Migraine, Fetal Growth Restriction Associated in Men

Fetal growth restriction is characterized by a birthweight below the tenth percentile, according to gender and gestational age.
Fetal growth restriction is characterized by a birthweight below the tenth percentile, according to gender and gestational age.

Fetal growth restriction (FGR) is associated with an elevated risk of migraine in adult men, but not women, according to the results of a population-based study published in PLOS One.1

FGR — characterized by a birthweight below the tenth percentile, according to gender and gestational age — is observed in 9% of newborns in the developed world, and can result due to a number of factors, the most common of which is placental insufficiency.2 FGR was found to be associated with cognitive dysfunction, delayed neurodevelopment, type 2 diabetes, and cardiovascular disease.2-4

In the current study, the researchers evaluated whether adults who were born with FGR also suffered from headaches. The population study leveraged 2 databases: the Nord-Trøndelag Health Survey (HUNT), which was conducted between 2006 and 2008 to assess headache disorders in Norwegians age ≥20 years, and the Norwegian Medical Birth Registry, which contains comprehensive records of body measurements taken at birth. A total of 7354 participants (mean age, 32.3) who had answered 2 questionnaires — with >200 health-related questions, including 14 headache-related questions — and for whom records of birthweight and gestational age were available were included in the study.

Headache characteristics (ie, occurrence, frequency, time, diagnosis) were determined based on the headache portion of the second questionnaire, formulated according to the International Classification of Headache Disorders II.5 A migraine diagnosis required: “(i) Headache attacks lasting ≤72 hours; (ii) Headache with at least 2 of the following characteristics: pulsating quality, unilateral location, moderate to severe intensity or aggravation by physical activity; (iii) During headache, at least 1 of the following: a) nausea and/or vomiting, b) photophobia and phonophobia.” A tension-type headache (TTH) diagnosis required: “(i) Headache at least 1 day a month; (ii) Headache with at least 2 of the following characteristics: bilateral location, pressing quality, mild to moderate intensity and no aggravation by physical activity; (iii) During headache no nausea or vomiting and no phonophobia or photophobia.”

Of study participants, 1335 were classified as having migraine (22.8 % of women; 10.5% of men), 1160 as having TTH, and 3723 as not having headache. Men born “very small for gestational age (VSGA)” (<third percentile) were more likely to present with migraine than men in the control group (7.5% vs 3.0%, P <.001).

An association was found between weight by gestational age and migraine: individuals categorized as VGSA had migraine with an odds ratio (OR) of 1.52 (95% CI, 1.10-2.10, P =.011), compared with individuals considered “appropriate for gestational age (AGA).” Gender had a strong effect on the association between migraine and FGR, with men with VSGA vs AGA showing an OR of 2.73, 95% CI, 1.63-4.58, P <.001). A similar tendency was found in women born both at small (SGA) and very small (VGSA) weights, although this effect was not significant. Men in the VGSA group were much more likely to present with migraine than men in the AGA group (20.9% vs 9.8%). No association was found between FGR and TTH.

The researchers advance several possible mechanisms for the higher prevalence of migraine in individuals born with FGR, citing animal studies showing an association between FGR and neurotransmitter imbalances, including increased glutamatergic activity, decreased GABAergic activity, as well as increased levels of serotonin, dopamine and norepinephrin, which “presents a potential mechanism for an increased propensity for developing migraine due to FGR,” according to the researchers.6-8

The investigators explain the gender differences in the association between FGR and migraine by the fact that “males are especially vulnerable to stressful perinatal events, and that reduced nutrient supply and hypoxia in utero might have greater consequences for the growing brain in males than in females.”


  • The number of study participants with both headache and FGR was low (n=112 with SGA; n=69 with VGSA), particularly for men (n=26 with SGA, n=22 with VSGA).
  • Headache diagnoses were based on a questionnaire vs clinical examination.
  • FGR was determined by weight at birth for gestational age vs fetal blood vessel ultrasound.


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  1. Børte S, Winsvold BS, Stensland SØ, Småstuen MC, Zwart JA. The effect of foetal growth restriction on the development of migraine and tension-type headache in adulthood. The HUNT Study. PLoS ONE. 2017;12(4):e0175908.
  2. Miller SL, Huppi PS, Mallard C. The consequences of fetal growth restriction on brain structure and neurodevelopmental outcome. J Physiol. 2016;594: 807-823. doi.org/10.1113/JP271402
  3. Roth CL, Sathyanarayana S. Mechanisms affecting neuroendocrine and epigenetic regulation of body weight and onset of puberty: potential implications in the child born small for gestational age (SGA). Rev Endocr Metab Disord. 2012;13:129-140. doi.org/10.1007/s11154-012-9212-x
  4. Demicheva E, Crispi F. Long-term follow-up of intrauterine growth restriction: cardiovascular disorders. Fetal Diagn Ther. 2014;36:143-153. doi.org/10.1159/000353633
  5. Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia. 2004;24(Suppl 1): 9-160.
  6. Hernández-andrade E, Cortés-camberos AJ, Díaz NF, et al. Altered levels of brain neurotransmitter from new born rabbits with intrauterine restriction. Neurosci Lett. 2015;584:60-65.
  7. Minkowski A, Chanez C, Priam M, et al. Long lasting effects of intrauterine malnutrition on neurotransmitters metabolism in the brain of developing rats. Prog Clin Biol Res. 1981;77:643-660.
  8. Jensen A, Klönne HJ, Detmer A, Carter AM. Catecholamine and serotonin concentrations in fetal guinea-pig brain: relation to regional cerebral blood flow and oxygen delivery in the growth-restricted fetus. Reprod Fertil Dev. 1996;8(3):355-364.
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