Timing van lip- en palatumsluiting bij patiënten met een schisis

Beoordeeld: 26-11-2021

Uitgangsvraag

Welke overwegingen (voor- en nadelen) spelen een rol bij het bepalen van het moment van het sluiten van de de lip, kaak en/of gehemeltespleet bij kinderen met een (cheilognatho)palatoschisis?

Aanbeveling

Sluit bij voorkeur de lip operatief in de eerste 6 maanden van het leven.

Sluit bij voorkeur het palatum durum en het palatum molle in het eerste levensjaar als een zo optimaal mogelijke spraak wordt nagestreefd.

Sluit bij voorkeur alleen het palatum molle in het eerste levensjaar en het palatum durum pas later als een zo optimaal mogelijke groei van de maxilla wordt nagestreefd.

Definieer een voorkeursaanpak binnen het schisisteam voor lipsluiting en palatumsluiting om ouders te adviseren in de besluitvorming. Ondersteun de besluitvorming door middel van schriftelijk of digitaal informatiemateriaal, zie module Prenatale medische counseling.

Overwegingen

Level of evidence (timing of closure)

The overall level of evidence regarding the timing of lip and/or palate closure is very low. The literature about the timing of palate closure is fragmented, and studies report different outcomes measures. No studies were found that compared different moments of lip closure.

Advantages and disadvantages of the different protocols

Unfortunately, no conclusions can be drawn from literature regarding the timing of lip and (hard) palatal closure. The literature does not answer the vivid discussion among professionals concerning the disadvantage of late palatal closure on speech development or the disadvantage of early palatal closure on maxillary growth. So, unfortunately, an optimal or uniform protocol on timing of palatal closure cannot be proposed based on literature. A complicating factor to study the effects of timing of repair of CLA/P is the fact that the skills of the surgeon are hard to measure but it is likely that these skills - including education, personal training, experience, workload, and working environment - are an important factor in the outcome. Also, a uniform and validated method to assess, quantify and document VPI is not available. Moreover, reliable, reproducible assessment of speech remains a challenging field. Comparable speech assessment requires both validated tools and systematic consensus training of the assessors, which is not always available. Therefore, calibration is a key element for possible future studies and trials, including the surgical part of any multicenter study.

In addition to timing there are two other factors relevant for lip and/or palatal closure, i.e., the technique of closure and the sequence of closure. The technique of closure is reviewed in module Technique of lip and/or palate closure. For this guideline the sequence of closure was not regarded as a key factor for long term outcome, but it is undeniable an important variable in many of the protocols of Dutch cleft teams. It therefore deserves attention.

The Scancleft studies show the most common used sequences of palatal closure. In Arm A and Arm B the lip and soft palate are closed first followed by the hard palate a later stage (in arm A within 12 months). In Arm C the lip is closed first and the whole palate is closed in one operation within 12 months of age. In Arm D the lip and hard palate (with a vomerine flap) are closed first, and the soft palate closed at a later stage but within 12 months after births. Another option is to close the soft palate first (as this is functionally the most important part of a full CLA/P) and to close the hard palate and lip together in the second operation, also within 12 months of age. This sequence was popularized in France under guidance René Malek of and forms one Arm in a RCT published by Richard (2006).

To make it more complex there is very limited evidence that it may be beneficial to adjust the protocol to the type of cleft, for example the width of the cleft. A study by Botticelli (2020) on a subgroup of the Scandcleft trials suggests that - from an orthodontic point of view - a wide posterior cleft might benefit from later hard palate closure. The thought of adjusting your protocol to the local situation sounds logic and surgeons do sometimes adjust the protocol in an individual case intuitively, but this is a complex area for research. Numbers for trials become extremely small in most centers when adjusting to subphenotyping the cleft and/or calculating relative dimensions, such as the width of the cleft in relation to the available tissue on the palatal shelve. This is an interesting field, but it has no implications for this guideline at present.

The velopharyngeal competence composite score (VPC-sum) as used in the study of Lohmander (2017) provides an indication of the velopharyngeal function by hypernasality, audible nasal air leakage, weakness of pressure consonants, and posterior nonoral articulation. No statistically significant differences in VPC-Sum or in hypernasality were found between the arms (Arm A versus Arm B).

The Scandcleft trials are of interest regarding possible differences in outcome due to variation in the sequence of closure of the palate during the first year of life. Although it was not a clinical question, the sequence of closure was part of the literature search. The working group has looked critically at the results of the Scandcleft trials regarding differences between Arm A, Arm C and Arm D and the RCT published by Richards in 2006. Kuseler (2020) did not find significant differences in facial growth between Arm A, C and D at age 8 years and Edwards (2006) did not find differences between the two arms in his study regarding speech and growth age 4 to 7 years. Therefore, sequence of closure of a complete CLA/P during the first year of life does not seem to affect speech and or growth at a later age.

Timing in the Netherlands:

According to the NVSCA website the treatment protocols of the Dutch cleft-teams can be summarized:

All teams except 1 close the lip at 3-4 months of age, one team closes the lip at 6 months of age.
All teams close the soft palate mostly in the second half of the first year of life.

Closure of the hard palate diverges from 3 months to 12 years of age and shows the largest discrepancy.

Even in 2021 there remains a scarcity of good studies. The available literature does not provide evidence for one single optimal/ best protocol to close CLA/P during the first year of life. Although the Scandcleft trials provide a lot of information, they show at the same time how difficult it is to design and run good prospective multicenter studies from birth to adulthood (Shaw, 2017).

The current revision of this module in the guideline therefore will not solve the practice variation between different cleft teams regarding the closure of clefts of the lip and/or palate. Therefore, we are unremittingly faced with different philosophies in examination and treatment of CLA/P. Lack of consensus is most evident in the timing hard palate closure. However, modesty should suit the (Dutch) cleft-teams regarding their local protocols, customs of preferences due to this lasting knowledge deficit. Based on the literature there is no evidence one cleft team can state they have better protocol compared to another team. Cleft teams should support parents in offering a clear explanation of their treatment protocol. Furthermore, it is advisable to share the knowledge and experience among the Dutch cleft teams to make progress in cleft care.

Therefore, the working group advises each cleft team to develop and present a team preferred treatment protocol and to document the results carefully and systematically for internal quality control and external comparison.

Although not supported by clinical research:

The working group advises to close the cleft lip in the first 6 months of life, as it is common practice in the Netherlands. This will allow the lip to function properly when the child starts babbling in the second half of the first year of life.
The working group advises to close the soft palate before 12 months to allow velum function to develop normally as babbling progresses to words around 1 year of age.

This advise regards – in line with this CPG – only healthy non-syndromic children. Especially before the palate is closed any signs of Obstructive Sleep Apnea (OSA) should be ruled out taking a throurough anamnesis and / or observation. When in doubt it is advised to do sleep studies and / or to postpone the palate closure.

Values and preferences of patients and their parents or guardians

Parents can be confused by the variety of surgical protocols and (sometimes strong) opinions on CLA/P treatment by teams or surgeons. They need unambiguous information and advice. Unfortunately, literature does not provide us with enough scientific evidence to support one of the protocols of timing of CLA/P closure over the other. Adversely the experience of a surgeon and his/her preferences for a certain technique is essential for optimal results. We advise that each team presents clearly what their vision on timing of CLA/P closure is, elaborated in a straightforward protocol.

Anesthesiology

Parents may have concerns about anesthesiology for their young children (<1 year). These concerns are considered and discussed in the clinical practice (https://richtlijnendatabase.nl/richtlijn/anesthesie_bij_kinderen/faciliteiten_bij_anesthesie_bij_kinderen.html). The recommendations of this guideline are leading for daily practice in the Netherlands.

Costs/Finances

In general, good results should be achieved in as little surgeries as possible in order to keep the burden on the child, the parents as low as possible, and to keep the health care system within acceptable finances. It is important to properly lay the surgical base in the first year of life, and to keep intermediate interventions during growth to a minimum. The final corrections can be made when the patients jaws finish their growth, whereby the patient can then assess and decide for himself or herself what he or she needs or what he or she considers to be desirable.

Acceptance, feasibility and implementation

There is still a lot of variation in surgical practice between the cleft teams, although there seems to be a trend towards early closure of the hard palate. Special interest groups within the NVSCA try to tackle this point. Within these groups, knowledge is shared, and appointments are made to standardize clinical practise as much as possible. In the Netherlands everyone has equal access to the cleft teams, so there will be no variation in accessibility of care. The different protocols of timing of lip and/or palate closure exist due to the experience, expertise and preferences of each surgeon and each cleft team. is important that the surgeon uses the (combination of different) technique(s) and the timing protocol in which he or she is most experienced in order to achieve the best result.

Rationale

The literature did not show a clear preference for timing of lip and/or palate closure, nor clear advantages and disadvantages of early or late closure of the palate. There is no medical indication for early lip closure (before 6 months), it is the preference of parents and social acceptance to close the lip early. To allow proper function soft palate closure should be performed within the first year of life. When closing the palate any signs of Obstructive Sleep Apnea (OSA) should be ruled out taking a throurough anamnesis and / or observation. When in doubt it is advised to do sleep studies and / or to postpone the palate closure.

A broad recommendation is given, partly due to the lack of scientific evidence, taking into account the experience and expertise of the cleft team.

Onderbouwing

Achtergrond

In case of a cleft of the palate there is an abnormal connection between the nasal and oral cavities. The posterior part of the nasal and oral cavities merge in the oropharynx. Under normal conditions the soft palate functions as a valve, actively closing the nasal cavity from the oral cavity on demand. This is an essential function to build up pressure for speech and to create a vacuum, for example for feeding. Therefore, a cleft palate - even if it is minor- causes functional impairment in drinking and speech.

Closure of the (soft and/or hard) palate intents to create a separation between the oral and nasal cavities to solve these problems. Evidently early closure aims to solve these problems faster compared to later closure. The plea for early closure is logical from a pure functional point of view. The problem with early closure relates to scar formation. Some degree of scar formation during surgical closure of the palate is inevitable, even with the best techniques and an experienced surgeon. Scar formation however can cause disturbance of growth of the upper jaw. It is thought that especially scar formation during closure of the hard palate is responsible for most of the noted growth disturbance. Early closure (<18 month) of the hard palate causes scar formation at a younger age and has therefore more time to affect growth of the maxilla compared with later closure.

Disturbed growth of the maxilla is not benign and leads to midface underdevelopment, class 3 malocclusion, and less prominence of the nose. Even the width of the upper jaw might stay small causing cross bite. These problems may require orthognathic surgery such as a Le Fort I osteotomy after growth has been completed around 18 years of age.

In summary: the classic teaching tells us that early closure favors function, late closure (especially of the hard palate) is better for growth, the holy grail being early closure without growth disturbance.

In view of the issues raised the timing of (partial) palatal closure seems important. Timing of closure of the cleft lip is less subject to debate. Lip closure does not seem to impair growth. Due to the esthetic importance the cleft lip is usually repaired in the first year of life, mostly in the first trimester after birth, frequently combined with primary correction of the nose (see module on cleft nose correction). Nevertheless, it is important to substantiate timing of lip closure with current literature.

This module does not address the timing of bonegrafting of the alveolar cleft. The focus is on soft tissue closure, achieving separation of the oral and nasal cavities.

Conclusies

1. Hard palate

1.1 Maxillary and midface growth (critical)

Very low

GRADE

The evidence is very uncertain about the effect of timing of hard palate closure on maxillary and midfacial growth.

Sources: (Heliövaara, 2017; Heliövaara, 2019; Karsten, 2017; Karsten, 2020; Küseler, 2020; Richard, 2006; Wada, 1990.)

1.2 Speech (velopharyngeal insufficiency) (critical)

Very low

GRADE

The evidence is very uncertain about the effect of timing of hard palate closure on speech.

Sources: (Lohmander, 2017; Richard, 2006; Willardsen, 2017; Williams, 2011)

1.3 Esthetics (patient, parent and/or doctor satisfaction) (critical)

GRADE

There is no GRADE assessment possible due to lack of studies.

1.4 Hearing (important)

Very low

GRADE

The evidence is very uncertain about the effect of timing of hard palate closure on hearing.

Sources: (Richard, 2006)

1.5 Feeding capability (important)

GRADE

There is no GRADE assessment possible due to lack of studies.

1.6 Postoperative complications (important)

Very low

GRADE

The evidence is very uncertain about the effect of timing of hard palate closure on postoperative complications.

Sources: (Rautio, 2017; Reddy, 2018; Richard, 2006; Williams, 2011)

2. Lip closure

GRADE

There is no GRADE assessment possible due to lack of studies.

Samenvatting literatuur

Description of studies

A total of 12 RCT studies was included in this literature summary. Most included studies are part of the Scandcleft trials (Heliövaare (2017); Heliövaare (2019), Karsten (2017); Karsten (2020), Küseler (2019), Lohmander (2017), Rautio (2017), Willardsen (2017)). In these trials, lip and soft palate closure at 3 to 4 months, and hard palate closure at 12 months served as a common method in each trial (Arm A, n= 75).

Trial 1 compared Arm A with hard palate closure at 36 months (Arm B, n=73). Which is of interest for this module.

Trial 2 compared Arm A with lip closure at 3 to 4 months and hard and soft palate closure at 12 months. Which is not included in the PICO.

Trial 3 compared Arm A with lip and hard palate closure at 3 to 4 months and soft palate closure at 12 months. Which is not included in the PICO.

The primary outcomes of the scandcleft trials were speech and dentofacial development, with a series of perioperative and longer-term secondary outcomes, perioperative complication rate, operation and hospitalization time, postoperative recovery and feeding, speech at 12 and 18 months and 3 years, symptomatic fistulae, hearing, burden of care, and parent satisfaction at age 5 years (till the age of 5 or 8).

Reddy (2018) describes a blocked RCT (not part of de Scandcleft trials) that compared a one-stage palatoplasty at age 12 to 13 months (group A) with a two-stage palatoplasty patients with soft palatoplasty at age 12 to 13 months and hard palatoplasty at age 24 to 25 months (group B). A total of 100 nonsyndromic unilateral cleft lip and palate patients were included. The two groups were compared on fistula rates at 3 years and hypernasality at 6 years. In addition, both groups were compared with a control group of 20 noncleft controls on hypernasality at 6 years.

Richard (2006) describes an RCT in which the effects of operating the soft palate first (n=23, at follow-up 16) versus operating hard palate first (n=24, at follow-up n=19) on facial growth are studied in unilateral complete cleft lip and palate patients. The anterior operation consisted of a lip repair by Millard rotation advancement, a nasal correction using the McComb procedure and a hard palate repair by a single layer vomerine flap. The posterior operation consisted of a soft palate repair with medial von Langenbeck incisions. The two operations were undertaken three months apart with the first operation at 19 months of age. Preoperative maxillary models, speech and velopharyngeal function and ontological examinations were performed. Patients were followed until the age of four to six years.

Wada (1990) is a RCT that describes the effects of one-stage palatal closure (unilateral cleft n=14, bilateral n=8) versus two-stage palatal closure (unilateral n=16, bilateral n=7) in patients with uni- and bilateral cleft lip and palate. Also, the maxillary growth was compared with 11 healthy controls. Lip repair was performed at five months of age. One-stage repair was performed at 20 months using mucoperiosteal palatal pushback procedure. Two-stage repair was performed with primary veloplasty at 20 month and double overlapping palatal hingeflap procedure at five years ten months. Maxillofacial cast models were examined. The children are followed until the age of ten years.

Williams (2011) describes a RCT in which different surgical techniques and different timings of surgery for cleft palate were compared in terms of speech outcome and risk of palatal fistulae in patients with a complete unilateral cleft lip and palate. A 2x2x2 factorial clinical trial was used in which each subject was randomly assigned to one of eight groups: one of two different lip repairs (Spina versus Millard), one of two different palate repairs (von Langenbeck versus Furlow) and one of two different ages at time of palatal surgery (9 to 12 months versus 15 to 18 months). All surgeries were performed by the same 4 surgeons. A total of 181 patients were operated at 9 to 12 months (Spina - Furlow = 35, Millard - Furlow = 43, Spina - Langenbeck = 51, Millard - Langenbeck = 52) and 195 at 15-18 months (Spina - Furlow = 48, Millard - Furlow = 47, Spina - Langenbeck = 46, Millard - Langenbeck = 54). Children were followed for at least the age of four years.

Results

1. Hard palate

1.1 Maxillary and midface growth (critical)

The dental arch relationship, measured with GOSLON Yardstick score, in children at five and eight years old is showed in the studies of Heliövaara (2017) and Heliövaara (2019), respectively. Children at five years of age (n=74) receiving the repairing of hard palate at 12 months (arm A) had a mean index score of 2.86 (SD 0.94) and 5-years old children (n=68) receiving the repairing of hard palate at 36 months (arm B) had a mean score of 2.58 (SD 0.87). This difference was not significant (p=0.06). At the age of 8 years, children in arm A (n=72) had a mean score of 3.03 (SD 0.85) and children in arm B (n=73) had a mean score of 2.82 (SD 0.81), p=0.137.

Karsten (2017) and Karsten (2020) present the occlusion as outcome of hard palate closure, measured with the Modified Huddart and Bodenham index (MHB), in children at five and eight years old. The total MHB score is sum of the anterior score and two posterior scores (cleft and non-cleft side) and ranges from +2 to -18). Children at the age of 5 in Arm A (n=75) had a mean total MHB score of -6.80 (SD 4.02) compared to 5-years old in Arm B (n=68) who had a mean total MHB score of -5.95 (SD 4.17). There was no significant difference between the groups: MD -0.86 (95% CI -2.21-0.50), p =0.21. Children at the age of 8 in Arm A (n=74) had a mean total MHB score of -9.57 (SD 5.53) compared to 8-years old in Arm B (n=73) who had a mean total MHB score of -8.51 (SD 5.67). There was no significant difference between the groups: MD -1.06 (95% CI -2.90-0.78), p =0.26.

Maxillary growth in 8 years old children is reported by Küseler (2020). Maxillary growth was assessed by cephalometric angles SNA (angle between selle, nasion, and subspinal point) and ANB (angle between maxilla and mandible) using lateral cephalograms. The mean ANB was 2.88 (95% CI 1.68 to 4.07) in the 8 years old children of Arm A (n=74) and the mean ANB was 3.55 (95% CI 2.44 to 4.67) in the 8 years old children of Arm B (n=72), p=0.12 (95%CI −0.19 to 1.66). The mean SNA was 78.42 (95% CI 76.63 - 80.20) in the 8 years old children of Arm A (n=74) and the mean SNA was 78.90 (95% CI 77.28 - 80.52) in the 8 years old children of Arm B (n=72), p=0.41 (95% CI −0.69 to 1.69).

Richard (2006) describes that there was no significant difference in overall facial growth between the different types of palatal closure sequencing.

Wada (1990) reports that in unilateral cleft palate patient’s maxillary growth after two-stage palatal closure was comparable to those of non-cleft controls regarding depth and height of the maxilla, while after one-stage closure aberrant maxillary development was observed. For patients with bilateral clefts, maxillary growth was similar in the one-stage and two-stage palatal closure groups.

Level of evidence of the literature

The level of evidence regarding the outcome maxillary and midface growth started at high as it was based on a RCT but was downgraded by three levels to very low due to study limitations (risk of bias, -1), the small study populations (imprecision, -1), and indirectness (-1).

1.2 Speech (velopharyngeal insufficiency) (critical)

Lohmander (2017) shows the effects of timing on the speech outcome hypernasality. Hypernasality was measured using two different methods: nasometry (nasalance score) and perceptual analysis. In the study of Reddy (2018) the one-stage palatoplasty group (group A, n=50) had a mean nasalance score of 20.61 ± 9.23 percent and group B (two-stage palatoplasty, n=50) had a mean score of 16.77 ± 2.15 percent, which is a significant difference between the groups (p = 0.006; 95% CI 1.16 to 6.53). The perceptual analysis of hypernasality did not show significant difference between the groups: group A had 18 patients with hypernasality on single words versus 20 patients in group B (p=0.837 and p = 1.000 for single words and sentences respectively). Compared to the noncleft control group, group A had a significant higher score on hypernasality (p=0.001, 95% CI 2.05 to 7.52). There was virtually no difference in the mean nasalance scores for patients in group B and subjects in group C (p=0.088, 95%CI −0.14 to 2.02).

Richard (2006) reports that there was hypernasal resonance significant enough to warrant surgery in five patients in the posterioir-anterior group and four in the anterior-posterior group. This difference was not statistically significant.

Willardsen (2017) evaluates the effect of timing on speech outcome in terms of consonant production, in children at five years old. The percent consonants correct (PCC) score showed a significant difference between the arms; a higher median PCC score in Arm A compared to Arm B (p=0.045). The median number of active cleft speech characteristics (CSCs) was significant higher in Arm B compared to Arm A (p=0.003).

Williams (2011) reports that of the patients operated early (9 to 12 months) 78% had hypernasality and 57% had nasal air emission versus 74% and 55% operated late (15 to 18 months) respectively. The odds ratio for hypernasality was 1.46 (95% CI: -0.84 to 2.54, p=0.12) and for nasal air emission 1.16 (95% CI: 0.72 to 1.85, p=0.49) for patients operated early versus patients operated late.

Level of evidence of the literature

The level of evidence regarding the outcome measure speech started at high as it was based on a RCT but was downgraded by three levels to very low due to study limitations (risk of bias, -1), the small study populations (imprecision, -1), and indirectness (-1).

1.3 Esthetics (patient, parent and/or doctor satisfaction) (critical)

No studies were identified that met the inclusion criteria and reported esthetic results as an outcome measure.

Level of evidence of the literature

The level of evidence regarding the outcome measure feeding capacity was not assessed due to lack of studies.

1.4 Hearing (important)

Richard (2006) reports that there was no significant difference in hearing status between the patients in the posterior-anterior group and the anterior-posterior group.

Level of evidence of the literature

The level of evidence regarding the outcome measure speech started at high as it was based on a RCT but was downgraded by three levels to very low due to study limitations (risk of bias, -2), and the small study populations (imprecision, -1).

1.5 Feeding capability (important)

The outcome feeding capacity was not reported in the included studies.

Level of evidence of the literature

The level of evidence regarding the outcome measure feeding capacity was not assessed due to lack of studies.

1.6 Postoperative complications (important)

Rautio (2017) presents surgical results of the Scandcleft studies, including complications after the surgery; major dehiscence of the palate needing fistula repair and number of patients who needed VPI surgery at the age of 5 years and extended to the moment that the youngest patient in the study was 5 years old (with updating until 9 years). In arm A a total of 6 patients (8%) had major dehiscence of the palate compared to a total of 4 patients (6%) in arm B (p=0.10). The number of patients who needed VPI surgery was 2 (3%) in arm A compared to 1 patient (1%) in arm B at the age of 5 years. After the extended period, a total of 18 patients (24%) needed VPI surgery in arm A compared to 18 patients (26%) in arm B.

Reddy (2018) reports four patients with fistula in the one-stage palatoplasty at age 12 to 13 months (group A, n=50), whereas in the two-stage palatoplasty two patients had fistulas: OR 2.1 (p = 0.409; 95% CI, 0.365 to 11.9).

Richard (2006) reports that there were 10 symptomatic fistulae in the anterior-posterior group and six in the posterior-anterior group (p> 0.05).

Williams (2011) describes that 44/181 patients operated early (9 to 12 months) developed a fistula, versus 37/195 in the late (15 to 18 months) operation group. The odds ratio for fistula formation in the early versus late group was 1.37 (95% CI: 0.84 to 2.22, p=0.21).

Level of evidence of the literature

The level of evidence regarding the outcome measure speech started at high as it was based on a RCT but was downgraded by three levels to very low due to study limitations (risk of bias, -2), and the small study populations (imprecision, -1).

2. Lip closure

No studies were found that compared lip closure before and after 3 months.

Level of evidence of the literature

The level of evidence was not assessed due to lack of studies.

Zoeken en selecteren

A systematic review of the literature was performed to answer the following question:

What is the effect of the timing of repairing cleft lip, alveolus and/or palate on maxillary and midface growth, speech, hearing, feeding capability, postoperative complications (fistulae), and esthetics (patient, parent and/or doctor satisfaction)?

P: patients with cleft lip, alveolus and/or palate;

I: closing hard palate before 18 months/ closing lips before 3 months;

C: closing hard palate after 18 months/ closing lips after 3 months;

O: maxillary and midface growth, speech, hearing, feeding capability, postoperative complications (fistulae), and esthetics (patient, parent and/or doctor satisfaction).

Relevant outcome measures

The working group considered the following outcome measures as critical for decision making: maxillary and midface growth, velopharyngeal insufficiency, and esthetics. The outcomes speech, hearing, feeding capability, and postoperative complications were considered as important outcome measures.

Studies should report at least one of the outcomes of interest: esthetics (patient, parent and/or doctor satisfaction), maxillary and midface growth, and velopharyngeal insufficiency. For the outcome measure speech, a follow-up until at least the age of 4 years was deemed sufficient, and for outcome measure hearing a follow-up length of at least 1 year after surgery was deemed sufficient. When papers reported a shorter follow-up time they were excluded.

A priori, the working group did not define the outcome measures listed above but used the definitions used in the studies.

The working group defined the criteria for minimal clinically (patient) important difference for the dichotomous outcome measures; RR < 0.80 of > 1.25)

No a priori criteria were set for the continuous outcome measures because it largely depends on its context. If no information was available about the clinically important difference of the outcome measure, a difference of ten percent between the groups was defined as a minimally clinically important difference.

Search and select (Methods)

A previous systematic search was performed for the 2018 edition of the guideline in the databases of Medline (through OVID), Embase and the Cochrane Library between 1980 and December 3rd, 2014. The initial search identified 516 references of which 40 were assessed on full text. After assessment of full text, 22 studies were excluded, and 18 studies were included. To update the previous search, the databases Medline (via OVID) and Embase (via Embase.com) were searched with relevant search terms until 15^th of January 2020. The detailed search strategy is depicted under the tab Methods. The updated systematic literature search resulted in 529 hits. Studies were selected based on the following criteria: studies investigated patients with CLA/P were selected if they compared two different moments in time for repairing CLA/P. A total 22 studies (2 reviews and 20 randomized controlled trials (RCTs)) were initially selected based on title and abstract screening. After reading the full text, the 2 review studies were excluded (see the table with reasons for exclusion under the tab Methods), and 9 RCTs were included and added to the results of the RCTs from the previous search. RCT's provide a higher level of evidence, therefore the (reviews of) observational studies of the previous search were removed from the analysis (n=15).

Referenties

Botticelli S, Küseler A, Marcusson A, Mølsted K, Nørholt SE, Cattaneo PM, Pedersen TK. (2020). Do Infant Cleft Dimensions Have an Influence on Occlusal Relations? A Subgroup Analysis Within an RCT of Primary Surgery in Patients With Unilateral Cleft Lip and Palate. Cleft Palate Craniofac J;57(3):378-388.
Heliövaara A, Küseler A, Skaare P, Shaw W, Mølsted K, Karsten A, Brinck E, Rizell S, Marcusson A, Sæle P, Hurmerinta K, Rønning E, Najar Chalien M, Bellardie H, Mooney J, Eyres P, Semb G. (2017). Scandcleft randomised trials of primary surgery for unilateral cleft lip and palate: 6. Dental arch relationships in 5 year-olds. J Plast Surg Hand Surg;51(1):52-57.
Heliövaara A, Skaare P, Küseler A, Shaw W, Mølsted K, Karsten A, Marcusson A, Brinck E, Rizell S, Sæle P, Najar Chalien M, Bellardie H, Mooney J, Eyres P, Semb G. (2020). Scandcleft randomized trials of primary surgery for unilateral cleft lip and palate. Dental arch relationships in 8 year-olds. Eur J Orthod;42(1):1-7.
Karsten A, Marcusson A, Hurmerinta K, Heliövaara A, Küseler A, Skaare P, Bellardie H, Rønning E, Shaw W, Mølsted K, Sæle P, Brinck E, Rizell S, Najal Chalier M, Eyres P, Semb G. (2018). Scandcleft randomised trials of primary surgery for unilateral cleft lip and palate: 7. Occlusion in 5 year-olds according to the Huddart and Bodenham index. J Plast Surg Hand Surg;51(1):58-63.
Karsten A, Marcusson A, Rizell S, Chalien MN, Heliövaara A, Küseler A, Skaare P, Brinck E, Shaw W, Bellardie H, Mooney J, Mølsted K, Sæle P, Eyres P, Semb G. (2020). Scandcleft randomized trials of primary surgery for unilateral cleft lip and palate: occlusion in 8-year-olds according to the Modified Huddart and Bodenham index. Eur J Orthod;42(1):15-23.
Lohmander A, Persson C, Willadsen E, Lundeborg I, Alaluusua S, Aukner R, Bau A, Boers M, Bowden M, Davies J, Emborg B, Havstam C, Hayden C, Henningsson G, Holmefjord A, Hölttä E, Kisling-Møller M, Kjøll L, Lundberg M, McAleer E, Nyberg J, Paaso M, Pedersen NH, Rasmussen T, Reisæter S, Søgaard Andersen H, Schöps A, Tørdal IB, Semb G. (2017). Scandcleft randomised trials of primary surgery for unilateral cleft lip and palate: 4. Speech outcomes in 5-year-olds - velopharyngeal competency and hypernasality. J Plast Surg Hand Surg;51(1):27-37.
Rautio J, Andersen M, Bolund S, Hukki J, Vindenes H, Davenport P, Arctander K, Larson O, Berggren A, Åbyholm F, Whitby D, Leonard A, Lilja J, Neovius E, Elander A, Heliövaara A, Eyres P, Semb G. (2017). Scandcleft randomised trials of primary surgery for unilateral cleft lip and palate: 2. Surgical results. J Plast Surg Hand Surg;51(1):14-20.
Reddy RR, Gosla Reddy S, Chilakalapudi A, Kokali S, Bronkhorst EM, Kummer AW, Bergé SJ, Kuijpers-Jagtman AM. (2018). Effect of One-Stage versus Two-Stage Palatoplasty on Hypernasality and Fistula Formation in Children with Complete Unilateral Cleft Lip and Palate: A Randomized Controlled Trial. Plast Reconstr Surg;142(1):42e-50e.
Richard B, Russell J, McMahon S, Pigott R. (2006). Results of randomized controlled trial of soft palate first versus hard palate first repair in unilateral complete cleft lip and palate. Cleft Palate-Craniofac J;43(3):329-38.
Shaw W, Semb G. (2017). The Scandcleft randomised trials of primary surgery for unilateral cleft lip and palate: 11. What next? J Plast Surg Hand Surg.;51(1):88-93.
Wada T, Tachimura T, Satoh K, Hara H, Hatano M, Sayan NB, et al. Maxillary growth after two-stage palatal closure in complete (unilateral and bilateral). clefts of the lip and palate from infancy until 10 years of age. Journal of the Osaka University Dental School 1990 Dec;30:53-63.
Willadsen E, Lohmander A, Persson C, Lundeborg I, Alaluusua S, Aukner R, Bau A, Boers M, Bowden M, Davies J, Emborg B, Havstam C, Hayden C, Henningsson G, Holmefjord A, Hölttä E, Kisling-Møller M, Kjøll L, Lundberg M, McAleer E, Nyberg J, Paaso M, Pedersen NH, Rasmussen T, Reisæter S, Andersen HS, Schöps A, Tørdal IB, Semb G. (2017). Scandcleft randomised trials of primary surgery for unilateral cleft lip and palate: 5. Speech outcomes in 5-year-olds - consonant proficiency and errors. J Plast Surg Hand Surg;51(1):38-51.
Williams WN, Seagle MB, Pegoraro-Krook MI, Souza TV, Garla L, Silva ML, et al. Prospective clinical trial comparing outcome measures between Furlow and von Langenbeck Palatoplasties for UCLP. Ann Plast Surg 2011 Feb;66(2):154-63.

Evidence tabellen

Research question: What is the effect of the timing of repairing cleft lip, alveolus and/or palate on maxillary and midface growth, speech, hearing, feeding capability, postoperative complications (fistulae), and esthetics (patient, parent and/or doctor satisfaction)?

Study reference	Study characteristics	Patient characteristics ²	Intervention (I)	Comparison / control (C) ³	Follow-up	Outcome measures and effect size ⁴	Comments
Heliövaare, 2017	Type of study: Three parallel group, randomised clinical trials in international multicenter study Setting: 10 cleft teams Country: five countries: Denmark, Finland, Norway, Sweden, and the UK Source of funding: n.r.	Inclusion criteria: Caucasian, born with a non-syndromic complete unilateral; CLA/P (a soft tissue bridge of 5mm or less was accepted), and one caregiver had the national language as the mother tongue and spoke it with the child. Exclusion criteria: - N total at baseline: 148 Included in the Scandcleft trial: Arm A n=75 Arm B n=73 Important prognostic factors²: n.r. Groups comparable at baseline? n.r.	Describe intervention (treatment/procedure/test): Lip and soft palate closure at 3–4 months, and hard palate closure at 12 months	Describe control (treatment/procedure/test): Lip and soft palate closure at 3–4 months, and hard palate closure at 36 months	Length of follow-up: 5 years Loss-to-follow-up: I: 1 C: 5 Incomplete outcome data: n.r.	Outcome measures and effect size (include 95%CI and p-value if available): Maxillary and midface growth: Mean index score Arm A: 2.86 (SD 0.94) Arm B: 2.58 (SD 0.87) P=0.06
Heliövaare, 2019	See Heliövaare, 2017 Source of funding: Finnish Association of Woman Dentists	See Heliövaare, 2017	See Heliövaare, 2017	See Heliövaare, 2017	Length of follow-up: 8 years Loss-to-follow-up: I: 3 C: 0 Incomplete outcome data: n.r.	Outcome measures and effect size (include 95%CI and p-value if available): Maxillary and midface growth: Mean index score Arm A: 3.03 (SD 0.85) Arm B: 2.82 (SD 0.81) P=0.137
Karsten, 2017	See Heliövaare, 2017	See Heliövaare, 2017	See Heliövaare, 2017	See Heliövaare, 2017	Length of follow-up: Loss-to-follow-up: I: 0 C: 5 Incomplete outcome data: n.r.	Outcome measures and effect size (include 95%CI and p-value if available): Maxillary and midface growth: Modified Huddart and Bodenham index I: -6.80 (SD 4.02) C: -5.95 (SD 4.17) MD -0.86 (95% CI -2.21-0.50) P =0.21
Karsten, 2020	See Heliövaare, 2017 Source of funding: grant from the Freemasons, Stockholm, Sweden	See Heliövaare, 2017	See Heliövaare, 2017	See Heliövaare, 2017	Length of follow-up: 8 years Loss-to-follow-up: I: C: Incomplete outcome data:	Outcome measures and effect size (include 95%CI and p-value if available): Maxillary and midface growth: Modified Huddart and Bodenham index I: -9.57 (SD 5.53) C: -8.51 (SD 5.67) MD: −1.06 (−2.90–0.78) P=0.26
Küseler, 2019	See Heliövaare, 2017	See Heliövaare, 2017	See Heliövaare, 2017	See Heliövaare, 2017	Length of follow-up: 8 years Loss-to-follow-up: I: 1 C: 1 Incomplete outcome data:	Outcome measures and effect size (include 95%CI and p-value if available): Maxillary and midface growth: cephalometric angles SNA: Arm A: 78.42 (95% CI 76.63 - 80.20) Arm B: 78.90 (95% CI 77.28 - 80.52) p=0.41 (95% CI −0.69 to 1.69) cephalometric angles ANB: Arm A: 2.88 (95% CI 1.68 – 4.07) Arm B: 3.55 (95% CI 2.44 - 4.67) p=0.12 (95%CI −0.19 to 1.66)
Lohmander, 2017	See Heliövaare, 2017 Source of funding: Swedish Research Council for Health, Working Life and Welfare, No. 2011–1443	See Heliövaare, 2017	See Heliövaare, 2017	See Heliövaare, 2017	Length of follow-up: 5 years Loss-to-follow-up: I: 3 C: 2 Incomplete outcome data:	Outcome measures and effect size (include 95%CI and p-value if available): Speech: VPC SUM score: Non-significant difference between groups: p=0.96 Hypernasality: Non-significant difference between groups: p=0.62
Rautio, 2017	See Heliövaare, 2017	See Heliövaare, 2017	See Heliövaare, 2017	See Heliövaare, 2017	Length of follow-up: 5-9 years’ Rates of fistula and surgery for VPI were assessed until the youngest patient of the study had reached the age of 5 years with updating until 9 years for the latter. Loss-to-follow-up: n.r. Incomplete outcome data: n.r.	Outcome measures and effect size (include 95%CI and p-value if available): Maxillary and midface growth: Speech: Hearing: Feeding capacity: Postoperative complications: Esthetics:
Reddy, 2018	Type of study: randomized controlled trial Setting: high-volume center that performs more than 700 primary cleft lip and/or palate operations every year Country: GSR Institute of Craniofacial and Facial Plastic Surgery, India Source of funding: partly funded by the former World Health Collaborating Centre, Radboudumc, Nijmegen, The Netherlands	Inclusion criteria: patients with nonsyndromic complete unilateral cleft lip and/or palate with a previously repaired cleft lip Exclusion criteria: patients with bilateral cleft lip and/or palate, patients with isolated cleft palate, patients younger than 12 months and older than 13 months, and patients with associated syndromic conditions. N total at baseline: 100 Important prognostic factors²: Sex: I: 70% M C: 60% M Groups comparable at baseline? n.r.	Describe intervention (treatment/procedure/test): The Bardach two-flap technique20 with optimal muscle dissection or levator myoplasty was performed for patients in group A (at age 12 to 13 months) as a single procedure. The levator myoplasty was performed by relieving the levator muscle from the posterior border of the hard palate and repositioning it medially to be sutured to the contralateral levator veli palatini muscle. The tensor veli palatini muscle was not disturbed from its attachment. We did not dissect the tensor veli palatini muscle in the soft palate. In noncleft palates, the tensor veli palatini is inserted into the palatine aponeurosis and the surface behind the transverse ridge on the horizontal part of the palatine bone. In patients with cleft palate, the tensor veli palatini muscle is also attached in the same area and therefore does not require any dissection.	Describe control (treatment/procedure/test): Soft palatoplasty with levator myoplasty (at age 12 to 13 months) and two-flap hard palatoplasty (at age 24 to 25 months) as a separate procedure.	Length of follow-up: fistula at 3 years and speech at 6 years Loss-to-follow-up: none Incomplete outcome data:	Outcome measures and effect size (include 95%CI and p-value if available): Speech: mean nasalance score I: 20.61 ± 9.2 C: 16.77 ± 2.15 p = 0.006 (95% CI 1.16 - 6.53) Hypernasality (perceptual): I: 18 patients C: 20 patients p = 0.837 Postoperative complications: Fistula I: 4 patients C: 2 patients OR: 2.1 (p=0.409, 95% CI, 0.365 - 11.9)
Richard 2006	Type of study: randomized controlled trial Setting: outpatients Country: United Kingdom Source of funding: non-commercial	Inclusion criteria: 1) children with non-syndromic unilateral cleft palate 2) age 3-60 months Exclusion criteria: - N total at baseline: I: Posterior-anterior (P-A): 23 C: Anterior-posterior (A-P): 24 Important prognostic factors²: For example age I: 18.7 months C: 18.8 months Sex: I: 67% M C: 46% M Groups comparable at baseline? Yes	Describe intervention (treatment/procedure/test): Posterior – anterior order of palate closure (The anterior operation consisted of a lip repair by Millard rotation advancement, a nasal correction using the McComb procedure and a hard palate repair by a single layer vomerine flap. The posterior operation consisted of a soft palate repair with medial von Langenbeck incisions. The two operations were undertaken 3 months apart with the first operation at 19 months of age.)	Describe control (treatment/procedure/test): Anterior-posterior order of palate closure: (The anterior operation consisted of a lip repair by Millard rotation advancement, a nasal correction using the McComb procedure and a hard palate repair by a single layer vomerine flap. The posterior operation consisted of a soft palate repair with medial von Langenbeck incisions. The two operations were undertaken 3 months apart with the first operation at 19 months of age.)	Length of follow-up: Until the age of 4-6 years Loss-to-follow-up: I: 6/23 (26%) 1 died, 5 lost contact C: 4/24 (17%) 1 syndromic, 3 lost contact Incomplete outcome data: Not reported	Outcome measures and effect size (include 95%CI and p-value if available): Maxillary growth: No significant differences in cephalometric measurements between groups Speech: No significant differences in speech between groups. Hearing loss: No significant differences in hearing status between groups. Fistula formation: No significant differences in prevalence of symptomatic fistulae between groups.	No power analysis for sample size is presented. Bias due to imprecision?
Wada 1990	Type of study: randomized controlled trial Setting: outpatients Country: Japan Source of funding: no funding	Inclusion criteria: 1) patients with unilateral or bilateral cleft palate Exclusion criteria: N total at baseline: One stage closure: Unilateral cleft: 14 Bilateral cleft: 8 Two stage closure: Unilateral cleft: 16 Bilateral cleft: 7 Important prognostic factors²: Not reported Groups comparable at baseline? Unclear	Describe intervention (treatment/procedure/test): Lip repair at 5 months by Tennison’s procedure Mucoperiosteal palatal pushback procedure at 20 months (one-stage closure)	Describe control (treatment/procedure/test): Lip repair at 5 months by Tennison’s procedure Primary veloplasty at 20 months Double overlapping palatal hingeflap procedure at 5 years 10 months (two-stage closure)	Length of follow-up: Until the age of 10 years Loss-to-follow-up: Not reported Incomplete outcome data: Not described	Outcome measures and effect size (include 95%CI and p-value if available): Maxillary growth: In the unilateral cleft palate patients the maxillary growth of the patients who underwent the two-stage closure was comparable to those of the non-cleft controls regarding depth and height of the maxilla, while the one-stage closure patients had aberrant maxillary development. For the patients with bilateral clefts, the maxillary growth was similar in the one-stage and two-stage palatal closure groups.
Willardsen, 2017	See Heliövaare, 2017 Source of funding: Swedish Research Council for Health, Working Life and Welfare, No. 2011–1443.	See Heliövaare, 2017	See Heliövaare, 2017	See Heliövaare, 2017	Length of follow-up: 5 years Loss-to-follow-up: I: 3 C: 2 Incomplete outcome data: n.r.	Outcome measures and effect size (include 95%CI and p-value if available): Speech: Percent consonants correct score (PCC): Median PCC score was higher in arm A compared with arm B (n=143). p=0.45 Cleft speech characteristics (CSCs). The median number of active CSCs is significant higher in in Arm B compared with Arm A. p=0.03
Williams 2009	Type of study: RCT Setting: outpatients 91 center) Country: United States of Amerika and Brazil Source of funding: non-commercial	Inclusion criteria: 1) patients with cleft lip at palate, of age and in good health for surgery Exclusion criteria: 1) family and patient did not show up for scheduled surgery date 2) condition that could interfere with speech development N total at baseline: Early surgery (E): 181 Late surgery (L): 195 Important prognostic factors²: Not reported Groups comparable at baseline? Unclear	Describe intervention (treatment/procedure/test): Palate closure at 9-12 months of age Spina – Furlow=35 Millard – Furlow= 43 Spina – von Langenbeck= 51 Millard – von Langenbeck= 52	Describe control (treatment/procedure/test): Palate closure at 15-18 months of age Spina – Furlow=48 Millard – Furlow= 47 Spina – von Langenbeck= 46 Millard – von Langenbeck= 54	Length of follow-up: Until at least the age of 4 years Loss-to-follow-up: After surgery 31/498 (6%) Reasons not described Incomplete outcome data: Not described	Outcome measures and effect size (include 95%CI and p-value if available): Odds ratio (OR) Speech: Hypernasality: E: 79% L: 73% OR (E versus L): 1.46 (95% CI: 0.84 – 2.54, p=0.12) Nasal air emission: E: 57% L: 54% OR (E versus L): 1.16 (95% CI: 0.72 – 1.85, p=0.49) Fistula formation: E: 44/181 L: 37 / 195 OR (E versus L): 1.37 (95% CI: 0.84 – 12.22, p=0.21)	Method of randomization and (presence or absence of) blinding unclear. Statistical analyses presented very adequately.

CLA/Pcleft lip, alveolus and/or palate

Notes:

1. Prognostic balance between treatment groups is usually guaranteed in randomized studies, but non-randomized (observational) studies require matching of patients between treatment groups (case-control studies) or multivariate adjustment for prognostic factors (confounders) (cohort studies); the evidence table should contain sufficient details on these procedures.
2. Provide data per treatment group on the most important prognostic factors ((potential) confounders).
3. For case-control studies, provide sufficient detail on the procedure used to match cases and controls.
4. For cohort studies, provide sufficient detail on the (multivariate) analyses used to adjust for (potential) confounders.

Risk of bias table for intervention studies (randomized controlled trials)

Study reference (first author, publication year)	Describe method of randomisation¹	Bias due to inadequate concealment of allocation?² (unlikely/likely/unclear)	Bias due to inadequate blinding of participants to treatment allocation?³ (unlikely/likely/unclear)	Bias due to inadequate blinding of care providers to treatment allocation?³ (unlikely/likely/unclear)	Bias due to inadequate blinding of outcome assessors to treatment allocation?³ (unlikely/likely/unclear)	Bias due to selective outcome reporting on basis of the results?⁴ (unlikely/likely/unclear)	Bias due to loss to follow-up?⁵ (unlikely/likely/unclear)	Bias due to violation of intention to treat analysis?⁶ (unlikely/likely/unclear)
Heliövaare, 2017	The randomisation was done by use of a dice by the trial coordinator. The coordinator then provided an envelope to be opened just before the first surgery containing the group allocation for the child. The envelope was opened on the morning of the first operation.	Unlikely	Unlikely	Unlikely (operator blinding is not possible, but raters of all outcomes were blinded)	Unlikely Ratings were performed by a blinded panel of 16 orthodontists who scored all models.	Unlikely	Unlikely	Unclear
Heliövaare, 2019	See Heliövaare, 2017	See Heliövaare, 2017	See Heliövaare, 2017	See Heliövaare, 2017	Unlikely Ratings were performed by a blinded panel of 11 orthodontists who scored all models.	See Heliövaare, 2017	See Heliövaare, 2017	See Heliövaare, 2017
Karsten, 2017	See Heliövaare, 2017	See Heliövaare, 2017	See Heliövaare, 2017	See Heliövaare, 2017	Unlikely The raters were blinded for patient and centre.	See Heliövaare, 2017	See Heliövaare, 2017	See Heliövaare, 2017
Karsten, 2020	See Heliövaare, 2017	See Heliövaare, 2017	See Heliövaare, 2017	See Heliövaare, 2017	Unlikely Dental casts were blindly assessed by four senior consultants in orthodontics from the participating cleft centres	See Heliövaare, 2017	See Heliövaare, 2017	See Heliövaare, 2017
Küseler, 2019	See Heliövaare, 2017	See Heliövaare, 2017	See Heliövaare, 2017	See Heliövaare, 2017	Unlikely Raters of all outcomes were blinded	See Heliövaare, 2017	See Heliövaare, 2017	See Heliövaare, 2017
Lohmander, 2017	See Heliövaare, 2017	See Heliövaare, 2017	See Heliövaare, 2017	See Heliövaare, 2017	Unlikely All assessments were performed blinded and individually using a laptop and the same type of headphones	See Heliövaare, 2017	See Heliövaare, 2017	See Heliövaare, 2017
Rautio, 2017	See Heliövaare, 2017	See Heliövaare, 2017	See Heliövaare, 2017	Unclear Two surgeons did all of the first surgeries for centre A. The second operation (hard palate closure) was done by more surgeons than the first operation. The same surgeon did the 1st and 2nd surgery in 47% of the cases	Unclear	See Heliövaare, 2017	See Heliövaare, 2017	See Heliövaare, 2017
Reddy, 2018	The randomization sequence was generated by a computer program using blocked randomization in block sizes of 20 in each block. Within each block, participants were randomly assigned numbers by a computerized program to one of the two treatment groups. The randomization was performed by one surgeon who did not perform the surgery	Unlikely	Unlikely The surgical interventions and the randomization procedure were explained to the parent(s) of each eligible patient. If the parents did not agree to be part of the study, the child was excluded from the trial.	Unlikely The surgeon (R.R.R.) was blinded to the randomization process. After assigning the treatment method, each patient’s parents were informed of the treatment plan by the surgeon who performed the randomization.	Unlikely The collected speech samples were presented in a random order to two qualified speech-language pathologists who were blinded to the subject’s identity and treatment	Unlikely	Unlikely	Unlikely
Richard 2006	“randomly allocated, stratified by block randomization”	Unclear	Unclear	Unlikely	Unclear	Unlikely	Unclear	Unclear
Wada 1990	“randomly assigned”	Unclear	Unclear	Unlikely	Unclear	Unlikely	Unclear	Unclear
Willardsen, 2017	See Heliövaare, 2017	See Heliövaare, 2017	See Heliövaare, 2017	See Heliövaare, 2017	Unlikely The transcribers were blinded to the randomisation of the children, and they only evaluated children connected to a cleft palate centre where they did not work.	See Heliövaare, 2017	See Heliövaare, 2017	See Heliövaare, 2017
Williams 2009	“block randomization plan”	Unclear	Unclear	Unlikely	Unclear	Unlikely	Unclear	Unclear

1. Randomisation: generation of allocation sequences have to be unpredictable, for example computer generated random-numbers or drawing lots or envelopes. Examples of inadequate procedures are generation of allocation sequences by alternation, according to case record number, date of birth or date of admission.
2. Allocation concealment: refers to the protection (blinding) of the randomisation process. Concealment of allocation sequences is adequate if patients and enrolling investigators cannot foresee assignment, for example central randomisation (performed at a site remote from trial location) or sequentially numbered, sealed, opaque envelopes. Inadequate procedures are all procedures based on inadequate randomisation procedures or open allocation schedules.
3. Blinding: neither the patient nor the care provider (attending physician) knows which patient is getting the special treatment. Blinding is sometimes impossible, for example when comparing surgical with non-surgical treatments. The outcome assessor records the study results. Blinding of those assessing outcomes prevents that the knowledge of patient assignement influences the proces of outcome assessment (detection or information bias). If a study has hard (objective) outcome measures, like death, blinding of outcome assessment is not necessary. If a study has “soft” (subjective) outcome measures, like the assessment of an X-ray, blinding of outcome assessment is necessary.
4. Results of all predefined outcome measures should be reported; if the protocol is available, then outcomes in the protocol and published report can be compared; if not, then outcomes listed in the methods section of an article can be compared with those whose results are reported.
5. If the percentage of patients lost to follow-up is large, or differs between treatment groups, or the reasons for loss to follow-up differ between treatment groups, bias is likely. If the number of patients lost to follow-up, or the reasons why, are not reported, the risk of bias is unclear.
6. Participants included in the analysis are exactly those who were randomized into the trial. If the numbers randomized into each intervention group are not clearly reported, the risk of bias is unclear; an ITT analysis implies that (a) participants are kept in the intervention groups to which they were randomized, regardless of the intervention they actually received, (b) outcome data are measured on all participants, and (c) all randomized participants are included in the analysis.

Table of excluded studies

Author and year	Reason for exclusion
Bannister, 2017	Scandcleft study, descriptive study of postoperative nursing care
Bartzela, 2010	Retrospective observational study
Berkowitz, 2005	Does not meet selection criteria
Botticelli, 2019	Subgroup analyses of Scandcleft arm A and B; Velopharyngeal competence (VPC) and hypernasality
Botticelli, 2020	Subgroup analyses of Scandcleft arm A and B; outcome dento-occlusal assessment
Da Silva Filho, 2000	Does not meet selection criteria (follow-up too short)
Deluke 1997	Does not meet selection criteria (case series)
Farronato 2014	Does not meet selection criteria
Feragen, 2017	Scandcleft study, parental report on social and emotional experiences
Feragen, 2017	Scandcleft study, parental report on treatment outcomes
Friede, 2001	Retrospective observational study
Fudalej, 2010	Does not meet selection criteria
Fudalej, 2011	Prospective observational studu
Gerke 2014	Does not meet selection criteria (congress abstract)
Goodacre, 2003	Does not meet inclusion criteria (lip closure)
Grobbelaar, 1994	Observational study
Gundlach, 2013	Retrospective observational study
Hammarström, 2019	Comparison Scandcleft arm A and C
Hudson 1994	Does not meet selection criteria (review, not systematic)
Jørgensen	Subgroup analyses of Scandcleft arm A and B; outcome obstruent correctness and error types
Kirschner, 2000	Retrospective observational study
Klintö, 2014	Does not meet selection criteria (follow-up too short)
Landheer, 2010	Retrospective observational study
Latham 2007	Does not meet selection criteria
Liao, 2006	Systematic review of retrospective and non-randomized studies
Lohmander, 2011	Does not meet selection criteria
Molsted, 2017	Not a comparison study
Nollet, 2005	Meta-analysis of mainly observational studies to assess determinants for treatment outcome
O’Gara, 1994	Does not meet selection criteria (follow-up too short)
Persson, 2020	Comparison Scandcleft arm A and D
Prasad, 2000	Does not meet selection criteria
Randag, 2014	Retrospective observational study
Reddy, 2017	Systematic review with search till 2015, no meta-analysis
Rizell, 2017	Scandcleft study, outcome dental anomalies
Rodrigues, 2019	Systematic review with search till 2018, included 5 cohort studies in qualitative analysis
Rohrich, 1996	Retrospective observational study
Rohrich 2000	Does not meet selection criteria (review, not systematic)
Semb, 2017	Background article about scandcleft studies
Shaw, 2017	Background article about scandcleft studies
Silva, 2001	Included in systematic review Yang, 2010
Tanino, 1997	Does not meet selection criteria
Wada, 1990	Does not meet selection criteria
Westberg	Comparison Scandcleft arm A and C
Willadsen, 2012	Does not meet selection criteria
Willardsen, 2019	Same study as Willardsen, 2017; results presented per center
Williams, 2011	Does not meet selection criteria
Yang, 2010	Systematic review of retrospective nonrandomized studies
Ysunza, 2010	Does not meet selection criteria
Ysunza, 1998	Prospective observational study
Zemann, 2011	Observational study

Verantwoording

Autorisatiedatum en geldigheid

Laatst beoordeeld : 26-11-2021

Laatst geautoriseerd : 26-11-2021

Geplande herbeoordeling : 01-01-2027

The Board of the Dutch Society for Plastic and Reconstructive Surgery (NVPC) will assess whether this guideline module is still up-to-date in 2026 at the latest. If necessary, a new working groupwill be appointed to revise the guideline module. The validity of the guideline or modules of the guideline may lapse earlier when new developments arise. As the holder of this guideline, the NVPC is chiefly responsible for keeping the guideline up to date.

Module¹

Responsible party²

Year of autorisation

Next assessment of actuality guideline³

Frequency of assessement of actuality⁴

Supervisor of actuality⁵

Relevant factors for changes in recommendations⁶

Timing repearing cleft lip, alveolus and/or palate

NVPC

2021

2026

every 5 years

NVPC

None

^[1] Name of module

² Responsible party for the module

³ maximum of 5 years

⁴ half a year, every (other,..) year

⁵ supervising party or parties

⁶ Current reseach, changes in organizations/restitions, new available rescourses

Other scientific organizations participating in the guideline or users of the guideline share the responsibility to inform the chiefly responsible party (NVPC) about relevant developments within their fields.

Initiatief en autorisatie

Initiatief:

Nederlandse Vereniging voor Plastische Chirurgie

Geautoriseerd door:

Nederlandse Vereniging voor Keel-Neus-Oorheelkunde en Heelkunde van het Hoofd-Halsgebied
Nederlandse Vereniging voor Kindergeneeskunde
Nederlandse Vereniging voor Obstetrie en Gynaecologie
Nederlandse Vereniging voor Plastische Chirurgie
Vereniging Klinische Genetica Nederland
Nederlands Instituut van Psychologen
Nederlandse Vereniging voor Mond- Kaak- en Aangezichtschirurgie
Nederlandse Verenging voor Schisis en Cranio Faciale Afwijkingen
Nederlandse Vereniging van Orthodontisten

Algemene gegevens

The revision of this guideline module was supported by Knowledge Institute Federation of Medical Specialists (https://www.demedischspecialist.nl/kennisinstituut) and was financed by the Quality Foundation of the Dutch Medical Specialists (SKMS). The funding organization did not have any influence on the content of the guideline in any way.

Doel en doelgroep

Objectives of the guideline

The aim of this guideline is to improve the care of children/patients with CLA/Ps in The Netherlands ranging from prenatal detection to young adulthood, substantiated by scientific knowledge from research where possible. ‘Improving’ also means providing insight in the differences in practices between cleft teams and discriminating between wanted and unwanted (i.e. scientifically based or non-scientifically based) practice variation. This resulted in recommentations for a more uniform treatment. However, the lack of high-quality studies and evidence remains a serious limiting factor and forced the working group to define some conclusions in a more generalized way than was wished for at the start.

Specific attention will be given to the following aspects:

reducing undesirable/unfounded practice variation in the working method and treatment protocols of the Dutch cleft teams, without hampering custom work, innovation or research;
making objective / evidence-based information about the treatment of CLA/Ps available and accessible to healthcare providers, patients, parents and other parties;
determine to what extent the existing organisation of care needs to be changed in order to meet the requirements regarding “state of the art” treatment of a child or adult with CLA/Psand the follow-up to this treatment.

In this manner, the guideline offers a tool to create more uniform care in the field of the prenatal and postnatal treatment of a child with CLA/Ps and the implementation of this care in the Netherlands.

Intended users of the guideline

The guideline is primarily intended for all healthcare professionals who are involved in caring for a child with CLA/Ps: general practitioners, midwives, gynaecologists, paediatricians, ENT physicians, plastic surgeons, maxillofacial surgeons, orthodontists, clinical geneticists, specialised nurses, speech therapists, (paediatric) dentists, medical psychologists, remedial educationalists and social workers. The secondary target group involves patients, parents and their surroundings.

Samenstelling werkgroep

A multidisciplinary working group was appointed by the Dutch Society for Plastic and Reconstructive Surgery in October 2019 to update the existing guidelines for clefts of the lip and palate. The original guidelines were initiated by the Dutch Society for Plastic and Reconstructive Surgery and this Society remains responsible for the revisions. The working group subsequently updated both the guideline for prenatal counsellling for clefts of the lip, alveolus, and/or palate (Counseling na prenataal vastgestelde schisis, 2011) and postnatal treatment (Behandeling van patiënten met een schisis, 2018). The working group consisted of representatives from all relevant specialties involved in the care for patients with cleft lip, alveolus and/or palate. Members were mandated by their professional organizations. The working group consisted of a mix of new members and members, who worked on previous editions as well. The group worked on the update of the guideline for two years. The working group is responsible for the full text of this guideline.

Working group

Dr. A.B. Mink van der Molen, MD, plastic surgeon, Universitair Medisch Centrum Utrecht, (chairman), NVPC
Dr. M.F. van Dooren, clinical geneticist, Erasmus MC Rotterdam, VKGN
Dr. M.J.H. van den Boogaard, clinical geneticist, Universitair Medisch Centrum Utrecht, VKGN
Dr. L.N.A. van Adrichem, MD, plastic surgeon, Universitair Medisch Centrum Utrecht, NVPC
Dr. H.F.N. Swanenburg de Veye, psychologist, Universitair Medisch Centrum Utrecht/Wilhelmina Kinderziekenhuis, Utrecht, NIP
Dr. C.J. Bax, MD, gynaecologist, Amsterdam UMC, NVOG
Prof. dr. C.C. Breugem, MD, plastic surgeon, Amsterdam Medical Center and Meander Medical Center, NVSCA
Drs. F. Bierenbroodspot, MD, Oral and maxillofacial surgeon, Isala, Zwolle, NVMKA
Drs. M. Haasnoot, MD, paediatrician, Wilhelmina Kinderziekenhuis, Utrecht, NVK
Drs. H.H.W. de Gier, MD, otolaryngologist, Erasmus MC Rotterdam, NVKNO
Dr. M.A.R Kuijpers, orthodontist, Radboud University Medical Center, NVvO
Dr. M.E.L. Nienhuijs, MD, Oral and maxillofacial surgeon, Radboud University Medical Center, NVSCA
Dr. D. de Haan, patient representative, Schisis Nederland

Advisory board

Drs. B. Spaan, dentist, CBT Vogellanden Zwolle, NVvK
I. Noureldin - Hop, orthopedagogue, NSDSK, NVO
M. J. Coerts, speech therapist, Amsterdam UMC, NVLF

With methodological support of

Drs. A.A. Lamberts, senior advisor, Knowledge Institute Federation of Medical Specialists
Dr. M. den Ouden - Vierwind, advisor, Knowledge Institute Federation of Medical Specialists

Belangenverklaringen

According to the KNMG-code, all members of the working group have declared in writing if, in the last five years, they have held a financially supported position with commercial businesses, organisations or institutions that may have a connection with the subject of the guidelines. Enquiries have also been made into personal financial interests, interests pertaining to personal relationships, interests pertaining to reputation management, interests pertaining to externally financed research, and interests pertaining to valorisation of knowledge. These Declarations of Interest can be requested from the secretariat of the Knowledge Institute of Medical Specialists. See below for an overview.

Member	Profession	Side jobs	Declared conflicting interests	Actions
Dr. A.B. Mink van der Molen	plastic surgeon,	None	None	No actions
Dr. M.F. van Dooren	clinical geneticist	Co-chair VKGN	None	No actions
Dr. M.J.H. van den Boogaard	clinical geneticist	None	None	No actions
Dr. L.N.A. van Adrichem	plastic surgeon	DGA van Adrichem Medical B.V. Chairman Concilium plastico chirurgicum Member Raad Opleiding Member BBC NVPC Advisor Hoofdmaatje Chairman Medical Council Equipe Zorgbedrijven Member Medicatie Commissie Equipe Zorgbedrijven Member stuurgroep STW project TU-Twente	None	No actions
Dr. H.F.N. Swanenburg de Veye	psychologist	None	None	No actions
Dr. C.J. Bax	gynaecologist	Volunteer hospice Member NIPT consortium Member committee quality documents NVOG Secretary committee Otterlo NVOG Treasurer working group infectious diseases NVOG	None	No actions
Dr. C.C. Breugem	plastic surgeon	None	None	No actions
Drs. F. Bierenbroodspot	Oral and maxillofacial surgeon	Working Group Esthetische Aangezichtschirurgie	None	No actions
Drs. M. Haasnoot	paediatrician	None	None	No actions
Dr. J. de Gier	otolaryngologist	Board member NVSCA	None	No actions
Dr. M. Kuijpers	orthodontist	Guideline committee Mondzorg voor jeugdigen preventie diagnostiek behandeling	None	No actions
Dr. M. Nienhuijs	Oral and maxillofacial surgeon	Boardmember NVSCA	None	No actions
Dr. D. de Haan	patient representative,	Teacher/ education advisor HU-PABO, Hogeschool Utrecht	None	No actions

Inbreng patiëntenperspectief

Patients were represented by Schisis Nederland. Schisis Nederland is an independent organization representing patients with CLA/Psand their parents in the Netherlands. Representatives from Schisis Nederland participated in the working group. The concept guideline module was presented to Schisis Nederland for their comments.

Qualitative estimation of possible financial impact under the Wkkgz / Kwalitatieve raming van mogelijke financiële gevolgen in het kader van de Wkkgz

In accordance with the Wet kwaliteit, klachten en geschillen zorg (Wkkgz), a qualitative estimation has been made whether the recommendations in the guideline may lead to substantial financial consequences. In carrying out this assessment, guideline modules were tested in various domains (see the flow chart).

The qualitative estimate shows that there is probably no substantial financial impact, see table below.

Module	Results qualitative estimation	Elucidation
Module Timing van lip- en palatumsluiting bij patiënten met een schisis	Likely no substantial financial impact	The recommendation(s) are not widely applicable (<5,000 patients) and are therefore expected to have no substantial financial consequences for public expenditure.

Methode ontwikkeling

Evidence based

Implementatie

Guideline implementation and practical applicability of the recommendations was taken into consideration during various stages of guideline development. Factors that may promote or hinder implementation of the guideline in daily practice were given specific attention. The guideline is distributed digitally among all relevant professional groups. The guideline can also be downloaded from the Dutch Society for Plastic and Reconstructive Surgery website: www.nvpc.nl, and the guideline website: www.richtlijnendatabase.nl. The implementation table can be found in the related products.

Werkwijze

AGREE

The guideline has been drafted in accordance with the requirements outlined in the ‘Guidelines 2.0’ report of the Guideline Advisory Committee of the Council on Science, Education and Quality (WOK). This report is based on the AGREE II instrument (Appraisal of Guidelines for Research & Evaluation II) (Brouwers, 2010), an instrument designed to assess the quality of guidelines with broad international support (Brouwers, 2010). The development of a evidence-based guideline module is described step-by-step in “Ontwikkeling van Medisch Specialistische Richtlijnen” of Knowledge Institute for Medical Specialists.

Inventory of the problem areas

During the preparation phase the working group used an inventory to find the problem areas. A report of this inventory can be found in the related products.

Primary questions and outcome measures

Based on the outcomes of the bottleneck analysis, the president and advisor formulated draft primary questions. These were discussed and defined together with the working group. Subsequently, the working groupdetermined which outcome measures were relevant for the patient for each primary question, examining both desired and undesirable effects. The working groupvaluated these outcomes based on their relative importance as crucial, important and unimportant.

Literature search and selection strategy

Specific search terms were used to identify published scientific studies related to each individual primary question in electronic databases like Medline, Cochrane, and Embase. Additionally, the references of the selected articles were screened for additional relevant studies. Studies offering the highest level of evidence were sought out first. Members of the working group selected articles identified by the search based on predetermined criteria. Theselected articles were used to answer the primary question. The searched databases, the search string or terms used during the search and selection criteria applied are listed in the module for each individual primary question.

Quality assessment of individual studies

Individual studies were assessed systematically based on predefined methodological quality criteria in order to assess the risk of biased study results. These assessments may be found in the column ‘Study quality assessment’ in an evidence table.

AMSTAR - for systematic reviews.
Cochrane - for randomized controlled trials.
ACROBAT-NRS - for observational studies.
QUADAS II - for diagnostic studies.

Summary of the literature

The relevant study results from all selected articles were presented clearly in evidence tables. The key findings from the literature are described in the literature summary. If studies were sufficiently similar in design, data were also summarized quantitatively (meta-analysis) using Review Manager 5.

Assessment of the level of scientific evidence

With regard to intervention questions, the level of scientific evidence was determined using the GRADE method. GRADE is short for ‘Grading Recommendations Assessment, Development and Evaluation’ (see http://www.gradeworkinggroup.org/)

GRADE distinguishes four grades of quality of evidence, i.e. high, moderate, low and very low. These grades indicate the degree of confidence in the conclusions in the literature ((Schünemann, 2013; Hultcrantz, 2017).

GRADE	Definition
High	There is a high degree of confidence that the true effect of treatment is very close to the estimated effect of treatment as reported in the conclusion in the literature. It is very unlikely that the conclusion drawn in the literature will change if further research is done.
Moderate	There is a moderate degree of confidence that the true effect of treatment is very close to the estimated effect of treatment as reported in the conclusion in the literature. It is possible that the conclusion drawn in the literature will change if further research is done.
Low	There is a limited degree of confidence that the true effect of treatment is very close to the estimated effect of treatment as reported in the conclusion in the literature. It is probable that the conclusion drawn in the literature will change if further research is done.
Very low	There is little confidence that the true effect of treatment is very close to the estimated effect of treatment as reported in the conclusion in the literature. The conclusion is very uncertain

According to the GRADE methodology the clinical decision threshold should play an important role in assessing the level of evidence (grading) in guidelines (Hultcrantz, 2017). To set the threshold all critical outcomes, and the considerations should be determined. The clinical decision threshold is not exactly the same as the Minimal Clinically Important Difference (MCID). In situations in which an intervention has no important disadvantages and low costs, the clinical decision threshold with regard to the efficiency of an intervention can be lower (closer to zero/ no effect) than MCID (Hultcrantz, 2017).

Formulation of conclusions

For interventions, the conclusion does not refer to one or more articles, but is drawn based on the body of evidence. The working group looked at the net benefits of each intervention. This was done by determining the balance between favourable and unfavourable effects for the patient.

With regard to questions about the value of diagnostic tests, harm or adverse effects, aetiology and prognosis, the scientific evidence is summarized in one or more conclusions, listing the level of evidence for the most relevant data.

Considerations

When making recommendations, scientific evidence was considered together with other key aspects, such as expertise of the group members, patient preferences, costs, availability of facilities and/or organizational aspects. Insofar as they are not part of the systematic literature review, these aspects are listed under ‘Considerations’. The considerations are written using a structured format based on the evidence-to-decision framework of the international GRADE Working Group, and part of the GRADE methodology (Alonso-Coello, 2016a; Alonso-Coello 2016b).

Formulation of recommendations

Recommendations provide an answer to the primary question and are based on the best scientific evidence available and the most important considerations. The level of scientific evidence and the importance given to considerations by the working group jointly determine the strength of the recommendation. In accordance with the GRADE method, a low level of evidence for conclusions in the systematic literature review does not rule out a strong recommendation, while a high level of evidence may be accompanied by weak recommendations (Agoritsas, 2017; Neumann, 2016). The strength of the recommendation is always determined by weighing all relevant arguments.

Preconditions (Organisation of care)

In the analysis of problem areas, the organisation of care (all those aspects that are preconditions for the provision of care) were explicitly taken into account. These aspects include coordination, communication, materials, financial means, work force and infrastructure. Preconditions that are relevant to the answering of a specific clinical question are part of the considerations related to that specific question.

Knowledge gaps

During the development of this guideline, systematic searches were conducted for research contributing to answering the primary questions. For each primary question, the working group determined whether (additional) scientific research is desirable.

Commentary and authorization phase

The draft guideline was submitted to the (scientific) organizations involved for comment. The guideline was also submitted to the following organizations for comment: Dutch College of General Practitioners (NHG), Healthcare Insurers Netherlands (ZN), The Dutch Healthcare Authority (NZA), the National Health Care Institute (ZINL), the Health Care Inspectorate (IGJ), Dutch Organisation of Hospitals (NVZ), Dutch Federation of Academic Hospitals (NFU), Dutch Organisation of Independent Clinics (ZKN), the Netherlands Patients Federation, Dutch Organisation of nurses and caregivers (V&VN), Dutch Association of Physician Assistants, and Collaborating Top Clinical Training Hospitals (STZ). Comments were collected and discussed with the working group. The draft guideline was updated and finalized by the working group based on the comments. The final guideline was submitted for authorization to the (scientific) organizations involved and authorized or approved by them.

Literature

Agoritsas T, Merglen A, Heen AF, Kristiansen A, Neumann I, Brito JP, Brignardello-Petersen R, Alexander PE, Rind DM, Vandvik PO, Guyatt GH. UpToDate adherence to GRADE criteria for strong recommendations: an analytical survey. BMJ Open. 2017 Nov 16;7(11):e018593. doi: 10.1136/bmjopen-2017-018593. PubMed PMID: 29150475; PubMed Central PMCID: PMC5701989.

Alonso-Coello P, Schünemann HJ, Moberg J, Brignardello-Petersen R, Akl EA, Davoli M, Treweek S, Mustafa RA, Rada G, Rosenbaum S, Morelli A, Guyatt GH, Oxman AD; GRADE Working Group. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 1: Introduction. BMJ. 2016 Jun 28;353:i2016. doi: 10.1136/bmj.i2016. PubMed PMID: 27353417.

Alonso-Coello P, Oxman AD, Moberg J, Brignardello-Petersen R, Akl EA, Davoli M, Treweek S, Mustafa RA, Vandvik PO, Meerpohl J, Guyatt GH, Schünemann HJ; GRADE Working Group. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 2: Clinical practice guidelines. BMJ. 2016 Jun 30;353:i2089. doi: 10.1136/bmj.i2089. PubMed PMID: 27365494.

Brouwers MC, Kho ME, Browman GP, et al. AGREE Next Steps Consortium. AGREE II: advancing guideline development, reporting and evaluation in health care. CMAJ. 2010;182(18):E839-42. doi: 10.1503/cmaj.090449. Epub 2010 Jul 5. Review. PubMed PMID: 20603348.

Hultcrantz M, Rind D, Akl EA, et al. The GRADE Working Group clarifies the construct of certainty of evidence. J Clin Epidemiol. 2017 Jul;87:4-13. doi: 10.1016/j.jclinepi.2017.05.006. Epub 2017 May 18. PubMed PMID: 28529184.

Medisch Specialistische Richtlijnen 2.0 (2012). Adviescommissie Richtlijnen van de Raad Kwalitieit. http://richtlijnendatabase.nl/over_deze_site/over_richtlijnontwikkeling.html.

Schünemann H, Brożek J, Guyatt G, et al. GRADE handbook for grading quality of evidence and strength of recommendations. Updated October 2013. The GRADE Working Group, 2013. Available from http://gdt.guidelinedevelopment.org/central_prod/_design/client/handbook/handbook.html.

Schünemann HJ, Oxman AD, Brozek J, et al. Grading quality of evidence and strength of recommendations for diagnostic tests and strategies. BMJ. 2008;336(7653):1106-10. doi: 10.1136/bmj.39500.677199.AE. Erratum in: BMJ. 2008;336(7654). doi: 10.1136/bmj.a139. PubMed PMID: 18483053.

Wessels M, Hielkema L, van der Weijden T. How to identify existing literature on patients' knowledge, views, and values: the development of a validated search filter. J Med Libr Assoc. 2016 Oct;104(4):320-324. PubMed PMID: 27822157; PubMed Central PMCID: PMC5079497.

Zoekverantwoording

Zoekacties zijn opvraagbaar. Neem hiervoor contact op met de Richtlijnendatabase.

Schisis

Schisis

Uitgangsvraag

Aanbeveling

Overwegingen

Onderbouwing

Achtergrond

Conclusies

Samenvatting literatuur

Zoeken en selecteren

Referenties

Evidence tabellen

Verantwoording

Autorisatiedatum en geldigheid

Initiatief en autorisatie

Algemene gegevens

Doel en doelgroep

Samenstelling werkgroep

Belangenverklaringen

Inbreng patiëntenperspectief

Methode ontwikkeling

Implementatie

Werkwijze

Zoekverantwoording

Bijlagen

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