Incidence of Paradoxical Adipose Hyperplasia After Cryolipolysis: A Systematic Review and Meta-Analysis

Abstract

Paradoxical adipose hyperplasia (PAH) is a rare complication of cryolipolysis, characterized by an unexpected overgrowth of adipocytes in the treatment area. Emerging literature suggests that PAH may be underrecognized and underreported. Because of the increasing popularity of cryolipolysis for nonsurgical fat reduction, we sought to identify the overall incidence of PAH as well as the incidence by sex and treatment device, time to diagnosis, and any additional complications of cryolipolysis. In this systematic review and meta-analysis, databases (MEDLINE, Embase, CINAHL, Web of Science, Scopus, and CENTRAL) were searched from inception to May 11, 2025, for studies reporting on PAH incidence in cryolipolysis patients. The primary outcome was the literature-pooled PAH incidence, estimated using a nonpairwise generalized linear mixed model for meta-analysis. Secondarily, we descriptively reviewed treatment devices utilized, time to PAH diagnosis, and additional cryolipolysis complications. Twenty-eight studies encompassing 13,078 patients were included in the review. Low-certainty evidence suggested that the pooled incidence of PAH was 0.22% (95% CI, 0.10-0.47), with 29 cases identified (1 in 455 patients). Sex-based risk differences were not statistically significant. Only 4 studies reported sufficient follow-up duration (≥16 weeks). PAH cases were reported with various devices and applicators, and although 10 of the 29 PAH cases (34.5%) involved the CoolCore applicator, insufficient data precluded device-based meta-analysis. Overall, the incidence of PAH following cryolipolysis appears to be higher than manufacturer reports. These findings emphasize the need for comprehensive risk disclosure, improved awareness and adverse event reporting, risk factor identification, and further investigation into the pathogenesis of PAH.

Level of Evidence: 3 (Therapeutic)

Paradoxical adipose hyperplasia (PAH) is a rare complication of cryolipolysis.¹ Cryolipolysis, also commonly known by the brand name “CoolSculpting” (Allergan Aesthetics, an AbbVie Company, Pleasanton, CA), is a United States FDA-cleared, noninvasive technique that employs controlled cooling to reduce localized fat deposits.¹ A topical applicator containing thermoelectric cooling plates and vacuum suctioning is applied to target adipose tissue in the treatment area. Lipid-rich tissues crystallize at higher temperatures than the surrounding water-rich tissues, explaining why adipocytes in the subcutaneous layer are targeted in cryolipolysis while the skin and surrounding tissues are spared.^2,3 It is this damage to the adipocyte that results in delayed apoptosis of the fat cells, and when combined with the body's subsequent inflammatory phagocytic response, this leads to gradual reduction of the superficial fat layer and improvements in body contours.^2,3

PAH was first reported as a complication of cryolipolysis in 2014.⁴ PAH typically manifests 2 to 4 months following treatment, presenting as a prominent and fibrotic fullness in the treatment area.⁵ Its reported incidence in the literature has ranged widely, from 0.00051% to 1%.¹ To date, only 1 systematic review has evaluated PAH following cryolipolysis, whereas no meta-analysis has been performed. In this 2017 systematic review by Ho and Jagdeo, 16 PAH cases were identified across 10 studies, with the authors suggesting that the incidence of PAH may be higher than previously considered.⁶

Given discrepancies among incidence rates in existing studies, underreporting of PAH in the literature remains likely.⁷ Because the popularity of cryolipolysis continues to rise with emerging advancements, including novel applicators, temperature optimization, and combination therapies, an up-to-date systematic review and meta-analysis is necessary to quantify the current incidence of PAH.¹ This complication measure will provide insight to both patients and care providers during the informed consent and decision-making process regarding fat reduction by cryolipolysis. Therefore, this systematic review and meta-analysis aims (1) to define the overall incidence of PAH among cryolipolysis patients and risk differences by sex and (2) to identify common applicators utilized in those who develop PAH, time to diagnosis, and any additional cryolipolysis complications.

METHODS

The requirement for institutional review board approval was waived because this work relied in its entirety on published primary research. This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines.^8,9 The study was prospectively registered on PROSPERO (CRD20251079626).

Search and Study Selection

A systematic search was conducted on MEDLINE (Ovid), Embase, CINAHL, Web of Science, Scopus, and CENTRAL from inception until May 11, 2025, without language restrictions. Database search strategies were informed by an expert medical librarian (Supplemental Table 1). Citations were reviewed to identify articles that were not captured in the search.

Eligibility Criteria

Studies were included if they (1) reported primary data on the incidence of PAH following cryolipolysis; (2) were accepted for publication in a peer-reviewed journal. Studies were excluded if they (1) performed cryolipolysis in nonhuman models; (2) performed cryolipolysis in vitro; (3) were only published as an abstract; and (4) were systematic reviews, meta-analyses, or conference proceedings.

Paired and independent reviewers (A.E.M. and P.R.) performed title and abstract screening, full-text screening, data extraction, and risk of bias (ROB) assessment. Discrepancies were resolved through discussion between the 2 reviewers.

Data Extraction and Risk of Bias Assessment

Data were extracted on study characteristics (publication year, location, and study design), patient demographics (mean age, sex, and mean BMI), the number of patients who received cryolipolysis, the number of patients who experienced PAH, treatment characteristics (treatment areas, device utilized, treatment time, and mean time to follow-up), and treatment effects (subcutaneous tissue reduction, other complications). ROB among the included studies was assessed according to study design. Observational cohort studies were assessed using the Cochrane's Risk of Bias in Non-Randomized Studies of Interventions tool (ROBINS-I).¹⁰ Randomized controlled trials were evaluated using the Cochrane RoB 2.0 tool.¹¹ Case series and cross-sectional studies were appraised using the Joanna Briggs Institute (JBI) Checklist for Case Series and Analytical Cross Sectional Studies.¹² For JBI evaluation, studies that satisfied ≤49%, 50% to 69%, and ≥70% items of the JBI Checklist were classified as high, moderate, and low ROB, respectively.^13,14 The evidence certainty of study outcomes was evaluated using the GRADE tool.¹⁵

Data Synthesis and Statistical Analysis

The primary measures were the overall literature-pooled incidence (proportion; with a 95% CI) of PAH among cryolipolysis patients and risk differences by sex. We descriptively analyzed devices utilized in PAH patients, time to diagnosis, and additional cryolipolysis complications.

A nonpairwise generalized linear mixed model meta-analysis of proportions was performed using a binomial distribution, logit link function, and maximum likelihood estimation of random effects. The pooled incidence of PAH was estimated with 95% CIs (α = .05). A subgroup analysis was conducted based on ROB categorization.¹⁶ Sensitivity analysis using the inverse-variance method was conducted. A random-effects meta-analysis computing a risk ratio (RR) with 95% CIs was performed to compare the incidence of PAH by sex (male vs female). The Mantel–Haenszel method was utilized with a continuity correction of 0.5 applied to studies containing zero events in either group. Relative risks with 95% CIs were pooled across studies using inverse-variance random-effects modeling.

RESULTS

The initial search yielded 890 unique studies (Figure 1). Citation screening identified 3 additional studies. Ultimately, 28 studies met criteria for inclusion in the systematic review. All studies were published between 2015 and 2025 (Supplemental Table 2).

Figure 1.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram.

Risk of Bias

Generally, included studies had a moderate ROB that predisposed to low GRADE certainty evidence when combined with the rarity of PAH (Supplemental Table 3). Key factors introducing bias included missing data (8 studies), unclear demographics/descriptions of study participants and settings (5 studies), and potential confounding (4 studies). Studies reliably classified interventions (24 studies) and did not deviate from these intended interventions (22 studies).

Overall Paradoxical Adipose Hyperplasia Incidence

Across 28 studies, there were 13,078 patients who received cryolipolysis treatment, of whom 29 were diagnosed with PAH (1 affected per 454.55 patients). The pooled incidence of PAH in cryolipolysis patients was 0.22% (95% CI, 0.10-0.47, I² = 0%; Figure 2). When performing subgroup analysis by ROB, as ROB decreased from moderate to low, the statistical heterogeneity decreased from 18% to 0% in the low ROB group. The pooled PAH incidence of the low ROB group was 0.48%. There was no significant publication bias (P = .08).

Figure 2.

Forest plot for the overall incidence of paradoxical adipose hyperplasia (PAH) following cryolipolysis.

Treatment Areas Involved

Nine studies indicated which treatment areas developed PAH, accounting for the affected areas in 28 individuals.^7,17-24 Of these 28 patients, 19 developed PAH in 1 area, 8 developed PAH in 2 areas, and 1 developed PAH in 5 areas. Affected areas included the lower abdomen (n = 15), flanks (n = 6), unspecified abdominal area (n = 5), thighs (n = 3), upper abdomen (n = 2), bra line (n = 2), submental (n = 1), pectoral/chest region (n = 1), breast (n = 1), lateral chest/upper back (n = 1), upper and lower abdomen (n = 1), mid-back (n = 1), and arms (n = 1).

Paradoxical Adipose Hyperplasia Incidence by Sex

Overall, 8 studies reported on the sex of patients who developed PAH. In a total cohort of 1,153 males (13.17%) and 7,602 females (86.83%), PAH occurred in 16 males (1.39%) and 11 females (0.14%).

Although 8 studies reported the sex distribution of PAH patients, 5 of these studies did not report the total number of males and females who received cryolipolysis.^{7,17-21,23,24} The remaining 3 studies that compared sex-based PAH incidence among cryolipolysis patients were meta-analyzed, encompassing 566 males and 3,115 females who underwent treatment, of whom 4 males and 3 females were affected. The relative risk of PAH did not significantly differ between males and females in the random-effects analysis (RR 5.31, 95% CI, 0.25-110.96, I² = 62%; Supplemental Figure 1). However, the limited number of studies reporting on sex-based data for this meta-analysis contributed to low power.

Qualitative Analysis

Devices Utilized in Paradoxical Adipose Hyperplasia

Devices and applicators implicated in reported PAH cases varied across studies, most commonly following use of the CoolSculpting system (Table 1). Because individual PAH cases may have involved multiple applicators across treatment cycles, the cumulative applicator count may exceed the number of distinct cases.

Table 1.

Cryolipolysis Devices Utilized in Paradoxical Adipose Hyperplasia Patients

Device/applicator	No. of reported patients with PAH
CoolCore	10
CoolSculpting Machine	4
“Large applicator”	4
Zeltiq EZ 8	4
CoolAdvantage CoolFit	2
CoolCurve+	2
CoolMax	2
CoolAdvantage CoolCurve	1
CoolAdvantage CoolCurve+	1
CoolAdvantage Core	1
CoolAdvantage Fit	1
CoolAdvantage Plus Core	1
CoolAdvantage Plus CoolCurve	1
CoolAdvantage Plus Curve+	1
CoolCurve	1
CoolSmooth PRO	1
Cooltech Define	1
CoreAdvantage	1
First-generation applicator (CoolSculpting 2016-2017)	1
Third-generation applicator (CoolSculpting Elite 2021-2023)	1
Zeltiq EZ 6.3	1

PAH, paradoxical adipose hyperplasia.

Sixteen cases involved first-generation applicators, including: CoolCore (n = 10), CoolMax (n = 2), CoolCurve+ (n = 2), CoolCurve (n = 1), and CoolSmooth PRO (n = 1).^7,20,22,24 Implicated Zeltiq-branded applicators (Zeltiq Aesthetics, an AbbVie Company, Pleasanton, CA) included the EZ 8 (n = 4) and EZ 6.3 (n = 1), also early models from the 2010s.^18,19,22 Ten cases involved second-generation CoolAdvantage applicators, including CoolAdvantage CoolFit (n = 2), CoolAdvantageCore (n = 1), CoreAdvantage (n = 1), CoolAdvantage Plus Core (n = 1), CoolAdvantage Plus Curve + (n = 1), CoolAdvantage Plus CoolCurve (n = 1), CoolAdvantage CoolCurve (n = 1), CoolAdvantage CoolCurve+ (n = 1), and CoolAdvantage Fit (n = 1).^7,24 Friedmann et al reported 1 case involving a first-generation applicator (CoolSculpting 2016-2017) and 1 involving a third-generation applicator (CoolSculpting Elite 2021-2023).²³ Four cases involved unspecified CoolSculpting applicators.¹⁷ One case involved the Cooltech Define system (Sinclair Global, New York, NY), without specifying the applicator.²⁵ Kelly et al described 4 cases involving a “large applicator,” without identifying the specific device.²¹

Given the lack of consistent device-specific incidence reporting for PAH, meta-analysis was not performed.

Paradoxical Adipose Hyperplasia Follow-Up Duration

Follow-up duration was inconsistently reported across the included studies (Supplemental Table 4). Of the 28 studies, 9 (32.1%) did not specify follow-up duration. Given that PAH typically develops >12 weeks after treatment, we qualitatively categorized studies by their maximum follow-up durations, where available, to assess their ability to detect PAH.²⁶ Twelve studies had follow-up durations of 12 weeks or less, which were considered insufficient for reliable detection of PAH. Three studies were classified as borderline, with follow-up >12 weeks but <16 weeks. Only 4 studies had sufficient follow-up of 16 weeks or more for the detection and diagnosis of PAH.

Time to Paradoxical Adipose Hyperplasia Diagnosis

Time to PAH diagnosis following cryolipolysis was reported in 6 studies.^{7,17-19,23,24} Across these, the average time to clinical recognition ranged widely, from 2.75 to 16.1 months posttreatment. Several studies reported substantial variability within their samples; Nikolis et al reported an average diagnosis at 16.1 months ± 10.6 months in their 9 cases, whereas Stroumza et al reported a mean diagnosis at 2.75 months with a narrow spread (±0.96 months) in 4 cases, reflecting differences in follow-up intervals and diagnostic awareness.^7,17 Despite variability, included studies suggested that PAH tends to be diagnosed between 3 and 9 months after cryolipolysis at a scheduled follow-up visit, often a few weeks to months after initial patient concerns and development of PAH. This is consistent with the timeframes described by previous studies.^5,26 Differences in time to diagnosis may be influenced by patient vigilance, provider familiarity with PAH, and the availability of timely follow-up visits.

Other Complications

We also summarized other non-PAH adverse events (AEs) following cryolipolysis treatment (Supplemental Table 5). Several studies reported AEs without specifying frequencies, which did not contribute to the quantitative case count but are reported descriptively below.

Altered sensory symptoms (eg, numbness, tingling, paresthesia, hypersensitivity, hypesthesia, dysesthesia, and pruritus) were the most frequently reported AE category, with 89 reported cases across 15 studies.^{17,20,22,23,27-37} Pain, tenderness, or discomfort following treatment was quantitatively reported in 83 cases, across 15 included studies.^{20,23,25,27,28,30,31,34-41} Pain and sensory symptoms were generally transient and self-limited, although outcomes were not uniformly reported. Erythema (47 cases across 13 studies) and bleeding under the skin, including ecchymosis, hematoma, or petechiae (39 cases across 14 studies), were also commonly reported AEs.^{17,19,20,23,27-39,41,42} These issues were typically self-limited and did not require intervention or treatment.

Less frequent AEs included swelling or edema (12 cases across 8 studies), vasovagal reaction (20 cases across 3 studies), postinflammatory hyperpigmentation (14 cases across 4 studies), induration or contour irregularities (12 cases across 2 studies), and panniculitis (13 cases across 2 studies).^{17,23,27-29,32,33,36-39}

Rare or isolated AEs included frostbite (3 cases in 1 study), nodule formation (3 cases in 1 study), and single reports of blanching, burning, laxity, and blistering.^27-29,37-39 These were typically not quantified across studies, and severity or clinical management was inconsistently reported.

DISCUSSION

Overall, this systematic review and meta-analysis found that the reported incidence of PAH following cryolipolysis was 0.22%. When PAH was first described in 2014, its incidence was reported as 0.0051%.⁴ In 2018, the manufacturer indicated a PAH incidence of 0.025%.¹⁷ Most recently in 2021, the manufacturer reported that PAH occurs in 0.033% of cryolipolysis patients.⁴³ Seemingly, the reported incidence of this complication has risen since its initial observation, which may be attributed to augmented awareness and improved reporting.⁷ The pooled incidence in this review is 6.67× higher than that of the most recent manufacturer report, supporting previous observations that this complication may occur more frequently than previously described.⁶ Among studies with follow-up periods exceeding 16 weeks, PAH incidence in the larger studies were found to be higher than previous reports. Friedmann et al identified 2 cases among 3262 patients (0.06%), whereas Stroumza et al reported 4 cases among 398 patients (1.01%).^17,23 In contrast, Park et al and Wanitphakdeedecha et al reported no cases of PAH, although the absence of events is likely attributable to their limited sample sizes (n = 10 and n = 20, respectively).^30,41

The exact mechanism underlying the pathogenesis of PAH has not yet been elucidated. However, various pathophysiological hypotheses include subapoptotic injury to adipocytes through poor contact with the cryolipolysis applicator, adipocyte hypertrophy, hypoxic injury, sympathetic denervation, and resident or circulating preadipocyte or stem cell recruitment.^4,17,44 Stroumza et al suggested that the massage performed after the cryolipolysis device application may induce trauma to adipocyte membranes, prompting inflammatory adipocytolysis.¹⁷ This process results in cavity formation in adipocyte membranes that initiates an inflammatory response, whereas irreparable holes lead to necrotic adipocytes. Although Jalian et al observed increased vascularization in PAH adipocytes, Seaman et al found reduced vascularization.^4,45 Future research investigating the pathogenesis of PAH to precisely delineate its causes could prompt more accurate diagnosis, preventative measure development, targeted treatment development, and improved patient outcomes.

Unfortunately, no definitive or causative risk factors for PAH have been identified to date.⁴ However, Kelly et al highlighted common characteristics found in all 4 patients who experienced PAH out of 510 cryolipolysis patients within their practice: Hispanic background, male sex, and treatment with a single large applicator in the lower abdomen.²¹ Interestingly, 2 twin brothers who received cryolipolysis with the large applicator at different facilities developed PAH in the lower abdomen, suggesting a potential genetic predisposition. Regarding sex, although we did not find a statistically significant difference in the relative risk of PAH in males vs females, this analysis is limited by the small number of studies (n = 3) which led to an unstable comparison estimate with a very wide confidence interval. Therefore, although no significant difference was found, a true sex-based difference may exist even if it could not be detected because of small sample sizes and substantial heterogeneity between studies (low power). In fact, the literature has found that 42% to 72% of PAH cases occur in males.^7,19,21 This finding concurs with our descriptive findings, as a greater number of males (n = 17) experienced PAH vs females (n = 12). Females comprised a greater portion of our study population (86.83%) compared with males (13.17%). This sex distribution mimics real-world data, because it has been reported that males comprise ∼15% of the cryolipolysis treatment population.⁷ The lower proportion of males undergoing the procedure combined with the greater proportion of males developing PAH indicates that there is an overrepresentation of PAH in males, suggesting that male sex may be a potential risk factor for PAH.⁷ Similarly, Jalian et al reported that PAH seems to be more common in male vs female patients.⁴ In the future, larger studies and improved reporting of demographics among cryolipolysis patients, and specifically those that experience PAH are needed to assess potential risk factors for this complication.

Most PAH cases involved at least 1 treatment cycle with first-generation CoolSculpting or Zeltiq-branded applicators (22 cases), followed by the second-generation CoolAdvantage line (10 cases), and an isolated case associated with the third-generation CoolSculpting Elite platform. These findings align with observations from a Canadian multicenter study by Nikolis et al, which reported a 75% reduction in PAH incidence following the adoption of newer CoolSculpting models.⁷ However, Friedmann et al found marginal differences in PAH incidence between generations, with 0.10% in first-generation applicators vs 0.12% in third-generation applicators across 1,835 cycles.²³ Our data further support a trend toward improved safety profiles with newer cryolipolysis applicators, although further studies are required to clarify the relationship between applicator design and PAH risk. The newer generation cryolipolysis devices require reduced treatment duration and tissue suction because of redesigned surface applicators that optimize cooling distribution, potentially preventing the development of PAH.^1,46 Where the earlier generation applicators were flat, rectangular-shaped cups, the third-generation applicators feature a redesigned C-shaped cup that is designed to optimize applicator contact with natural contours of the body.¹

Variations in PAH incidence rates across studies suggest that PAH is likely underreported and underdiagnosed.¹⁹ Although the complication itself is benign, PAH may be a source of significant distress for patients.⁷ Other contributors to its underreporting may include the long duration of follow-up needed to detect PAH, patients presenting to alternate providers who did not perform the primary cryolipolysis treatment, and the fact that patients can mistake PAH for inadequate treatment response. These factors may help to explain why the manufacturer-reported incidence of PAH is lower in comparison to the estimated incidence of this review. To date, there has been no report of a case of PAH that has spontaneously resolved. Reported treatments have included corrective liposuction and lipectomy, which may be further unsettling to patients given that the appeal of pursuing cryolipolysis in the first place is often its noninvasive nature.⁷

Common AEs following cryolipolysis included altered sensory symptoms, pain, tenderness, discomfort, and erythema. The generally transient, self-limited nature of these complications and resolution without treatment suggests that cryolipolysis is well tolerated and safe in most patients, although rare but serious complications such as PAH can occur.

Future research should prioritize two key areas. First, efforts should be directed toward identifying common risk factors, such as genetic predisposition, sex, or treatment parameters to improve patient selection and risk reduction. Second, further investigation is needed to elucidate the pathophysiology of PAH to inform preventative and novel targeted treatment options, ultimately enhancing patient safety and outcomes in aesthetic medicine.

We recognize several limitations of this systematic review and meta-analysis. Although the mean time to PAH development following cryolipolysis is typically 2 to 4 months, the follow-up durations of included studies may have been insufficient to detect cases of PAH, potentially leading to an underestimation of the true incidence of this complication. Specifically, only 4 studies had follow-up durations of at least 16 weeks. Monitoring for PAH in patients who have undergone cryolipolysis is critical to improve the accuracy of reporting in the literature, which currently limits the scope of this systematic review. To minimize ambiguity, we only included studies that explicitly reported the number of patients who developed PAH, including studies that found zero incidence. This approach may have introduced reporting bias by excluding potentially relevant studies that did not specifically name the complication, which may further underestimate the true incidence. Eight studies had a ROB because of missing data, which may have impacted the accuracy of the pooled incidence estimate. Some of the missing data may reflect cases where PAH developed but was misclassified as a procedure failure rather than a complication. Insufficient reporting of applicator or treatment settings in several studies limited our ability to assess this variable as a potential risk factor. With regard to other cryolipolysis-related AEs, limited studies reported AEs numerically, and many may have underreported transient or mild effects. Although no statistically significant difference in relative risk of PAH was found between sexes, our analysis may have had insufficient power to assess this variable. Only 3 studies were included, and the wide confidence interval indicates substantial uncertainty of our estimate. Research is needed with larger datasets reporting on PAH incidence between males and females.

CONCLUSIONS

This systematic review and meta-analysis found that PAH is a rare but increasingly recognized complication of cryolipolysis, with a pooled incidence of 0.22%—notably higher than rates previously reported by manufacturers. Although uncommon, our findings support growing evidence that PAH may be underreported and underdiagnosed, given its delayed onset and potential misattribution to treatment failure. This analysis also reveals gaps in the literature, including inconsistent reporting of treatment parameters, follow-up durations, AEs, and patient demographics, thus emphasizing the importance of posttreatment monitoring for patients after cryolipolysis. Although the condition itself is benign, treatment of PAH often requires surgical intervention, which undermines the appeal of cryolipolysis as a noninvasive procedure. No definitive risk factors for PAH have been established, although our analysis suggests a possible male predominance. Although sex-based risk did not reach statistical significance through meta-analysis, descriptive data and previous literature support that males may be at elevated risk, underscoring the need for further research with adequate power.

Supplemental Material

This article contains supplemental material located online at https://doi.org/10.1093/asjof/ojaf142.

Disclosures

The authors declared no potential conflicts of interest with respect to the research, authorship, and publication of this article. Dr Ahmad is a key opinion leader for Lumisque Inc. (Weston, FL) and InMode (Irvine, CA) and a consultant for Allergan Aesthetics (Irvine, CA).

Funding

The authors received no financial support for the research, authorship, and publication of this article, including payment of the article processing charge.