Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, UK.
The Generation R Study Group, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands.
Transl Psychiatry. 2023 Jul 13;13(1):256. doi: 10.1038/s41398-023-02552-w.
Autism is more prevalent in males and males on average score higher on measures of autistic traits. Placental function is affected significantly by the sex of the fetus. It is unclear if sex differences in placental function are associated with sex differences in the occurrence of autistic traits postnatally. To assess this, concentrations of angiogenesis-related markers, placental growth factor (PlGF) and soluble fms-like tyrosine kinase (sFlt-1) were assessed in maternal plasma of expectant women in the late 1 (mean= 13.5 [SD = 2.0] weeks gestation) and 2 trimesters (mean=20.6 [SD = 1.2] weeks gestation), as part of the Generation R Study, Rotterdam, the Netherlands. Subsequent assessment of autistic traits in the offspring at age 6 was performed with the 18-item version of the Social Responsiveness Scale (SRS). Associations of placental protein concentrations with autistic traits were tested in sex-stratified and cohort-wide regression models. Cases with pregnancy complications or a later autism diagnosis (n = 64) were also assessed for differences in placenta-derived markers. sFlt-1 levels were significantly lower in males in both trimesters but showed no association with autistic traits. PlGF was significantly lower in male pregnancies in the 1 trimester, and significantly higher in the 2 trimester, compared to female pregnancies. Higher PlGF levels in the 2 trimester and the rate of PlGF increase were both associated with the occurrence of higher autistic traits (PlGF-2: n = 3469,b = 0.24 [SE = 0.11], p = 0.03) in both unadjusted and adjusted linear regression models that controlled for age, sex, placental weight and maternal characteristics. Mediation analyses showed that higher autistic traits in males compared to females were partly explained by higher PlGF or a faster rate of PlGF increase in the second trimester (PlGF-2: n = 3469, ACME: b = 0.005, [SE = 0.002], p = 0.004). In conclusion, higher PlGF levels in the 2 trimester and a higher rate of PlGF increase are associated with both being male, and with a higher number of autistic traits in the general population.
自闭症在男性中更为普遍，男性在自闭症特征的测量中平均得分更高。胎盘功能受到胎儿性别的显著影响。目前尚不清楚胎盘功能的性别差异是否与出生后自闭症特征的性别差异有关。为了评估这一点，在荷兰鹿特丹的 Generation R 研究中，评估了孕晚期（平均 13.5 [SD=2.0] 周妊娠）和 2 个孕中期（平均 20.6 [SD=1.2] 周妊娠）孕妇的母体血浆中与血管生成相关的标记物胎盘生长因子（PlGF）和可溶性 fms 样酪氨酸激酶 1（sFlt-1）的浓度。随后在 6 岁时使用社会反应量表（SRS）的 18 项版本对后代的自闭症特征进行评估。在性别分层和队列全回归模型中测试了胎盘蛋白浓度与自闭症特征的相关性。有妊娠并发症或后期自闭症诊断的病例（n=64）也评估了胎盘衍生标志物的差异。在两个孕中期，男性的 sFlt-1 水平显著低于女性，但与自闭症特征无关。与女性妊娠相比，男性妊娠在 1 个孕中期 PlGF 水平显著降低，在 2 个孕中期显著升高。与较高的自闭症特征相关的 2 个孕中期较高的 PlGF 水平和 PlGF 增加率均相关（PlGF-2：n=3469，b=0.24 [SE=0.11]，p=0.03），在未调整和调整后的线性回归模型中均如此，这些模型控制了年龄、性别、胎盘重量和母体特征。中介分析表明，男性自闭症特征高于女性，部分原因是第二孕期 PlGF 较高或 PlGF 增加率较快（PlGF-2：n=3469，ACME：b=0.005，[SE=0.002]，p=0.004）。总之，第二孕期较高的 PlGF 水平和较高的 PlGF 增加率与男性和普通人群中自闭症特征的数量较多有关。
