Impact of Cleft lip and Palate on Mother-to-Infant Bonding: a Cross-Sectional Study in the Japan Environment and Children's Study

Background Cleft lip and/or palate (CL/P) is among the most prevalent congenital birth defects. They negatively affect maternal psychological status and may consequently result in higher prevalence of child maltreatment. However, the association of CL/P births with bonding disorders still remains unclear. To address this question, we examined the impact of CL/P birth on mother-to-infant bonding, using the nationwide birth cohort study, Japan Environment and Children's Study. Methods This study was conducted as a nationwide birth cohort study of the Japan environment and children’s study (JECS), an ongoing nationwide birth cohort study in Japan. 104,065 of foetuses in fteen regional centres in JECS were enrolled. Finally, the participants consisted of 79,140 mother-infant pairs, of which 211 mothers with CL/P infants were included in our analyses. Results First, no increased risk of bonding disorders was observed among all the mothers with CL/P births (odds ratio [95% CI]; 0.97 [0.63-1.48], p = 0.880), and advanced maternal age or multiple parity would adversely affect the associations between bonding disorders and CL/P births, respectively. Thus, after stratication with a combination of maternal age and parity, a signicant association of CL/P birth with bonding disorders was found only among advanced-age multiparae (OR [95% CI] = 2.51 [1.17-5.37], p = 0.018), but it was weakened after additional adjustment for maternal depression. Conclusion CL/P birth may increase the risk of bonding disorders among advanced-age multiparae possibly through maternal depression. This nding provides valuable information for the provision of multidisciplinary cleft care.


Background
Cleft lip and/or cleft palate (CL/P), namely cleft lip with or without cleft palate (CL±P), and isolated cleft palate (CP) is among the most common birth defects and happen at a rate of approximately 1 in 700 births [1]. A nationwide survey in Japan showed that the prevalence of CL/P per 10,000 births was in a range of 14.4-24.8 [2,3], which is slightly higher than the global prevalence. CL/P can be repaired with craniofacial plastic surgeries [2,4]; however, parents of infants with CL/P generally suffer from childcare issues such as lower weight gain due to di culties in direct breastfeeding and higher risk for upper respiratory infection [5][6][7]. Mothers of infants with CL/P, though a controversial issue, tend to show negative moods such as depression and anxiety [8,9]. Johns et al. found a higher tendency of postpartum depression among older mothers of infants with CL/P [9]. Importantly, Van Horne et al. reported an unfortunate fact that children with CL/P have higher prevalence rates of child maltreatment compared with children with other congenital diseases [10,11]. Furthermore, there is evidence suggesting impairment of attachment in mother-infant dyads with children with CL/P [12][13][14]. Boztepe et al. also indicated that, in comparison with congenital heart disease, the visibility of cleft lip was more likely to adversely affect the emotional connection between mother and infant among hospital visiting mothers [15]. Thus, CL/P birth may in uence mother-infant attachment. However, the impact of CL/P birth on maternal emotional involvement with infants still remains unclear.
A mother's emotional involvements with her infant during the perinatal period has been recognized as mother-to-infant bonding [16,17]. Bonding disorders have been acknowledged as a predictor for the impairment of infants' development due to poor childcare with lower maternal attachment and sensitivity [17][18][19]. Recently, the Mother-to-Infant Bonding Scale (MIBS), which is based on Kumar's Mother-Infant Bonding Questionnaire [16], has been used for quantitative screening of bonding disorders in motherinfant dyads among the general population [20]. Bonding disorders have been found to have strong relationships with maternal postpartum depression [21,22] and lifestyle behaviours (drinking and smoking habits). The parity status impacts mother-to-infant bonding partly because of sibling competition for maternal attention [23,24]. In particular, because congenital anomaly was one of the physiological characteristics in abuse among siblings [25][26][27], the parity status would confound motherto-infant bonding with prevalence of CL/P birth. Thus, a better understanding of mother-to-infant bonding after CL/P birth will promote developments in multidisciplinary cleft care.
The aim of this study was to investigate the in uence of CL/P birth on bonding disorders using a largescale sample of the Japan Environment and Children's Study (JECS), a nationwide, multicentre, prospective birth cohort in Japan.

Study design and participants
The present study is based on the jecs-an-20180131 dataset, which was released in March 2018. In brief, pregnant women in their rst trimester were recruited at the rst prenatal examination in cooperating hospitals or at local government o ces from January 2011 until March 2014. After obtaining informed written consent, participants completed self-administered and medical records/transcripts, and subsequently underwent clinical measurements by medical doctors and trained nurses. To con rm the health status, check-up for both mother and infant was conducted at delivery and 1 month later. We enrolled 104,065 of foetuses in fteen regional centres in JECS. In the xed data of the JECS, 3,921 were miscarriages, stillbirths, and unknown; 1,889 were multiple births. Among the 98,255 mother-infant pairs, 10,045 pairs did not reply to the questionnaire sent out at 1 year after childbirth, and 9,070 pairs with other congenital disease(s) without CL/P were excluded from the analysis. A nal sample size of 79,140 mother-infant pairs was included in this study ( Figure.  Prevalence of CL/P (exposure measure) The data on CL/P and other congenital anomalies were ascertained from medical records/transcripts, which were lled by a doctor, a midwife, a nurses or a trained research coordinator at delivery and at 1 month of age onto JECS transcription forms [3,28,29]. The details of data processing, validation, and veri cation with regards to congenital anomalies were previously described [3]. There are three types of CL/P: cleft lip, cleft palate, or cleft lip with palate. A checkbox for each type was listed on the transcription form. A tick was entered into the corresponding checkbox when any interests of CL/P were observed.
Using the xed JECS dataset, Mezawa et al. reported that total prevalence rates of CL/P per 10,000 births was 24.8 [3].
Furthermore, to examine the in uence of visibility of CL/P on the mother-to-infant bonding, the mothers of infants with CL/P were divided into two groups: (1) CL±P group (mothers of infants with cleft lip with or without cleft palate) and (2) CP group (mothers of infants with isolated cleft palate).
Mother-to-Infant Bonding Scale (MIBS: outcome measure) The MIBS is a self-report scale consisting of 10 items with responses based on a 4-point scale (from 0 to 3), and is used to evaluate mother-to-infant bonding at 1 year after childbirth. The total score ranges from 0 to 30, and higher scores indicate worse mother-to-infant bonding. The MIBS had been translated into Japanese and validated in a previous study [20]. Cronbach's alpha of the MIBS for the current sample was 0.73. Because the optimal cut-off score is 4/5 [17], the presence of bonding disorders in motherinfant dyads was de ned as ≥5 in this study.

Covariates
In addition to maternal smoking during pregnancy, maternal drinking habits during pregnancy was assessed with a self-administered questionnaire [30]. Maternal age at delivery, parity, and infant sex were ascertained from medical records/transcripts lled by doctors, midwifes, nurses, or trained research coordinators. In a follow-up questionnaire after birth, participants also reported feeding pattern and Kessler Psychological Distress Scale scores (K6) at 1 year. The design of the questionnaire has been previously described in detail [28,29,31].
Using the data from self-administered and medical records/transcripts, an advanced-age mother was de ned as ≥35 years old [32,33]. In addition, participants were categorized into the following groups by parity ('primipara' or 'multipara'). Smoking status was divided into three categories: 'never', 'stopped smoking before or during pregnancy', or 'current smoking'. Alcohol consumption was divided into three categories: 'never', 'stopped drinking', or 'current drinking'. Categories for infant sex were 'male' or 'female', and categories for feeding pattern were 'breastfeeding', 'formula', or 'mixed'.

Statistical analysis
Continuous variables were presented as medians with interquartile ranges, and categorical variables were presented as numbers and percentages (Table. 1). With regard to missing data, we applied the 'missing at random' assumption, and used multiple imputation with the multivariate normal imputation method [34]. The numbers of participants with missing data in each of the variables are shown in Supplementary  Table 1. An imputation model including all variables were independently applied for 10 copies of the data, each with missing values suitably imputed. Estimates of the variables were averaged to compute a single mean estimate and adjusted standard errors using Rubin's rule [35]. We performed crude and multivariate logistic regression analyses using the hierarchical multiple regression model for potential covariates to examine the association of bonding disorders with the prevalence of CL/P birth within each subgroup. These analyses were performed after adjustment for potential confounding factors, including maternal smoking and drinking habits, feeding pattern, and infant sex (model 1). All parameters in model 1 plus maternal depression (model 2) were included. The OR and 95% CI were calculated for bonding disorders. The results of the multiple imputation analyses are shown in Tables 2 and 3. All statistical analyses were performed using SPSS (version 24.0; IBM Corp., Armonk, NY, USA). In the analysis of the data, P values <0.05 were considered statistically signi cant.

Results
The median age of the participants was 31 years (interquartile range: 28-35 years), and the mean MIBS and K6 scores were 1.94 (standard deviation [SD]: 2.29) and 2.79 (SD: 3.61), respectively (Supplemental Table 1). The total numbers (%) of infants born with cleft lip with or without palate or isolated cleft palate in the present study were 64 (0.08), 90 (0.11), and 57 (0.07), respectively. Interestingly, the mean maternal MIBS scores (SD) of dyads with infants with CL/P were similar to those of the healthy infants (

Discussion
Our present results using the nationwide data from a large-scale birth cohort study in Japan showed no signi cant association between maternal bonding disorders and CL/P births among all the participants (OR [95% CI]; 0.97 [0.63-1.48], p = 0.880). However, our nding revealing the signi cant association of CL/P birth with maternal bonding disorders among advanced-age multiparae may serve as valuable information for multidisciplinary cleft care providers.
To the best of our knowledge, this is the rst report showing the impact of CL/P birth on mother-to-infant bonding, though only among advanced-age multiparae. Maternal depression, which has been acknowledged as a predictor for bonding disorders [21,22], statistically impacts the association of maternal bonding disorders with CL/P birth, because mothers with CL/P birth are generally troubled with more childcare issues with regards to feeding and breathing developments [5][6][7]. Furthermore, because the visual impacts of cleft lip possibly in uence the processing of maternal-to-infant bonding, as suggested by Boztepe et al [15], we focused on whether the prevalence of cleft lip was associated with bonding disorders among advanced-age multiparae. Consequently, the signi cant association of bonding disorders with prevalence of CL±P birth did not remain after the adjustment using all covariates (OR [95% CI] = 2.31 [0.93-5.73], p = 0.072). Although possibly due to the smaller sample size of mothers having infants with CL/P, it would be of further interest to examine the confounding effects by visibility of cleft lip in future studies with the appropriate design.
Our results indicated that the association between bonding disorders and CL/P birth strongly varies according to parity and maternal age at delivery. Similar to the increasing trends of advanced maternal age and multiple parity on the association between bonding disorders and CL/P birth (Supplemental Table 2), their combined strati cation showed a signi cant association between bonding disorders and CL/P among advanced-age multiparae. A review of relevant studies indicated that the impacts of advanced maternal age and/or parity on mother-to-infant bonding are under some debate; however, several studies have reported adverse effects of older maternal age and multiparity on mother-to-infant bonding [36][37][38][39]. Because older mothers generally experience a more severe delivery and have more issues regarding childcare due to physical and psychological limitations [40,41], advanced maternal age may impact mother-to-infant bonding among mothers of infants with CL/P. Meanwhile, as shown in our results (Table 1), multiparity generally contributes to m better other-to-infant bonding [42,43]. Therefore, we speculated that the impact of multiparae status on mothers with CL/P birth on bonding disorders may be related to the presence of healthy siblings. The recurrence rate of nonsyndromic CL/P among siblings is reportedly very low, 2.3-4.6% [44,45]. Tanimura et al., using nationwide data in Japan, pointed out that comparison with siblings by parents may be a common risk factor for child maltreatment [27]. The authors also found that children with congenital anomalies suffer from higher risk of maltreatment [25][26][27]. In order to further examine these ndings, careful longitudinal observations are necessary because most mothers of infants with CL/P in other groups of this survey (younger primiparae, younger multiparae, and advanced-age primiparae) have the potential with aging to be in advanced -age multiparae when giving birth to a health sibling.
This study has several strengths and limitations. Since the Japanese nationwide survey covered approximately 45% of infants born in multi-subject area during 2013, our results, mostly based on the Japanese general population, allowed us to compare the experimental participants with abundant controls [28]. In terms of study limitations, rst, this was a cross-sectional study using a 1-time measurement of mother-to-infant bonding as the outcome. Future longitudinal studies with more appropriate designs that consider episodes of child maltreatment are warranted. Second, this study's data collection methods did not include a query about prenatal diagnoses. Johns et al. suggested that receiving prenatal diagnosis decreased maternal depressive symptoms among mothers of infants with CL/P [9]. Thus, our ndings may be limited because the possibility of arti cial abortion related to congenital anomaly after prenatal diagnosis as a selection bias cannot be ruled out.
This cross-sectional study using Japanese nationwide data indicated that mothers with CL/P births had similar rates of bonding disorders as the general population; however, advanced-age multiparae had a signi cantly higher risk of bonding disorders.