Harlow Center for Biological Psychology and the Department of Psychology, University of Wisconsin, Madison, WI 53715, USA
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Abstract |
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Key words: birth weight/intergenerational trends/intrauterine constraint/Macaca mulatta/reproductive health
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Introduction |
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This primate population is unique in that detailed birth and pedigree records have been compiled on every animal born to this closed breeding colony since it was founded over 40 years ago. Based on these archives, we discovered that the birth weights of rhesus monkeys, like humans, followed a matrilineal transmission pattern, with an infant's weight being highly associated with those of its mother and its maternal relatives across several generations (Price et al., 1999). Because the care and nutrition provided under laboratory conditions has remained fairly uniform, the observed trends within matrilines were more probably attributable to intrauterine factors characterizing the lineage than to lifestyle differences between families, a confounding factor that often complicates human studies of familial birth weight patterns. Further, we found that improved resource availability in the laboratory versus the feral environment led to larger infants in association with increased maternal pregravid weight and pregnancy weight gain, suggesting that gestational processes may govern the rate of prenatal development by monitoring maternal energy balance. Even more striking, the increase in birth weight was considerably larger for the female offspring and essentially eliminated the typical sexual dimorphism in infant birth weight within four generations. As the daughters provide the uterine milieu for the next generation, a mechanism that adjusts the growth of female fetuses in response to local resources may offer an efficient means for selection toward the optimal birth weight sustainable by the environment.
For our earlier analyses we considered only the data derived from average-for-date (AFD) births. However, women who deliver a large- or small-for-gestational age infant are more likely to produce another such birth and those who were themselves born small-for-date are at greater risk of poor pregnancy outcomes (Bakketeig et al., 1979; Hackman et al., 1983
; Klebanoff et al., 1984
; Magnus et al., 1997
; Skjærven et al., 1997
). Thus, we have now extended our analyses to focus on the inheritance patterns and reproductive consequences for small-for-date (SFD) and large-for-date (LFD) monkeys. In addition, as nearly all the first-degree descendants within a lineage were half, rather than full, siblings, we had a novel opportunity to distinguish the maternal from the paternal contributions to the familial birth weight patterns.
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Materials and methods |
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Experimental design (see Figure 1)
Female monkeys were time-mated by housing them with a breeder male during a 4-day period at the time of ovulation. Once conception occurred, females were typically housed individually in stainless steel cages (0.8x0.8x0.8 m) for the remainder of pregnancy. The neonates were first observed between 06.0007.00 hours, and most (>75%) were weighed on the day of birth. Because infants lost and then regained ~5% of their body weight over the first week of life, birth weights taken beyond the first day were adjusted according to the formula: birth weight + 0.174 x4 3.27 x3 + 17.786 x2 27.118 x, where x = the number of days after birth that the weight was first recorded. This formula was derived by fitting a polynomial function to the birth weights that were recorded between days 1 and 7 of life. Neonates not weighed within the first week of life (<1%) were excluded from the analyses. These elimination criteria yielded a multigenerational database on 2354 singleton infants (2170 live born, 184 stillborn) born during the last 40 years.
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Statistics
All statistical tests were conducted using procedures in the Statistical Package for the Social Sciences, Version 8.0 (SPSS Inc., Chicago, IL, USA). For the index infants and their offspring, the main effects of proband grouping and sex on birth weight were assessed by two-way analysis of variance (ANOVA), with Scheffé's tests used for pairwise comparisons by group and gender (significance established at P < 0.05). The birth weights of the probands' relatives were compared with those of the corresponding AFD using independent sample t-tests, with a Bonferroni correction for multiple comparisons (two-tailed, with significance established at P < 0.025). To evaluate whether familial patterns in birth weight were equivalent for both sexes, mean birth weights of proband brothers and sisters were compared with AFD males and females, respectively, using independent sample t-test, with a Bonferroni correction for multiple comparisons (two-tailed, with significance established at P < 0.00625).
The incidence of stillbirth, preterm birth, growth restriction and macrosomia among the offspring of SFD and LFD proband females was evaluated using odds ratios (95% confidence intervals) with the infants of AFD control females as the reference group. Odds ratios associated with Fisher's exact test having P < 0.05 were considered statistically significant.
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Results |
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The influence of birth weight in females extended to other aspects of their reproductive functioning. Females born SFD were significantly older than other mothers when giving birth to their first infant (6.03 ± 0.32 versus 5.07 ± 0.17 years; P < 0.01). They also experienced a higher rate of neonatal mortality and were at greater risk of delivering preterm and SFD infants, particularly among the female progeny (P < 0.05 in all cases; Table I). Despite the lower birth weights and poorer outcomes of their offspring, females born SFD still had pregravid weights comparable to those of AFD-born mothers (6.21± 0.16 versus 6.42 ± 0.08 kg for SFD and AFD females respectively), suggesting they were neither of small stature nor in poor health. In contrast, females born LFD had higher pregravid weights (6.91 ± 0.21 versus 6.42 ± 0.08 kg; P < 0.05) and were more likely to produce LFD infants (P < 0.05) than AFD mothers. Moreover, the incidence of aberrant pregnancy outcomes (specifically, stillbirth and prematurity) for LFD-born females did not differ from control pregnancies.
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Discussion |
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Our data from the rhesus monkey confirm and extend earlier human studies: the birth weights of maternal relatives followed that of the proband, with the mothers and maternal half-siblings of LFD and SFD infants respectively heavier or lighter than AFD controls at birth. Conversely, the mean birth weights of the probands' paternal relatives did not differ from those of AFD infants, suggesting that the maternal influence was more pervasive for both SFD and LFD fetal growth patterns in this species. In human studies, assortive mating may contribute to the increased birth weight observed among paternal family members of LFD infants, but in our monkey colony the breeding of half- rather than full-siblings eliminated this potential confounding factor from our analyses. Accordingly, these findings concur with an early report in humans that detected a significant association between birth weights of maternal, but not paternal, half-siblings (Morton, 1955).
Beyond the matrilineal constraint, birth weight varied by infant sex in a predictable manner. Though males weighed more at birth than females overall, the SFD infants did not exhibit this typical malefemale dimorphism. The absence of this difference among SFD probands supports the assertion that maternal constraint overrides the influence of other variables, such as infant sex, at the lower end of the birth weight distribution. As dramatic was the finding that the consequences of maternal constraint were much more pervasive for female descendants within the SFD matrilines. The daughters and maternal half-sisters of the SFD probands weighed significantly less than AFD females and their daughters at birth, whereas the birth weights of their half-brothers and sons, while apparently somewhat reduced, were not different from the AFD males. In contrast, the operation of other factors in promoting fetal growth is evident at the upper end of the birth weight continuum: in addition to the expression of the male-female dimorphism in birth weight of LFD probands, both the maternal half-brothers and -sisters showed a similar degree of growth acceleration when compared to AFD controls.
Our presentation of transgenerational patterns in birth weight indicates that one pregnancy should not be viewed as an independent event, but as a manifestation of the reproductive health of a female's lineage overall. As described for women (Hackman et al., 1983; Klebanoff et al., 1984
; Coutinho et al., 1997
; Skjærven, et al., 1997
), a female monkey's birth weight had important consequences for her later reproductive performance. In addition to selectively restricting the prenatal growth of their daughters, females born SFD were nearly a year older than other monkeys at the birth of their first infant, and they were at greater risk for delivering a stillbirth and for bearing live infants that were either SFD or premature, particularly if the offspring was a daughter. While females born LFD were more likely to produce LFD infants, they did not experience such adverse reproductive consequences. Given the finding that a mother's own intrauterine experience can directly influence her daughters' fetal development (and subsequently, their reproductive performance), it could take several generations to ameliorate the impact of a poor pregnancy outcome within a family. If similar mechanisms operate in humans, these uterine-mediated, intergenerational factors might help to clarify the persistence of low birth weight births among high-risk populations, despite the initiation of prenatal interventions aimed at improving pregnancy outcomes (Raine et al., 1994
; Coutinho et al., 1997
).
Some advocate that birth weight is a marker for events occurring both before and after birth, as the social and environmental conditions that produce low birth weight infants are likely to continue operating on the child postnatally (Bartely et al., 1994; Paneth, 1994
). While of potential significance in humans, this observation is particularly relevant in the context of the matriarchal social organization of the rhesus monkey. Daughters remain in the troop and are destined to occupy the social position of their mothers, whereas the status of the dispersing sons that emigrate from the group is more labile (Berman, 1988
). Though the postnatal rearing environment clearly directs the learning of complex social behaviours, uterine factors operating prenatally could facilitate the process of rank acquisition. Accordingly, in environments where female-biased philopatry (and consequently, female/female resource competition) prevails, daughters of low-ranking mothers may benefit more than sons from a mechanism that restricts fetal growth and programmes the endocrine and metabolic axes in utero to acclimatize to a poorer quality of life. Yet, even in a laboratory environment that provided all essential resources, SFD mothers and their daughters experienced higher perinatal mortality and impaired reproductive performance, indicating that any survival advantages conferred to the neonate by intrauterine programming might come at the cost of reduced fecundity in adulthood.
Though the term `maternal constraint' may be taken to imply that the mother is physically incapable of carrying a fetus too large for her to bear, our data are consistent with human studies demonstrating that maternal pregravid weight does not differ significantly between SFD and AFD mothers (Ounsted et al., 1986). Thus, maternal stature, as reflected by her weight at the time of fertile mating, was not sufficient to account for the restricted fetal development experienced by the daughters of SFD mothers. Rather, intrauterine constraint more probably reflects altered maternal metabolic processes or uterine/placental transport mechanisms that limit the provision of nutrients to the fetus. Studies in both rodents (Pollard, 1986
; Pinto and Shetty, 1995
) and humans (Skjærven et al., 1997
) have suggested that prenatal stress and undernutrition can lead to deviant fetal and infant growth patterns that persist for several generations. Our findings extend these conclusions to suggest that they may be mediated through a special relationship between mothers and daughters by means of a gestational imprinting that takes place during fetal development.
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Acknowledgments |
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Notes |
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References |
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Submitted on April 30, 1999; accepted on October 22, 1999.