Although no constraint-related factor had a large overall influence on craniosynostosis and some data were too sparse to allow for a well grounded scientific inference, our study found that plurality and nulliparity were both associated with a two fold increased risk for metopic craniosynostosis, plurality was associated with sagittal synostosis only when including cases with fertility treatments, and macrosomia had almost twice the risk of developing coronal craniosynostosis. Contrary to our hypothesis, prematurity and low birth weight were associated with craniosynostosis, rather than macrosomia and post-term gestation. Although the 4 hypothesized constraint-related factors were not associated with craniosynostosis when all suture types were combined, some types of craniosynostosis were associated with individual constraint-related factors.
Approximately 8% of all craniosynostosis cases are familial, with such cases usually transmitted as an autosomal dominant trait with incomplete penetrance and variable expressivity. Familial types account for 14.4% of coronal synostosis, 6% of sagittal synostosis, and 5.6% of metopic synostosis, while lambdoidal synostosis is almost never familial [Lajeunie et al., 2005
]. The lower prevalence of familial cases for sagittal, metopic and lambdoidal synostosis, when compared with coronal synostosis may suggest a greater environmental influence.
Published results have been mixed regarding associations between constraint-related factors and nonsyndromic craniosynostosis [Alderman et al., 1988
; Boulet et al., 2008
; Reefhuis et al., 2003
; Singer et al., 1999
]. A study by Alderman et al. of 173 children with craniosynostosis and 759 control infants showed an association between multiple gestation and craniosynostosis (OR 3.0, 95% CI 1.2–7.1), but no association with parity [Alderman et al., 1988
]. A study from Western Australia of 170 case infants and 522 control infants examined constraint-related factors including prolonged gestation >42 weeks, plurality, and macrosomia, and none of these were significantly associated with craniosynostosis [Singer et al., 1999
]. Similar to our findings, these investigators found an association between preterm delivery (< 37 weeks) and craniosynostosis (OR 2.9; 95% CI 1.8, 4.8) [Singer et al., 1999
]. Källén et al. conducted an investigation using Swedish health registries and found an association with high parity (of 4 or more) (OR 1.7; 95% CI 1.2–2.4) for all forms of craniosynostosis, but no significant linear trend except for sagittal synostosis (p for linear trend = 0.01). Reefhuis et al found no association between multiple births nor primigravidity and craniosynostosis [Reefhuis et al., 2003
]. Most recently Boulet et al. showed an increased prevalence of craniosynostosis among multiple births and infants with a birth weight >4000g [Boulet et al., 2008
We found that the association of craniosynostosis with constraint-related factors varied by suture type and that these covariates were difficult to disentangle, despite having access to a large number of subjects. Fertility treatments and plurality are strongly associated with each other [Aston et al., 2008
; Hoekstra et al., 2008
], and fertility treatments may be associated with craniosynostosis [Reefhuis et al., 2003
]. When we excluded subjects with fertility treatments, however, results for plurality were essentially unchanged for all suture types.
Gestational age and size at birth are highly correlated with each other and for analytic completeness our study and others have assessed the opposite ends of each factor. For low birth weight, it is important to distinguish between intrauterine growth restriction, which often demonstrates catch-up growth, and fetal growth deficiency, where typically no catch-up growth occurs. Fetal growth deficiency that continues after birth is associated with numerous syndromes and other problems [Rimoin and Graham 1989
; Snijders et al., 1993
]. It is possible that one of the many risk factors for prematurity is fetal constraint, yet based on the available dataset, we cannot determine the impact of fetal constraint on preterm delivery. Longitudinal studies have demonstrated evidence that constrained infants from multiple births are commonly born preterm with a low birth weight and typically show prompt postnatal catch-up growth [Dubois et al., 2007
; Ijzerman et al., 2001
; van Dommelen et al., 2008
], and this has also been shown for infants with late fetal growth restriction [Harvey et al., 1979
On the opposite end of the spectrum, post-maturity or prolonged gestation is associated with large for gestational infants [Chervenak 1992
] and has a higher incidence of birth complications [Shea et al., 1998
]. Although our study did not demonstrate evidence for an association between prolonged gestation and craniosynostosis, prolonged gestation has been associated with craniosynostosis in an animal model. In a murine study where fetal constraint was generated using a cervical clip and by delaying birth by 2–3 days, 88% of the 26 treated pregnant mice had evidence of craniosynostosis [Koskinen-Moffett 1986
]. However, not all animal studies demonstrate such a strong association with craniosynostosis. Some hypothesize that a murine model is not an ideal system to study constraint, given that multiple gestation pregnancies are typical and the gestational period results in the birth of offspring that are significantly less developed.
Although low birth weight and early gestational delivery were not part of our proposed proxies for fetal constraint, both were assessed and found to be associated with the risk of developing craniosynostosis. Although speculative, it is possible that late gestational constraint could lead to early delivery of a fetus that is small in size due to premature delivery. Because of a consistent relationship between craniosynostosis and low birth weight/preterm delivery, factors involving preterm labor and delivery should be explored in more detail. Size at birth may potentially be more influenced by maternal size than by the intrinsic growth determinants of the fetus [Brooks et al., 1995
; Drooger et al., 2005
]. Many factors contribute to the occurrence of low birth weight, including genetic and environmental factors such as parity, pregnancy spacing, maternal age and size, blood pressure, race, health, smoking, alcohol intake, twinning and intrauterine constraint [Cogswell and Yip 1995
; Drooger et al., 2005
; Opitz et al., 1985
]. The influence of fetal constraint on size at birth has been studied in animal models, with the best example from 1938 where Walton and Hammond bred Shire horses (large) with the much smaller Shetland ponies and varied only the maternal breed (size). Birth weight correlated with maternal breed and size [Walton A. and Hammond J. 1938
]. This suggests that late-gestational growth restriction due to small maternal size is compensated by rapid postnatal catch-up growth. Human studies reported similar observations for babies born after ovum donation, and their size at birth correlated more strongly with the ovum recipients than the ovum donors with respect to birth weight [Brooks et al., 1995
]. It would be of interest to know in this cohort if low birth weight/preterm delivery is more common among fetuses delivered to short-statured mothers with tall partners, and whether or not such fetuses show prompt postnatal catch-up growth, as is frequently seen with multiple gestation infants carried to near term.
As has been documented in other studies of craniosynostosis, [Boulet et al., 2008
; Singer et al., 1999
], we also noted a male and non-Hispanic white predominance among the cases, compared to controls. Both of these variables could be associated with larger head size at birth, and this might suggest a role for fetal head constraint [Madan et al., 2002
]. The association between macrosomia and pre-existing maternal diabetes is well accepted [Spellacy et al., 1985
]. Because pre-existing diabetes is also associated with an increased risk for malformations, this factor was considered to be a criterion for exclusion of both cases and controls, even though isolated craniosynostosis is not a diabetes-related malformation [Correa et al., 2008
]. Although we used an accepted definition of macrosomia (birth weight >4000g) as a surrogate for (unmeasured) large size in late gestational development, it is still unclear when in gestation premature suture fusion occurs, thus making it difficult to define the window of fetal development when the calvarial sutures are influenced by teratogens or the influences of size on fetal head constraint.
As the largest population-based study completed to date, our study had several strengths in assessing these four constraint-related factors. Not only were we able to assess an appropriate control population, we also have the statistical power to adjust for the available confounders. Also, all cases were clearly identified and reviewed by a clinical geneticist to ensure the study’s inclusion criteria were met. However, our study also had several limitations. Attempts were made to exclude infants with craniosynostosis of known etiology (e.g., single-gene disorders and chromosome abnormalities) through careful review of information abstracted from medical records. However, infants mildly affected with these conditions and infants with Muenke syndrome were quite likely to have been inappropriately included, since molecular testing was not routinely performed on these infants. If molecular testing was pursued clinically and found to be abnormal, then these infants were excluded from the study. We assumed that syndromic cases might be more frequent among infants with coronal involvement; thus we analyzed infants with sagittal, metopic and coronal involvement separately. There were too few infants of multiple sutural involvement or lambdoid involvement to perform a meaningful analysis, so these groups were not analyzed separately from infants with either sagittal, coronal or metopic involvement.
We acknowledge that although multiple gestation, macrosomia, post dates, and nulliparity are relatively easy to ascertain using a maternal questionnaire and though they are good measures of general constraint, they may not reflect fetal head constraint, which is the issue in question. The four factors we chose are either poor proxies for fetal head constraint or not major factors in the overall cause of non-syndromic craniosynostosis, which is likely a multifactorial defect of heterogeneous etiology. Yet these were the variables available in this very large dataset that systematically ascertained data using one of the most comprehensive questionnaires administered to both case and control mothers. Another limitation is that the NBDPS does not routinely ascertain information on in utero
positioning or amniotic fluid status (e.g., oligohydramnios) across all sites. The risk of recall bias, for example, relying on parental recall of use of fertility treatment instead of abstracting data from all medical records, was another weakness. Also, information was collected by telephone several months after delivery and the interval between delivery and phone interview was different between the cases and controls. Although fetal head constraint cannot be directly measured, we were unable to study constraint-related factors that had been previously reported in case studies of non-syndromic craniosynostosis. These unavailable and therefore unstudied factors included the sensation of early descent of the fetal head into the lower uterine segment [Graham et al., 1979
], abnormal birth presentation which has an increased rate of preterm birth [Higginbottom et al., 1980
], and the presence of uterine malformations which may also be associated with preterm birth, malpresentation and craniosynostosis [Graham and Smith 1980
]. Such factors could potentially limit fetal movement and cause fetal constraint. We could not evaluate whether combinations of factors leading to fetal head constraint might have synergistic effects that increase the risk of craniosynostosis. And finally, it was unfortunate that this study had no postnatal follow-up data to determine whether or not fetuses that delivered early with low birth weight ultimately caught up in growth, which might suggest they delivered early because of fetal constraint in late gestation.
Although uncertainties remain regarding the influence of fetal head constraint, we conclude that no single constraint-related factor assessed in this study contributed greatly to the risk of craniosynostosis. Here we have demonstrated some evidence of suture-specific environmental influences, but these constraint-related factors and others will need further investigation in order to increase our understanding of the underlying causes of craniosynostosis.