You are what your mother eats: evidence for maternal pre-conception diet influencing fetal sex in humans.

    - http://journals.royalsociety.org/content/w260687441pp64w5/fulltext.pdf

Fiona Mathews^1*, Paul J. Johnson² and Andrew Neil³

¹ School of Biosciences, University of Exeter, Hatherly Laboratories, Prince of Wales Road, Exeter, EX4 4PS, UK.

² Wildlife Conservation Research Unit, Department of Zoology, University of Oxford, South Parks Road, Oxford, OX1 3PS, UK.

³ Division of Public Health and Primary Health Care, Institute of Health Sciences, University of Oxford, PO Box 777, Oxford, OX3 7LF, UK

*Author for correspondence (f.mathews@exeter.ac.uk)

Electronic supplementary material (ESM)

Discussion of measurement error in dietary studies

The within-subject variability associated with dietary assessments will attenuate the observed associations between the outcome and exposure measure, depressing odds ratios towards zero. The sources of this variability are measurement error (the difference between true intake and that actually recorded), and the variation of individuals around their true mean due temporal variation in diet (when measured repeatedly with a valid instrument). The depression of the strength of associations occurs because of the statistical phenomenon of regression to the mean, where true values are less extreme than those measured. The phenomenon arises as follows. Any group of individuals with a measured exposure x will be a mixture of individuals with true values that are higher and lower than x. However, if there is a bell-shaped distribution of these true measurements - as is usually the case - then it follows that individuals with true values closer to the population mean will predominate, and there will be few people with extreme values. Thus the mean true exposure for a group with a measured exposure x will be intermediate between x and the population mean. The overall effect is to flatten the slope of regression lines. The importance of this kind of error has only been recognised relatively recently. By comparison, the more familiar type of error (random between-person) implies that an over-estimation for some individuals is counterbalanced by underestimation for others, so that the mean for a large group of subjects is the true mean of the group. This increases the width of confidence intervals without affecting the slope of regression lines. It is important to note that either type of error will not act to generate of spurious relationships in our data: this would generally require differential misreporting of diet by women carrying male rather than female fetuses (Willett 1990; Clayton & Gill 1991).

Evolutionary context

In humans, the extended period of juvenile dependency means that the unit cost of producing offspring is high, and males appear more expensive than females (Clutton-Brock & Iason 1986; Frank 1987; Hrdy 1999). Bearing male offspring may also be expensive in the long-term by increasing mortality in women (Helle et al. 2002; Hurt et al. 2006) – though this is disputed (Cesarini et al. 2007) – and reducing the lifetime reproductive output of subsequent offspring (Rickard et al. 2007). According to evolutionary theory, these are circumstances in which differential investment in a particular sex according to resource availability is to be expected (Koziel & Ulijaszek 2001). Most research has focused on the relationship between parental status (measured by financial resources etc.) and offspring sex. There are a variety of scenarios where high status might be expected to confer more benefits on the reproductive success of a male than a female child. For example, in most societies, inheritance of wealth and property passes to sons rather than daughters (Hrdy & Judge 1993) whereas women seek mates of high status more than men do and tend to marry up the socio-economic scale (Buss 1989; Lazarus 2002). High status men can therefore gain more mates and obtain them earlier than lower status ones, whereas this is less true for women (Buss 1992). Yet only about half of the known studies of parental status and offspring sex have found associations in the expected direction (Lazarus 2002).

Several competing hypotheses, developed with other species, have been proposed to explain associations between resource availability and the differential investment in offspring of one sex rather than the other. These include the Trivers-Willard effect (when resources are plentiful, parents should invest in males since these achieve a greater increase in reproductive success from a given level of investment)

(Trivers & Willard 1973) and the cost of reproduction hypothesis (females in poor condition should not invest in the more costly sex to minimise the risk of failure and/or to increase the prospects that they will breed again successfully in the future) (Myers 1978; Gangestad & Simpson 1990). Local conditions, such as competition or co-operation between non-dispersive offspring and their parents or kin, may also determine parental investment patterns, since they will influence the parent’s inclusive fitness (Clark 1978; Borgerhoff Mulder 1998). Finally, according to Fisher’s theory, selection should favour shifts in sex ratio against any current population bias (Werren & Charnov 1978). This could explain the increase in birth sex ratio during war time (James 1971; Graffelman & Hoekstra 2000) since local adult sex ratios are low at such times. Such Fisherian effects may counteract the influence of maternal resource availability, and make wartime datasets difficult to interpret (Stein et al. 2004). Unfortunately it is hard to provide definitive tests of such theories using observational data from humans, due to the difficulty of obtaining long-term datasets. Distinguishing between the relevant theories would require not only the measurement of the reproductive output of the parent and the cost of each sex, but also the reproductive success of all offspring.

Table 1. Usual daily dietary intakes^*of women between 16 and 28 week’s gestation by fetal sex.

	median (lower, upper quartile) male fetus female fetus (n=327) (n=334)		Chi-square	p-value
energy (kcal)	2218 (1828, 2692)	2165 (1808, 2636)	53122.0	0.287
fat (g)	81.2 (65.2, 105.6)	83.4 (66.7, 100.1)	55355.0	0.860
% energy from fat	33.7 (30.5, 36.8)	34.4 (31.3, 36.9)	52087.5	0.139
protein (g)	87.3 (72.0, 105.4)	85.1 (67.9, 103.7)	52980.5	0.262
% energy from protein	15.7 (13.9, 17.2)	15.6 (13.9, 17.2)	55226.0	0.825
carbohydrate (g)	321 (264, 385)	306 (253, 373)	51632.0	0.097
% energy from carbohydrate	57.5 (53.8, 61.1)	56.4 (52.8, 60.2)	51025.0	0.057
vitamin C (mg)	108 (74, 148)	108 (69, 148)	54942.0	0.738
vitamin E (mg)	6.9 (5.5, 8.6)	6.9 (5.7, 8.4)	55007.5	0.758
ß-carotene (µg)	1477 (998, 2525)	1591 (942, 2478)	54442.0	0.593
retinol (µg)	424 (311, 579)	425 (305, 558)	54246.0	0.540
vitamin B12 (µg)	6.4 (4.6, 9.9)	6.4 (4.0, 9.3)	53220.0	0.305
folate (µg)	366 (299, 452)	347 (286, 432)	50856.0	0.049
iron (mg)	12.5 (10.4, 15.3)	12.3 (10.1, 14.9)	52192.0	0.151
zinc (mg)	10.6 (9.0, 13.4)	10.8 (8.4, 13.6)	54503.5	0.610
sodium (mg)†	3870 (3151, 4690)	3720 (2985, 4631)	51213.0	0.067
calcium (mg)	1323 (1013, 1613)	1269 (936, 1665)	53261.0	0.313
potassium (mg)	4314 (3706, 5057)	4217 (3391, 5105)	52798.0	0.232

Borgerhoff Mulder, M. 1998 Brothers and sisters: how sibling interactions affect optimal parental allocations. Hum. Nature 9, 119-162.

Buss, D.M. 1989 Sex-differences in human mate preferences – evolutionary hypothesis tested in 37 cultures. Behav. Brain. Sci. 12, 1-14.

Buss, D.M. 1992 Mate preference mechanisms: Consequences for partner choice and intrasexual competition. In The Adapted Mind: Evolutionary Psychology and the Generation of Culture (eds. J.H. Barkow, L. Cosmides & J. Tooby), pp. 250-266. New York: Oxford University Press.

Cesarini, D., Lindqvist, E. & Wallace, B. 2007. Maternal longevity and the sex of offspring in pre-industrial Sweden. Ann. Hum. Biol. 34, 535-546.

Clark, A.B. 1978 Sex-ratio and local resource competition in a prosimian primate. Science 201, 163-166.

Clayton, D. & Gill, C. 1991 Covariate measurement errors in nutritional epidemiology: effects and remedies. In Design Concepts in Nutritional Epidemiology (eds. B.M. Margetts & M. Nelson) pp. 79-96. Oxford: Oxford University Press.

Clutton-Brock, T.H. & Iason, G.R. 1986 Sex ratio variation in mammals. Q. Rev. Biol. 61, 339-374.

Frank SA. 1987 Individual and population sex allocation patterns. Theor. Popn. Biol. 31: 47-74.

Gangestad, S.W. & Simpson, J.A. 1990 Toward an evolutionary history of female sociosexual variation. J. Personality 58: 69-96.

Graffelman, J. & Hoekstra, R.F. 2000 A statistical analysis of the effect of warfare on the human secondary sex ratio. Hum. Biol. 72, 433-445.

Helle, S., Lummaa, V., & Jokela, J. 2002 Sons reduced maternal longevity in preindustrial humans. Science 296, 1085-1085.

Hrdy, S.B. 1999 Mother Nature: A History Of Mothers, Infants And Natural Selection New York: Random House.

Hurt, L.S., Ronsmans, C., Quidgley, M. 2006 Does the number of sons born affect long-term mortality of parents? A cohort study in rural Bangladesh. Proc. R. Soc. B 273, 149-155.

James, W.H. 1971 Cycle day of insemination, coital rate and sex ratio. Lancet I, 112-114.

Koziel, S. & Ulijaszek, S.J. 2001 Waiting for Trivers and Willard: do the rich really favour sons? Am. J. Phys. Anthropol. 115, 71-79.

Lazarus, J. 2002 Human sex ratios: Adaptations and mechanisms, problems and prospects. In Sex ratios: concepts and research methods. (ed. I.C.W Hardy) pp. 287-311. Cambridge: Cambridge University Press

Myers, J.H. 1978 Sex ratio adjustment under food stress: maximization of quality or numbers of offspring? Am. Nat. 112, 381-388.

Pérusse, D. 1993 Cultural and reproductive success in industrial societies – testing the relationship at the proximate and ultimate levels. Behav. Brain Sci. 16, 267-283.

Rickard, I.J., Russell, A.F. & Lummaa, V. 2007. Producing sons reduces lifetime reproductive success of subsequent offspring in pre-industrial Finns. Proc. R. Soc. B. 274, 2981-2988.

S. B. Hrdy & Judge, D.S. 1993 Darwin and the puzzle of primogeniture. Hum. Nature 4, 1-45.

Stein, A.D., Zybert, P.A. & Lumley, L.H. 2004 Acute undernutrition is not associated with excess of females at birth in humans: the Dutch Hunger Winter. Proc. R. Soc. B 271, S138-S141.

Trivers, R.L. & Willard, D.E. 1973 Natural selection of parental ability to vary the sex ratio of offspring. Science 179, 90-92.

Werren, J.H. & Charnov, E.L. 1978 Facultative sex ratios and population dynamics Nature 272, 349-350.

Willett, W. 1990 Nutritional Epidemiology New York: Oxford University Press.