Injury to the anterior cruciate ligament (ACL) of the knee is a serious athletic injury, potentially career altering. Additionally, injury may lead to lifelong sequela including knee instability, altered gait, and early onset osteoarthritis. Return-to-play rates after ACL injury are estimated as low as 49.4% in a study of soccer players (6). Even if the ACL is repaired, an increased risk for reinjury exists along with deficits in sensorimotor control, coordination, and posture of the injured limb (9,15,30,39). In specific sports, such as soccer, basketball, volleyball, and gymnastics, women have much higher injury rates (1,3,4,11,13,20,24). One of the largest differences exists among soccer players where women are 1.75–2.4 times more likely to sustain an ACL injury in soccer than men (3,6).
It has been postulated that sex hormones, namely estrogen, predispose women to ACL injury (38). A systematic review demonstrated that more ACL injuries in women occurred during the follicular and ovulatory phases of the menstrual cycle when estrogen levels are high (12). Injury counts deviated from the expected by about 35%, with fewer than expected injuries occurring during the luteal phase (12). The underlying mechanism for this phenomenon is most likely increased anterior knee laxity coincident with elevated serum estrogen levels (31,40). Estrogen has been shown to decrease collagen content in soft tissues and decrease ACL tensile strength (17,32). Some of the sex differences in ACL injury incidences are likely due to cyclically elevated levels of estrogen in women.
Progestins are the active compounds in oral contraceptives (OC), and their supplementation disrupts the normal menstrual cycle and prevents ovulation by suppressing follicular development and rupture. Estrogen levels are depressed due to halting of follicular development. Theoretically, decreased serum estrogen levels may equate to stronger ligaments and soft tissues, including the ACL. It has been suggested that OC use among athletes decreases the number of traumatic injuries and prevents a premenstrual fall in physical fitness (22). Athletes have also reported better stability while using OC (21). However, retrospective studies have reported no difference in athletic ACL injury rates between OC users versus nonusers (2,28).
The purpose of our study was to examine whether OC use was protective against ACL injury requiring surgical reconstruction in commercially insured women under age 40 yr.
Administrative, medical claims, and prescription drug data from private insurance partners to Clinformatics Data Mart, a large commercial insurance database, were used for this study. All data had been deidentified before manipulation. This study was exempt from an institutional IRB approval. Claims data from enrollees registered between the years 2002 and 2012 were used.
We performed a case–control study using all Clinformatics Data Mart enrollees for the 11-yr period 2002–2012 in the United States. Women age 15–39 yr with a minimum of 12 months continuous enrollment previous to index or ACL reconstruction date were included in this study.
Cases were defined as patients who underwent surgical reconstruction of the cruciate ligaments, either the ACL or posterior cruciate ligament (PCL), as defined by ICD-9-CM procedure codes. The codes used to define cases included: triad knee repair (81.43) and other repair of the cruciate ligaments (81.45). The 81.45 code potentially included cases of isolated PCL repair. However, one report found that 99.3% of 81.45 codes involved repair of the ACL in the outpatient setting (18). That same study also reported that by 2006, only 5% of inpatient 81.45 codes involved a PCL repair. The date of reconstruction was used as the event date for matching and determination of continuous enrollment. Two further congruent studies were performed changing only the definition of case. In one, cases were selected to include a non-knee ligamentous injury and were defined by Ankle injury, including ICD-9-CM codes for ankle sprain (845.00–09) and ankle dislocation (837.0–1). For the other, we defined cases of injury not involving the lower extremity or directly associated with ligaments. That cohort was defined by ICD-9-CM codes for superficial injury of the shoulder and upper arm (912.0–9).
Controls were matched to cases based on an index date matched to case ACL reconstruction date. Controls had to meet the same inclusion criteria of cases. Three controls were matched to every one case based on event/index date, age, and region.
Cases and controls were excluded from this study if there was a documented history of a hormonally disruptive condition. Conditions used for exclusion included polycystic ovarian syndrome, hysterectomy, Turner syndrome, follicular cyst of ovary, unspecified ovarian cyst, acquired atrophy of the ovary or fallopian tube, benign neoplasm of the ovary, malignant neoplasm of the ovary, oophorectomy, and pregnant state/ectopic (only the previous 12 months were considered). Enrollees with documented use of nonoral, hormonal-based contraceptives were also excluded. These forms of contraception included emergency contraception, implantable devices, hormonally impregnated intrauterine devices, injectable contraceptives, and patch contraceptives.
OC use was determined from a 12-month look back from event/index date. OC were identified in the pharmaceutical data using National Drug Codes. Pharmacy claims data allowed us to extract the type(s) of OC prescriptions filled as well as the number of days each prescription fill covered. This permitted us to analyze OC use as both a binary variable (any pharmacy claim for OC) and a class variable as long-term use, longer than 90 d of prescription filled, and short-term use, 90 d or less. This cutoff has been previously reported as a breaking point for continuous versus trial OC use (27). Pharmacy claims data also included the name brand of all OC used. This allowed us to consider monophasic and multiphasic OC use as well as progestin therapy and combined progestin and estrogen therapy as potential confounders.
Covariates included were the presences of asthma or type 1 diabetes mellitus and the use of injectable, oral, or inhaled corticosteroids or antibiotics. An Elixhauser Comorbidity Index was also calculated for each patient (36). This index was treated as a class variable for analysis with classes of 0, 1, 2, and 3+. To help control for previous lower extremity injury that may indicate a higher injury risk, we created a variable called “high risk.” Patients were labeled as high risk if during the 12-month look back they had a history of Achilles bursitis/tendinitis, tibialis tendinitis, dislocation of the knee, dislocation of the ankle, sprains or strains of the knee and leg, sprains or strains of the ankle and foot, nontraumatic rupture of muscle, nontraumatic compartment syndrome of the lower extremity, stress fracture of the tibia or fibula, and stress fracture of the metatarsal. Absence of any of these conditions labeled a patient as low risk.
Conditional logistic regression was used to estimate the odds of exposure to OC in patients undergoing ACL surgical reconstruction. Unadjusted and adjusted odds ratios (OR) and their 95% CI were the statistics reported for these estimates. In our general model, all ages were included, and OC use was treated as a binary variable. Following models were all stratified by age to account for a significant interaction. These models examined OC use as a duration (>90 d vs <90 d use), OC type (monophasic vs multiphasic), and OC formulation (progestin vs progestin with estrogen). All multivariable models were adjusted for all covariates mentioned in the previous section. SAS 9.3 (SAS Institute Inc., Cary, NC) was used to perform all analyses. Alpha was set at 0.05 for significance.
The study identified 26.7 million women enrolled in Clinformatics Data Mart from 2002 to 2012. Of these, 12,819 underwent an ACL reconstruction and met the inclusion/exclusion criteria for this study. A summary chart of case selection is presented in Figure 1. All cases were matched 1/3 to controls.
A summary of case and control cohort study variables is presented in Table 1. The mean age for both cases and controls was 24.11 yr with a standard deviation of 8.12 yr. The age group 15–19 yr had the highest incidence of ACL reconstruction, and, more specifically, those cases were concentrated among ages 15–18 yr (Fig. 2). Cases had a higher raw percentage of OC users than controls (23.39% vs 22.82%, respectively, P < 0.0001). Cases had significantly higher percentages of enrollees labeled high risk, receiving steroid injection, prescribed inhaled or oral steroids, prescribed antibiotics, and diagnosed with asthma (P < .0001 for all comparisons). Type 1 diabetes mellitus was more common among controls (P < 0.0001).
OR obtained by conditional logistic regression for all exposure variables and covariates are presented in Table 2. The adjusted OR from the multivariate model defined in Table 2 showed that cases did not differ from controls in OC use (adjusted OR, 0.99; 95% CI, 0.94–1.04). Of note, cases were nearly three times more likely to be considered high risk (adjusted OR, 2.76; 95% CI, 2.52–3.03) and approximately two times (adjusted OR, 2.08; 95% CI, 1.84–2.34) more likely to have received a steroid injection compare to controls.
Formal testing determined there was a significant interaction between age and OC use (P = <0.0001). Stratification by 5-yr age groups revealed that cases in age groups 15–19 yr were significantly less likely to use OC than controls (adjusted OR, 0.82; 95% CI, 0.75–0.91; P < 0.0001). Table 3 contains all unadjusted OR and adjusted OR for OC use for all 5-yr age groups. Cases in age groups, 25–29 yr and 30–34 yr, were significantly more likely to have used OC than controls. Sensitivity analysis revealed that the duration of OC use may modify the effect of OC use on ACL injury risk. Specifically, enrollees using OC for 90 d or less had a lower adjusted OR than those using OC for longer than 90 d in the logistic model concerning all ages (P = 0.0185, Table 2). Differences in duration of use for individual age groups, however, was not consistent.
Multivariate analysis of OC formulation (progesterone only vs combined therapy), in total and by 5-yr age groups, revealed no remarkable findings or trends. Analysis by dosage, monophasic (includes progesterone only OC) and triphasic, revealed that monophasic formulations had a lower adjusted OR than triphasic formulations (P = 0.0248, Table 2). These differences in adjusted OR between formulations within each age group, however, were not significant.
In our parallel studies concerning alternate case definitions, 134,299 cases of ankle injury and 4490 cases of superficial injury of the upper extremity were identified within Clinformatics DataMart meeting our inclusion/exclusion criteria. All identified cases were matched 1/3 to controls. Patterns reported for the case cohort of ACL injures do not extend to these two groups. Although OC did significantly interact with age (P < 0.0001) in both ankle injury and superficial injury of the upper extremity cohorts, cases among the age group 15–19 yr were more likely to use OC than controls (P < 0.0005, Table 4). No significant trends were noted for these two cohorts in terms of OC formulation (progesterone only vs combination therapy) or dosage (mono vs triphasic).
Among the Scandinavian joint registries, the mean age of those undergoing ACL reconstruction was 27 yr (19). A similar database at Kaiser Permanente in the United States reported an average age of 27.8 yr for those undergoing reconstruction (19). Our cases had an average age of 24.11 yr with most injuries occurring in the age group 15–19 yr (Fig. 2). The slightly lower average is most likely due to the exclusion of women age 40 yr or older in our study. ACL injury in children 12 yr or younger is rare, and one report found that only 3% of injuries presenting to a sports medicine clinic were in children 14 yr or younger (16). Girls age 15–20 yr have the highest number of ACL injuries by a wide margin (26). Girls age 11 to 20 yr also have the highest percentage of injuries that eventually underwent surgical reconstruction at 55% (23). Reconstruction rates decrease over the next two decades of age groups, and reconstruction percentages were reported to be about 48% for ages 21–30 yr and 32% for ages 31–40 yr. Younger populations are 1.5 to two times more likely to undergo reconstruction (8).
Women age 15–19 yr who underwent surgical ACL repair were 1.22 times more likely to not use OC than controls in the 12 months before injury (P < 0.0001). For the age group 25–39 yr, cases were more likely to use OC than controls in rates ranging from 1.1 to 1.16 or higher. Reported OR increased as age increase until the age group 35–39 yr. In a meta-analysis, women in their follicular and ovulatory phases sustained injury at approximately 1.35 times more than expected (12). Our results show that OC users had about 18% fewer ACL injuries than OC nonusers in the 15–19 age group. This modest decrease accounts for about half of the maximum expected effect suggesting that hormones appear to play a role, but are not the sole cause, in ACL injury associated with menstrual cycle hormonal changes.
According to our data, women age 15 to 19 yr were most at risk for undergoing ACL reconstruction (45.69% of cases), and OC use in this age group had the greatest influence on that outcome such that OC users are less likely to be cases than nonusers. Pubertal changes in this age group may explain the high number of cases and protection granted by OC use. Puberty, starting around ages 10 to 11 yr and ending around 15 to 17 yr in girls, incurs a rather steep rise in estrogen levels increasing the magnitude of knee joint laxity compared with older populations and compared with Tanner stage-matched males (25,37). Additionally, pubertal changes that may contribute to an increased risk of ACL injury include rapid limb growth with muscle inadequacy and incoordination as the neuromuscular system lags in development behind limb growth (37). In fact, sex differences in ACL injury rates do not exist before puberty and are only observed beginning around ages 10 to 11 yr in girls, the same as the onset of puberty (4,29,33). Thus, two independent factors, increased ligament laxity due to the presence of estrogen and neuromuscular developmental lag, likely contribute to an increased risk of ACL injury in pubescent females. Which of these two factors has a greater influence on injury risk or even how the two might interact is currently not known. The evidence from this and previous studies suggest that regulatory effects of OC on estrogen levels may reduce the overall risk for ACL injury in young women by reducing or eliminating only the estrogen-driven risk factor of cyclic ligament laxity. Neuromuscular inadequacy, leading to potentially higher loads being transferred to the knee and ACL, still remains a potential risk factor for injury that would be unaffected by OC use.
In the years after puberty and beyond, unprecedented rises in estrogen levels are rare. Additionally, the neuromuscular system has adapted to the now adult body. The presence of fewer risk factors to ACL injury in the postpubescent woman may explain both the decreased incidence of ACL injury as well as the decreased association of OC use and ACL injury. Acquired coordination and adaptation may be preventing the same injuries that could have occurred in a younger individual.
Additionally, age-related socioeconomic variables are potentially at play in regards to OC use and ACL injury distribution in risk. As seen in Figure 2, ACL reconstruction rates are vaguely bimodal. Ages 15–19 yr have the highest incidence, followed by a trough ages 22–31 yr, and then a much higher plateau for ages 32–39 yr. Speculatively, women falling into this 22–31-yr-old trough have fewer opportunities to participate in competitive sports (postcollege) and may be having children, which would further limit OC use and athletic participation. It is also possible that women older than 30 yr, when ACL reconstruction increases again, may be using OC at greater rates than the previous generation, especially if they are athletic. There is no current data on OC use habits of older athletes, and a true comparison to younger age groups cannot be made. Most likely, socioeconomic factors beyond the scope of this paper do influence the age interaction we see between OC reconstruction rates and OC use.
Trends and associations reported between OC use and ACL did not extend to injury of the ankle or shoulder as demonstrated in our parallel studies. It is altogether possible that ankle ligaments do not respond to estrogen in the same manner as ACLs do (2). Ericksen et al. (10) assessed ankle anterior–posterior and inversion–eversion laxity in men and women to determine if the hormonal milieu 5 d before and 5 d after ovulation had any measurable effect. Though women were found to have greater inversion–eversion laxity than men, there was no time course difference in anterior–posterior or inversion–eversion laxity within women. Menstrual cycle hormones had no effect on ankle ligament laxity. In another study, investigators found no differences in ankle or knee laxity in relationship to the changing levels of estrogen throughout the menstrual cycle (5). Their findings regarding knee laxity are not supported by a multitude of research that did find differences in knee laxity throughout the menstrual cycle; whereas contrary data on ankle laxity has not been demonstrated (40). If ankle ligament laxity does not vary as does ACL laxity, OC use should not have the same effect on ankle sprains that we have demonstrated it has on ACL injuries requiring surgical reconstruction. OC use habits in regards to ACL injury requiring reconstruction appear to be unique.
Several limitations may have influenced the final outcome of this study. First, the present study does not accurately differentiate between athletic, recreational, or accidental ACL injuries. Injury risk is adjusted for by included covariates, but they are not an indicator of athletic status. Second, this study only assessed the OC use habits of ACL injuries requiring surgical reconstruction and not all ACL injury diagnoses. It is reported that most ACL injuries occur in athletes, and those injuries resulting from athletic participation are much more likely to be surgically repaired than those occurring due to other means (6,7,34,38). This implies that cases in this study are more likely to be athletes than controls. Furthermore, athletes are more likely to use OC than nonathletes; and participation in athletics that risk the ACL (i.e., soccer, volleyball, basketball, etc) decreases as age increase (2,14,21,35). This limitation may explain the trend we report of increasing adjusted OR with age regarding OC use and ACL injury requiring surgical reconstruction. Third, claims data did not allow us to adjust for relevant variables including body mass index, height, weight, ethnicity, or cause of injury. Fourth, we assumed that a filled prescription indicated proper use and duration of the medication by the patient, though it is possible that patients modified or missed doses. Lastly, due to the nature of the claims data, we did not record how close OC use was to the original ACL injury or ACL surgical reconstruction. Thus, a short duration of OC use before an ACL reconstruction could have occurred and terminated months before the surgery took place.
This research represents the first population-based study of OC use in women sustaining ACL injury and receiving surgical reconstruction. It is also the first study to report that women age 15–19 yr who use OC receive 18% fewer ACL reconstructions than age-matched nonusers. Our findings specifically apply to ACL injury because no such associations were established for ligamentous ankle injury or upper extremity injury. These results strengthen previously reported associations between ACL injury and menstrual cycle hormone fluctuations and imply that pharmacologic intervention might be a viable method for preventing these injuries. It has previously been reported that athletes are about twice as likely to use OC as nonathletes (2,14,21). This occurs presumably due to reports of OC users having the benefit of predictable and shorter menses and therefore more consistent performance along with a greater feeling of stability during competition and training (21,22). The prevention of ACL injury is an additional reason to consider and favor OC use in young athletes. Prospective efforts are not only warranted but necessary to establish a causative relationship between the two.
This project was not supported by private or public funding agencies. The authors have no conflicts of interest to disclose. Results of this study do not constitute endorsement by the ACSM.
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