Objective
We sought to identify risk factors for congenital microcephaly in extremely low gestational age newborns.
Study Design
Demographic, clinical, and placental characteristics of 1445 infants born before the 28th week were gathered and evaluated for their relationship with congenital microcephaly.
Results
Almost 10% of newborns (n = 138), rather than the expected 2.2%, had microcephaly defined as a head circumference >2 SD below the median. In multivariable models, microcephaly was associated with nonwhite race, severe intrauterine growth restriction, delivery for preeclampsia, placental infarction, and being female. The risk factors for a head circumference between <1 and >2 SD below the median were similar to those of microcephaly.
Conclusion
Characteristics associated with fetal growth restriction and preeclampsia are among the strongest correlates of microcephaly among children born at extremely low gestational ages. The elevated risk of a small head among nonwhites and females might reflect the lack of appropriate head circumference standards.
Microcephaly in the newborn is characterized by disproportionately small head circumference for a given gestational age (GA). A variety of antenatal exposures contribute to the risk of congenital microcephaly, including genetic and chromosomal anomalies, infectious exposures, drug or chemical exposure, phenylketonuria, and high levels of ionizing radiation. However, congenital microcephaly is frequently observed in pregnancies that were free of these insults and can be associated with antenatal complications such as severe intrauterine growth restriction (IUGR), suggesting that a disordered intrauterine environment may also be an antecedent.
Congenital microcephaly predicts reduced brain growth, particularly reduction in forebrain development. and reduced intellectual ability in the adult. Among term-born infants with a head circumference 2 SD below the mean, 50% will have reduced cognitive attainment. This rises to 82% among those whose head circumference is >3 SD below the mean. This progression in developmental limitation with reduced head size suggests that microcephaly and its later associations exist along a continuum of dysfunction. Investigations into the antecedents of microcephaly will therefore need to be aware that imposing a break point in the definition of microcephaly is to some degree artificial. Given the potential adverse developmental outcomes in these infants, we sought to identify the antenatal antecedents of congenital microcephaly in extremely low GA newborns (ELGAN).
Materials and Methods
The ELGAN study was designed to identify characteristics and exposures that increase the risk of structural and functional neurologic disorders in ELGAN. During the years 2002 through 2004, women delivering >23.0 but <28.0 weeks’ gestation at 1 of 14 participating institutions in 11 cities in 5 states were asked to enroll in the study. The enrollment and consent processes were approved by the individual institutional review boards.
Mothers were approached for consent either upon antenatal admission or shortly after delivery, depending on clinical circumstance and institutional preference. Only nonanomalous and infants free of obvious chromosomal abnormality were enrolled. Ultimately, 1249 mothers of 1506 infants consented to participate. Approximately 260 women were either missed or did not consent.
Demographic and pregnancy variables
After delivery, a trained research nurse interviewed each mother in her native language using a structured data collection form and following procedures documented in a manual. The mother’s report of her own characteristics and exposures, as well as the sequence of events leading to preterm delivery were taken as truth, even when her medical record provided discrepant information.
Shortly after the mother’s discharge, the research nurse reviewed the maternal chart using a second structured data collection form. The medical record was reviewed for information about events following admission.
The clinical circumstances that led to each maternal admission and ultimately to each preterm delivery were operationally defined using both data from the maternal interview and data abstracted from the medical record.
Newborn variables
The GA estimates were based on a hierarchy of the quality of available information. Most desirable were estimates based on the dates of embryo retrieval or intrauterine insemination or last menstrual period with confirming fetal ultrasound before the 14th week (62%). When these were not available, reliance was placed sequentially on a fetal ultrasound at ≥14 weeks (29%), last menstrual period without fetal ultrasound (7%), and GA recorded in the log of the neonatal intensive care unit (1%).
The birthweight Z-score is the number of SD the infant’s birthweight is above or below the median weight of infants at the same GA in a standard data set.
The head circumference was measured as the largest possible occipital-frontal circumference. Measurements were rounded to the closest 0.1 cm. All head circumferences are presented as Z-scores because newborns were assessed at different GA at birth (23-27 weeks). These Z-scores were based on standards in the Oxford, United Kingdom, dataset.
Placentas were biopsied under sterile conditions. In all, 82% of the samples were obtained within 1 hour of delivery. The microbiologic procedures are described in detail elsewhere. Placentas were examined grossly in keeping with the guidelines of the 1991 College of American Pathologists Conference. Procedures and definitions of histologic terms are presented elsewhere.
Data analysis
We evaluated the generalized null hypothesis that the risk of a small head circumference is not associated with maternal demographic characteristics, pregnancy exposures and characteristics, characteristics of the newborn, or characteristics of the placenta. We adjusted for GA using groups of weeks (23-24, 25-26, 27). This procedure does just as well as adjusting for each week of gestation and results in fewer groups.
Several definitions for microcephaly have been proposed. We define microcephaly as a head circumference Z-score of <–2 (ie, >2 SD below the GA-specific median). We use the term “minicephalic” to indicate the larger set of children with head circumference Z-scores ≥–2 but <–1. By and large, what applies to the infants with microcephaly also applies to those with minicephaly. To minimize repetition of this statement, we reserve comments for the situations when this generalization does not apply. For the ease of reading the “Results” section, we use the term “small head circumference” to encompass both the microcephaly and minicephaly groups.
Because our 2 small head circumference Z-score groups are mutually exclusive and each is appropriately compared to the same referent group (those with head circumference Z-score ≥–1), we created multinomial logistic regression models to identify the contribution of relevant characteristics and exposures to the risk of each head circumference outcome. We began by including all variables that appeared to be related to microcephaly. Using manual backward selection, we then sequentially dropped the least significant variable and assessed the model with the remaining variables. A model was complete when all of the variables that remained were associated with the outcome at a level of P < .1. The dropped variables were individually reintroduced to see if they now contributed to the complete model. The contribution of each antecedent to the model is presented as a risk ratio with 95% confidence intervals.
Results
In a normal distribution, 2.2% of measurements are >2 SD below the mean. In our sample of ELGAN, almost 10% of infants (138/1445) were microcephalic at birth. In all, 22% (317/1445) were minicephalic when only 13.8% is expected. A notable portion of the head circumference Z-score distribution in our sample lies to the left of the expected normal distribution ( Figure ). In all, 31% (138 + 317/1445) of the ELGAN sample had a small head circumference Z-score.
Maternal education, marital status, (financial) self-support, and receipt of public insurance were not associated with microcephaly ( Table 1 ). Microcephaly was more common among women who identified themselves as nonwhite. Mothers with an advanced maternal age (>35 years) tended to have babies at reduced risk of microcephaly. Higher prepregnancy body mass index was associated with higher risk for both microcephaly and minicephaly.
| Maternal characteristic | Head circumference Z-score a | n | ||
|---|---|---|---|---|
| <–2 | ≥–2 to <–1 | |||
| Racial identity | White | 7 | 18 | 821 |
| Black | 12 | 27 | 419 | |
| Other | 13 | 28 | 181 | |
| Hispanic | Yes | 10 | 23 | 175 |
| No | 9 | 21 | 1258 | |
| Age, y | <21 | 11 | 26 | 206 |
| 21-35 | 11 | 22 | 930 | |
| >35 | 7 | 18 | 245 | |
| Education, y | <12 | 9 | 23 | 235 |
| 12 (HS) | 11 | 26 | 378 | |
| >12 to <16 | 11 | 21 | 332 | |
| 16 (College) | 9 | 18 | 234 | |
| >16 | 6 | 16 | 171 | |
| Marital status | Single | 10 | 27 | 639 |
| Not single | 9 | 18 | 806 | |
| Self-support b | Yes | 9 | 22 | 891 |
| No | 10 | 22 | 181 | |
| Medicaid b | Yes | 10 | 26 | 578 |
| No | 9 | 19 | 803 | |
| Prepregnancy BMI | <18.5 | 8 | 19 | 106 |
| ≥18.5 to <25 | 8 | 20 | 650 | |
| ≥25 to <30 | 11 | 25 | 279 | |
| ≥30 | 12 | 24 | 312 | |
| Maximum no. of infants | 138 | 317 | 1445 | |
a External standard is Oxford, United Kingdom, dataset;
Maternal smoking, whether before or during pregnancy, was not associated with microcephaly ( Table 2 ). Similarly, self-reported vaginal bleeding, antepartum fever, vaginitis, or urinary tract infections were not associated with an increased risk of a microcephalic newborn. While multigravidity was not associated with microcephaly, mothers with a birth interval of >2 years were at higher risk of having a microcephalic baby. The use of conception assistance was associated with a modestly reduced risk of having a microcephalic, but not a minicephalic baby. Maternal ingestion of a nonsteroidal antiinflammatory drug was associated with a reduced risk of microcephaly, but not of minicephaly.
| Exposures and characteristics | Head circumference Z-score a | n | ||
|---|---|---|---|---|
| <–2 | ≥–2 to <–1 | |||
| Smoking prepregnancy b | Yes | 8 | 23 | 359 |
| No | 10 | 21 | 1012 | |
| Smoking during pregnancy b | Yes | 8 | 25 | 205 |
| No | 10 | 21 | 1166 | |
| Years since last pregnancy | <1 | 7 | 23 | 163 |
| 1-2 | 8 | 17 | 235 | |
| ≥2 | 11 | 23 | 417 | |
| Conception assistance | Yes | 7 | 17 | 271 |
| No | 10 | 23 | 1096 | |
| Vaginal bleeding | ||||
| ≤12 wk b | Yes | 8 | 21 | 522 |
| No | 10 | 23 | 844 | |
| >12 wk b | Yes | 7 | 21 | 392 |
| No | 11 | 22 | 974 | |
| Illnesses this pregnancy | ||||
| Fever b | Yes | 10 | 25 | 83 |
| No | 10 | 22 | 1282 | |
| Vaginal/cervical infection | Yes | 7 | 24 | 187 |
| No | 10 | 22 | 1179 | |
| UTI b | Yes | 10 | 25 | 219 |
| No | 10 | 21 | 1147 | |
| Medications | ||||
| Any b | Yes | 10 | 22 | 159 |
| No | 6 | 23 | 1206 | |
| Aspirin b | Yes | 8 | 26 | 80 |
| No | 10 | 22 | 1280 | |
| NSAID b | Yes | 4 | 27 | 99 |
| No | 10 | 21 | 1260 | |
| Acetaminophen b | Yes | 11 | 21 | 697 |
| No | 8 | 22 | 662 | |
| Antibiotic b | Yes | 10 | 24 | 430 |
| No | 9 | 21 | 930 | |
| Maximum no. of infants | 138 | 317 | 1445 | |
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