Study suggests preventive strategies needed during pregnancy and pediatric follow-up

Children who had intrauterine growth restriction (IUGR) and who were small for gestational age (SGA) had significantly lower cognitive scores at age 12 years versus kids born appropriate for gestational age, according to a systemic review and meta-analysis.

Among 89 samples from 60 studies (n=52,822 children), associations were consistent for preterm (standardized mean difference −0.27, 95% CI −0.38 to −0.17) and term-born children (SMD −0.39, 95% CI −0.50 to −0.28), reported Chiara Sacchi, PhD, of the University of Padova in Italy, and co-authors.

In addition, there were higher effect sizes reported for term-born IUGR, a condition in which a fetus cannot achieve its genetically determined potential growth, and appropriate-for-gestational-age (AGA) group comparisons (SMD −0.58, 95% CI −0.82 to −0.35), they wrote in JAMA Pediatrics.

The authors also found that for borderline intellectual impairment (BII) — defined as mental, cognitive, or IQ scores at least 1 standard deviation below the mean cognitive score — there was a significantly increased risk in the preterm children who had IUGR and were SGA (odds ratio 1.57, 95% CI 1.40-1.77) versus AGA children.

“These results suggest an association between preterm IUGR and SGA and neurodevelopmental sequelae, they wrote.

While the results of the meta-analyses looking at cognitive scores and BII in preterm and term-born children found no significant cognitive differences between the IUGR and SGA subgroups, the authors noted that “the putative etiopathological differences between the 2 were not addressed.”

Other study limitations included potential publication bias and the fact that data on demographic and perinatal variables were not consistently available, so the authors could not study the association of potentially relevant factors, such as sex or family socioeconomic status, with outcomes.

Still, “These important results emphasize the urgent need for improving IUGR prevention as well as antenatal detection and management, including for term IUGR and SGA,” stated Emmanuel Bujold, MD, MSc, and Paul Guerby, MD, PhD, both of the Université Laval, in Québec City, Québec, Canada, in an editorial accompanying the study.

They stressed that ultrasonography early in the third trimester, paired with serial measurement of the fundal height during pregnancy, has proven inadequate for detecting IUGR. Instead, “late third-trimester ultrasonography (approximately 35-37 weeks) combined with Doppler ultrasonography (uterine artery, middle cerebral artery, and fetal umbilical artery) would significantly improve the detection and the diagnosis of IUGR.”

Other detection tools on the horizon include biochemical markers, such as placental growth factor and soluble FMS-like tyrosine kinase 1, that could detect “early uteroplacental insufficiency and identify women at greater risk for whom universal third-trimester ultrasonography may not be possible,” Bujold and Guerby explained.

They also pointed out that severe complications may be preventable during the first trimester “the most severe complications can be detected as early as the first trimester of pregnancy with the early initiation of aspirin. In a 2010 study, Bujold and co-authors reported that aspirin use started before 16 weeks of gestation in women at high risk of preeclampsia was linked with a significant reduction of IUGR.

However, Bujold and Guerby acknowledged that “The current challenge is to identify the women at high risk of IUGR who could benefit from aspirin.”

Finally, they suggested that the obstetric community should consider an “inverted pyramid of antenatal care,” with a focus on “the early recognition of pregnancy complications and their primary prevention.”

Sacchi and co-authors searched major medical publishing platforms for English-language, peer-reviewed literature from January 2000 to February 2020. Studies made the cut for the analysis if they included assessment of cognitive outcomes (full-scale IQ or a cognitive subscale), inclusion of an AGA group as comparison group, and inclusion of gestational age at birth and completion of cognitive assessment up to age 12 years. The authors followed the MOOSE reporting guidelines.

They reported that preterm children who had IUGR and were SGA were 1.57 times more likely than those with AGA to have BII (cognitive score <1 SD) and 2.77 times more likely to have intellectual impairment (cognitive score <2 SDs).

While Sacchi’s group acknowledged that “The biological mechanisms that could explain our findings are not fully understood,” there is the likelihood that antenatal brain developmental processes are involved.

“Placental insufficiency, exposing the fetus with IUGR to undernutrition and decrease in growth rate, is likely to affect in utero brain developmental processes,” they noted. “Such suboptimal trophic inputs may lead to the structural and functional brain alterations observed in infants who had IUGR, which potentially underscore the emergence of high-order cognitive processes.”

Sacchi and co-authors stated that future research should look at “putative antenatal and pregnancy-related risk factors for IUGR and SGA as well as childhood cognitive outcomes,” along with better way to diagnose and detect IGUR; separate antenatal from perinatal effects; and targeted interventions to “boost the cognitive profile of children who had IUGR and were SGA.”

  1. Children who had intrauterine growth restriction (IUGR), and who were small for gestational age (SGA), had significantly lower cognitive scores at age 12 years compared with children born appropriate for gestational age.

  2. The obstetric community should consider an “inverted pyramid of antenatal care,” with a focus on “the early recognition of pregnancy complications and their primary prevention.”

Shalmali Pal, Contributing Writer, BreakingMED™

Sacchi and co-authors, as well as Guerby and Bujold, reported no relationships relevant to the contents of this paper to disclose.

Cat ID: 41

Topic ID: 83,41,730,41,138,683,192,925