Introduction
It has been suggested that intra-uterine growth retardation (IUGR) does not affect the brain in the fetus and newborn because of a "brain-sparing phenomenon." That the head circumference of IUGR infants at birth is not affected and that the infants' neurological outcomes are relatively normal have been provided as arguments in support of the brain-sparing hypothesis.

However, we hypothesized that IUGR infants may suffer from subtle brain injury not obviously apparent; this is seen in such infants who manifest, with increased frequency, cognitive functional deficits in school age. The brain injury may be mediated by an increased vulnerability to hypoxic-ischemic (HI) injury in the IUGR fetuses.

Our study objectives were to: 1) test whether IUGR increases vulnerability of the brain to hypoxic ischemic (HI) injury; 2) see if long-term learning and memory functions are more predictive of such subtle brain injury than are standard neurological tests.

Methods
In time-mated pregnant rats, we ligated the uterine artery on day 20. After delivery, on day 7 of age, we induced hypoxic ischemic injury: Ligation of the right carotid artery was followed by 8% oxygen breathing for 2 hours (Levine-Vannucci Model). The pups were reared by their mothers. Outcome measures:

1. Structured CNS examinations up to day 60;
2. Morris water maze (MWM) testing, using the EthoVision (Noldus Information Technology) video tracking system, on days 27-32; 42-46; and 56-60; and
3. 8-arm radial arm maze (RAM) on days 70-73.

Results
The IUGR pups were predictably smaller. Data from MWM (mean and SD seconds to find the hidden platform) are shown below.

Table 1. Morris water maze: latency time to the hidden platform.

Pups in the IUGR plus hypoxic-ischemic group fared the worst, with significant impairment in learning and memory functions by day 60, compared to all other groups on respective days (*; p<0.05; two-way ANOVA).

The median days for achieving neurological milestones were similar in the four groups: 8 days for cliff avoiding and surface righting; 14 days for walking, and 16 days for head lifting and eye opening. Similarly, RAM tests results were similar in all groups (not shown).

Conclusions
With superimposed hypoxic-ischemic injury, IUGR impairs specific learning and memory skills. The "brain-sparing" effect of IUGR thus may be selective. Place-memory and learning tested in MWM were impaired markedly, but reward-based memory and learning tested in RAM were not. Such differential and selective vulneribility of neuronal pathways involved in learning and memory may explain the higher rates for cognitive deficits in school-age children, IUGR at birth.

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