Association of cleft lip and palate on mother-to-infant bonding: a cross-sectional study in the Japan Environment and Children’s Study (JECS)

Background Cleft lip and/or palate is among the most prevalent congenital birth defects, and negatively affects maternal psychological status and may consequently result in higher prevalence of child maltreatment. However, the association of childbirths of infants with cleft lip and/or palate with maternal emotional involvement still remains unclear. We examined the association between childbirths of infants with cleft lip and/or palate and mother-to-infant bonding, using data from the Japan Environment and Children’s Study, a nationwide birth cohort study. Methods A cross-sectional study using the jecs-an-20,180,131 dataset was performed. A total 104,065 fetuses in 15 regional centres in Japan were enrolled after obtaining informed written consent. The Mother-to-Infant Bonding Scale, a self-report scale consisting of 10 items, was used to evaluate maternal bonding at one year after childbirth. Finally, the participants consisted of 79,140 mother-infant pairs, of which 211 mothers of infants with cleft lip and/or palate were included in our analyses. Multivariable logistic regression analysis using multiple imputation for missing data was performed to calculate the odds ratio and 95% confidence interval in the estimation of the association between bonding disorders and childbirths with cleft lip and/or palate. Results No increased risk of bonding disorders was observed among all the mothers of infants with cleft lip and/or palate (odds ratio [95% confidence interval]; 0.97 [0.63–1.48], p = 0.880), however, advanced maternal age or multiple parity may adversely affect the associations between bonding disorders and cleft lip and/or palate, respectively. After stratification with a combination of maternal age and parity, a significant association of cleft lip and/or palate with bonding disorders was found only among advanced-age multiparae (odds ratio [95% confidence interval] = 2.51 [1.17–5.37], p = 0.018), but it was weakened after additional adjustment for maternal depression. Conclusions Childbirths of infants with cleft lip and/or palate may increase the risk of bonding disorders among advanced-age multiparae, possibly through maternal depression. This finding 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) are 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 [1][2][3], which is 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 parenting and/or caregiving 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 reportedly 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 that children with CL/P have higher prevalence rates (7.62% as cumulative probability) of child maltreatment in the U.S. state of Texas, compared with children with congenital diseases such as Down syndrome and spina bi da (approximately 5%) [10]. Most of this maltreatment was in the form of supervisory neglect (about 70%); however, a signi cantly higher risk of medical neglect was also observed [10,11]. Boztepe et al. also indicated that, in comparison with congenital heart disease, cleft lip was more likely to adversely affect maternal emotional connection toward the infant possibly due to the visual aspects of the condition [12]. Indeed, there is increasing evidence suggesting potential impairments of infant-maternal attachments among children with CL/P [13][14][15]. However, the impact of CL/P birth on maternal emotional involvement toward infants still remains unclear.
Recently, in distinction to the attachment consisting of bidirectional interactions in mother-infant dyads for making children safe [15,16], maternal affectionate feelings toward the infant during the perinatal period, referred to as "mother-to-infant bonding" has been found to prevent poor infant development and child maltreatment [16][17][18]. Bonding disorders, less maternal affection and behaviour toward the infant have been acknowledged as predictors of impairment in infant development due to child maltreatment [16,[18][19][20]. Recently, the Mother-to-Infant Bonding Scale (MIBS), which is based on Kumar's Mother-Infant Bonding Questionnaire [17], has been used for quantitative screening of bonding disorders in motherinfant dyads among the general population [21]. Recent cohort studies, including longitudinal studies, have provided increasingly more evidence [18,22]. Brockington et al. found that bonding disorders were diagnosed in 29% of mothers with maternal postpartum depression. Indeed, as associated with lifestyle behaviours (drinking and smoking habits) [23], the parity status impacts mother-to-infant bonding because of more requirements regarding maternal attention, especially when a new infant with congenital diseases arrives [24,25]. Thus, the parity status would confound mother-to-infant bonding with CL/P birth. Taken together, a better understanding the antecedents of maternal bonding issues 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 and the MIBS.

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 foetuses in 15 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. 1).

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 [3,26,27]. 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) as a group with less visible issues.
Mother-to-Infant Bonding Scale (MIBS: outcome measure) The MIBS is a self-report scale consisting of 10 items with responses based on a four-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 [21]. Cronbach's alpha of the MIBS for the current sample was 0.73. Because the optimal cut-off score is 4/5 [16], 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 [28]. 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 after childbirth. The design of the questionnaire has been previously described in detail [26, 27,29].
Using the data from self-administered and medical records/transcripts, an advanced-age mother was de ned as ≥35 years old [30]. 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 [31].
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 [32]. 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.

Participants' baseline characteristics
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 ( Table 3. CP, a group with less visible issues than CL±P did not also have any signi cant association with bonding disorders (OR [95% CI]; 1.76 [0.28-10.93], p = 0.545). In addition, there were no signi cant associations between bonding disorders with CL±P or CP births in the other three groups (younger primiparae, younger multiparae. or advanced-age primiparae).

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 in terms of the practical bene ts of the MIBS in screening for maternal bonding issues in CL/P births.
To the best of our knowledge, this is the rst report showing the association of CL/P birth with mother-toinfant bonding, though only among advanced-age multiparae. Maternal depression, which has been acknowledged as a predictor for bonding disorders [22,23], statistically impacts the association of maternal bonding disorders with CL/P birth, because mothers with CL/P birth are generally troubled with more parenting and/or caregiving issues with regard to feeding and breathing developments [5][6][7]. Furthermore, because the visual impacts of cleft lip possibly in uence the processing of maternal-toinfant bonding as suggested by Boztepe et al [12], 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). This nding may be due to the smaller sample size of mothers having infants with CL/P. Further examination of the confounding effects by visibility of cleft lip in future studies with the appropriate design is warranted.
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 birth 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 [33][34][35][36]. Older mothers generally experience a more severe delivery and have more issues regarding parenting due to physical and psychological limitations [37,38]. Meanwhile, as shown in our results (Table 1), multiparity generally contributes to better mother-to-infant bonding [39,40]. Therefore, we speculated that the signi cant association between CL/P birth and bonding disorders among between multiparous mothers may be related to the presence of healthy siblings. It should be noted that the recurrence rate of nonsyndromic CL/P among siblings is reportedly low, 3.2 -9.1% [41,42]. Similarly, Van Horne et al. reported that child maltreatment among children with CL/P increases as the number of siblings increases [11]. Tanimura et al., using nationwide data in Japan, pointed out that sibling comparison by parents (potentially including caregiving with congenital anomalies) may be a common risk factor for child maltreatment [43]. Differences in caregiving among siblings adversely impact maternal feelings and behaviours toward CL/P infants, whose care typically involves more daily-life stressors [44], and may lead to maternal bonding issues. In order to further examine these ndings, careful longitudinal observations among mothers of infants with CL/P are necessary because there may be potential impacts on the attachments of children with CL/P from maternal feelings and/or behaviours, even when the mother is giving birth to a new healthy 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 [26]. In terms of study limitations, rst, this was a cross-sectional study using a one-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 antenatal diagnosis and/or screening. Johns et al. suggested that receiving antenatal diagnosis decreases 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 antenatal diagnosis as a selection bias cannot be ruled out. Third, it has been well established that parent-child interactions, which involve the child's characteristics, affect parental feelings and responses [45], and fewer father and infant variables is an important limitation of the study.

Conclusions
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, and the MIBS may be useful in understanding antecedents of their bonding issues.
HM, RN, TA, and NY participated in data acquisition. ST, MT, and HM developed the study concept and participated in its design. TK, KI, and RN helped develop the study concept. ST, MT, and HM critically revised the manuscript. All authors have read and approved the nal version of the manuscript. Percentages and numbers of healthy infants and infants with CL/P may not sum to 100 or total numbers owing to rounding. Table 2. Association of bonding disorders with the prevalence of CL/P birth.