IJE Advance Access originally published online on February 14, 2008
International Journal of Epidemiology 2008 37(2):250-252; doi:10.1093/ije/dyn009
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Commentary: On ‘Transmission through the female line of a mechanism constraining human fetal growth’—does it exist?
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, PO Box 281, SE-171 77 Stockholm, Sweden. E-mail: Sven.Cnattingius{at}ki.se
Accepted 20 December 2007
In 1986, just before the start of the era of studies focusing on ‘fetal programming of adult disease’, Margaret Ounsted and colleagues1 published a timely observational study, focusing on birth weight and fetal growth across generations.
Previously, results from animal studies, including the classical cross-breeding studies between large Shire horses and Shetland ponies, had strongly suggested that the maternal effect on fetal growth overrides the paternal effect. Moreover, in another animal study, the maternal effect on fetal growth restriction was larger than the maternal effect on fetal growth enhancement.
Ounsted and colleagues used information on birth weight from relatives of infants (‘probands’) being born ‘small-for-gestational age’ (SGA; less than 2 standard deviations (SD) below the mean birth weight for gestational age), ‘large-for-gestational age’ (LGA; more than 2 SD above the mean) and ‘appropriate-for-gestational age’ (AGA; between –2 and +2 SD). In all relatives to LGA probands, birth weight was above the average. Mothers of LGA infants had (after adjustment for sex), higher birth weight than fathers of LGA infants. Among relatives of LGA probands, the birth weights decreased with increasing genetic distance both on the maternal and paternal lines. In contrast, when studying relatives of SGA probands, the maternal line was, irrespective of genetic distance, more important than the paternal line. Not only birth weight of mothers, but also birth weights of relatives on the maternal side (mother's siblings and aunt's children) showed larger birth weight deficits than father's birth weight and birth weights of relatives on the father's side.
The main conclusions of Ounsted and colleagues were:
- Fetal growth over generations is largely dependent on maternal transmission, while the paternal contribution is less. This indicates that maternal genetic effects are of more importance than paternal genetic effects.
- In addition to a genetic pathway, a mechanism triggering fetal growth restriction may be transmitted over generations through the female line.
From twin studies, estimates of heritability in birth weight and birth weight for gestational age range between 40% and 50%.6 By use of large population-based family data, it has lately been possible to study the contribution of maternal and fetal genetic effects. A Norwegian study found that maternal and fetal genetic factors accounted for 22 and 31% of the variation in birth weight, respectively.7 A Swedish study compared the liability of SGA offspring in families joined by full siblings (i.e. the liability of SGA offspring in pairs of sisters, brothers and sister–brother pairs). Thirty-seven percent of the variation in the liability of SGA births was attributable to fetal genetic effects and 9% to maternal genetic effects.8
Thus, both mothers and fathers contribute to the fetal genetic effect, and fathers cannot contribute to fetal growth by any other biologic mechanism. In mothers, there are also a number of other plausible mechanisms to consider. Social and environmental factors (for example, smoking, nutrition and physical activity) influence fetal growth, and such factors may also persist over generations.
Few studies have supported the hypothesis proposed by Ounsted et al.1 that the intergenerational growth-constraining effect carried by mothers is larger than corresponding growth-enhancing effect. Some supportive evidence can be derived from a study reporting that mothers with two SGA infants had lower birth weights than mothers with only one SGA infant, while no such effect was observed among fathers.4 However, results from a nation-wide Swedish study do not support this hypothesis. Among mothers born SGA (
2 SD), rates of very (2 SD) and moderately (–2 to 1 SD) SGA infants were 6.7 and 26.3%, respectively. Among mothers born large for gestational age (LGA, defined as > +2 SD), rates of very (> +2 SD) and moderately (+2 to <+1 SD) LGA infants were 7.4 and 22.1%, respectively.9 Hyppönen et al.5 found no intergenerational birth weight associations for mothers who were very small or large at birth. The Swedish study of offspring in families joined by siblings found no effect of the shared sibling environment (i.e. similarities in intrauterine, childhood and adolescent environment) for the liability of SGA birth.8
Even if we assume that such a mechanism exists, we are still groping for the underlying causes. Both maternal nutrition and smoking are causally related to fetal growth. The mean reduction in birth weight is around 250 g both in offspring to mothers exposed to the Dutch hunger winter in the third trimester10 and in offspring prenatally exposed to maternal smoking.11 In offspring, birth weight is reduced if the mother was prenatally exposed to the Dutch famine,10 but unaffected by grandmother's smoking.12 Prenatal smoking exposure usually means being exposed to fetal growth constraint (by smoking) throughout pregnancy. During the Dutch hunger winter, the exposure to fetal growth constraint (by famine) was restricted to a part of pregnancy, and the reduction in birth weight was largest among those exposed in the third trimester. However, in the second generation, trimester of exposure was not a determinant of birth weight, other than through its effects on mother's birth weight.10
Today there is limited evidence that there is, in addition to a genetic effect, also an intergenerational fetal growth constraining mechanism transmitted through the female line. However, environmental factors influencing fetal growth and the intrauterine environment among mothers may have other adverse health effects in offspring. For example, offspring of mothers with low birth weight have also an increased risk of perinatal mortality.13 Given the considerable interest in studies based on the hypothesis that fetal growth influences subsequent risks of chronic diseases, we have only seen the beginning of studies focusing on parental birth characteristics and long-term offspring health outcomes.
Conflict of interest: None declared.
 |
References |
|---|
 Top References |
|---|
1 Ounsted M, Scott A, Ounsted C. ransmission through the female line of a mechanism constraining human fetal growth. Ann Hum Biol (1986) 13:143–51. Reprinted Int J Epidemiol 10.1093/ije/dyn008.[CrossRef][Web of Science][Medline]
2 Coutinho R, David RJ, Collins JW Jr. Relation of parental birth weights to infant birth weight among African Americans and whites in Illinois: a transgenerational study. Am J Epidemiol (1997) 146:804–9.
3 Klebanoff MA, Mednick BR, Schulsinger C, Secher NJ, Shiono PH. Father's effect on infant birth weight. Am J Obstet Gynecol (1998) 178:1022–26.[CrossRef][Web of Science][Medline]
4 Magnus P, Bakketeig LS, Hoffman H. Birth weight of relatives by maternal tendency to repeat small-for-gestational-age (SGA) births in successive pregnancies. Acta Obstet Gynecol Scand Suppl (1997) 165:35–38.[Medline]
5 Hypponen E, Power C, Davey Smith G. Parental growth at different life stages and offspring birthweight: an intergenerational cohort study. Paediatr Perinat Epidemiol (2004) 18:168–77.[CrossRef][Web of Science][Medline]
6 Clausson B, Lichtenstein P, Cnattingius S. Genetic influence on birthweight and gestational length determined by studies in offspring of twins. Br J Obstet Gynaecol (2000) 107:375–81.[Web of Science]
7 Lunde A, Melve KK, Gjessing HK, Skjaerven R, Irgens LM. Genetic and environmental influences on birth weight, birth length, head circumference, and gestational age by use of population-based parent-offspring data. Am J Epidemiol (2007) 165:734–41.
8 Svensson AC, Pawitan Y, Cnattingius S, Reilly M, Lichtenstein P. Familial aggregation of small-for-gestational-age births: the importance of fetal genetic effects. Am J Obstet Gynecol (2006) 194:475–79.[CrossRef][Web of Science][Medline]
9 Selling KE, Carstensen J, Finnstrom O, Sydsjo G. Intergenerational effects of preterm birth and reduced intrauterine growth: a population-based study of Swedish mother-offspring pairs. Br J Obstet Gynaecol (2006) 113:430–40.
10 Stein AD, Lumey LH. he relationship between maternal and offspring birth weights after maternal prenatal famine exposure: the Dutch Famine Birth Cohort Study. Hum Biol (2000) 72:641–54.[Web of Science][Medline]
11 Surgeon General 2001. Health consequences of tobacco use among women. Reproductive outcomes. In: Women and smoking A report of the Surgeon General. (2001) Rockville, MD: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office of Smoking and Health. 272–307.
12 Hypponen E, Davey Smith G, Power C. Effects of grandmothers’ smoking in pregnancy on birth weight: intergenerational cohort study. Br Med J (2003) 327:898.
13 Skjaerven R, Wilcox AJ, Oyen N, Magnus P. Mothers’ birth weight and survival of their offspring: population based study. Br Med J (1997) 314:1376–80.
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||