Cranial Asymmetry Versus Microcephaly: Implications for Practice During the Zika Virus Epidemic Texas Medicine August 2017

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The Journal — August 2017

Tex Med. 2017;113(9):e1. 

By Sophia Tsakiri, MD; Nikolaos Zacharias, MD; Jose Garcia, MD, SM; and Lynnette Mazur, MD, MPH

Drs Tsakiri, Garcia, and Mazur, Department of Pediatrics, UTHealth at Houston; and Dr Zacharias, Department of Obstetrics and Gynecology, UTHealth at Houston. Send correspondence to Sophia Tsakiri, MD, Lyndon Baines Johnson General Hospital, 5656 Kelley Street, Suite 2NT-91-002g, Houston, TX 77026; email: Sophia.Tsakiri[at]uth[dot]tmc[dot]edu.

Congenital microcephaly can be the result of genetic, teratogenic, mechanical, infectious, and other factors affecting the fetal brain. Transient craniofacial asymmetries and cranial molding can mimic congenital microcephaly caused by brain abnormalities or neurotropic infectious pathogens, including Zika. We present two neonates who were born with head circumference at or below the 3rd percentile for gestational age, and had improving head measurements at discharge from the nursery and resolution of the microcephaly by the second month of life. The diagnostic workup of the first patient revealed congenital cranial bone asymmetry and molding, and the second patient's workup revealed cranial molding. Other etiologies for their microcephaly were excluded. These two cases highlight the importance of standardized serial head circumference measurements as part of the workup for neonatal microcephaly. Clinical exclusion of transient congenital craniofacial asymmetries and cranial molding could be a cost-effective first step in the diagnostic workup of microcephaly. 


Anthropometrics are used prenatally and postnatally to assess fetal and neonatal growth. Head size is a proxy for brain growth. Microcephaly may originate in utero and can be the result of genetic, teratogenic, mechanical, infectious, and other factors affecting the fetal brain. Congenital Zika virus (ZIKV) syndrome is a leading cause of microcephaly in endemic areas. 

We present two neonates who were born with head circumference (HC) at or below the 3rd percentile for gestational age and had improving head measurements at discharge from the nursery.  

Case 1: A symmetrically growth-restricted, small for gestational age singleton female infant was born vaginally at 38 weeks and 3 days of gestation to a Hispanic mother who had traveled to El Salvador during her fourth month of pregnancy. Prenatal sonography at 13 weeks and 4 days demonstrated an embryonic crown-rump length at 27% for age and was otherwise unremarkable. Prenatal sonography at 21 weeks and 2 days of gestation demonstrated a fetal HC at 39% for age, a fetal weight at 37% for age, and was otherwise unremarkable. The birth weight was 2206 grams (0.6th percentile) and the HC was 29 cm (0.2nd percentile). The forehead was flattened, and cranial molding was present. The infant was hospitalized for 3 days because of microcephaly. Cytomegalovirus (CMV), toxoplasmosis, and rubella serologic studies were negative. A brain magnetic resonance imaging showed flattening of the frontal bone. Maternal Zika immunoglobulin M enzyme-linked immunoassay was negative. Neonatal serum real-time reverse transcription polymerase chain reaction was negative for ZIKV, dengue, and chikungunya viruses. During the hospitalization, the HC increased to 31 cm (1st percentile) by the third day of life. The patient was discharged with a diagnosis of frontal bone flattening and resolving congenital cranial molding. Her HC at 14 days of life was 32 cm (2nd percentile) and at 39 days of life was 36 cm (35th percentile). 

Case 2: A singleton male infant was born vaginally at 36 weeks and 1 day of gestation to a Hispanic teenager with limited prenatal care. The mother reported no history of exposure to ZIKV. Prenatal sonography at 23 weeks and 2 days of gestation demonstrated a fetal HC at 53% for age, a fetal weight at 50% for age, and was otherwise unremarkable. The birth weight was 2600 grams (35th percentile), the HC was 30 cm (3rd percentile), and molding was present. The infant was hospitalized for prematurity, respiratory distress, head growth restriction, and feeding difficulties. Serologic studies CMV, toxoplasmosis, and rubella were negative. A neonatal brain ultrasound and magnetic resonance imaging were unremarkable. Maternal and neonatal ZIKV testing were declined by the local Department of Health due to lack of maternal exposure to ZIKV. During the birth hospitalization, the HC increased to 32.5cm (27th percentile) by the seventh day of life. The patient was discharged home on the 11th day of life with a diagnosis of improving congenital cranial molding. His HC at day 13 was 33 cm (26th percentile), at day 50 was 37 cm (60th percentile), and at day 63 was 38 cm (66th percentile), increasing parallel to body growth. 


Accurate assessment of the fetal and neonatal head size and growth is essential for the diagnosis of microcephaly or of head growth restriction. A rapid growth phase is expected in the last half of the pregnancy, in the absence of nutritional, medical, economic, or care-related constraints. Early growth patterns of term infants are similar across human populations. Preterm growth generally follows intrauterine growth rates and shows a unique acceleration during the weeks before birth. 

The Society for Maternal-Fetal Medicine recently published the criteria and standard reference for diagnosing fetal microcephaly, when the HC by prenatal ultrasound is 3 standard deviations or more below the mean for gestational age.1 Preterm and term newborn growth standards obtained from population-based studies were most recently revised by Fenton and Kim2 in 2013 and by the International Fetal and Newborn Growth Consortium for the 21st century (INTERGROWTH-21st)3 in 2015. The US National Birth Defects Prevention Network published prevalence estimates for microcephaly from 30 participating births defects databases for the period 2009 to 2013, studying more than 11 million live births.4 They described a pooled prevalence for microcephaly of 8.7 cases per 10,000 live-born babies. Prevalence of microcephaly was higher among newborns of Hispanics, mothers younger than 20 years, mothers older than 40 years, preterm babies, low-birth-weight babies, and multiple pregnancies. Though specific prevalence data for cranial molding and craniofacial asymmetries were not reported, molding was recognized as a factor complicating the accuracy of diagnosing microcephaly. The authors acknowledged finding variation of the definition of microcephaly across the databases, with common cut-offs for the HC at lower than the 3rd, 5th, or 10th percentile for age. In our practice, we define microcephaly as a HC smaller than the 3rd percentile for gestational age, according to the 2013 Fenton growth charts for neonates. Due to the known risk for neurodevelopmental delays among infants with asymmetric head growth restriction,5 we also offer comprehensive evaluation of newborns who have HC measurements significantly smaller than their weight measurement, as had our second patient. 

Infections of CMV, toxoplasmosis, and rubella during pregnancy can cause fetal and neonatal microcephaly. Suspicion of an epidemiologic link between ZIKV maternal infection and fetal embryopathy occurred in 2015 during the ZIKV epidemic in Central and South America. Congenital ZIKV syndrome is characterized by microcephaly, cerebral ventriculomegaly, cerebellar hypoplasia, central nervous system (CNS) calcifications, arthrogryposis, or other CNS, ocular, and musculoskeletal abnormalities.6 On the most recent report from the US Zika Pregnancy Registry (USZPR), among 442 pregnancies with possible ZIKV infection, 26 fetuses or infants were found to have birth defects potentially related to ZIKV, 18 of whom (4% of possibly infected pregnancies) had microcephaly.7 Microcephaly, thus, was markedly more prevalent in the USZPR than in the general population. Practicing in Texas with documented ZIKV travel-associated disease and with gravid travelers from Central and South America, we often take care of pregnant women and newborns with potential exposure to ZIKV during pregnancy, namely a travel history to endemic areas, clinical disease, asymptomatic exposure of the mother, or exposure of her sexual partner(s). Prenatal care providers now routinely screen pregnant women for such history to identify fetuses and infants at risk for ZIKV embryopathy, per the Centers for Disease Control and Prevention guidelines. Current algorithms for the diagnostic workup of newborns born to mothers with potential ZIKV exposure are based on newborn findings consistent with congenital ZIKV syndrome, including microcephaly.8

Transient neonatal craniofacial asymmetries can lead to self-resolving microcephaly. Craniofacial asymmetries are common at birth.9 Most are the result of in utero or intrapartum molding, subcutaneous or subperiosteal cranial hematomas, torticollis, and deformational asymmetries. They are diagnosed by a careful examination of the neonatal head. Some can be suspected prenatally by ultrasound or can be expected due to the presence of prenatal factors such as extremes of fetal position, uterine crowding, uterine leiomyomata, or oligohydramnios.  

The incidence of cranial molding in full-term and preterm neonates is unknown. Such molding is considered a physiologic, transient, self-limiting deformation of the skull and is related to prolonged labor forces applied to the fetal head, regardless of mode of delivery. An older study described 38 newborns with molding at birth and increasing diameters of their heads in the first 3 days of life.10 Although we know that cranial molding improves in the first days of life, the natural course of molding is unknown. Detailed day-by-day head measurements of molded neonatal heads are lacking from the medical literature. Resolution of cranial molding was evident at 1 month of life on our first patient and at 1 week on the other. 

Neonatal microcephaly deserves comprehensive workup for underlying brain abnormalities or neurotropic infectious pathogens, including ZIKV, according to published algorithms. Craniofacial asymmetries and molding can mislead medical practitioners to underestimate the newborn head size and to overestimate the risk for congenital infection-induced microcephaly. Pediatricians are advised to perform standardized measurements of the fetal head with nonstretching measuring tape. When available, fetal ultrasonography can provide information on the prenatal head growth pattern. This information combined with the pregnancy history, the results of prenatal testing, a thorough physical examination of the newborn, and serial HC measurements in the first week of life may be critical to confirming or ruling out microcephaly or head growth restriction. 

Newborns with abnormal prenatal screens or fetal head growth patterns or with physical characteristics of Zika-associated or other embryopathy will be candidates for early advanced testing. Newborns with normal prenatal screens, normal prenatal growth and ultrasound findings, benign postnatal examination, and steadily improving HC may be candidates for targeted screening and longer observation. Neonatal blood and urine specimens as well as placental specimens can be preserved within 48 hours of birth for later ZIKV testing, according to the CDC recommendations, while the medical team is weighing the clinical evidence for congenital microcephaly or symptomatic infection and while the maternal testing is in progress. Even if the laboratory and radiologic workup is delayed for a few days until the determination of microcephaly can be made, it ought to be offered to candidate neonates before the initial discharge from the birthing facility. Transient craniofacial asymmetries and molding can be self-resolving, whereas ZIKV and other fetal and neonatal CNS pathogens may lead to nonreversible or progressive microcephaly and to progressive and lifelong disabilities. Early detection of infection, reliable follow-up, and access to specialty resources give the pediatrician and the parents an explanation for the microcephaly and aim at enhanced quality of life for the patient. 

Utilization of resources is becoming pronounced in known ZIKV endemic areas, such as South and Central America, in areas of travel-associated exposure, and in areas of emerging local transmission, such as Florida and Texas. Before the ZIKV epidemic, the median hospital charge estimate for congenital microcephaly in Texas was $22,754, and the median hospital length of stay was 5 days.11 The incremental cost of comprehensive ZIKV-associated microcephaly workup, including advanced brain imaging, laboratory testing, prolonged hospitalization, and specialty care costs, is projected to be even higher. The emotional toll to families and the burden to human and laboratory resources is likely significant, too, though difficult to quantify. The clinical exclusion of transient congenital craniofacial asymmetries and cranial molding, via serial HC measurements, is a possible cost-effective first step in the diagnostic workup of microcephaly.

We conclude that standardized serial circumference measurements of the newborn head are integral to the workup of transient neonatal craniofacial asymmetries mimicking infection-induced congenital microcephaly.  


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  3. Villar J, Giuliani F, Bhutta ZA, et al. Postnatal growth standards for preterm infants: the Preterm Postnatal Follow-up Study in the INTEGROWTH-21st Project. Lancet Glob Health. 2015;3(11):e681–e691.
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  8. Russell K, Oliver SE, Lewis L, et al. Update: Interim guidance for the evaluation and management of infants with possible congenital Zika virus infection ― United States, August 2016. MMWR Morb Mortal Wkly Rep. 2016;65(33):870–878. 
  9. Stellwagen L, Hubbard E, Chambers C, Jones KL. Torticollis, facial asymmetry and plagiocephaly in normal newborns. Arch Dis Child. 2008;93(10):827–831. 
  10. Kriewall TJ, Stys SJ, McPherson GK. Neonatal head shape after delivery: an index of molding. J Perinat Med. 1977;5(6):260–267.
  11. Moffitt KB, Case AP, Farag NH, Canfield MA. Hospitalization charges for children with birth defects in Texas, 2001 to 2010. Birth Defects Rest A Clin Mol Teratol. 2016;106(3):155–163.  

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Last Updated On

August 02, 2017

Originally Published On

July 25, 2017

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