Iron deficiency anemia early in pregnancy appears to increase the risk of neurodevelopmental disorders, including autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and intellectual disability (ID) in offspring.
Results of a large population-based study showed the risk of ASD and ADHD in children whose mothers had anemia in early pregnancy was 44% and 37% higher, respectively, compared with those children born to mothers without early prenatal anemia. The risk of intellectual disability was highest, at 120%.
Interestingly, anemia diagnosed after the 30 weeks' gestation was not associated with an increased risk for any of these conditions.
"It is part of standard antenatal care to screen pregnant women for low hemoglobin levels, and this is important to continue," senior author Renee Gardner, PhD, of Karolinska Institute, Stockholm, Sweden, told Medscape Medical News.
"Our study suggests that it may be even more important than we have previously understood to boost low iron levels among women who are considering becoming pregnant or who are within the early weeks of pregnancy," she said.
The study was published online September 18 in JAMA Psychiatry.
Subtle Impact
"I am interested in how maternal nutrition affects the developing nervous system. We know that deficiencies in certain nutrients in the mother can have a profound effect on the developing brain and nervous system — for example, we know that folate can help to prevent neural tube defects," Gardner said.
For the study, the researchers drew on data from the Stockholm Youth Cohort, a prospective, cohort study of individuals born between January 1, 1984 and December 31, 2011.
The study included 532,232 children (51.3% male) between ages 6 and 29 years at the end of follow-up (mean [SD] age, 17.6 [7.1] years) and their 299,768 mothers.
Among the women, 5.8% were diagnosed with anemia during pregnancy; of these diagnoses, 5% occurred before 30 weeks' gestation, while 90.9% occurred after 30 weeks' gestation.
Covariates studied by the researchers included maternal age, income, educational level, body mass index (BMI), history of psychiatric hospitalization, interpregnancy interval (IPI), infection during pregnancy, and whether the child was a first-born.
The researchers used conditional logistic regression models to compare full siblings exposed to anemia with unexposed siblings, adjusting for sex, birth year, and IPI to evaluate the possibility of shared genetic liability as a potential confounder.
Neurodevelopmental Impact
Characteristics of women with anemia, compared with those without anemia, included:
Overweight and obesity
Older age (> 40 years)
Psychiatric history
Higher income
Primiparous women
IPI > 5 years
Hospitalization for infection during pregnancy
Characteristics of women with earlier-onset anemia (≤ 30 weeks' gestation) included:
Lower educational level
Lower income
Underweight
Younger age (< 25 years)
The children whose mothers were diagnosed with anemia at ≤ 30 weeks were more likely to be born preterm (odds ratio [OR], 7.10; 95% confidence interval [CI], 6.28 - 8.03) or small for gestational age (OR, 2.81; 95% CI, 2.26 - 3.50), compared with those whose mothers were not diagnosed with anemia.
On the other hand, children whose mothers were diagnosed with anemia at later than 30 weeks' gestation were more likely to be born post-term and large for gestational age (OR, 1.56; 95% CI, 1.49 - 1.62; and OR, 1.76; 95% CI, 1.66 - 1.87, respectively).
Children born to mothers with anemia during the first 30 weeks of pregnancy had the highest risk of ASD, ADHD, and ID, compared with mothers who were diagnosed after 30 weeks and mothers who did not have anemia at any point in the pregnancy.
Table. Percentage of Children Born to Mother With and Without Anemia
| Disorder |
Anemia at ≤ 30 Weeks |
Anemia at > 30 Weeks |
No Anemia |
| ASD |
4.9% |
3.8% |
3.5% |
| ADHD |
9.3% |
7.2% |
7.1% |
| ID |
3.1% |
1.1% |
1.3% |
ASD=autism spectrum disorder; ADHD=attention-deficit hyperactivity disorder; ID=intellectual disability
When the researchers adjusted for socioeconomic, maternal, and pregnancy-related factors, they found that anemia at ≤ 30 weeks' gestation was associated with increased risk of diagnosis of ASD, ADHD, and ID in offspring (OR, 1.44; 95% CI, 1.13 - 1.84; OR, 1.37; 95% CI, 1.14 - 1.64; and OR, 2.20; 95% CI, 1.61 - 3.01, respectively) in models that included those three factors.
The matched sibling analysis yielded similar findings, although the association was higher for ASD compared with the primary analysis.
Preterm birth — especially when labor was induced — accounted for approximately one third of the association between anemia at ≤ 30 weeks' gestation and risk of ASD, ADHD, and ID.
"Anemia that occurred during the first 30 weeks seemed to be a different phenomenon than anemia that occurred later on in pregnancy," said Gardner.
"The fetus begins to take up iron more rapidly around 30 weeks and babies born to mothers who were diagnosed with anemia later in pregnancy tended to weigh more at birth and were more likely to be born at term — between 37 and 42 weeks of pregnancy," she added.
"Babies born to mothers who were diagnosed with anemia earlier on tended to be smaller and were more likely to be born preterm, and the mothers were also more likely to have complicated pregnancies," Gardner explained.
"It’s possible that a lack of iron or other nutrients for a longer period of time during pregnancy influences brain development," she said.
New Insight
Commenting on the findings for Medscape Medical News, Rebecca J. Schmidt, PhD, an associate professor and molecular epidemiologist at University of California Davis School of Medicine who was not involved with the study, said it is "definitely the largest study to address the topic for these [adverse neurodevelopmental] outcomes, especially as thoroughly as these authors have, with examination of major confounders, timing, sibling analyses, mediation analyses, and multiple overlapping neurodevelopmental outcomes."
The results were not surprising, she said, "given [that] it is well-established that iron is necessary for proper neurodevelopment."
Schmidt said, however, that the impact of early anemia on outcomes in offspring was surprising. "It is generally thought that iron deficiency is more of a concern later in pregnancy, but this study, and our previous work, suggests that anemia, and maybe iron sufficiency, going into pregnancy could be most important for neurodevelopmental outcomes."
The study "provides evidence that clinicians need to pay close attention to anemia — and potentially subclinical iron insufficiency — in moms-to-be, starting at the very beginning of pregnancy, and maybe even before," Schmidt added.
Gardner noted that it is important for women to discuss their iron intake, "especially any intake of supplemental iron, with their care provider, to ensure that their intake is adequate but not excessive [since] too much iron can be toxic for the mother and the baby."
The study was supported by grants from the Swedish Research Council/Vetenskapsrådet and the Strategic Research Area Neuroscience (StratNeuro) at the Karolinska Institutet. The Psychiatry Sweden register linkage was supported by a grant from the Swedish Research Council/Vetenskapsrådet. Gardner reported receiving grants from Vetenskapsrådet and the Strategic Research Area Neuroscience (StratNeuro) during the conduct of the study. The other authors and Schmidt have disclosed no relevant financial relationships.
JAMA Psychiatry. Published online September 18, 2019. Full text
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Cite this: Anemia in Early Pregnancy Linked to Autism, ADHD, Intellectual Disability in Kids - Medscape - Sep 24, 2019.
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