growth cannot be altered, some interventions carried out postnatally may help prevent the 1 Morris JK, Rankin J, Garne E, etal . Prevalence of microcephaly in Europe: population based study. BMJ 2016;354:i4721. 10.1136/bmj.i4721 27623840 progression of microcephaly in certain conditions. For example, 2 Bhide P, Kar A. Birth prevalence of microcephaly in India. Bull World Health Organ 2016. dietary interventions in infants diagnosed with phenylketonuria36 3 Reefhuis J, Gilboa SM, Anderka M, etal. National Birth Defects Prevention Study. The National Birth Defects Prevention Study: A review of the methods. Birth Defects Res A or enhancing postnatal nutrition if microcephaly is due to Clin Mol Teratol 2015;103:656-69. 10.1002/bdra.23384 26033852 inadequate maternal nutrition37 can enhance head circumference, 4 Dolk H. The predictive value of microcephaly during the first year of life for mental retardation at seven years. Dev Med Child Neurol 1991;33:974-83. as shown in a retrospective study of 193 growth restricted 10.1111/j.1469-8749.1991.tb14813.x 1743426 children. A review of the literature has shown that infants with 5 Centers for Disease Control and Prevention, National Center on Birth Defects and Developmental Disabilities. Facts about microcephaly. 2016. www.cdc.gov/ncbddd/ microcephaly due to congenital cytomegalovirus infection or birthdefects/microcephaly.html. such as de Lange syndrome may benefit from early 6 Leibovitz Z, Daniel-Spiegel E, Malinger G, etal . Prediction of microcephaly at birth using interventional programmes and occupational therapy.38 39 three reference ranges for fetal head circumference: can we improve prenatal diagnosis?Ultrasound Obstet Gynecol 2016;47:586-92. 10.1002/uog.15801 26511765 7 Gelber SE, Grünebaum A, Chervenak FA. Prenatal screening for microcephaly: an update after three decades. J Perinat Med 2017;45:167-70. 10.1515/jpm-2016-0220 27662643 What is the risk of microcephaly in a 8 Chervenak FA, Jeanty P, Cantraine F, etal . The diagnosis of fetal microcephaly. Am J Obstet Gynecol 1984;149:512-7. 10.1016/0002-9378(84)90027-9 6742021 subsequent pregnancy? 9 Drooger JC, Troe JWM, Borsboom GJJM, etal . Ethnic differences in prenatal growth and the association with maternal and fetal characteristics. Ultrasound Obstet Gynecol The risk in a subsequent pregnancy depends on the underlying 2005;26:115-22. 10.1002/uog.196210.1002/uog.1962 16038011 cause, and counselling needs to be individualised accordingly. 10 Sarris I, Ioannou C, Chamberlain P, etal. International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH‐21st). Intra- and interobserver variability If the underlying cause is autosomal dominant then the risk of in fetal ultrasound measurements. Ultrasound Obstet Gynecol 2012;39:266-73. recurrence is 1:2 (50%) if one of the parents is affected and 1:4 10.1002/uog.10082 22535628

11 Melamed N, Yogev Y, Danon D, Mashiach R, Meizner I, Ben-Haroush A. Sonographic http://www.bmj.com/ (25%) if the pattern is autosomal recessive. The risk of estimation of fetal head circumference: how accurate are we?Ultrasound Obstet Gynecol microcephaly due to past infection is minimal. 2011;37:65-71. 10.1002/uog.7760 20661958 12 Pilu G, Malinger G. VISUOG – Microcephaly. http://www.visuog.com/Page/view.jsp? id=6499122244886988132 Postnatal counselling 13 von der Hagen M, Pivarcsi M, Liebe J, etal . Diagnostic approach to microcephaly in childhood: a two-center study and review of the literature. Dev Med Child Neurol When counselling women postnatally, take into account the 2014;56:732-41. 10.1111/dmcn.12425 24617602 gestational age at onset of microcephaly, any antenatal insult 14 Woods CG. Human microcephaly. Curr Opin Neurobiol 2004;14:112-7. 10.1016/j.conb.2004.01.003 15018946 such as intracranial haemorrhage, any syndromic features, and 15 Woods CG, Parker A. Investigating microcephaly. Arch Dis Child 2013;98:707-13. any family history of microcephaly.40 Depending on the 10.1136/archdischild-2012-302882 23814088 on 29 September 2021 by guest. Protected copyright. 16 Harris SR. Measuring head circumference: Update on microcephaly. Can Fam circumstances, you may need to involve a clinical geneticist, Physician 2015;61:680-4.26505062 virologist, or specialist in paediatric infectious diseases. 17 Ivanovic DM, Leiva BP, Pérez HT, etal . Head size and intelligence, learning, nutritional status and brain development. Head, IQ, learning, nutrition and brain. Neuropsychologia Although there are no robust data, it is advisable to wait for six 2004;42:1118-31. 10.1016/j.neuropsychologia.2003.11.022 15093150 months before conceiving if primary congenital infection with 18 O’Connell EJ, Feldt RH, Stickler GB. Head circumference, mental retardation, and growth 25 41 failure. Pediatrics 1965;36:62-6.14313368 Toxoplasma or cytomegalovirus is confirmed. 19 Gordon-Lipkin E, Gentner M, Leppert M. Neurodevelopmental outcomes in infants with microcephaly. 2016 Child Society Annual Meeting. October 26-29, 2016; Information for patients Vancouver, BC. Abstract 188. 20 Gordon-Lipkin E, Gentner MB, German R, Leppert ML. Neurodevelopmental outcomes • Microcephaly support group (https://contact.org.uk/medical-information/ in 22 children with microcephaly of different etiologies. J Child Neurol 2017;32:804-9. conditions/m/microcephaly/)—Provides information and advice about 10.1177/0883073817707301 28482742 microcephaly 21 Pryor HB, Thelander H. Abnormally small head size and intellect in children. J Pediatr 1968;73:593-8. 10.1016/S0022-3476(68)80275-6 5678001 • The Brain Charity. Microcephaly (www.thebraincharity.org.uk/how-we- 22 Pedicelli S, Peschiaroli E, Violi E, Cianfarani S. Controversies in the definition and can-help/practical-help/information-advice/a-z-of-conditions/44-m/341- treatment of idiopathic short stature (ISS). J Clin Res Pediatr Endocrinol 2009;1:105-15. microcephaly)—National support for neurological conditions 10.4008/jcrpe.v1i3.53 21274395 • Contact a Family. Microcephaly (www.cafamily.org.uk/medical- 23 Bromley B, Benacerraf BR. Difficulties in the prenatal diagnosis of microcephaly. J information/conditions/m/microcephaly)—Patients can contact other Ultrasound Med 1995;14:303-6. 10.7863/jum.1995.14.4.303 7602690 families with a child with microcephaly and can also get online support 24 FASP. https://www.gov.uk/government/publications/fetal-anomaly-screening-programme- and advice standards. Public Health England. 2015. 25 Paquet C, Yudin MHSociety of Obstetricians and Gynaecologists of Canada. Toxoplasmosis in pregnancy: prevention, screening, and treatment. J Obstet Gynaecol Can 2013;35:78-81. 10.1016/S1701-2163(15)31053-7 23343802 26 Bonalumi S, Trapanese A, Santamaria A, D’Emidio L, Mobili L. Cytomegalovirus infection Education into practice in pregnancy: review of the literature. J Prenat Med 2011;5:1-8.22439067 27 Perche O, Menuet A, Marcos M, etal . Combined deletion of two Condensin II system • To what extent does this article increase your confidence in assessing genes (NCAPG2 and MCPH1) in a case of severe microcephaly and mental deficiency. risk factors for fetal microcephaly when seeing a pregnant woman at Eur J Med Genet 2013;56:635-41. 10.1016/j.ejmg.2013.07.007 24013099 her booking visit? 28 Pfau RB, Thrush DL, Hamelberg E, etal . MCPH1 deletion in a newborn with severe • How might you offer counselling to a woman who had a diagnosis of microcephaly and premature chromosome condensation. Eur J Med Genet 2013;56:609-13. fetal microcephaly in a previous pregnancy? What might you do 10.1016/j.ejmg.2013.09.007 24080358 differently as a result of reading this article? 29 Griffi PD, Bradburn M, Campbell MJ, etal . Use of MRI in the diagnosis of fetal brain abnormalities in utero (MERIDIAN): a multicentre, prospective cohort study. Lancet • Do you follow up babies diagnosed with fetal microcephaly antenatally 2017;389:538-46. 10.1016/S0140-6736(16)31723-8 27988140 to confirm the prenatal diagnosis and monitor the neonatal outome? 30 Royal College of Obstetricians and Gynaecologists (RCOG). Placenta praevia, placenta accreta and vasa praevia: diagnosis and management - Green-top Guideline No.27. Royal College of Obstetricians and Gynaecologists, 2011.

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31 Malinger G, Lerman-Sagie T, Watemberg N, Rotmensch S, Lev D, Glezerman M. A normal 37 Miller LC, Chan W, Litvinova A, Rubin A, Tirella L, Cermak S. Medical diagnoses and second-trimester ultrasound does not exclude intracranial structural pathology. Ultrasound growth of children residing in Russian orphanages. Acta Paediatr 2007;96:1765-9. Obstet Gynecol 2002;20:51-6. 10.1046/j.1469-0705.2002.00743.x 12100418 10.1111/j.1651-2227.2007.00537.x 17971188

32 Benacerraf BR, Shipp TD, Bromley B, Levine D. What does magnetic resonance imaging 38 Bale JFJr. Congenital cytomegalovirus infection. Handb Clin Neurol 2014;123:319-26. BMJ: first published as 10.1136/bmj.k2232 on 4 June 2018. Downloaded from add to the prenatal sonographic diagnosis of ventriculomegaly?J Ultrasound Med 10.1016/B978-0-444-53488-0.00015-8 25015493 2007;26:1513-22. 10.7863/jum.2007.26.11.1513 17957045 39 Mikołajewska E. Interdisciplinary therapy in Cornelia de Lange syndrome - review of the 33 Malinger G, Ben-Sira L, Lev D, Ben-Aroya Z, Kidron D, Lerman-Sagie T. Fetal brain literature. Adv Clin Exp Med 2013;22:571-7.23986218 imaging: a comparison between magnetic resonance imaging and dedicated 40 Ashwal S, Michelson D, Plawner L, Dobyns WBQuality Standards Subcommittee of the neurosonography. Ultrasound Obstet Gynecol 2004;23:333-40. American Academy of Neurology and the Practice Committee of the Child Neurology 10.1002/uog.1016 15065181 Society. Practice Parameter: Evaluation of the child with microcephaly (an evidence-based 34 Stoler-Poria S, Lev D, Schweiger A, Lerman-Sagie T, Malinger G. Developmental outcome review). Neurology 2009;73:887-97. 10.1212/WNL.0b013e3181b783f7 19752457 of isolated fetal microcephaly. Ultrasound Obstet Gynecol 2010;36:154-8. 41 Moienafshari R, Bar-Oz B, Ford-Jones L, Koren G. How long should someone wait after 10.1002/uog.7556 20069548 CMV infection to start pregnancy?Can Fam Physician 1998;44:2381-2.9839051 35 Kurtz AB, Wapner RJ, Rubin CS, Cole-Beuglet C, Ross RD, Goldberg BB. Ultrasound Published by the BMJ Publishing Group Limited. For permission to use (where not already criteria for in utero diagnosis of microcephaly. J Clin Ultrasound 1980;8:11-6. 10.1002/jcu.1870080104 6766470 granted under a licence) please go to http://group.bmj.com/group/rights-licensing/ 36 Williams RA, Mamotte CDS, Burnett JR. Phenylketonuria: an inborn error of phenylalanine permissions metabolism. Clin Biochem Rev 2008;29:31-41.18566668 http://www.bmj.com/ on 29 September 2021 by guest. Protected copyright.

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Figures BMJ: first published as 10.1136/bmj.k2232 on 4 June 2018. Downloaded from

Fig 1 Range of microcephaly. (Adapted from Centers for Disease Control and Prevention5) http://www.bmj.com/ on 29 September 2021 by guest. Protected copyright.

Fig 2 Suggested approach to further investigation and management of fetal microcephaly based on expert opinion22

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