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 (). In all, 31% (138 + 317/1445) of the ELGAN sample had a small head circumference Z-score.
Observed and expected distributions of birth head circumference Z-scores
Maternal education, marital status, (financial) self-support, and receipt of public insurance were not associated with microcephaly (). 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.
Distribution of birth head circumference Z-score groups in relation to social and demographic characteristics of mother
Maternal smoking, whether before or during pregnancy, was not associated with microcephaly (). 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.
Distribution of children with small head circumference growth in strata defined by pregnancy characteristics and exposures during pregnancy
Children whose mother presented in labor or with abruption were at lowest risk of microcephaly while those delivered for maternal or fetal indications were at a notably increased risk of microcephaly (). This increase was much less prominent for a minicephaly. Correlates of delivery for preeclampsia and fetal indications, including receipt of magnesium for seizure prophylaxis, and of no labor, were also strongly associated with an increased risk of a small head. Among infants delivered after preterm premature membrane rupture, the latency interval between rupture and delivery was unrelated to the risk of having either microcephaly or minicephaly. Receipt of a complete course of antenatal corticosteroid (regardless of whether betamethasone or dexamethasone) was not associated with an increased risk of microcephaly. Girls were at greater risk than boys of having a small head circumference. The risk of microcephaly was lowest in the youngest GA groups, and regardless of GA, most elevated in those with the lowest birthweight Z-scores ().
Distribution of head circumference groups in strata defined by delivery or newborn characteristics
Risk ratios (and 95% confidence intervals) of each head circumference entity associated with each placental organism or group of organisms
Among infants delivered vaginally, those whose placenta harbored an organism (or multiple organisms) were almost 3 times more likely than others to be microcephalic, although these increased risks were not statistically significant (). On the other hand, the recovery of multiple organisms, especially Mycoplasma, was associated with statistically significant increased risks of minicephaly.
Risk ratios (and 95% confidence intervals) of each head circumference entity associated with each histologic characteristic
Among infants delivered by cesarean section, and therefore at lower risk of having their placenta contaminated by passage through the vagina, recovery of ≥2 organisms, and the recovery of normal vaginal flora were associated with a significantly reduced risk of microcephaly. On the other hand, recovery of Pro-pionibacterium species and other skin organisms was associated with increased risk of microcephaly.
Among infants delivered vaginally, those whose placenta had inflammation of the chorion/decidua were at increased risk of a small head (). The increased risk associated with umbilical cord vasculitis did not quite achieve statistical significance. On the other hand, the risk of minicephaly was increased among infants whose fetal stem and umbilical cord vessels were inflamed.
In contrast, among infants delivered by cesarean section, umbilical cord vasculitis was associated with reduced risk of microcephaly. Placenta lesions in this subsample associated with increased risk of microcephaly included thrombosis of fetal stem vessels, infarct, and increased syncytial knots. Infarct and increased syncytial knots were also associated with increased risks of minicephaly.
In an attempt to identify if the risk of a small head required both organism recovery and a histologic response, we created multivariable models with a variable for organism recovery, a variable for the histologic characteristic of interest, and an interaction term for these 2 variables. No interaction term was statistically significant for models of the risk of microcephaly (data not shown). Interaction terms for organism recovery and decidual hemorrhage/fibrin deposition in the cesarean section sample conveyed information about reduced risk of minicephaly.
Multinomial regression is displayed in . By and large, what is seen for microcephaly is also seen for minicephaly, but usually with a less elevated risk ratio. The only exception was an almost statistically significant increased risk of minicephaly, but not microcephaly among those exposed to any antenatal corticosteroid. The variables that contributed significantly to the risk of a small head even in the presence of potentially confounding variables were mother’s self-identification as nonwhite, a birthweight Z-score<−2, delivery for a maternal or fetal indication, a mother who was not married, and being female. Although not achieving statistical significance, low GA was associated with a reduced risk of microcephaly.