Clinical Review

Pediatric nail psoriasis is a condition that has not been extensively studied. The prevalence of nail alterations in pediatric patients with psoriasis varies among different studies, ranging from 17% to 39.2%.¹ Nail pitting, onycholysis associated with subungual hyperkeratosis, paronychia, and pachyonychia are the most frequent features of psoriatic nail involvement in children.^2,3 The management of nail psoriasis in children and adolescents is critical due to the quality-of-life impact, from potential functional impairment issues to the obvious cosmetic problems, which can aggravate the psychologic distress and social embarrassment of patients with psoriasis. Despite the emergence of modern potent systemic agents to treat chronic plaque psoriasis, nail psoriasis often is refractory to treatment.⁴ Coupled with the limited on-label options for psoriasis treatment in children, the management of nail psoriasis in this special patient group constitutes an even greater therapeutic challenge. This report aims to summarize the limited existing data on the successful management of nail psoriasis in the pediatric population.

Reviewing the Literature on Nail Psoriasis

We conducted a search of PubMed articles indexed for MEDLINE, Embase, and Scopus using the following Medical Subject Headings key terms: nail psoriasis and children, juvenile, pediatric. Additional articles were identified from the reference lists of the retrieved articles and citations. Our search included reports in the English language published from 2000 to 2019. The selection process included the following 2 steps: screening of the titles and abstracts, followed by evaluation of the selected full-text articles.

Topical Treatments for Nail Psoriasis

Because most systemic antipsoriatic treatments that can be administered in adult patients have not yet been granted an official license for administration in children, topical treatments are considered by many physicians as the preferred first-line therapy for psoriatic nail involvement in pediatric patients.^5,6 However, only scarce data are available in the literature concerning the successful use of local agents in pediatric patients with psoriasis.

The main limitation of local treatments relates mostly to their impaired penetration into the affected area (nails). To optimize drug penetration, some authors suggest the use of potent keratolytic topical preparations to reduce the nail volume and facilitate drug absorption.⁷ A popular suggestion is trimming the onycholytic nail plate followed by 40% urea avulsion to treat subungual hyperkeratosis⁸ or simply the use of occlusive 40% urea in petroleum jelly.⁹ Other approaches include clipping the onycholytic nail over the diseased nail bed or processing the nail plate through grinding or even drilling holes with the use of mechanical burrs or ablative lasers to enhance the penetration of the topical agent.⁷

A frequent approach in pediatric patients is clipping the detached nails combined with daily application of calcipotriene (calcipotriol) and steroids, such as betamethasone dipropionate.^5,8 Reports on the use of regimens with clobetasol propionate ointment 0.05% under occlusion, with or without the concomitant use of calcipotriol solution 0.005%, also are present in the literature but not always with satisfactory results.^10,11 Another successfully administered topical steroid is mometasone furoate cream 0.1%.¹² Although the use of intralesional triamcinolone acetonide also has demonstrated encouraging outcomes in isolated reports,¹³ associated adverse events, such as pain and hematomas, can result in tolerability issues for pediatric patients.⁷

Piraccini et al¹⁴ described the case of an 8-year-old patient with pustular nail psoriasis who showed improvement within 3 to 6 months of treatment with topical calcipotriol 5 μg/g as monotherapy applied to the nail and periungual tissues twice daily. Another approach, described by Diluvio et al,¹⁵ is the use of tazarotene gel 0.05% applied once daily to the affected nail plates, nail folds, and periungual skin without occlusion. In a 6-year-old patient with isolated nail psoriasis, this treatment regimen demonstrated notable improvement within 8 weeks.¹⁵

Systemic Treatments for Nail Psoriasis

Data on the successful administration of systemic agents in pediatric patients also are extremely scarce. Due to the lack of clinical trials, everyday practice is mostly based on isolated case series and case reports.

Methotrexate—Lee¹¹ described the case of an 11-year-old girl with severe, symptomatic, 20-nail psoriatic onychodystrophy who showed a complete response to oral methotrexate 5 mg/wk after topical clobetasol propionate and calcipotriol failed. Improvement was seen as early as 4 weeks after therapy initiation, and complete resolution of the lesions was documented after 9 and 13 months of methotrexate therapy for the fingers and toes, respectively.¹¹ The successful use of methotrexate in the improvement of psoriatic nail dystrophy in a pediatric patient also was documented by Teran et al.¹⁶ In this case, a 9-year-old girl with erythrodermic psoriasis, psoriatic arthritis, and severe onychodystrophy showed notable amelioration of all psoriatic manifestations, including the nail findings, with systemic methotrexate therapy (dose not specified).¹⁶ Notably, the authors reported that the improvement of onychodystrophy occurred with considerable delay compared to the other psoriatic lesions,¹⁶ indicating the already-known refractoriness of nail psoriasis to the various therapeutic attempts.^9-15

Acitretin—Another agent that has been linked with partial improvement of acrodermatitis continua of Hallopeau (ACH)–associated onychodystrophy is acitretin. In a case series of 15 pediatric patients with pustular psoriasis, a 5-year-old boy with severe nail involvement presented with partial amelioration of nail changes with acitretin within the first 6 weeks of treatment using the following regimen: initial dosage of 0.8 mg/kg/d for 6 weeks, followed by 0.3 mg/kg/d for 4 weeks.¹⁷

Biologics—The emerging use of biologics in pediatric psoriasis also has brought important advances in the successful management of nail psoriasis in children and adolescents.^18-21 Wells et al¹⁸ presented the case of an 8-year-old girl with nail psoriasis, psoriatic arthritis, and plaque psoriasis who showed complete resolution of all psoriatic manifestations, including nail involvement, within 3 months of treatment with secukinumab 150 mg subcutaneously every 4 weeks. Prior failed treatments included various systemic agents (ie, subcutaneous methotrexate 20 mg/m², etanercept 0.8 mg/kg weekly, adalimumab 40 mg every 2 weeks) as well as topical agents (ie, urea, tazarotene, corticosteroids) and intralesional triamcinolone.¹⁸

Infliximab also has been successfully used for pediatric nail psoriasis. Watabe et al¹⁹ presented the case of an 8-year-old girl with psoriatic onychodystrophy in addition to psoriatic onycho-pachydermo-periostitis. Prior therapy with adalimumab 20 mg every other week combined with methotrexate 10 mg weekly failed. She experienced notable amelioration of the nail dystrophy within 3 months of using a combination of infliximab and methotrexate (infliximab 5 mg/kg intravenously on weeks 0, 2, and 6, and every 8 weeks thereafter; methotrexate 10 mg/wk).¹⁹

Cases in which infliximab has resulted in rapid yet only transient restoration of psoriatic onychodystrophy also are present in the literature. Pereira et al²⁰ reported that a 3-year-old patient with severe 20-digit onychodystrophy in addition to pustular psoriasis had complete resolution of nail lesions within 2 weeks of treatment with infliximab (5 mg/kg at weeks 0, 2, and 6, and then every 7 weeks thereafter), which was sustained over the course of 1 year. The therapy had to be discontinued because of exacerbation of the cutaneous symptoms; thereafter, etanercept was initiated. Although the patient noted major improvement of all skin lesions under etanercept, only moderate amelioration of the psoriatic nail lesions was demonstrated.²⁰

Dini et al²¹ described a 9-year-old girl with severe ACH-associated psoriatic onychodystrophy who showed complete clearance of all lesions within 8 weeks of treatment with adalimumab (initially 80 mg, followed by 40 mg after 1 week and then 40 mg every other week). Prior treatment with potent topical corticosteroids, cyclosporine (3 mg/kg/d for 6 months), and etanercept (0.4 mg/kg twice weekly for 3 months) was ineffective.²¹

Phototherapy—Other systemic agents with reported satisfactory outcomes in the treatment of psoriatic onychodystrophy include thalidomide combined with UVB phototherapy. Kiszewski et al²² described a 2-year-old patient with ACH and severe 19-digit onychodystrophy. Prior failed therapies included occluded clobetasol ointment 0.05%, occluded pimecrolimus 0.1%, and systemic methotrexate, while systemic acitretin (0.8 mg⁄kg⁄d) resulted in elevated cholesterol levels and therefore had to be interrupted. Improvement was seen 2 months after the initiation of a combined broadband UVB and thalidomide (50 mg⁄d) treatment, with no documented relapses after discontinuation of therapy.²²

Narrowband UVB (311 nm) also has been used as monotherapy for ACH-associated onychodystrophy, as demonstrated by Bordignon et al.²³ They reported a 9-year-old patient who showed partial improvement of isolated onychodystrophy of the fourth nail plate of the left hand after 36 sessions of narrowband UVB using a 311-nm filtering handpiece with a square spot size of 19×19 mm.²³

Conclusion

Nail psoriasis constitutes a type of psoriasis that is not only refractory to most treatments but is accompanied by substantial psychological and occasionally functional burden for the affected individuals.²⁴ Data concerning therapeutic options in the pediatric population are extremely limited, and therefore the everyday practice often involves administration of off-label medications, which can constitute a dilemma for many physicians, especially for safety.¹⁰ We suggest a simple therapeutic algorithm for the management of pediatric nail psoriasis based on the summarized data that are currently available in the literature. This algorithm is shown in the eFigure.

As progressively more agents—especially biologics—receive approval for use in plaque psoriasis in pediatric patients,²⁵ it is expected that gradually more real-life data on their side efficacy for plaque psoriasis of the nails in children also will come to light. Furthermore, their on-label use in pediatric psoriasis patients will facilitate further relevant clinical trials to this target group so that the potential of these medications in the management of nail psoriasis can be fully explored.

Pediatric nail psoriasis is a condition that has not been extensively studied. The prevalence of nail alterations in pediatric patients with psoriasis varies among different studies, ranging from 17% to 39.2%.¹ Nail pitting, onycholysis associated with subungual hyperkeratosis, paronychia, and pachyonychia are the most frequent features of psoriatic nail involvement in children.^2,3 The management of nail psoriasis in children and adolescents is critical due to the quality-of-life impact, from potential functional impairment issues to the obvious cosmetic problems, which can aggravate the psychologic distress and social embarrassment of patients with psoriasis. Despite the emergence of modern potent systemic agents to treat chronic plaque psoriasis, nail psoriasis often is refractory to treatment.⁴ Coupled with the limited on-label options for psoriasis treatment in children, the management of nail psoriasis in this special patient group constitutes an even greater therapeutic challenge. This report aims to summarize the limited existing data on the successful management of nail psoriasis in the pediatric population.

Reviewing the Literature on Nail Psoriasis

We conducted a search of PubMed articles indexed for MEDLINE, Embase, and Scopus using the following Medical Subject Headings key terms: nail psoriasis and children, juvenile, pediatric. Additional articles were identified from the reference lists of the retrieved articles and citations. Our search included reports in the English language published from 2000 to 2019. The selection process included the following 2 steps: screening of the titles and abstracts, followed by evaluation of the selected full-text articles.

Topical Treatments for Nail Psoriasis

Because most systemic antipsoriatic treatments that can be administered in adult patients have not yet been granted an official license for administration in children, topical treatments are considered by many physicians as the preferred first-line therapy for psoriatic nail involvement in pediatric patients.^5,6 However, only scarce data are available in the literature concerning the successful use of local agents in pediatric patients with psoriasis.

The main limitation of local treatments relates mostly to their impaired penetration into the affected area (nails). To optimize drug penetration, some authors suggest the use of potent keratolytic topical preparations to reduce the nail volume and facilitate drug absorption.⁷ A popular suggestion is trimming the onycholytic nail plate followed by 40% urea avulsion to treat subungual hyperkeratosis⁸ or simply the use of occlusive 40% urea in petroleum jelly.⁹ Other approaches include clipping the onycholytic nail over the diseased nail bed or processing the nail plate through grinding or even drilling holes with the use of mechanical burrs or ablative lasers to enhance the penetration of the topical agent.⁷

A frequent approach in pediatric patients is clipping the detached nails combined with daily application of calcipotriene (calcipotriol) and steroids, such as betamethasone dipropionate.^5,8 Reports on the use of regimens with clobetasol propionate ointment 0.05% under occlusion, with or without the concomitant use of calcipotriol solution 0.005%, also are present in the literature but not always with satisfactory results.^10,11 Another successfully administered topical steroid is mometasone furoate cream 0.1%.¹² Although the use of intralesional triamcinolone acetonide also has demonstrated encouraging outcomes in isolated reports,¹³ associated adverse events, such as pain and hematomas, can result in tolerability issues for pediatric patients.⁷

Piraccini et al¹⁴ described the case of an 8-year-old patient with pustular nail psoriasis who showed improvement within 3 to 6 months of treatment with topical calcipotriol 5 μg/g as monotherapy applied to the nail and periungual tissues twice daily. Another approach, described by Diluvio et al,¹⁵ is the use of tazarotene gel 0.05% applied once daily to the affected nail plates, nail folds, and periungual skin without occlusion. In a 6-year-old patient with isolated nail psoriasis, this treatment regimen demonstrated notable improvement within 8 weeks.¹⁵

Systemic Treatments for Nail Psoriasis

Data on the successful administration of systemic agents in pediatric patients also are extremely scarce. Due to the lack of clinical trials, everyday practice is mostly based on isolated case series and case reports.

Methotrexate—Lee¹¹ described the case of an 11-year-old girl with severe, symptomatic, 20-nail psoriatic onychodystrophy who showed a complete response to oral methotrexate 5 mg/wk after topical clobetasol propionate and calcipotriol failed. Improvement was seen as early as 4 weeks after therapy initiation, and complete resolution of the lesions was documented after 9 and 13 months of methotrexate therapy for the fingers and toes, respectively.¹¹ The successful use of methotrexate in the improvement of psoriatic nail dystrophy in a pediatric patient also was documented by Teran et al.¹⁶ In this case, a 9-year-old girl with erythrodermic psoriasis, psoriatic arthritis, and severe onychodystrophy showed notable amelioration of all psoriatic manifestations, including the nail findings, with systemic methotrexate therapy (dose not specified).¹⁶ Notably, the authors reported that the improvement of onychodystrophy occurred with considerable delay compared to the other psoriatic lesions,¹⁶ indicating the already-known refractoriness of nail psoriasis to the various therapeutic attempts.^9-15

Acitretin—Another agent that has been linked with partial improvement of acrodermatitis continua of Hallopeau (ACH)–associated onychodystrophy is acitretin. In a case series of 15 pediatric patients with pustular psoriasis, a 5-year-old boy with severe nail involvement presented with partial amelioration of nail changes with acitretin within the first 6 weeks of treatment using the following regimen: initial dosage of 0.8 mg/kg/d for 6 weeks, followed by 0.3 mg/kg/d for 4 weeks.¹⁷

Biologics—The emerging use of biologics in pediatric psoriasis also has brought important advances in the successful management of nail psoriasis in children and adolescents.^18-21 Wells et al¹⁸ presented the case of an 8-year-old girl with nail psoriasis, psoriatic arthritis, and plaque psoriasis who showed complete resolution of all psoriatic manifestations, including nail involvement, within 3 months of treatment with secukinumab 150 mg subcutaneously every 4 weeks. Prior failed treatments included various systemic agents (ie, subcutaneous methotrexate 20 mg/m², etanercept 0.8 mg/kg weekly, adalimumab 40 mg every 2 weeks) as well as topical agents (ie, urea, tazarotene, corticosteroids) and intralesional triamcinolone.¹⁸

Infliximab also has been successfully used for pediatric nail psoriasis. Watabe et al¹⁹ presented the case of an 8-year-old girl with psoriatic onychodystrophy in addition to psoriatic onycho-pachydermo-periostitis. Prior therapy with adalimumab 20 mg every other week combined with methotrexate 10 mg weekly failed. She experienced notable amelioration of the nail dystrophy within 3 months of using a combination of infliximab and methotrexate (infliximab 5 mg/kg intravenously on weeks 0, 2, and 6, and every 8 weeks thereafter; methotrexate 10 mg/wk).¹⁹

Cases in which infliximab has resulted in rapid yet only transient restoration of psoriatic onychodystrophy also are present in the literature. Pereira et al²⁰ reported that a 3-year-old patient with severe 20-digit onychodystrophy in addition to pustular psoriasis had complete resolution of nail lesions within 2 weeks of treatment with infliximab (5 mg/kg at weeks 0, 2, and 6, and then every 7 weeks thereafter), which was sustained over the course of 1 year. The therapy had to be discontinued because of exacerbation of the cutaneous symptoms; thereafter, etanercept was initiated. Although the patient noted major improvement of all skin lesions under etanercept, only moderate amelioration of the psoriatic nail lesions was demonstrated.²⁰

Dini et al²¹ described a 9-year-old girl with severe ACH-associated psoriatic onychodystrophy who showed complete clearance of all lesions within 8 weeks of treatment with adalimumab (initially 80 mg, followed by 40 mg after 1 week and then 40 mg every other week). Prior treatment with potent topical corticosteroids, cyclosporine (3 mg/kg/d for 6 months), and etanercept (0.4 mg/kg twice weekly for 3 months) was ineffective.²¹

Phototherapy—Other systemic agents with reported satisfactory outcomes in the treatment of psoriatic onychodystrophy include thalidomide combined with UVB phototherapy. Kiszewski et al²² described a 2-year-old patient with ACH and severe 19-digit onychodystrophy. Prior failed therapies included occluded clobetasol ointment 0.05%, occluded pimecrolimus 0.1%, and systemic methotrexate, while systemic acitretin (0.8 mg⁄kg⁄d) resulted in elevated cholesterol levels and therefore had to be interrupted. Improvement was seen 2 months after the initiation of a combined broadband UVB and thalidomide (50 mg⁄d) treatment, with no documented relapses after discontinuation of therapy.²²

Narrowband UVB (311 nm) also has been used as monotherapy for ACH-associated onychodystrophy, as demonstrated by Bordignon et al.²³ They reported a 9-year-old patient who showed partial improvement of isolated onychodystrophy of the fourth nail plate of the left hand after 36 sessions of narrowband UVB using a 311-nm filtering handpiece with a square spot size of 19×19 mm.²³

Conclusion

Nail psoriasis constitutes a type of psoriasis that is not only refractory to most treatments but is accompanied by substantial psychological and occasionally functional burden for the affected individuals.²⁴ Data concerning therapeutic options in the pediatric population are extremely limited, and therefore the everyday practice often involves administration of off-label medications, which can constitute a dilemma for many physicians, especially for safety.¹⁰ We suggest a simple therapeutic algorithm for the management of pediatric nail psoriasis based on the summarized data that are currently available in the literature. This algorithm is shown in the eFigure.

As progressively more agents—especially biologics—receive approval for use in plaque psoriasis in pediatric patients,²⁵ it is expected that gradually more real-life data on their side efficacy for plaque psoriasis of the nails in children also will come to light. Furthermore, their on-label use in pediatric psoriasis patients will facilitate further relevant clinical trials to this target group so that the potential of these medications in the management of nail psoriasis can be fully explored.

Pediatric nail psoriasis is a condition that has not been extensively studied. The prevalence of nail alterations in pediatric patients with psoriasis varies among different studies, ranging from 17% to 39.2%.¹ Nail pitting, onycholysis associated with subungual hyperkeratosis, paronychia, and pachyonychia are the most frequent features of psoriatic nail involvement in children.^2,3 The management of nail psoriasis in children and adolescents is critical due to the quality-of-life impact, from potential functional impairment issues to the obvious cosmetic problems, which can aggravate the psychologic distress and social embarrassment of patients with psoriasis. Despite the emergence of modern potent systemic agents to treat chronic plaque psoriasis, nail psoriasis often is refractory to treatment.⁴ Coupled with the limited on-label options for psoriasis treatment in children, the management of nail psoriasis in this special patient group constitutes an even greater therapeutic challenge. This report aims to summarize the limited existing data on the successful management of nail psoriasis in the pediatric population.

Reviewing the Literature on Nail Psoriasis

We conducted a search of PubMed articles indexed for MEDLINE, Embase, and Scopus using the following Medical Subject Headings key terms: nail psoriasis and children, juvenile, pediatric. Additional articles were identified from the reference lists of the retrieved articles and citations. Our search included reports in the English language published from 2000 to 2019. The selection process included the following 2 steps: screening of the titles and abstracts, followed by evaluation of the selected full-text articles.

Topical Treatments for Nail Psoriasis

Because most systemic antipsoriatic treatments that can be administered in adult patients have not yet been granted an official license for administration in children, topical treatments are considered by many physicians as the preferred first-line therapy for psoriatic nail involvement in pediatric patients.^5,6 However, only scarce data are available in the literature concerning the successful use of local agents in pediatric patients with psoriasis.

The main limitation of local treatments relates mostly to their impaired penetration into the affected area (nails). To optimize drug penetration, some authors suggest the use of potent keratolytic topical preparations to reduce the nail volume and facilitate drug absorption.⁷ A popular suggestion is trimming the onycholytic nail plate followed by 40% urea avulsion to treat subungual hyperkeratosis⁸ or simply the use of occlusive 40% urea in petroleum jelly.⁹ Other approaches include clipping the onycholytic nail over the diseased nail bed or processing the nail plate through grinding or even drilling holes with the use of mechanical burrs or ablative lasers to enhance the penetration of the topical agent.⁷

A frequent approach in pediatric patients is clipping the detached nails combined with daily application of calcipotriene (calcipotriol) and steroids, such as betamethasone dipropionate.^5,8 Reports on the use of regimens with clobetasol propionate ointment 0.05% under occlusion, with or without the concomitant use of calcipotriol solution 0.005%, also are present in the literature but not always with satisfactory results.^10,11 Another successfully administered topical steroid is mometasone furoate cream 0.1%.¹² Although the use of intralesional triamcinolone acetonide also has demonstrated encouraging outcomes in isolated reports,¹³ associated adverse events, such as pain and hematomas, can result in tolerability issues for pediatric patients.⁷

Piraccini et al¹⁴ described the case of an 8-year-old patient with pustular nail psoriasis who showed improvement within 3 to 6 months of treatment with topical calcipotriol 5 μg/g as monotherapy applied to the nail and periungual tissues twice daily. Another approach, described by Diluvio et al,¹⁵ is the use of tazarotene gel 0.05% applied once daily to the affected nail plates, nail folds, and periungual skin without occlusion. In a 6-year-old patient with isolated nail psoriasis, this treatment regimen demonstrated notable improvement within 8 weeks.¹⁵

Systemic Treatments for Nail Psoriasis

Data on the successful administration of systemic agents in pediatric patients also are extremely scarce. Due to the lack of clinical trials, everyday practice is mostly based on isolated case series and case reports.

Methotrexate—Lee¹¹ described the case of an 11-year-old girl with severe, symptomatic, 20-nail psoriatic onychodystrophy who showed a complete response to oral methotrexate 5 mg/wk after topical clobetasol propionate and calcipotriol failed. Improvement was seen as early as 4 weeks after therapy initiation, and complete resolution of the lesions was documented after 9 and 13 months of methotrexate therapy for the fingers and toes, respectively.¹¹ The successful use of methotrexate in the improvement of psoriatic nail dystrophy in a pediatric patient also was documented by Teran et al.¹⁶ In this case, a 9-year-old girl with erythrodermic psoriasis, psoriatic arthritis, and severe onychodystrophy showed notable amelioration of all psoriatic manifestations, including the nail findings, with systemic methotrexate therapy (dose not specified).¹⁶ Notably, the authors reported that the improvement of onychodystrophy occurred with considerable delay compared to the other psoriatic lesions,¹⁶ indicating the already-known refractoriness of nail psoriasis to the various therapeutic attempts.^9-15

Acitretin—Another agent that has been linked with partial improvement of acrodermatitis continua of Hallopeau (ACH)–associated onychodystrophy is acitretin. In a case series of 15 pediatric patients with pustular psoriasis, a 5-year-old boy with severe nail involvement presented with partial amelioration of nail changes with acitretin within the first 6 weeks of treatment using the following regimen: initial dosage of 0.8 mg/kg/d for 6 weeks, followed by 0.3 mg/kg/d for 4 weeks.¹⁷

Biologics—The emerging use of biologics in pediatric psoriasis also has brought important advances in the successful management of nail psoriasis in children and adolescents.^18-21 Wells et al¹⁸ presented the case of an 8-year-old girl with nail psoriasis, psoriatic arthritis, and plaque psoriasis who showed complete resolution of all psoriatic manifestations, including nail involvement, within 3 months of treatment with secukinumab 150 mg subcutaneously every 4 weeks. Prior failed treatments included various systemic agents (ie, subcutaneous methotrexate 20 mg/m², etanercept 0.8 mg/kg weekly, adalimumab 40 mg every 2 weeks) as well as topical agents (ie, urea, tazarotene, corticosteroids) and intralesional triamcinolone.¹⁸

Infliximab also has been successfully used for pediatric nail psoriasis. Watabe et al¹⁹ presented the case of an 8-year-old girl with psoriatic onychodystrophy in addition to psoriatic onycho-pachydermo-periostitis. Prior therapy with adalimumab 20 mg every other week combined with methotrexate 10 mg weekly failed. She experienced notable amelioration of the nail dystrophy within 3 months of using a combination of infliximab and methotrexate (infliximab 5 mg/kg intravenously on weeks 0, 2, and 6, and every 8 weeks thereafter; methotrexate 10 mg/wk).¹⁹

Cases in which infliximab has resulted in rapid yet only transient restoration of psoriatic onychodystrophy also are present in the literature. Pereira et al²⁰ reported that a 3-year-old patient with severe 20-digit onychodystrophy in addition to pustular psoriasis had complete resolution of nail lesions within 2 weeks of treatment with infliximab (5 mg/kg at weeks 0, 2, and 6, and then every 7 weeks thereafter), which was sustained over the course of 1 year. The therapy had to be discontinued because of exacerbation of the cutaneous symptoms; thereafter, etanercept was initiated. Although the patient noted major improvement of all skin lesions under etanercept, only moderate amelioration of the psoriatic nail lesions was demonstrated.²⁰

Dini et al²¹ described a 9-year-old girl with severe ACH-associated psoriatic onychodystrophy who showed complete clearance of all lesions within 8 weeks of treatment with adalimumab (initially 80 mg, followed by 40 mg after 1 week and then 40 mg every other week). Prior treatment with potent topical corticosteroids, cyclosporine (3 mg/kg/d for 6 months), and etanercept (0.4 mg/kg twice weekly for 3 months) was ineffective.²¹

Phototherapy—Other systemic agents with reported satisfactory outcomes in the treatment of psoriatic onychodystrophy include thalidomide combined with UVB phototherapy. Kiszewski et al²² described a 2-year-old patient with ACH and severe 19-digit onychodystrophy. Prior failed therapies included occluded clobetasol ointment 0.05%, occluded pimecrolimus 0.1%, and systemic methotrexate, while systemic acitretin (0.8 mg⁄kg⁄d) resulted in elevated cholesterol levels and therefore had to be interrupted. Improvement was seen 2 months after the initiation of a combined broadband UVB and thalidomide (50 mg⁄d) treatment, with no documented relapses after discontinuation of therapy.²²

Narrowband UVB (311 nm) also has been used as monotherapy for ACH-associated onychodystrophy, as demonstrated by Bordignon et al.²³ They reported a 9-year-old patient who showed partial improvement of isolated onychodystrophy of the fourth nail plate of the left hand after 36 sessions of narrowband UVB using a 311-nm filtering handpiece with a square spot size of 19×19 mm.²³

Conclusion

Nail psoriasis constitutes a type of psoriasis that is not only refractory to most treatments but is accompanied by substantial psychological and occasionally functional burden for the affected individuals.²⁴ Data concerning therapeutic options in the pediatric population are extremely limited, and therefore the everyday practice often involves administration of off-label medications, which can constitute a dilemma for many physicians, especially for safety.¹⁰ We suggest a simple therapeutic algorithm for the management of pediatric nail psoriasis based on the summarized data that are currently available in the literature. This algorithm is shown in the eFigure.

As progressively more agents—especially biologics—receive approval for use in plaque psoriasis in pediatric patients,²⁵ it is expected that gradually more real-life data on their side efficacy for plaque psoriasis of the nails in children also will come to light. Furthermore, their on-label use in pediatric psoriasis patients will facilitate further relevant clinical trials to this target group so that the potential of these medications in the management of nail psoriasis can be fully explored.

Short-term hormonal contraceptives remain the most popular class of reversible contraceptives in the United States, despite the availability of longer-acting methods. Oral contraceptives (OCs), contraceptive patches, and contraceptive vaginal rings are extensively used not only because these methods are easy to initiate but also because their ongoing use remains under the control of the woman herself and also provides her with a wide range of important noncontraceptive benefits.

Despite the more than 60 years of innovation that have made hormonal contraceptives safer, more tolerable, and more convenient, there has been room for improvement. Over the last few years, 4 new hormonal methods have been introduced, and each addresses different limitations and problems associated with the existing, often generic, products.

Compared with the traditional norethindrone pill (Micronor and generics), a new drospirenone progestin-only pill (POP) increases ovulation suppression, offers an improved cyclical bleeding profile, and relaxes the tight missed-pill rules that are usually associated with POPs.

In contrast with the older norelgestromin patch (Evra, Xulane), a new contraceptive transdermal patch significantly decreases total estrogen exposure and pairs its estrogen with levonorgestrel, the progestin associated with the lowest venous thromboembolism (VTE) risk in combined hormonal pills.

While existing combination OCs are formulated with the potent estrogen ethinyl estradiol (EE), a new combination pill, formulated with estetrol (E4) and drospirenone, introduces the first new estrogen (estetrol) used in a contraceptive in more than 50 years. Estetrol, a native estrogen, has selective tissue activity with minimal hepatic and breast impacts. Combined with drospirenone, this formulation offers women good contraceptive efficacy and bleeding patterns.

A new contraceptive vaginal ring introduces a new long-acting, specific progestin (segesterone acetate) and pairs it with low-dose EE. These hormones are packaged in a soft vaginal ring that provides up to 13 cycles of contraceptive protection (3 weeks in/1 week out) with one ring, greatly increasing convenience for women.

Each of these new products represents important incremental improvement over existing options.

Continue to: 1. The drospirenone-only OC...

The new POP with drospirenone 4 mg (Slynd), which received US Food and Drug Administration (FDA) approval in 2019, is packaged in a 24/4 formulation (24 hormonally active tablets followed by 4 inactive tablets). This formulation results in more predictable bleeding than does the 0.35-mg norethindrone POP, which contains 28 hormonally active tablets in each pack. In the US clinical trials of drospirenone 4 mg, scheduled bleeding decreased from 81% in cycle 1 to 20% in cycle 13. Unscheduled spotting and bleeding decreased from 61% to 40% in the same timeframe. Notably, this bleeding pattern was well tolerated; only 0.4% of trial participants discontinued this drospirenone POP due to problems with irregular bleeding or amenorrhea.

In contrast to the continuous norethindrone POP, which is not sufficiently dosed to consistently suppress ovulation, the 4-mg daily dose of drospirenone in this new POP is higher than the 3 mg used in commonly prescribed combination OCs that contain EE and drospirenone. This results in a POP that has more consistent ovulation suppression. Because this drospirenone POP is appropriately dosed and based on a longer-acting progestin, it is more forgiving of inconsistent pill taking. Accordingly, the missed-pill rules for this pill are the same as with combination estrogen-progestin OCs.¹ The package labeling cites a first-year failure rate of 4%, but this includes unconfirmed pregnancies. The Pearl Index from the North American trials, based on confirmed pregnancies in nonbreastfeeding women, was 2.9.²

The package labeling for this drospirenone POP includes few contraindications. Conditions that preclude use include the US Medical Eligibility Criteria for contraception Category 4 condition (breast cancer in the last 5 years), renal impairment, and adrenal insufficiency. Other standard contraindications are listed in the prescribing information. Serum potassium levels should be checked (one time only) in the first cycle only for women who chronically use medications that could cause hyperkalemia, such as nonsteroidal anti-inflammatory drugs.

Given the ovulation suppression associated with this drospirenone POP, the safety of a progestin-only method, and the persistent popularity of OC pills, this pill should greatly increase the use of POPs beyond their traditional niche of postpartum and breastfeeding women. The advent of the drospirenone POP means that clinicians now have better options for women who have contraindications to estrogen and desire to control their own contraceptive use. It would be a logical consideration for over-the-counter accessibility.

2. Transdermal patch with ethinyl estradiol/levonorgestrel

The new EE/levonorgestrel transdermal contraceptive patch (Twirla) is soft and flexible, about the same size as other contraceptive patches, and contains EE 2.3 mg/levonorgestrel 2.6 mg. It provides total estrogen exposure that is similar to that of OCs with EE 30 µg and distinctly lower than estrogen levels seen with the original norelgestromin-containing patch or its 2 subsequent generic versions.³ This EE/levonorgestrel patch uses a new 5-layer drug delivery system that focuses the steroids for absorption beneath the patch; there is no peripheral spread of drug around the patch (FIGURE 1).

Transdermal patches offer the convenience of once-a-week dosing. One patch is used each week for 3 consecutive weeks followed by a patch-free week. Patches can be worn on the abdomen, buttock, or trunk (except breasts). Patches should not be placed consecutively on the same site; after a week’s rest, however, the first site can be reused. All transdermal contraceptive products are indicated for use only by women with a body mass index (BMI) <30 kg/m².⁴

While no head-to-head trials have compared this new lower-dose patch with older patches, each patch was compared against a standardized pill, so meaningful comparisons can be made.

In each case, the circulating estrogen levels associated with use of the EE/levonorgestrel patch were considerably lower than those of the comparator pill, while the older norelgestromin patch consistently delivered higher total estrogen levels than its 35-µg comparator pill (TABLE).³ Along these lines, no VTE events occurred in women in the clinical trial of the new patch among women with a BMI <30 kg/m².⁴

Women with a BMI <25 kg/m² experienced lower Pearl Index (PI) pregnancy rates (3.5%) compared with women with a BMI between 25 and 30 kg/m² (5.7%), according to clinical trial data cited in the package labeling. All the modern PI criteria were used to calculate these failure rates. Cycles in which no coitus occurred were excluded. Similarly, cycles in which another contraceptive method (for example, condoms) was added (even once) were excluded. Frequent pregnancy testing was done in the study centers and by the women at home. Bleeding patterns were well accepted; only 2.2% of study participants exited the study early due to menstrual disorders of any kind. Similarly, 3.1% of women discontinued use because of application site disorders. Women should be advised to press down on the patch edges after emerging from water exposure. Replacement patches are rapidly available from the manufacturer should permanent complete patch detachment occur.

Larger-scale phase 4 trials will be conducted to study the impact of this lower-dose patch on VTE rates.

Continue to: 3. A 1-year contraceptive vaginal ring...

The need to obtain new supplies every month or every 3 months contributes to high rates of contraceptive failure and unintended pregnancy among women using short-acting hormonal contraceptives (pills, patches, and vaginal rings).⁵ A woman-controlled contraceptive that would provide 1 year of protection against unintended pregnancy represents a step forward. A contraceptive vaginal ring (CVR) that releases the novel progestin segesterone acetate and EE provides woman-controlled contraception for up to 1 year. This CVR (Annovera) received FDA approval in 2018 and has been marketed in the United States since 2020.

The segesterone acetate/EE CVR is a soft, flexible ring that is opaque white in color and fabricated from nonbiodegradable silicone (FIGURE 2). The outside diameter is 5.6 cm, compared with the 5.4-cm outer diameter of the etonogestrel/EE vaginal ring (NuvaRing). The segesterone acetate/EE CVR has 2 channels: one releases segesterone acetate only and the other releases segesterone acetate and EE. In contrast with the etonogestrel/EE CVR, the segesterone acetate/EE CVR does not need to be refrigerated when stored.⁶

Continue to: 4. An OC with a novel estrogen...

4. An OC with a novel estrogen

Even as use of intrauterine devices and contraceptive implants continues to grow, OCs remain the reversible contraceptive most used by US women. While OCs have been widely studied and represent a safe method of contraception for most reproductive-age women, combination estrogen-progestin OCs are well recognized to increase the risk of VTE. Although the primary role of the progestin component of combination OCs is to suppress ovulation, estrogen is included in combination OCs to stimulate endometrial proliferation, thereby causing predictable bleeding. EE, the potent synthetic estrogen used in the great majority of current OC formulations, induces hepatic production of prothrombotic proteins while inhibiting synthesis of antithrombotic proteins. While the lower EE doses (10–35 µg) in today’s OC formulations are associated with a lower VTE risk than older OCs that contained higher doses of estrogen, VTE continues to represent the principal health risk associated with use of combination OCs. Accordingly, development of a combination OC that has less impact on risk of VTE would be appealing.

In April 2021, the FDA approved an OC formulation that combines 15 mg of the novel estrogen estetrol with 3 mg of drospirenone (Nextstellis). This dose of drospirenone is the same as that used in commonly prescribed EE/drospirenone OC formulations. Also known as E4, estetrol is a natural estrogen synthesized by the fetal liver. Plant-derived E4 is used in this new OC.

Depending on the tissue, E4 acts differently than other estrogens. Similar to other estrogens, E4 acts as an agonist on the nuclear receptor to produce beneficial effects in bone, vaginal mucosa, and heart.⁸ Unlike other estrogens, E4 inhibits proliferation of mammary gland cells and has a neutral impact on the liver.⁹

In contrast with EE, E4 is not inhibited by the liver’s P450 enzymes; accordingly, the risk of drug-drug interactions is reduced. Because E4 is primarily excreted through the urine and not through the biliary tract, the risk of gallstone formation may be lower than with an EE OC. Likewise, E4 has substantially less impact on triglycerides, which are increased with EE. Finally, because of E4’s reduced effect on the liver, the impact on clotting parameters is less than that observed with an OC formulated with EE.¹⁰ This latter observation raises the possibility that VTE risk is lower with the E4/drospirenone OC than an OC formulated with EE.

A 13-cycle phase 3 trial of the E4/drospirenone OC conducted in the United States and Canada enrolled 1,864 women aged 16 to 50 years, including 1,674 who were aged 16 to 35 years.¹¹ Among women in this latter age group, the PI was 2.65 per 100 woman-years. Bleeding/cycle control patterns were similar to those observed in recent trials of other combination contraceptives. Likewise, the proportion of trial participants who discontinued the study due to adverse effects was similar to or lower than that noted in recent trials of other combination contraceptives. Of particular note, no cases of VTE were noted among trial participants of any BMI, a finding which contrasts with recent phase 3 trials of other combination contraceptives. The result of this pivotal trial suggests that the theoretic advantages of E4 when used in a combination OC formulation may translate into a safer, effective, and well-tolerated contraceptive.

Refinements in hormonal contraceptives continue

The 4 new short-acting hormonal contraceptives we reviewed represent enhancements on existing pills, patches, and rings. We hope that, financially, women will have access to these innovative methods and, in particular, that third-party payers will facilitate women’s access to these enhanced short-acting hormonal contraceptives. ●

Short-term hormonal contraceptives remain the most popular class of reversible contraceptives in the United States, despite the availability of longer-acting methods. Oral contraceptives (OCs), contraceptive patches, and contraceptive vaginal rings are extensively used not only because these methods are easy to initiate but also because their ongoing use remains under the control of the woman herself and also provides her with a wide range of important noncontraceptive benefits.

Despite the more than 60 years of innovation that have made hormonal contraceptives safer, more tolerable, and more convenient, there has been room for improvement. Over the last few years, 4 new hormonal methods have been introduced, and each addresses different limitations and problems associated with the existing, often generic, products.

Compared with the traditional norethindrone pill (Micronor and generics), a new drospirenone progestin-only pill (POP) increases ovulation suppression, offers an improved cyclical bleeding profile, and relaxes the tight missed-pill rules that are usually associated with POPs.

In contrast with the older norelgestromin patch (Evra, Xulane), a new contraceptive transdermal patch significantly decreases total estrogen exposure and pairs its estrogen with levonorgestrel, the progestin associated with the lowest venous thromboembolism (VTE) risk in combined hormonal pills.

While existing combination OCs are formulated with the potent estrogen ethinyl estradiol (EE), a new combination pill, formulated with estetrol (E4) and drospirenone, introduces the first new estrogen (estetrol) used in a contraceptive in more than 50 years. Estetrol, a native estrogen, has selective tissue activity with minimal hepatic and breast impacts. Combined with drospirenone, this formulation offers women good contraceptive efficacy and bleeding patterns.

A new contraceptive vaginal ring introduces a new long-acting, specific progestin (segesterone acetate) and pairs it with low-dose EE. These hormones are packaged in a soft vaginal ring that provides up to 13 cycles of contraceptive protection (3 weeks in/1 week out) with one ring, greatly increasing convenience for women.

Each of these new products represents important incremental improvement over existing options.

Continue to: 1. The drospirenone-only OC...

The new POP with drospirenone 4 mg (Slynd), which received US Food and Drug Administration (FDA) approval in 2019, is packaged in a 24/4 formulation (24 hormonally active tablets followed by 4 inactive tablets). This formulation results in more predictable bleeding than does the 0.35-mg norethindrone POP, which contains 28 hormonally active tablets in each pack. In the US clinical trials of drospirenone 4 mg, scheduled bleeding decreased from 81% in cycle 1 to 20% in cycle 13. Unscheduled spotting and bleeding decreased from 61% to 40% in the same timeframe. Notably, this bleeding pattern was well tolerated; only 0.4% of trial participants discontinued this drospirenone POP due to problems with irregular bleeding or amenorrhea.

In contrast to the continuous norethindrone POP, which is not sufficiently dosed to consistently suppress ovulation, the 4-mg daily dose of drospirenone in this new POP is higher than the 3 mg used in commonly prescribed combination OCs that contain EE and drospirenone. This results in a POP that has more consistent ovulation suppression. Because this drospirenone POP is appropriately dosed and based on a longer-acting progestin, it is more forgiving of inconsistent pill taking. Accordingly, the missed-pill rules for this pill are the same as with combination estrogen-progestin OCs.¹ The package labeling cites a first-year failure rate of 4%, but this includes unconfirmed pregnancies. The Pearl Index from the North American trials, based on confirmed pregnancies in nonbreastfeeding women, was 2.9.²

The package labeling for this drospirenone POP includes few contraindications. Conditions that preclude use include the US Medical Eligibility Criteria for contraception Category 4 condition (breast cancer in the last 5 years), renal impairment, and adrenal insufficiency. Other standard contraindications are listed in the prescribing information. Serum potassium levels should be checked (one time only) in the first cycle only for women who chronically use medications that could cause hyperkalemia, such as nonsteroidal anti-inflammatory drugs.

Given the ovulation suppression associated with this drospirenone POP, the safety of a progestin-only method, and the persistent popularity of OC pills, this pill should greatly increase the use of POPs beyond their traditional niche of postpartum and breastfeeding women. The advent of the drospirenone POP means that clinicians now have better options for women who have contraindications to estrogen and desire to control their own contraceptive use. It would be a logical consideration for over-the-counter accessibility.

2. Transdermal patch with ethinyl estradiol/levonorgestrel

The new EE/levonorgestrel transdermal contraceptive patch (Twirla) is soft and flexible, about the same size as other contraceptive patches, and contains EE 2.3 mg/levonorgestrel 2.6 mg. It provides total estrogen exposure that is similar to that of OCs with EE 30 µg and distinctly lower than estrogen levels seen with the original norelgestromin-containing patch or its 2 subsequent generic versions.³ This EE/levonorgestrel patch uses a new 5-layer drug delivery system that focuses the steroids for absorption beneath the patch; there is no peripheral spread of drug around the patch (FIGURE 1).

Transdermal patches offer the convenience of once-a-week dosing. One patch is used each week for 3 consecutive weeks followed by a patch-free week. Patches can be worn on the abdomen, buttock, or trunk (except breasts). Patches should not be placed consecutively on the same site; after a week’s rest, however, the first site can be reused. All transdermal contraceptive products are indicated for use only by women with a body mass index (BMI) <30 kg/m².⁴

While no head-to-head trials have compared this new lower-dose patch with older patches, each patch was compared against a standardized pill, so meaningful comparisons can be made.

In each case, the circulating estrogen levels associated with use of the EE/levonorgestrel patch were considerably lower than those of the comparator pill, while the older norelgestromin patch consistently delivered higher total estrogen levels than its 35-µg comparator pill (TABLE).³ Along these lines, no VTE events occurred in women in the clinical trial of the new patch among women with a BMI <30 kg/m².⁴

Women with a BMI <25 kg/m² experienced lower Pearl Index (PI) pregnancy rates (3.5%) compared with women with a BMI between 25 and 30 kg/m² (5.7%), according to clinical trial data cited in the package labeling. All the modern PI criteria were used to calculate these failure rates. Cycles in which no coitus occurred were excluded. Similarly, cycles in which another contraceptive method (for example, condoms) was added (even once) were excluded. Frequent pregnancy testing was done in the study centers and by the women at home. Bleeding patterns were well accepted; only 2.2% of study participants exited the study early due to menstrual disorders of any kind. Similarly, 3.1% of women discontinued use because of application site disorders. Women should be advised to press down on the patch edges after emerging from water exposure. Replacement patches are rapidly available from the manufacturer should permanent complete patch detachment occur.

Larger-scale phase 4 trials will be conducted to study the impact of this lower-dose patch on VTE rates.

Continue to: 3. A 1-year contraceptive vaginal ring...

The need to obtain new supplies every month or every 3 months contributes to high rates of contraceptive failure and unintended pregnancy among women using short-acting hormonal contraceptives (pills, patches, and vaginal rings).⁵ A woman-controlled contraceptive that would provide 1 year of protection against unintended pregnancy represents a step forward. A contraceptive vaginal ring (CVR) that releases the novel progestin segesterone acetate and EE provides woman-controlled contraception for up to 1 year. This CVR (Annovera) received FDA approval in 2018 and has been marketed in the United States since 2020.

The segesterone acetate/EE CVR is a soft, flexible ring that is opaque white in color and fabricated from nonbiodegradable silicone (FIGURE 2). The outside diameter is 5.6 cm, compared with the 5.4-cm outer diameter of the etonogestrel/EE vaginal ring (NuvaRing). The segesterone acetate/EE CVR has 2 channels: one releases segesterone acetate only and the other releases segesterone acetate and EE. In contrast with the etonogestrel/EE CVR, the segesterone acetate/EE CVR does not need to be refrigerated when stored.⁶

Continue to: 4. An OC with a novel estrogen...

4. An OC with a novel estrogen

Even as use of intrauterine devices and contraceptive implants continues to grow, OCs remain the reversible contraceptive most used by US women. While OCs have been widely studied and represent a safe method of contraception for most reproductive-age women, combination estrogen-progestin OCs are well recognized to increase the risk of VTE. Although the primary role of the progestin component of combination OCs is to suppress ovulation, estrogen is included in combination OCs to stimulate endometrial proliferation, thereby causing predictable bleeding. EE, the potent synthetic estrogen used in the great majority of current OC formulations, induces hepatic production of prothrombotic proteins while inhibiting synthesis of antithrombotic proteins. While the lower EE doses (10–35 µg) in today’s OC formulations are associated with a lower VTE risk than older OCs that contained higher doses of estrogen, VTE continues to represent the principal health risk associated with use of combination OCs. Accordingly, development of a combination OC that has less impact on risk of VTE would be appealing.

In April 2021, the FDA approved an OC formulation that combines 15 mg of the novel estrogen estetrol with 3 mg of drospirenone (Nextstellis). This dose of drospirenone is the same as that used in commonly prescribed EE/drospirenone OC formulations. Also known as E4, estetrol is a natural estrogen synthesized by the fetal liver. Plant-derived E4 is used in this new OC.

Depending on the tissue, E4 acts differently than other estrogens. Similar to other estrogens, E4 acts as an agonist on the nuclear receptor to produce beneficial effects in bone, vaginal mucosa, and heart.⁸ Unlike other estrogens, E4 inhibits proliferation of mammary gland cells and has a neutral impact on the liver.⁹

In contrast with EE, E4 is not inhibited by the liver’s P450 enzymes; accordingly, the risk of drug-drug interactions is reduced. Because E4 is primarily excreted through the urine and not through the biliary tract, the risk of gallstone formation may be lower than with an EE OC. Likewise, E4 has substantially less impact on triglycerides, which are increased with EE. Finally, because of E4’s reduced effect on the liver, the impact on clotting parameters is less than that observed with an OC formulated with EE.¹⁰ This latter observation raises the possibility that VTE risk is lower with the E4/drospirenone OC than an OC formulated with EE.

A 13-cycle phase 3 trial of the E4/drospirenone OC conducted in the United States and Canada enrolled 1,864 women aged 16 to 50 years, including 1,674 who were aged 16 to 35 years.¹¹ Among women in this latter age group, the PI was 2.65 per 100 woman-years. Bleeding/cycle control patterns were similar to those observed in recent trials of other combination contraceptives. Likewise, the proportion of trial participants who discontinued the study due to adverse effects was similar to or lower than that noted in recent trials of other combination contraceptives. Of particular note, no cases of VTE were noted among trial participants of any BMI, a finding which contrasts with recent phase 3 trials of other combination contraceptives. The result of this pivotal trial suggests that the theoretic advantages of E4 when used in a combination OC formulation may translate into a safer, effective, and well-tolerated contraceptive.

Refinements in hormonal contraceptives continue

The 4 new short-acting hormonal contraceptives we reviewed represent enhancements on existing pills, patches, and rings. We hope that, financially, women will have access to these innovative methods and, in particular, that third-party payers will facilitate women’s access to these enhanced short-acting hormonal contraceptives. ●

Short-term hormonal contraceptives remain the most popular class of reversible contraceptives in the United States, despite the availability of longer-acting methods. Oral contraceptives (OCs), contraceptive patches, and contraceptive vaginal rings are extensively used not only because these methods are easy to initiate but also because their ongoing use remains under the control of the woman herself and also provides her with a wide range of important noncontraceptive benefits.

Despite the more than 60 years of innovation that have made hormonal contraceptives safer, more tolerable, and more convenient, there has been room for improvement. Over the last few years, 4 new hormonal methods have been introduced, and each addresses different limitations and problems associated with the existing, often generic, products.

Compared with the traditional norethindrone pill (Micronor and generics), a new drospirenone progestin-only pill (POP) increases ovulation suppression, offers an improved cyclical bleeding profile, and relaxes the tight missed-pill rules that are usually associated with POPs.

In contrast with the older norelgestromin patch (Evra, Xulane), a new contraceptive transdermal patch significantly decreases total estrogen exposure and pairs its estrogen with levonorgestrel, the progestin associated with the lowest venous thromboembolism (VTE) risk in combined hormonal pills.

While existing combination OCs are formulated with the potent estrogen ethinyl estradiol (EE), a new combination pill, formulated with estetrol (E4) and drospirenone, introduces the first new estrogen (estetrol) used in a contraceptive in more than 50 years. Estetrol, a native estrogen, has selective tissue activity with minimal hepatic and breast impacts. Combined with drospirenone, this formulation offers women good contraceptive efficacy and bleeding patterns.

A new contraceptive vaginal ring introduces a new long-acting, specific progestin (segesterone acetate) and pairs it with low-dose EE. These hormones are packaged in a soft vaginal ring that provides up to 13 cycles of contraceptive protection (3 weeks in/1 week out) with one ring, greatly increasing convenience for women.

Each of these new products represents important incremental improvement over existing options.

Continue to: 1. The drospirenone-only OC...

The new POP with drospirenone 4 mg (Slynd), which received US Food and Drug Administration (FDA) approval in 2019, is packaged in a 24/4 formulation (24 hormonally active tablets followed by 4 inactive tablets). This formulation results in more predictable bleeding than does the 0.35-mg norethindrone POP, which contains 28 hormonally active tablets in each pack. In the US clinical trials of drospirenone 4 mg, scheduled bleeding decreased from 81% in cycle 1 to 20% in cycle 13. Unscheduled spotting and bleeding decreased from 61% to 40% in the same timeframe. Notably, this bleeding pattern was well tolerated; only 0.4% of trial participants discontinued this drospirenone POP due to problems with irregular bleeding or amenorrhea.

In contrast to the continuous norethindrone POP, which is not sufficiently dosed to consistently suppress ovulation, the 4-mg daily dose of drospirenone in this new POP is higher than the 3 mg used in commonly prescribed combination OCs that contain EE and drospirenone. This results in a POP that has more consistent ovulation suppression. Because this drospirenone POP is appropriately dosed and based on a longer-acting progestin, it is more forgiving of inconsistent pill taking. Accordingly, the missed-pill rules for this pill are the same as with combination estrogen-progestin OCs.¹ The package labeling cites a first-year failure rate of 4%, but this includes unconfirmed pregnancies. The Pearl Index from the North American trials, based on confirmed pregnancies in nonbreastfeeding women, was 2.9.²

The package labeling for this drospirenone POP includes few contraindications. Conditions that preclude use include the US Medical Eligibility Criteria for contraception Category 4 condition (breast cancer in the last 5 years), renal impairment, and adrenal insufficiency. Other standard contraindications are listed in the prescribing information. Serum potassium levels should be checked (one time only) in the first cycle only for women who chronically use medications that could cause hyperkalemia, such as nonsteroidal anti-inflammatory drugs.

Given the ovulation suppression associated with this drospirenone POP, the safety of a progestin-only method, and the persistent popularity of OC pills, this pill should greatly increase the use of POPs beyond their traditional niche of postpartum and breastfeeding women. The advent of the drospirenone POP means that clinicians now have better options for women who have contraindications to estrogen and desire to control their own contraceptive use. It would be a logical consideration for over-the-counter accessibility.

2. Transdermal patch with ethinyl estradiol/levonorgestrel

The new EE/levonorgestrel transdermal contraceptive patch (Twirla) is soft and flexible, about the same size as other contraceptive patches, and contains EE 2.3 mg/levonorgestrel 2.6 mg. It provides total estrogen exposure that is similar to that of OCs with EE 30 µg and distinctly lower than estrogen levels seen with the original norelgestromin-containing patch or its 2 subsequent generic versions.³ This EE/levonorgestrel patch uses a new 5-layer drug delivery system that focuses the steroids for absorption beneath the patch; there is no peripheral spread of drug around the patch (FIGURE 1).

Transdermal patches offer the convenience of once-a-week dosing. One patch is used each week for 3 consecutive weeks followed by a patch-free week. Patches can be worn on the abdomen, buttock, or trunk (except breasts). Patches should not be placed consecutively on the same site; after a week’s rest, however, the first site can be reused. All transdermal contraceptive products are indicated for use only by women with a body mass index (BMI) <30 kg/m².⁴

While no head-to-head trials have compared this new lower-dose patch with older patches, each patch was compared against a standardized pill, so meaningful comparisons can be made.

In each case, the circulating estrogen levels associated with use of the EE/levonorgestrel patch were considerably lower than those of the comparator pill, while the older norelgestromin patch consistently delivered higher total estrogen levels than its 35-µg comparator pill (TABLE).³ Along these lines, no VTE events occurred in women in the clinical trial of the new patch among women with a BMI <30 kg/m².⁴

Women with a BMI <25 kg/m² experienced lower Pearl Index (PI) pregnancy rates (3.5%) compared with women with a BMI between 25 and 30 kg/m² (5.7%), according to clinical trial data cited in the package labeling. All the modern PI criteria were used to calculate these failure rates. Cycles in which no coitus occurred were excluded. Similarly, cycles in which another contraceptive method (for example, condoms) was added (even once) were excluded. Frequent pregnancy testing was done in the study centers and by the women at home. Bleeding patterns were well accepted; only 2.2% of study participants exited the study early due to menstrual disorders of any kind. Similarly, 3.1% of women discontinued use because of application site disorders. Women should be advised to press down on the patch edges after emerging from water exposure. Replacement patches are rapidly available from the manufacturer should permanent complete patch detachment occur.

Larger-scale phase 4 trials will be conducted to study the impact of this lower-dose patch on VTE rates.

Continue to: 3. A 1-year contraceptive vaginal ring...

The need to obtain new supplies every month or every 3 months contributes to high rates of contraceptive failure and unintended pregnancy among women using short-acting hormonal contraceptives (pills, patches, and vaginal rings).⁵ A woman-controlled contraceptive that would provide 1 year of protection against unintended pregnancy represents a step forward. A contraceptive vaginal ring (CVR) that releases the novel progestin segesterone acetate and EE provides woman-controlled contraception for up to 1 year. This CVR (Annovera) received FDA approval in 2018 and has been marketed in the United States since 2020.

The segesterone acetate/EE CVR is a soft, flexible ring that is opaque white in color and fabricated from nonbiodegradable silicone (FIGURE 2). The outside diameter is 5.6 cm, compared with the 5.4-cm outer diameter of the etonogestrel/EE vaginal ring (NuvaRing). The segesterone acetate/EE CVR has 2 channels: one releases segesterone acetate only and the other releases segesterone acetate and EE. In contrast with the etonogestrel/EE CVR, the segesterone acetate/EE CVR does not need to be refrigerated when stored.⁶

Continue to: 4. An OC with a novel estrogen...

4. An OC with a novel estrogen

Even as use of intrauterine devices and contraceptive implants continues to grow, OCs remain the reversible contraceptive most used by US women. While OCs have been widely studied and represent a safe method of contraception for most reproductive-age women, combination estrogen-progestin OCs are well recognized to increase the risk of VTE. Although the primary role of the progestin component of combination OCs is to suppress ovulation, estrogen is included in combination OCs to stimulate endometrial proliferation, thereby causing predictable bleeding. EE, the potent synthetic estrogen used in the great majority of current OC formulations, induces hepatic production of prothrombotic proteins while inhibiting synthesis of antithrombotic proteins. While the lower EE doses (10–35 µg) in today’s OC formulations are associated with a lower VTE risk than older OCs that contained higher doses of estrogen, VTE continues to represent the principal health risk associated with use of combination OCs. Accordingly, development of a combination OC that has less impact on risk of VTE would be appealing.

In April 2021, the FDA approved an OC formulation that combines 15 mg of the novel estrogen estetrol with 3 mg of drospirenone (Nextstellis). This dose of drospirenone is the same as that used in commonly prescribed EE/drospirenone OC formulations. Also known as E4, estetrol is a natural estrogen synthesized by the fetal liver. Plant-derived E4 is used in this new OC.

Depending on the tissue, E4 acts differently than other estrogens. Similar to other estrogens, E4 acts as an agonist on the nuclear receptor to produce beneficial effects in bone, vaginal mucosa, and heart.⁸ Unlike other estrogens, E4 inhibits proliferation of mammary gland cells and has a neutral impact on the liver.⁹

In contrast with EE, E4 is not inhibited by the liver’s P450 enzymes; accordingly, the risk of drug-drug interactions is reduced. Because E4 is primarily excreted through the urine and not through the biliary tract, the risk of gallstone formation may be lower than with an EE OC. Likewise, E4 has substantially less impact on triglycerides, which are increased with EE. Finally, because of E4’s reduced effect on the liver, the impact on clotting parameters is less than that observed with an OC formulated with EE.¹⁰ This latter observation raises the possibility that VTE risk is lower with the E4/drospirenone OC than an OC formulated with EE.

A 13-cycle phase 3 trial of the E4/drospirenone OC conducted in the United States and Canada enrolled 1,864 women aged 16 to 50 years, including 1,674 who were aged 16 to 35 years.¹¹ Among women in this latter age group, the PI was 2.65 per 100 woman-years. Bleeding/cycle control patterns were similar to those observed in recent trials of other combination contraceptives. Likewise, the proportion of trial participants who discontinued the study due to adverse effects was similar to or lower than that noted in recent trials of other combination contraceptives. Of particular note, no cases of VTE were noted among trial participants of any BMI, a finding which contrasts with recent phase 3 trials of other combination contraceptives. The result of this pivotal trial suggests that the theoretic advantages of E4 when used in a combination OC formulation may translate into a safer, effective, and well-tolerated contraceptive.

Refinements in hormonal contraceptives continue

The 4 new short-acting hormonal contraceptives we reviewed represent enhancements on existing pills, patches, and rings. We hope that, financially, women will have access to these innovative methods and, in particular, that third-party payers will facilitate women’s access to these enhanced short-acting hormonal contraceptives. ●

Uterine fibroids are a common condition that affects up to 80% of reproductive-age women.¹ Many women with fibroids are asymptomatic, but some experience symptoms that profoundly disrupt their lives, such as abnormal uterine bleeding, pelvic pain, and bulk symptoms including bladder and bowel dysfunction.² Although hysterectomy remains the definitive treatment for symptomatic fibroids, many women seek more conservative management. Hormonal treatment, such as contraceptive pills, levonorgestrel intrauterine devices, and gonadotropin-releasing hormone analogs, can improve heavy menstrual bleeding and anemia.³ Additionally, uterine artery embolization is a nonsurgical uterine-sparing option. However, these treatments are not ideal options for women who want to conceive.⁴ For reproductive-age women who desire future fertility, myomectomy has been the standard of care. Unfortunately, by the time patients become symptomatic from their fibroids and seek care, they may have numerous and/or sizable fibroids that result in high blood loss, surgical scarring, and the probable need for cesarean delivery (FIGURES 1 and 2).⁵

For patients who desire future conception, treatment of uterine fibroids poses a challenge in which optimizing symptomatic improvement must be balanced with protecting fertility and improving reproductive outcomes. In recent years, high-intensity focused ultrasound (FUS) and radiofrequency ablation (RFA) have been presented as less invasive, uterine-sparing alternatives for fibroid treatment that could potentially provide that balance.

In this article, we briefly review the available uterine-sparing fibroid treatments and their outcomes and then focus specifically on RFA as a possible option to address the fibroid treatment gap for reproductive-age women who desire future fertility.

Overview of uterine-sparing treatments

Two approaches can be pursued for conservative fibroid treatment: fibroid removal and fibroid necrosis (TABLE 1). We focus this review on outcomes for the most widely available of these treatments.

Myomectomy

For reproductive-age women who wish to conceive, surgical removal of fibroids has been the standard of care for symptomatic patients. Myomectomy can be performed via laparotomy, laparoscopy, robot-assisted surgery, and hysteroscopy. The mode of surgery depends on the fibroid characteristics (size, number, and location) and the surgeon’s skill set. Although some variation in the data exists, overall surgical outcomes, including blood loss, postoperative pain, and length of stay, are generally more favorable for minimally invasive approaches compared with laparotomy, with no significant differences in fibroid recurrence or reproductive outcomes (live birth rate, miscarriage rate, and cesarean delivery rate).⁶ This comes at the expense of longer operating time compared with laparotomy.⁷

While improvement in abnormal uterine bleeding and pelvic pain is reliable and usually significant after myomectomy,⁸ reproductive implications also warrant consideration. Myomectomy is associated with subsequent uterine adhesion formation, with some studies finding rates up to 83% to 94% depending on the surgical approach and the number of fibroids removed.⁹ These adhesions can impair fertility success.¹⁰ Myomectomy also is associated with high rates of cesarean delivery,⁵ invasive placentation (including placenta accreta spectrum),¹¹ and uterine rupture.¹² While the latter 2 complications are rare, they potentially can be catastrophic and should be kept in mind.

Continue to: Uterine artery embolization...

Uterine artery embolization

As a nonsurgical alternative to myomectomy, uterine artery embolization (UAE) has gained popularity as a conservative fibroid treatment since it was introduced in 1995. It is less invasive than myomectomy, a benefit for patients who decline surgery or are not ideal candidates for surgery.¹³ Evidence suggests that UAE produces overall comparable symptomatic improvement compared with myomectomy. One study showed no significant differences between UAE and myomectomy in terms of decreased uterine volume and menstrual bleeding at 6-month follow-up.¹⁴ In terms of long-term outcomes, a large multicenter study showed no significant difference in reintervention rates at 7 years posttreatment between UAE and myomectomy (8.9% vs 11.2%, respectively), and a significantly higher rate of improved menstrual bleeding with UAE (79.4% vs 49.5%), with no significant difference in bulk symptoms.¹⁵ The evidence is not entirely consistent, as other studies have shown increased rates of reintervention with UAE,^8,16 but overall UAE can be considered a reasonable alternative to myomectomy in terms of symptomatic improvement.

Pregnancy outcomes data, however, are mixed, and UAE often is not recommended for patients with future fertility plans. In a large review article that compared minimally invasive fibroid treatments, UAE was associated with a lower live birth rate compared with myomectomy and ablation techniques (60.6% for UAE, 75.6% for myomectomy, and 70.5% for ablation), and it also had the highest rate of miscarriage (27.4% for UAE vs 19.0% for myomectomy and 11.9% for ablation) and abnormal placentation.¹² While UAE remains an effective option for conservative treatment of symptomatic fibroids, it appears to have a worse impact on reproductive outcomes compared with myomectomy or ablative treatments.

Magnetic resonance–guided focused ultrasound

Emerging as a noninvasive ablation treatment for fibroids, magnetic resonance–guided focused ultrasound (MRgFUS) uses targeted high-intensity ultrasound pulses to cause thermal and mechanical fibroid tissue disruption.¹⁷ Data on this treatment are less robust given that it is newer than myomectomy or UAE. One study showed a decrease in fibroid volume by 12% at 1 month and 15% at 6 months, with 37.1% of patients reporting marked improvement in symptoms and an additional 31.4% reporting partial improvement; these are modest numbers compared with other treatment approaches.¹⁸ Another study showed more favorable outcomes, with 74% of patients reporting clinically significant improvement in bleeding and pain, and a 12.7% reintervention rate, comparable to rates reported for UAE and myomectomy.¹⁹

Because MRgFUS is newer than UAE or myomectomy, data are limited in terms of pregnancy outcomes, particularly because initial trials excluded women with future fertility plans due to lack of knowledge regarding pregnancy safety. A follow-up case series from one of the initial studies showed a decreased miscarriage rate compared with UAE, a term delivery rate of 93%, and a similar rate of abnormal placentation.²⁰ A more recent systematic review concluded that reproductive outcomes were noninferior to myomectomy; however, the outcomes data for MRgFUS were heterogenous and many studies did not report pregnancy rates.²¹

Overall, MRgFUS appears to be an effective alternative approach for symptomatic fibroids, but the long-term data are not yet conclusive and information on pregnancy safety and outcomes largely is lacking. Recent reviews have not made definitive statements on whether MRgFUS should be offered to patients desiring future fertility.

Continue to: RFA is a promising option...

RFA is a promising option

RFA is another noninvasive fibroid ablation technique that has become more widely adopted in recent years. Here, we describe the basics of RFA and its impact on fibroid symptoms and reproductive outcomes.

The RFA technique

RFA uses hyperthermic energy from a handpiece and real-time ultrasound for targeted coagulative necrosis via a laparoscopic (L-RFA) or transcervical (TC-RFA) approach.²² A comparison between the 2 devices available on the market in the United States is shown in TABLE 2. Ultrasound guidance allows placement of radiofrequency needles directly into the fibroid to target local treatment to the fibroid tissue only. Once the fibroid undergoes coagulative necrosis, the process of fibroid resorption and volume reduction occurs over weeks to months, depending on the fibroid size.

Impact on fibroid symptoms

Both laparoscopic and transcervical RFA approaches have shown significant decreases in pelvic pain and heavy menstrual bleeding associated with fibroids and a low reintervention rate that emphasizes the durability of their impact.

A feasibility and safety study of a TC-RFA device prior to the primary clinical trials found only a 4.3% reintervention rate in the first 18 months postprocedure.²³ The pivotal clinical trial of a TC-RFA device that followed also reported a low 5.5% reintervention rate in the first 24 months postprocedure, with significant improvement in health-related quality-of-life and high patient satisfaction²⁴ (results shown in TABLE 2, along with trial results for an L-RFA device). A subsequent study of TC-RFA reported that symptomatic improvement persisted at 3-year follow-up, with a 9.2% reintervention rate comparable to existing fibroid treatments such as myomectomy and UAE.²⁵ The original L-RFA trial also has shown similar positive results at 2-year follow-up, with a low reintervention rate of 4.8% after treatment, and similar patient satisfaction and quality-of-life improvements as TC-RFA.²⁶ While long-term data are limited by only recent approval by the Food and Drug Administration (FDA) of a TC-RFA device in 2018, one study followed clinical trial patients for a mean duration of 64 months. This study found no surgical reinterventions in the first 3.5 years posttreatment and a persistent reduction in fibroid symptoms from baseline 64.9 points to 27.6 points, as assessed by a validated symptom severity scale (out of 100 points).²⁷ Similar improvements in health-related quality-of life-were also found to persist for years posttreatment.⁴

In a large systematic review that compared L-RFA, MRgFUS, UAE, and myomectomy, L-RFA had similar improvement rates in quality-of-life and symptom severity scores compared with myomectomy, with no significant difference in reintervention rates.²⁸ This review also noted minimal heterogeneity among RFA meta-analyses data in contrast to significant heterogeneity among UAE and myomectomy data.

Reproductive outcomes

Similar to MRgFUS, the initial studies of RFA devices largely excluded women with future fertility plans, as data on safety were lacking. However, many RFA devices are now on the market across the globe, and subsequent pregnancies have been tracked and reported.

A large case series that included clinical trials and commercial settings reported a miscarriage rate (13.3%) similar to that of the general obstetric population and no cases of uterine rupture, invasive placentation, preterm delivery, or placental abruption.²⁹ Other case series have reported live birth rates similar those with myomectomy, and safe and favorable pregnancy outcomes with RFA have been supported by larger systematic reviews of all ablation techniques.¹²

Continue to: Uterine impact...

Uterine impact

One study of TC-RFA patients showed a greater than 65% reduction in fibroid volume (with a 90% reduction in fibroid volume for fibroids larger than 6 cm prior to RFA), and 54% of patients reported complete resolution of symptoms, with another 36% reporting decreased symptoms.³⁰ Similar decreases in fibroid volume, ranging from 65% to 84%, have been reported in numerous follow-up studies, with significant decreases in bleeding and pain in 78% to 88% of patients.^23,31-33 Additionally, a large secondary analysis of a TC-RFA clinical trial showed that patients did not have any significant decrease in uterine wall thickness or integrity on follow-up with magnetic resonance imaging compared with baseline measurements, and they did not have any new myometrial scars (assessed as nonperfused linear areas).²²

As with other ablation techniques, most data on RFA pregnancy outcomes come from case series, and further research and evaluation are needed. Existing studies, however, have demonstrated promising aspects of RFA that argue its usefulness in women with fertility plans.

A prospective trial that evaluated intrauterine adhesion formation with use of a TC-RFA device found no new adhesions on 6-week follow-up hysteroscopy compared with baseline pre-RFA hysteroscopy.³⁴ Because intrauterine adhesion formation and uterine rupture are both significant concerns with other uterine-sparing fibroid treatment approaches such as myomectomy, these findings suggest that RFA may be a better alternative for women who are planning future pregnancies, as they may have increased fertility success and decreased catastrophic complications.

The consensus is growing that RFA is a safe and effective option for women who desire minimally invasive fibroid treatment and want to preserve fertility.

Unique benefits of RFA

In this article, we highlight RFA as an emerging treatment option for fibroid management, particularly for women who desire a uterine-sparing approach to preserve their reproductive options. Although myomectomy has been the standard of care for many years, with UAE as the alternative nonsurgical treatment, neither approach provides the best balance between symptomatic improvement and reproductive outcomes, and neither is without pregnancy risks. In addition, many women with symptomatic fibroids do not desire future conception but decline fibroid removal for religious or personal reasons. RFA offers these women an alternative minimally invasive option for uterine-sparing fibroid treatment.

RFA presents a unique “incision-free” fibroid treatment that is truly minimally invasive. This technique minimizes the risks associated with myomectomy, such as intra-abdominal adhesions, intrauterine adhesions (Asherman syndrome), need for cesarean delivery, and pregnancy complications such as uterine rupture or invasive placentation. Furthermore, the evolution of an RFA transcervical approach has enabled treatment with no abdominal or uterine incisions, thus offering all the above reproductive benefits as well as the operative benefits of a faster recovery, less pain, and less risk of intraperitoneal surgical complications.

While many women desire uterine-sparing fibroid treatment even without future fertility plans, the larger question is whether we should treat fibroids more strategically for women who desire future fertility. Myomectomy and UAE are effective and reliable in terms of fibroid symptomatic improvement, but RFA promises more beneficial reproductive outcomes. The ability to avoid uterine myometrial incisions and still attain significant symptomatic improvement should be prioritized in these patients.

Currently, RFA is not approved by the FDA as a fertility-enabling treatment, and these patients have been largely excluded from RFA studies. However, the reproductive-age patient who desires future conception may benefit most from RFA. Furthermore, RFA technology also could address the gap in uterine-sparing treatment for reproductive-age women with adenomyosis. Although a complete review of adenomyosis treatment is beyond the scope of this article, recent studies show that RFA produces similar improvement in both uterine volume and symptom severity in women with adenomyosis.^35-37 ●

Uterine fibroids are a common condition that affects up to 80% of reproductive-age women.¹ Many women with fibroids are asymptomatic, but some experience symptoms that profoundly disrupt their lives, such as abnormal uterine bleeding, pelvic pain, and bulk symptoms including bladder and bowel dysfunction.² Although hysterectomy remains the definitive treatment for symptomatic fibroids, many women seek more conservative management. Hormonal treatment, such as contraceptive pills, levonorgestrel intrauterine devices, and gonadotropin-releasing hormone analogs, can improve heavy menstrual bleeding and anemia.³ Additionally, uterine artery embolization is a nonsurgical uterine-sparing option. However, these treatments are not ideal options for women who want to conceive.⁴ For reproductive-age women who desire future fertility, myomectomy has been the standard of care. Unfortunately, by the time patients become symptomatic from their fibroids and seek care, they may have numerous and/or sizable fibroids that result in high blood loss, surgical scarring, and the probable need for cesarean delivery (FIGURES 1 and 2).⁵

For patients who desire future conception, treatment of uterine fibroids poses a challenge in which optimizing symptomatic improvement must be balanced with protecting fertility and improving reproductive outcomes. In recent years, high-intensity focused ultrasound (FUS) and radiofrequency ablation (RFA) have been presented as less invasive, uterine-sparing alternatives for fibroid treatment that could potentially provide that balance.

In this article, we briefly review the available uterine-sparing fibroid treatments and their outcomes and then focus specifically on RFA as a possible option to address the fibroid treatment gap for reproductive-age women who desire future fertility.

Overview of uterine-sparing treatments

Two approaches can be pursued for conservative fibroid treatment: fibroid removal and fibroid necrosis (TABLE 1). We focus this review on outcomes for the most widely available of these treatments.

Myomectomy

For reproductive-age women who wish to conceive, surgical removal of fibroids has been the standard of care for symptomatic patients. Myomectomy can be performed via laparotomy, laparoscopy, robot-assisted surgery, and hysteroscopy. The mode of surgery depends on the fibroid characteristics (size, number, and location) and the surgeon’s skill set. Although some variation in the data exists, overall surgical outcomes, including blood loss, postoperative pain, and length of stay, are generally more favorable for minimally invasive approaches compared with laparotomy, with no significant differences in fibroid recurrence or reproductive outcomes (live birth rate, miscarriage rate, and cesarean delivery rate).⁶ This comes at the expense of longer operating time compared with laparotomy.⁷

While improvement in abnormal uterine bleeding and pelvic pain is reliable and usually significant after myomectomy,⁸ reproductive implications also warrant consideration. Myomectomy is associated with subsequent uterine adhesion formation, with some studies finding rates up to 83% to 94% depending on the surgical approach and the number of fibroids removed.⁹ These adhesions can impair fertility success.¹⁰ Myomectomy also is associated with high rates of cesarean delivery,⁵ invasive placentation (including placenta accreta spectrum),¹¹ and uterine rupture.¹² While the latter 2 complications are rare, they potentially can be catastrophic and should be kept in mind.

Continue to: Uterine artery embolization...

Uterine artery embolization

As a nonsurgical alternative to myomectomy, uterine artery embolization (UAE) has gained popularity as a conservative fibroid treatment since it was introduced in 1995. It is less invasive than myomectomy, a benefit for patients who decline surgery or are not ideal candidates for surgery.¹³ Evidence suggests that UAE produces overall comparable symptomatic improvement compared with myomectomy. One study showed no significant differences between UAE and myomectomy in terms of decreased uterine volume and menstrual bleeding at 6-month follow-up.¹⁴ In terms of long-term outcomes, a large multicenter study showed no significant difference in reintervention rates at 7 years posttreatment between UAE and myomectomy (8.9% vs 11.2%, respectively), and a significantly higher rate of improved menstrual bleeding with UAE (79.4% vs 49.5%), with no significant difference in bulk symptoms.¹⁵ The evidence is not entirely consistent, as other studies have shown increased rates of reintervention with UAE,^8,16 but overall UAE can be considered a reasonable alternative to myomectomy in terms of symptomatic improvement.

Pregnancy outcomes data, however, are mixed, and UAE often is not recommended for patients with future fertility plans. In a large review article that compared minimally invasive fibroid treatments, UAE was associated with a lower live birth rate compared with myomectomy and ablation techniques (60.6% for UAE, 75.6% for myomectomy, and 70.5% for ablation), and it also had the highest rate of miscarriage (27.4% for UAE vs 19.0% for myomectomy and 11.9% for ablation) and abnormal placentation.¹² While UAE remains an effective option for conservative treatment of symptomatic fibroids, it appears to have a worse impact on reproductive outcomes compared with myomectomy or ablative treatments.

Magnetic resonance–guided focused ultrasound

Emerging as a noninvasive ablation treatment for fibroids, magnetic resonance–guided focused ultrasound (MRgFUS) uses targeted high-intensity ultrasound pulses to cause thermal and mechanical fibroid tissue disruption.¹⁷ Data on this treatment are less robust given that it is newer than myomectomy or UAE. One study showed a decrease in fibroid volume by 12% at 1 month and 15% at 6 months, with 37.1% of patients reporting marked improvement in symptoms and an additional 31.4% reporting partial improvement; these are modest numbers compared with other treatment approaches.¹⁸ Another study showed more favorable outcomes, with 74% of patients reporting clinically significant improvement in bleeding and pain, and a 12.7% reintervention rate, comparable to rates reported for UAE and myomectomy.¹⁹

Because MRgFUS is newer than UAE or myomectomy, data are limited in terms of pregnancy outcomes, particularly because initial trials excluded women with future fertility plans due to lack of knowledge regarding pregnancy safety. A follow-up case series from one of the initial studies showed a decreased miscarriage rate compared with UAE, a term delivery rate of 93%, and a similar rate of abnormal placentation.²⁰ A more recent systematic review concluded that reproductive outcomes were noninferior to myomectomy; however, the outcomes data for MRgFUS were heterogenous and many studies did not report pregnancy rates.²¹

Overall, MRgFUS appears to be an effective alternative approach for symptomatic fibroids, but the long-term data are not yet conclusive and information on pregnancy safety and outcomes largely is lacking. Recent reviews have not made definitive statements on whether MRgFUS should be offered to patients desiring future fertility.

Continue to: RFA is a promising option...

RFA is a promising option

RFA is another noninvasive fibroid ablation technique that has become more widely adopted in recent years. Here, we describe the basics of RFA and its impact on fibroid symptoms and reproductive outcomes.

The RFA technique

RFA uses hyperthermic energy from a handpiece and real-time ultrasound for targeted coagulative necrosis via a laparoscopic (L-RFA) or transcervical (TC-RFA) approach.²² A comparison between the 2 devices available on the market in the United States is shown in TABLE 2. Ultrasound guidance allows placement of radiofrequency needles directly into the fibroid to target local treatment to the fibroid tissue only. Once the fibroid undergoes coagulative necrosis, the process of fibroid resorption and volume reduction occurs over weeks to months, depending on the fibroid size.

Impact on fibroid symptoms

Both laparoscopic and transcervical RFA approaches have shown significant decreases in pelvic pain and heavy menstrual bleeding associated with fibroids and a low reintervention rate that emphasizes the durability of their impact.

A feasibility and safety study of a TC-RFA device prior to the primary clinical trials found only a 4.3% reintervention rate in the first 18 months postprocedure.²³ The pivotal clinical trial of a TC-RFA device that followed also reported a low 5.5% reintervention rate in the first 24 months postprocedure, with significant improvement in health-related quality-of-life and high patient satisfaction²⁴ (results shown in TABLE 2, along with trial results for an L-RFA device). A subsequent study of TC-RFA reported that symptomatic improvement persisted at 3-year follow-up, with a 9.2% reintervention rate comparable to existing fibroid treatments such as myomectomy and UAE.²⁵ The original L-RFA trial also has shown similar positive results at 2-year follow-up, with a low reintervention rate of 4.8% after treatment, and similar patient satisfaction and quality-of-life improvements as TC-RFA.²⁶ While long-term data are limited by only recent approval by the Food and Drug Administration (FDA) of a TC-RFA device in 2018, one study followed clinical trial patients for a mean duration of 64 months. This study found no surgical reinterventions in the first 3.5 years posttreatment and a persistent reduction in fibroid symptoms from baseline 64.9 points to 27.6 points, as assessed by a validated symptom severity scale (out of 100 points).²⁷ Similar improvements in health-related quality-of life-were also found to persist for years posttreatment.⁴

In a large systematic review that compared L-RFA, MRgFUS, UAE, and myomectomy, L-RFA had similar improvement rates in quality-of-life and symptom severity scores compared with myomectomy, with no significant difference in reintervention rates.²⁸ This review also noted minimal heterogeneity among RFA meta-analyses data in contrast to significant heterogeneity among UAE and myomectomy data.

Reproductive outcomes

Similar to MRgFUS, the initial studies of RFA devices largely excluded women with future fertility plans, as data on safety were lacking. However, many RFA devices are now on the market across the globe, and subsequent pregnancies have been tracked and reported.

A large case series that included clinical trials and commercial settings reported a miscarriage rate (13.3%) similar to that of the general obstetric population and no cases of uterine rupture, invasive placentation, preterm delivery, or placental abruption.²⁹ Other case series have reported live birth rates similar those with myomectomy, and safe and favorable pregnancy outcomes with RFA have been supported by larger systematic reviews of all ablation techniques.¹²

Continue to: Uterine impact...

Uterine impact

One study of TC-RFA patients showed a greater than 65% reduction in fibroid volume (with a 90% reduction in fibroid volume for fibroids larger than 6 cm prior to RFA), and 54% of patients reported complete resolution of symptoms, with another 36% reporting decreased symptoms.³⁰ Similar decreases in fibroid volume, ranging from 65% to 84%, have been reported in numerous follow-up studies, with significant decreases in bleeding and pain in 78% to 88% of patients.^23,31-33 Additionally, a large secondary analysis of a TC-RFA clinical trial showed that patients did not have any significant decrease in uterine wall thickness or integrity on follow-up with magnetic resonance imaging compared with baseline measurements, and they did not have any new myometrial scars (assessed as nonperfused linear areas).²²

As with other ablation techniques, most data on RFA pregnancy outcomes come from case series, and further research and evaluation are needed. Existing studies, however, have demonstrated promising aspects of RFA that argue its usefulness in women with fertility plans.

A prospective trial that evaluated intrauterine adhesion formation with use of a TC-RFA device found no new adhesions on 6-week follow-up hysteroscopy compared with baseline pre-RFA hysteroscopy.³⁴ Because intrauterine adhesion formation and uterine rupture are both significant concerns with other uterine-sparing fibroid treatment approaches such as myomectomy, these findings suggest that RFA may be a better alternative for women who are planning future pregnancies, as they may have increased fertility success and decreased catastrophic complications.

The consensus is growing that RFA is a safe and effective option for women who desire minimally invasive fibroid treatment and want to preserve fertility.

Unique benefits of RFA

In this article, we highlight RFA as an emerging treatment option for fibroid management, particularly for women who desire a uterine-sparing approach to preserve their reproductive options. Although myomectomy has been the standard of care for many years, with UAE as the alternative nonsurgical treatment, neither approach provides the best balance between symptomatic improvement and reproductive outcomes, and neither is without pregnancy risks. In addition, many women with symptomatic fibroids do not desire future conception but decline fibroid removal for religious or personal reasons. RFA offers these women an alternative minimally invasive option for uterine-sparing fibroid treatment.

RFA presents a unique “incision-free” fibroid treatment that is truly minimally invasive. This technique minimizes the risks associated with myomectomy, such as intra-abdominal adhesions, intrauterine adhesions (Asherman syndrome), need for cesarean delivery, and pregnancy complications such as uterine rupture or invasive placentation. Furthermore, the evolution of an RFA transcervical approach has enabled treatment with no abdominal or uterine incisions, thus offering all the above reproductive benefits as well as the operative benefits of a faster recovery, less pain, and less risk of intraperitoneal surgical complications.

While many women desire uterine-sparing fibroid treatment even without future fertility plans, the larger question is whether we should treat fibroids more strategically for women who desire future fertility. Myomectomy and UAE are effective and reliable in terms of fibroid symptomatic improvement, but RFA promises more beneficial reproductive outcomes. The ability to avoid uterine myometrial incisions and still attain significant symptomatic improvement should be prioritized in these patients.

Currently, RFA is not approved by the FDA as a fertility-enabling treatment, and these patients have been largely excluded from RFA studies. However, the reproductive-age patient who desires future conception may benefit most from RFA. Furthermore, RFA technology also could address the gap in uterine-sparing treatment for reproductive-age women with adenomyosis. Although a complete review of adenomyosis treatment is beyond the scope of this article, recent studies show that RFA produces similar improvement in both uterine volume and symptom severity in women with adenomyosis.^35-37 ●

Uterine fibroids are a common condition that affects up to 80% of reproductive-age women.¹ Many women with fibroids are asymptomatic, but some experience symptoms that profoundly disrupt their lives, such as abnormal uterine bleeding, pelvic pain, and bulk symptoms including bladder and bowel dysfunction.² Although hysterectomy remains the definitive treatment for symptomatic fibroids, many women seek more conservative management. Hormonal treatment, such as contraceptive pills, levonorgestrel intrauterine devices, and gonadotropin-releasing hormone analogs, can improve heavy menstrual bleeding and anemia.³ Additionally, uterine artery embolization is a nonsurgical uterine-sparing option. However, these treatments are not ideal options for women who want to conceive.⁴ For reproductive-age women who desire future fertility, myomectomy has been the standard of care. Unfortunately, by the time patients become symptomatic from their fibroids and seek care, they may have numerous and/or sizable fibroids that result in high blood loss, surgical scarring, and the probable need for cesarean delivery (FIGURES 1 and 2).⁵

For patients who desire future conception, treatment of uterine fibroids poses a challenge in which optimizing symptomatic improvement must be balanced with protecting fertility and improving reproductive outcomes. In recent years, high-intensity focused ultrasound (FUS) and radiofrequency ablation (RFA) have been presented as less invasive, uterine-sparing alternatives for fibroid treatment that could potentially provide that balance.

In this article, we briefly review the available uterine-sparing fibroid treatments and their outcomes and then focus specifically on RFA as a possible option to address the fibroid treatment gap for reproductive-age women who desire future fertility.

Overview of uterine-sparing treatments

Two approaches can be pursued for conservative fibroid treatment: fibroid removal and fibroid necrosis (TABLE 1). We focus this review on outcomes for the most widely available of these treatments.

Myomectomy

For reproductive-age women who wish to conceive, surgical removal of fibroids has been the standard of care for symptomatic patients. Myomectomy can be performed via laparotomy, laparoscopy, robot-assisted surgery, and hysteroscopy. The mode of surgery depends on the fibroid characteristics (size, number, and location) and the surgeon’s skill set. Although some variation in the data exists, overall surgical outcomes, including blood loss, postoperative pain, and length of stay, are generally more favorable for minimally invasive approaches compared with laparotomy, with no significant differences in fibroid recurrence or reproductive outcomes (live birth rate, miscarriage rate, and cesarean delivery rate).⁶ This comes at the expense of longer operating time compared with laparotomy.⁷

While improvement in abnormal uterine bleeding and pelvic pain is reliable and usually significant after myomectomy,⁸ reproductive implications also warrant consideration. Myomectomy is associated with subsequent uterine adhesion formation, with some studies finding rates up to 83% to 94% depending on the surgical approach and the number of fibroids removed.⁹ These adhesions can impair fertility success.¹⁰ Myomectomy also is associated with high rates of cesarean delivery,⁵ invasive placentation (including placenta accreta spectrum),¹¹ and uterine rupture.¹² While the latter 2 complications are rare, they potentially can be catastrophic and should be kept in mind.

Continue to: Uterine artery embolization...

Uterine artery embolization

As a nonsurgical alternative to myomectomy, uterine artery embolization (UAE) has gained popularity as a conservative fibroid treatment since it was introduced in 1995. It is less invasive than myomectomy, a benefit for patients who decline surgery or are not ideal candidates for surgery.¹³ Evidence suggests that UAE produces overall comparable symptomatic improvement compared with myomectomy. One study showed no significant differences between UAE and myomectomy in terms of decreased uterine volume and menstrual bleeding at 6-month follow-up.¹⁴ In terms of long-term outcomes, a large multicenter study showed no significant difference in reintervention rates at 7 years posttreatment between UAE and myomectomy (8.9% vs 11.2%, respectively), and a significantly higher rate of improved menstrual bleeding with UAE (79.4% vs 49.5%), with no significant difference in bulk symptoms.¹⁵ The evidence is not entirely consistent, as other studies have shown increased rates of reintervention with UAE,^8,16 but overall UAE can be considered a reasonable alternative to myomectomy in terms of symptomatic improvement.

Pregnancy outcomes data, however, are mixed, and UAE often is not recommended for patients with future fertility plans. In a large review article that compared minimally invasive fibroid treatments, UAE was associated with a lower live birth rate compared with myomectomy and ablation techniques (60.6% for UAE, 75.6% for myomectomy, and 70.5% for ablation), and it also had the highest rate of miscarriage (27.4% for UAE vs 19.0% for myomectomy and 11.9% for ablation) and abnormal placentation.¹² While UAE remains an effective option for conservative treatment of symptomatic fibroids, it appears to have a worse impact on reproductive outcomes compared with myomectomy or ablative treatments.

Magnetic resonance–guided focused ultrasound

Emerging as a noninvasive ablation treatment for fibroids, magnetic resonance–guided focused ultrasound (MRgFUS) uses targeted high-intensity ultrasound pulses to cause thermal and mechanical fibroid tissue disruption.¹⁷ Data on this treatment are less robust given that it is newer than myomectomy or UAE. One study showed a decrease in fibroid volume by 12% at 1 month and 15% at 6 months, with 37.1% of patients reporting marked improvement in symptoms and an additional 31.4% reporting partial improvement; these are modest numbers compared with other treatment approaches.¹⁸ Another study showed more favorable outcomes, with 74% of patients reporting clinically significant improvement in bleeding and pain, and a 12.7% reintervention rate, comparable to rates reported for UAE and myomectomy.¹⁹

Because MRgFUS is newer than UAE or myomectomy, data are limited in terms of pregnancy outcomes, particularly because initial trials excluded women with future fertility plans due to lack of knowledge regarding pregnancy safety. A follow-up case series from one of the initial studies showed a decreased miscarriage rate compared with UAE, a term delivery rate of 93%, and a similar rate of abnormal placentation.²⁰ A more recent systematic review concluded that reproductive outcomes were noninferior to myomectomy; however, the outcomes data for MRgFUS were heterogenous and many studies did not report pregnancy rates.²¹

Overall, MRgFUS appears to be an effective alternative approach for symptomatic fibroids, but the long-term data are not yet conclusive and information on pregnancy safety and outcomes largely is lacking. Recent reviews have not made definitive statements on whether MRgFUS should be offered to patients desiring future fertility.

Continue to: RFA is a promising option...

RFA is a promising option

RFA is another noninvasive fibroid ablation technique that has become more widely adopted in recent years. Here, we describe the basics of RFA and its impact on fibroid symptoms and reproductive outcomes.

The RFA technique

RFA uses hyperthermic energy from a handpiece and real-time ultrasound for targeted coagulative necrosis via a laparoscopic (L-RFA) or transcervical (TC-RFA) approach.²² A comparison between the 2 devices available on the market in the United States is shown in TABLE 2. Ultrasound guidance allows placement of radiofrequency needles directly into the fibroid to target local treatment to the fibroid tissue only. Once the fibroid undergoes coagulative necrosis, the process of fibroid resorption and volume reduction occurs over weeks to months, depending on the fibroid size.

Impact on fibroid symptoms

Both laparoscopic and transcervical RFA approaches have shown significant decreases in pelvic pain and heavy menstrual bleeding associated with fibroids and a low reintervention rate that emphasizes the durability of their impact.

A feasibility and safety study of a TC-RFA device prior to the primary clinical trials found only a 4.3% reintervention rate in the first 18 months postprocedure.²³ The pivotal clinical trial of a TC-RFA device that followed also reported a low 5.5% reintervention rate in the first 24 months postprocedure, with significant improvement in health-related quality-of-life and high patient satisfaction²⁴ (results shown in TABLE 2, along with trial results for an L-RFA device). A subsequent study of TC-RFA reported that symptomatic improvement persisted at 3-year follow-up, with a 9.2% reintervention rate comparable to existing fibroid treatments such as myomectomy and UAE.²⁵ The original L-RFA trial also has shown similar positive results at 2-year follow-up, with a low reintervention rate of 4.8% after treatment, and similar patient satisfaction and quality-of-life improvements as TC-RFA.²⁶ While long-term data are limited by only recent approval by the Food and Drug Administration (FDA) of a TC-RFA device in 2018, one study followed clinical trial patients for a mean duration of 64 months. This study found no surgical reinterventions in the first 3.5 years posttreatment and a persistent reduction in fibroid symptoms from baseline 64.9 points to 27.6 points, as assessed by a validated symptom severity scale (out of 100 points).²⁷ Similar improvements in health-related quality-of life-were also found to persist for years posttreatment.⁴

In a large systematic review that compared L-RFA, MRgFUS, UAE, and myomectomy, L-RFA had similar improvement rates in quality-of-life and symptom severity scores compared with myomectomy, with no significant difference in reintervention rates.²⁸ This review also noted minimal heterogeneity among RFA meta-analyses data in contrast to significant heterogeneity among UAE and myomectomy data.

Reproductive outcomes

Similar to MRgFUS, the initial studies of RFA devices largely excluded women with future fertility plans, as data on safety were lacking. However, many RFA devices are now on the market across the globe, and subsequent pregnancies have been tracked and reported.

A large case series that included clinical trials and commercial settings reported a miscarriage rate (13.3%) similar to that of the general obstetric population and no cases of uterine rupture, invasive placentation, preterm delivery, or placental abruption.²⁹ Other case series have reported live birth rates similar those with myomectomy, and safe and favorable pregnancy outcomes with RFA have been supported by larger systematic reviews of all ablation techniques.¹²

Continue to: Uterine impact...

Uterine impact

One study of TC-RFA patients showed a greater than 65% reduction in fibroid volume (with a 90% reduction in fibroid volume for fibroids larger than 6 cm prior to RFA), and 54% of patients reported complete resolution of symptoms, with another 36% reporting decreased symptoms.³⁰ Similar decreases in fibroid volume, ranging from 65% to 84%, have been reported in numerous follow-up studies, with significant decreases in bleeding and pain in 78% to 88% of patients.^23,31-33 Additionally, a large secondary analysis of a TC-RFA clinical trial showed that patients did not have any significant decrease in uterine wall thickness or integrity on follow-up with magnetic resonance imaging compared with baseline measurements, and they did not have any new myometrial scars (assessed as nonperfused linear areas).²²

As with other ablation techniques, most data on RFA pregnancy outcomes come from case series, and further research and evaluation are needed. Existing studies, however, have demonstrated promising aspects of RFA that argue its usefulness in women with fertility plans.

A prospective trial that evaluated intrauterine adhesion formation with use of a TC-RFA device found no new adhesions on 6-week follow-up hysteroscopy compared with baseline pre-RFA hysteroscopy.³⁴ Because intrauterine adhesion formation and uterine rupture are both significant concerns with other uterine-sparing fibroid treatment approaches such as myomectomy, these findings suggest that RFA may be a better alternative for women who are planning future pregnancies, as they may have increased fertility success and decreased catastrophic complications.

The consensus is growing that RFA is a safe and effective option for women who desire minimally invasive fibroid treatment and want to preserve fertility.

Unique benefits of RFA

In this article, we highlight RFA as an emerging treatment option for fibroid management, particularly for women who desire a uterine-sparing approach to preserve their reproductive options. Although myomectomy has been the standard of care for many years, with UAE as the alternative nonsurgical treatment, neither approach provides the best balance between symptomatic improvement and reproductive outcomes, and neither is without pregnancy risks. In addition, many women with symptomatic fibroids do not desire future conception but decline fibroid removal for religious or personal reasons. RFA offers these women an alternative minimally invasive option for uterine-sparing fibroid treatment.

RFA presents a unique “incision-free” fibroid treatment that is truly minimally invasive. This technique minimizes the risks associated with myomectomy, such as intra-abdominal adhesions, intrauterine adhesions (Asherman syndrome), need for cesarean delivery, and pregnancy complications such as uterine rupture or invasive placentation. Furthermore, the evolution of an RFA transcervical approach has enabled treatment with no abdominal or uterine incisions, thus offering all the above reproductive benefits as well as the operative benefits of a faster recovery, less pain, and less risk of intraperitoneal surgical complications.

While many women desire uterine-sparing fibroid treatment even without future fertility plans, the larger question is whether we should treat fibroids more strategically for women who desire future fertility. Myomectomy and UAE are effective and reliable in terms of fibroid symptomatic improvement, but RFA promises more beneficial reproductive outcomes. The ability to avoid uterine myometrial incisions and still attain significant symptomatic improvement should be prioritized in these patients.

Currently, RFA is not approved by the FDA as a fertility-enabling treatment, and these patients have been largely excluded from RFA studies. However, the reproductive-age patient who desires future conception may benefit most from RFA. Furthermore, RFA technology also could address the gap in uterine-sparing treatment for reproductive-age women with adenomyosis. Although a complete review of adenomyosis treatment is beyond the scope of this article, recent studies show that RFA produces similar improvement in both uterine volume and symptom severity in women with adenomyosis.^35-37 ●

A new contraceptive method should ideally provide improved access or a higher quality and safety option. Although unintended pregnancy rates in the United States are decreasing, significant disparities across race and socioeconomic status remain,¹ and these disparities actually doubled from 1994 to 2011 even though the overall unintended pregnancy rate decreased.^1-3 Specifically, people of color, those with lower income, and people with lower education levels had higher rates of unintended pregnancies than did White people with higher education and income, suggesting disparate access to contraception services.¹ Thus, as new contraceptive methods are introduced, we must assess if they have the potential to address this disparity as well as continue to provide higher quality and safer options.

In this Update, we critically review the phase 3 data on efficacy and safety for 3 new methods that were introduced to the US market over the past year to evaluate their impact on the current contraceptive landscape.

The first method, newly approved by the US Food and Drug Administration (FDA), is a combined oral contraceptive (OC) that contains a novel endogenous estrogen, estetrol, or E4 (Nextstellis). E4 is a natural estrogen produced in the fetal liver that has lower potency and a longer half-life than estradiol. Nextstellis is a monophasic 24/4 OC pill that contains E4 14.2 mg and drospirenone 3 mg in each of the 24 hormone-containing pills. Most combined hormonal contraceptives (CHCs) in the United States today contain synthetically made ethinyl estradiol (EE) due to its high potency and oral bioavailability. Outside of the reproductive system, EE upregulates the production of hepatic proteins and alters procoagulant and anticoagulant factors, which results in an overall increase in venous thromboembolic (VTE) risk among CHC users.²

After widespread use of combined oral contraceptives (COCs) started in the 1960s, data emerged regarding increased VTE risk.³ Subsequent research discovered that the type of estrogen used in CHCs directly correlates with the thrombosis risk due to the hepatic upregulation with both first- and second-pass metabolism. Although this risk was reduced as the EE dose decreased below 50 µg and concurrent VTE risk factors were contraindicated, CHC users still faced a 2-fold increase in VTE risk compared with nonusers.^4,5 EE in contraceptive formulations increases VTE risk, likely related to upregulation of procoagulant factors and decreasing anticoagulant proteins.² By contrast, a phase 2 trial of Nextstellis demonstrated more neutral effects of E4/drospirenone on hemostatic parameters compared with EE/levonorgestrel or EE/drospirenone.⁶ Furthermore, E4/drospirenone exhibited lower increases in hepatic proteins, such as angiotensinogen, triglycerides, and sex-hormone binding globulin.⁷ These findings together suggest that this novel CHC pill has a more favorable cardiovascular adverse effect profile compared with currently available CHCs.

The second contraceptive method is a new transdermal patch that contains EE and levonorgestrel (Twirla); this is in contrast to the available EE/norelgestromin contraceptive patch (Xulane). Transdermal contraceptive patches can offer some users easier adherence as compared with a daily OC.⁸ Until this past year, the only transdermal contraceptive available in the United States was Xulane, which contains a daily dose of EE 35 µg and norelgestromin 150 µg. Norelgestromin is eventually metabolized to levonorgestrel derivatives.⁹ Twirla is administered in the same manner as Xulane and contains a daily hormone exposure equivalent to a COC containing EE 30 µg and levonorgestrel 120 µg. Similar to EE/norelgestromin, the EE/levonorgestrel patch also is contraindicated in obese patients (body mass index [BMI] ≥30 kg/m²) due to decreased efficacy and increased risk for VTE. Additionally, phase 3 data demonstrated decreasing efficacy of Twirla in overweight users (BMI ≥25–30 kg/m²), perhaps further limiting the population that may benefit from this contraceptive method.¹⁰ These issues with efficacy and weight likely are related to the fact that levonorgestrel distribution is weight dependent, with evidence of lower plasma levels in obese individuals.^11-13

The third new method is a prescription vaginal contraceptive gel with lactic acid, citric acid, and potassium bitartrate (Phexxi) designed to prevent pregnancy by maintaining an acidic vaginal environment that is inhospitable to sperm. For many decades, vaginal contraceptives, including vaginal spermicidal gels, provided easy access to a nonhormonal and flexible method of moderately effective contraception for many users. Phexxi is a prescription vaginal pH regulator administered as a gel and active for 1 hour after application. All previous vaginal gels sold in the United States are applied similarly, are available over the counter, and include nonoxynol-9, which is a surfactant that damages sperm cell membranes. Recent data from a phase 3 trial demonstrated similar contraceptive effectiveness of Phexxi when compared with available nonoxynol-9 alternatives.¹⁴

Continue to: New OC with the novel estrogen E4 demonstrates good safety profile for VTE...

New OC with the novel estrogen E4 demonstrates good safety profile for VTE

Creinin MD, Westhoff CL, Bouchard C, et al. Estetrol-drospirenone combination oral contraceptive: North American phase 3 efficacy and safety results. Contraception. 2021;104:222-228.

The COC E4/drospirenone was evaluated in 2 parallel multinational studies. Here, we review the North American data that are more relevant for the US population; the European-Russian data also are published.¹⁵

Study examined 1 year’s use of E4/drospirenone

The US–Canadian trial conducted by Creinin and colleagues enrolled 1,864 participants aged 16 to 50 years to evaluate contraceptive efficacy, bleeding patterns, and adverse events with 1-year use (13 cycles) of E4/drospirenone. The primary efficacy group included 1,524 women aged 16 to 35. This study enrolled healthy, heterosexually active participants with a BMI ≤35 kg/m² and regular menses from 70 sites in the United States and 7 sites in Canada. The dropout rate was 45%, comparable to that in other contraceptive studies. Participants used E4/drospirenone cyclically, taking 1 hormone-containing pill daily for 24 days followed by 4 days of placebo pills.

Contraceptive efficacious, no VTE observed

The researchers reported efficacy as a Pearl Index (PI) of 2.65 pregnancies per 100 woman-years in participants aged 16 to 35 and an overall 13-cycle life-table pregnancy rate of 2.06%. The PI did not differ among nonobese and obese participants in multivariable analysis. Most users experienced scheduled withdrawal bleeding; only 13% to 18% reported absence of scheduled bleeding. Unscheduled bleeding was typically spotting (55.2%), and this decreased with treatment duration from 30% in cycle 1 to 15% to 20% in cycle 5 and on.

Overall, 28.9% of participants reported treatment-related adverse events (AEs), which most commonly were headache (5.0%), metrorrhagia (4.6%), and nausea (3.8%). Investigators reported a minimal change in mean (SD) BMI of 0.4 (1.7) kg/m² from baseline after 1 year of E4/drospirenone use, and only 0.5% of participants discontinued use due to weight gain. The most common reasons for AE-related treatment discontinuation included metrorrhagia (0.9%), menorrhagia (0.8%), and vaginal hemorrhage (0.5%). Importantly, no cases of VTE occurred in this study of estetrol despite 23% of participants being obese, a known risk factor for VTE.

Continue to: Efficacy of a new EE/levonorgestrel transdermal patch may be lower in overweight, obese women...

Efficacy of a new EE/levonorgestrel transdermal patch may be lower in overweight, obese women

Nelson AL, Kaunitz AM, Kroll R; SECURE Investigators. Efficacy, safety, and tolerability of a levonorgestrel/ethinyl estradiol transdermal delivery system: phase 3 clinical trial results. Contraception. 2021;103:137-143.

To assess the contraceptive efficacy, tolerability, and safety of the transdermal patch Twirla (EE/levonorgestrel) over 1 year of treatment (13 cycles), Nelson and colleagues conducted an open-label, multicenter, US-based phase 3 trial of participants aged 18 years and older with regular cycles. There were no restrictions based on BMI. On average, the study population was overweight, with a mean BMI of 28.3 kg/m² , and 35% of the population was considered obese (BMI ≥30 kg/m²).

Study design

A total of 2,032 participants enrolled in the study, with separate populations defined for specific analysis on safety, contraceptive efficacy, and cycle control. The primary efficacy group included 1,736 participants. Fifty-one percent discontinued the study, most commonly due to “women’s decision” (15%) and lost to follow-up (11%). Users received bleeding diaries and returned periodically throughout the study for evaluation for efficacy, adherence, and adverse events.

Efficacy associated with BMI

The study results demonstrated an overall PI of 5.8 pregnancies per 100 woman-years for users aged younger than 35. TABLE 2 demonstrates the overall trend of efficacy in relation to BMI.^10,15-19 Participants with a higher BMI were found to have a higher PI, revealing lower contraceptive efficacy in more overweight and obese patients. The overall cumulative pregnancy rate over 13 cycles was 5.3%

Participants reported decreasing frequency of bleeding/spotting days over the treatment duration of 13 cycles, from a mean (SD) of 6.2 (4.5) days in cycle 1 to 4.9 (3.5) days in cycle 13. Unscheduled bleeding episodes remained high throughout the study period. Initially, 60% of users reported 1 or more days of unscheduled bleeding in cycle 1, and 42% still reported unscheduled bleeding in cycle 13. In light of this, only 45 participants (2.2%) discontinued the study due to bleeding issues, suggesting perhaps that the bleeding was light. Overall, users experienced acceptable wearability of the patch, and the rate of detachment decreased over the study period from 9.9% in cycle 1 to 2.4% in cycle 13. There were also low rates (0.5%) of moderate to severe irritation. Itching at the adhesion site decreased slightly from 13.1% in cycle 2 to 9.6% in cycle 13.

In general, 27.2% of patch users experienced a study-related AE, most reported as mild to moderate. Nausea (4.1%) and headaches (3.6%) were the most common hormone-related AE. Importantly, 4 obese users experienced 5 VTEs (deep vein thrombosis, n = 2; pulmonary embolism, n = 3) between cycle 5 and 13. Three of these users had additional VTE risk factors, such as air travel and a family history of clots. No users who were of normal weight or overweight experienced VTE.

Continue to: Novel vaginal pH buffering spermicide is a new Rx-only option...

Novel vaginal pH buffering spermicide is a new Rx-only option

Thomas MA, Chappell BT, Maximos B, et al. A novel vaginal pH regulator: results from the phase 3 AMPOWER contraception clinical trial. Contracept X. 2020;2:100031.

In an open-label phase 3 study, Thomas and colleagues enrolled 1,384 participants aged 18 to 35 with regular cycles at 112 sites in the United States to assess the contraceptive efficacy, safety, and acceptability of Phexxi vaginal gel (lactic acid, citric acid, and potassium bitartrate) over 7 cycles (6 months). Participants were required to have at least 3 episodes of heterosexual vaginal intercourse per cycle and return throughout the treatment duration for study visits. Fifty-three percent of participants did not complete the study, most frequently due to loss to follow-up (18.1%) and participant withdrawal (12.3%). Most participants were White (69%) and had an average (SD) age of 27.7 (4.5) years.

Efficacy and AE rates

The investigators reported a cumulative pregnancy rate of 13.7% over 7 cycles (6 months). In this study, 45.2% of women experienced 1 AE, and most were noted to be mild (23.9%) to moderate (18.7%). The most reported AE was vulvovaginal burning (20.0%), followed by vulvovaginal pruritus (11.2%), urinary tract infection (5.7%), and vulvovaginal pain (3.8%). Less than 2% of participants discontinued the study due to an AE. Burning and itching decreased with time and with decreased frequency of use. When used twice per day compared with once per day, burning rates decreased from 4.6% to 2.1%, and itching rates decreased from 1.0% to 0.7%. Serious AEs were uncommon, occurring in 1.3% of users; only 1, cystitis, was noted to be “probably” related to the treatment. ●

A new contraceptive method should ideally provide improved access or a higher quality and safety option. Although unintended pregnancy rates in the United States are decreasing, significant disparities across race and socioeconomic status remain,¹ and these disparities actually doubled from 1994 to 2011 even though the overall unintended pregnancy rate decreased.^1-3 Specifically, people of color, those with lower income, and people with lower education levels had higher rates of unintended pregnancies than did White people with higher education and income, suggesting disparate access to contraception services.¹ Thus, as new contraceptive methods are introduced, we must assess if they have the potential to address this disparity as well as continue to provide higher quality and safer options.

In this Update, we critically review the phase 3 data on efficacy and safety for 3 new methods that were introduced to the US market over the past year to evaluate their impact on the current contraceptive landscape.

The first method, newly approved by the US Food and Drug Administration (FDA), is a combined oral contraceptive (OC) that contains a novel endogenous estrogen, estetrol, or E4 (Nextstellis). E4 is a natural estrogen produced in the fetal liver that has lower potency and a longer half-life than estradiol. Nextstellis is a monophasic 24/4 OC pill that contains E4 14.2 mg and drospirenone 3 mg in each of the 24 hormone-containing pills. Most combined hormonal contraceptives (CHCs) in the United States today contain synthetically made ethinyl estradiol (EE) due to its high potency and oral bioavailability. Outside of the reproductive system, EE upregulates the production of hepatic proteins and alters procoagulant and anticoagulant factors, which results in an overall increase in venous thromboembolic (VTE) risk among CHC users.²

After widespread use of combined oral contraceptives (COCs) started in the 1960s, data emerged regarding increased VTE risk.³ Subsequent research discovered that the type of estrogen used in CHCs directly correlates with the thrombosis risk due to the hepatic upregulation with both first- and second-pass metabolism. Although this risk was reduced as the EE dose decreased below 50 µg and concurrent VTE risk factors were contraindicated, CHC users still faced a 2-fold increase in VTE risk compared with nonusers.^4,5 EE in contraceptive formulations increases VTE risk, likely related to upregulation of procoagulant factors and decreasing anticoagulant proteins.² By contrast, a phase 2 trial of Nextstellis demonstrated more neutral effects of E4/drospirenone on hemostatic parameters compared with EE/levonorgestrel or EE/drospirenone.⁶ Furthermore, E4/drospirenone exhibited lower increases in hepatic proteins, such as angiotensinogen, triglycerides, and sex-hormone binding globulin.⁷ These findings together suggest that this novel CHC pill has a more favorable cardiovascular adverse effect profile compared with currently available CHCs.

The second contraceptive method is a new transdermal patch that contains EE and levonorgestrel (Twirla); this is in contrast to the available EE/norelgestromin contraceptive patch (Xulane). Transdermal contraceptive patches can offer some users easier adherence as compared with a daily OC.⁸ Until this past year, the only transdermal contraceptive available in the United States was Xulane, which contains a daily dose of EE 35 µg and norelgestromin 150 µg. Norelgestromin is eventually metabolized to levonorgestrel derivatives.⁹ Twirla is administered in the same manner as Xulane and contains a daily hormone exposure equivalent to a COC containing EE 30 µg and levonorgestrel 120 µg. Similar to EE/norelgestromin, the EE/levonorgestrel patch also is contraindicated in obese patients (body mass index [BMI] ≥30 kg/m²) due to decreased efficacy and increased risk for VTE. Additionally, phase 3 data demonstrated decreasing efficacy of Twirla in overweight users (BMI ≥25–30 kg/m²), perhaps further limiting the population that may benefit from this contraceptive method.¹⁰ These issues with efficacy and weight likely are related to the fact that levonorgestrel distribution is weight dependent, with evidence of lower plasma levels in obese individuals.^11-13

The third new method is a prescription vaginal contraceptive gel with lactic acid, citric acid, and potassium bitartrate (Phexxi) designed to prevent pregnancy by maintaining an acidic vaginal environment that is inhospitable to sperm. For many decades, vaginal contraceptives, including vaginal spermicidal gels, provided easy access to a nonhormonal and flexible method of moderately effective contraception for many users. Phexxi is a prescription vaginal pH regulator administered as a gel and active for 1 hour after application. All previous vaginal gels sold in the United States are applied similarly, are available over the counter, and include nonoxynol-9, which is a surfactant that damages sperm cell membranes. Recent data from a phase 3 trial demonstrated similar contraceptive effectiveness of Phexxi when compared with available nonoxynol-9 alternatives.¹⁴

Continue to: New OC with the novel estrogen E4 demonstrates good safety profile for VTE...

New OC with the novel estrogen E4 demonstrates good safety profile for VTE

Creinin MD, Westhoff CL, Bouchard C, et al. Estetrol-drospirenone combination oral contraceptive: North American phase 3 efficacy and safety results. Contraception. 2021;104:222-228.

The COC E4/drospirenone was evaluated in 2 parallel multinational studies. Here, we review the North American data that are more relevant for the US population; the European-Russian data also are published.¹⁵

Study examined 1 year’s use of E4/drospirenone

The US–Canadian trial conducted by Creinin and colleagues enrolled 1,864 participants aged 16 to 50 years to evaluate contraceptive efficacy, bleeding patterns, and adverse events with 1-year use (13 cycles) of E4/drospirenone. The primary efficacy group included 1,524 women aged 16 to 35. This study enrolled healthy, heterosexually active participants with a BMI ≤35 kg/m² and regular menses from 70 sites in the United States and 7 sites in Canada. The dropout rate was 45%, comparable to that in other contraceptive studies. Participants used E4/drospirenone cyclically, taking 1 hormone-containing pill daily for 24 days followed by 4 days of placebo pills.

Contraceptive efficacious, no VTE observed

The researchers reported efficacy as a Pearl Index (PI) of 2.65 pregnancies per 100 woman-years in participants aged 16 to 35 and an overall 13-cycle life-table pregnancy rate of 2.06%. The PI did not differ among nonobese and obese participants in multivariable analysis. Most users experienced scheduled withdrawal bleeding; only 13% to 18% reported absence of scheduled bleeding. Unscheduled bleeding was typically spotting (55.2%), and this decreased with treatment duration from 30% in cycle 1 to 15% to 20% in cycle 5 and on.

Overall, 28.9% of participants reported treatment-related adverse events (AEs), which most commonly were headache (5.0%), metrorrhagia (4.6%), and nausea (3.8%). Investigators reported a minimal change in mean (SD) BMI of 0.4 (1.7) kg/m² from baseline after 1 year of E4/drospirenone use, and only 0.5% of participants discontinued use due to weight gain. The most common reasons for AE-related treatment discontinuation included metrorrhagia (0.9%), menorrhagia (0.8%), and vaginal hemorrhage (0.5%). Importantly, no cases of VTE occurred in this study of estetrol despite 23% of participants being obese, a known risk factor for VTE.

Continue to: Efficacy of a new EE/levonorgestrel transdermal patch may be lower in overweight, obese women...

Efficacy of a new EE/levonorgestrel transdermal patch may be lower in overweight, obese women

Nelson AL, Kaunitz AM, Kroll R; SECURE Investigators. Efficacy, safety, and tolerability of a levonorgestrel/ethinyl estradiol transdermal delivery system: phase 3 clinical trial results. Contraception. 2021;103:137-143.

To assess the contraceptive efficacy, tolerability, and safety of the transdermal patch Twirla (EE/levonorgestrel) over 1 year of treatment (13 cycles), Nelson and colleagues conducted an open-label, multicenter, US-based phase 3 trial of participants aged 18 years and older with regular cycles. There were no restrictions based on BMI. On average, the study population was overweight, with a mean BMI of 28.3 kg/m² , and 35% of the population was considered obese (BMI ≥30 kg/m²).

Study design

A total of 2,032 participants enrolled in the study, with separate populations defined for specific analysis on safety, contraceptive efficacy, and cycle control. The primary efficacy group included 1,736 participants. Fifty-one percent discontinued the study, most commonly due to “women’s decision” (15%) and lost to follow-up (11%). Users received bleeding diaries and returned periodically throughout the study for evaluation for efficacy, adherence, and adverse events.

Efficacy associated with BMI

The study results demonstrated an overall PI of 5.8 pregnancies per 100 woman-years for users aged younger than 35. TABLE 2 demonstrates the overall trend of efficacy in relation to BMI.^10,15-19 Participants with a higher BMI were found to have a higher PI, revealing lower contraceptive efficacy in more overweight and obese patients. The overall cumulative pregnancy rate over 13 cycles was 5.3%

Participants reported decreasing frequency of bleeding/spotting days over the treatment duration of 13 cycles, from a mean (SD) of 6.2 (4.5) days in cycle 1 to 4.9 (3.5) days in cycle 13. Unscheduled bleeding episodes remained high throughout the study period. Initially, 60% of users reported 1 or more days of unscheduled bleeding in cycle 1, and 42% still reported unscheduled bleeding in cycle 13. In light of this, only 45 participants (2.2%) discontinued the study due to bleeding issues, suggesting perhaps that the bleeding was light. Overall, users experienced acceptable wearability of the patch, and the rate of detachment decreased over the study period from 9.9% in cycle 1 to 2.4% in cycle 13. There were also low rates (0.5%) of moderate to severe irritation. Itching at the adhesion site decreased slightly from 13.1% in cycle 2 to 9.6% in cycle 13.

In general, 27.2% of patch users experienced a study-related AE, most reported as mild to moderate. Nausea (4.1%) and headaches (3.6%) were the most common hormone-related AE. Importantly, 4 obese users experienced 5 VTEs (deep vein thrombosis, n = 2; pulmonary embolism, n = 3) between cycle 5 and 13. Three of these users had additional VTE risk factors, such as air travel and a family history of clots. No users who were of normal weight or overweight experienced VTE.

Continue to: Novel vaginal pH buffering spermicide is a new Rx-only option...

Novel vaginal pH buffering spermicide is a new Rx-only option

Thomas MA, Chappell BT, Maximos B, et al. A novel vaginal pH regulator: results from the phase 3 AMPOWER contraception clinical trial. Contracept X. 2020;2:100031.

In an open-label phase 3 study, Thomas and colleagues enrolled 1,384 participants aged 18 to 35 with regular cycles at 112 sites in the United States to assess the contraceptive efficacy, safety, and acceptability of Phexxi vaginal gel (lactic acid, citric acid, and potassium bitartrate) over 7 cycles (6 months). Participants were required to have at least 3 episodes of heterosexual vaginal intercourse per cycle and return throughout the treatment duration for study visits. Fifty-three percent of participants did not complete the study, most frequently due to loss to follow-up (18.1%) and participant withdrawal (12.3%). Most participants were White (69%) and had an average (SD) age of 27.7 (4.5) years.

Efficacy and AE rates

The investigators reported a cumulative pregnancy rate of 13.7% over 7 cycles (6 months). In this study, 45.2% of women experienced 1 AE, and most were noted to be mild (23.9%) to moderate (18.7%). The most reported AE was vulvovaginal burning (20.0%), followed by vulvovaginal pruritus (11.2%), urinary tract infection (5.7%), and vulvovaginal pain (3.8%). Less than 2% of participants discontinued the study due to an AE. Burning and itching decreased with time and with decreased frequency of use. When used twice per day compared with once per day, burning rates decreased from 4.6% to 2.1%, and itching rates decreased from 1.0% to 0.7%. Serious AEs were uncommon, occurring in 1.3% of users; only 1, cystitis, was noted to be “probably” related to the treatment. ●

A new contraceptive method should ideally provide improved access or a higher quality and safety option. Although unintended pregnancy rates in the United States are decreasing, significant disparities across race and socioeconomic status remain,¹ and these disparities actually doubled from 1994 to 2011 even though the overall unintended pregnancy rate decreased.^1-3 Specifically, people of color, those with lower income, and people with lower education levels had higher rates of unintended pregnancies than did White people with higher education and income, suggesting disparate access to contraception services.¹ Thus, as new contraceptive methods are introduced, we must assess if they have the potential to address this disparity as well as continue to provide higher quality and safer options.

In this Update, we critically review the phase 3 data on efficacy and safety for 3 new methods that were introduced to the US market over the past year to evaluate their impact on the current contraceptive landscape.

The first method, newly approved by the US Food and Drug Administration (FDA), is a combined oral contraceptive (OC) that contains a novel endogenous estrogen, estetrol, or E4 (Nextstellis). E4 is a natural estrogen produced in the fetal liver that has lower potency and a longer half-life than estradiol. Nextstellis is a monophasic 24/4 OC pill that contains E4 14.2 mg and drospirenone 3 mg in each of the 24 hormone-containing pills. Most combined hormonal contraceptives (CHCs) in the United States today contain synthetically made ethinyl estradiol (EE) due to its high potency and oral bioavailability. Outside of the reproductive system, EE upregulates the production of hepatic proteins and alters procoagulant and anticoagulant factors, which results in an overall increase in venous thromboembolic (VTE) risk among CHC users.²

After widespread use of combined oral contraceptives (COCs) started in the 1960s, data emerged regarding increased VTE risk.³ Subsequent research discovered that the type of estrogen used in CHCs directly correlates with the thrombosis risk due to the hepatic upregulation with both first- and second-pass metabolism. Although this risk was reduced as the EE dose decreased below 50 µg and concurrent VTE risk factors were contraindicated, CHC users still faced a 2-fold increase in VTE risk compared with nonusers.^4,5 EE in contraceptive formulations increases VTE risk, likely related to upregulation of procoagulant factors and decreasing anticoagulant proteins.² By contrast, a phase 2 trial of Nextstellis demonstrated more neutral effects of E4/drospirenone on hemostatic parameters compared with EE/levonorgestrel or EE/drospirenone.⁶ Furthermore, E4/drospirenone exhibited lower increases in hepatic proteins, such as angiotensinogen, triglycerides, and sex-hormone binding globulin.⁷ These findings together suggest that this novel CHC pill has a more favorable cardiovascular adverse effect profile compared with currently available CHCs.

The second contraceptive method is a new transdermal patch that contains EE and levonorgestrel (Twirla); this is in contrast to the available EE/norelgestromin contraceptive patch (Xulane). Transdermal contraceptive patches can offer some users easier adherence as compared with a daily OC.⁸ Until this past year, the only transdermal contraceptive available in the United States was Xulane, which contains a daily dose of EE 35 µg and norelgestromin 150 µg. Norelgestromin is eventually metabolized to levonorgestrel derivatives.⁹ Twirla is administered in the same manner as Xulane and contains a daily hormone exposure equivalent to a COC containing EE 30 µg and levonorgestrel 120 µg. Similar to EE/norelgestromin, the EE/levonorgestrel patch also is contraindicated in obese patients (body mass index [BMI] ≥30 kg/m²) due to decreased efficacy and increased risk for VTE. Additionally, phase 3 data demonstrated decreasing efficacy of Twirla in overweight users (BMI ≥25–30 kg/m²), perhaps further limiting the population that may benefit from this contraceptive method.¹⁰ These issues with efficacy and weight likely are related to the fact that levonorgestrel distribution is weight dependent, with evidence of lower plasma levels in obese individuals.^11-13

The third new method is a prescription vaginal contraceptive gel with lactic acid, citric acid, and potassium bitartrate (Phexxi) designed to prevent pregnancy by maintaining an acidic vaginal environment that is inhospitable to sperm. For many decades, vaginal contraceptives, including vaginal spermicidal gels, provided easy access to a nonhormonal and flexible method of moderately effective contraception for many users. Phexxi is a prescription vaginal pH regulator administered as a gel and active for 1 hour after application. All previous vaginal gels sold in the United States are applied similarly, are available over the counter, and include nonoxynol-9, which is a surfactant that damages sperm cell membranes. Recent data from a phase 3 trial demonstrated similar contraceptive effectiveness of Phexxi when compared with available nonoxynol-9 alternatives.¹⁴

Continue to: New OC with the novel estrogen E4 demonstrates good safety profile for VTE...

New OC with the novel estrogen E4 demonstrates good safety profile for VTE

Creinin MD, Westhoff CL, Bouchard C, et al. Estetrol-drospirenone combination oral contraceptive: North American phase 3 efficacy and safety results. Contraception. 2021;104:222-228.

The COC E4/drospirenone was evaluated in 2 parallel multinational studies. Here, we review the North American data that are more relevant for the US population; the European-Russian data also are published.¹⁵

Study examined 1 year’s use of E4/drospirenone

The US–Canadian trial conducted by Creinin and colleagues enrolled 1,864 participants aged 16 to 50 years to evaluate contraceptive efficacy, bleeding patterns, and adverse events with 1-year use (13 cycles) of E4/drospirenone. The primary efficacy group included 1,524 women aged 16 to 35. This study enrolled healthy, heterosexually active participants with a BMI ≤35 kg/m² and regular menses from 70 sites in the United States and 7 sites in Canada. The dropout rate was 45%, comparable to that in other contraceptive studies. Participants used E4/drospirenone cyclically, taking 1 hormone-containing pill daily for 24 days followed by 4 days of placebo pills.

Contraceptive efficacious, no VTE observed

The researchers reported efficacy as a Pearl Index (PI) of 2.65 pregnancies per 100 woman-years in participants aged 16 to 35 and an overall 13-cycle life-table pregnancy rate of 2.06%. The PI did not differ among nonobese and obese participants in multivariable analysis. Most users experienced scheduled withdrawal bleeding; only 13% to 18% reported absence of scheduled bleeding. Unscheduled bleeding was typically spotting (55.2%), and this decreased with treatment duration from 30% in cycle 1 to 15% to 20% in cycle 5 and on.

Overall, 28.9% of participants reported treatment-related adverse events (AEs), which most commonly were headache (5.0%), metrorrhagia (4.6%), and nausea (3.8%). Investigators reported a minimal change in mean (SD) BMI of 0.4 (1.7) kg/m² from baseline after 1 year of E4/drospirenone use, and only 0.5% of participants discontinued use due to weight gain. The most common reasons for AE-related treatment discontinuation included metrorrhagia (0.9%), menorrhagia (0.8%), and vaginal hemorrhage (0.5%). Importantly, no cases of VTE occurred in this study of estetrol despite 23% of participants being obese, a known risk factor for VTE.

Continue to: Efficacy of a new EE/levonorgestrel transdermal patch may be lower in overweight, obese women...

Efficacy of a new EE/levonorgestrel transdermal patch may be lower in overweight, obese women

Nelson AL, Kaunitz AM, Kroll R; SECURE Investigators. Efficacy, safety, and tolerability of a levonorgestrel/ethinyl estradiol transdermal delivery system: phase 3 clinical trial results. Contraception. 2021;103:137-143.

To assess the contraceptive efficacy, tolerability, and safety of the transdermal patch Twirla (EE/levonorgestrel) over 1 year of treatment (13 cycles), Nelson and colleagues conducted an open-label, multicenter, US-based phase 3 trial of participants aged 18 years and older with regular cycles. There were no restrictions based on BMI. On average, the study population was overweight, with a mean BMI of 28.3 kg/m² , and 35% of the population was considered obese (BMI ≥30 kg/m²).

Study design

A total of 2,032 participants enrolled in the study, with separate populations defined for specific analysis on safety, contraceptive efficacy, and cycle control. The primary efficacy group included 1,736 participants. Fifty-one percent discontinued the study, most commonly due to “women’s decision” (15%) and lost to follow-up (11%). Users received bleeding diaries and returned periodically throughout the study for evaluation for efficacy, adherence, and adverse events.

Efficacy associated with BMI

The study results demonstrated an overall PI of 5.8 pregnancies per 100 woman-years for users aged younger than 35. TABLE 2 demonstrates the overall trend of efficacy in relation to BMI.^10,15-19 Participants with a higher BMI were found to have a higher PI, revealing lower contraceptive efficacy in more overweight and obese patients. The overall cumulative pregnancy rate over 13 cycles was 5.3%

Participants reported decreasing frequency of bleeding/spotting days over the treatment duration of 13 cycles, from a mean (SD) of 6.2 (4.5) days in cycle 1 to 4.9 (3.5) days in cycle 13. Unscheduled bleeding episodes remained high throughout the study period. Initially, 60% of users reported 1 or more days of unscheduled bleeding in cycle 1, and 42% still reported unscheduled bleeding in cycle 13. In light of this, only 45 participants (2.2%) discontinued the study due to bleeding issues, suggesting perhaps that the bleeding was light. Overall, users experienced acceptable wearability of the patch, and the rate of detachment decreased over the study period from 9.9% in cycle 1 to 2.4% in cycle 13. There were also low rates (0.5%) of moderate to severe irritation. Itching at the adhesion site decreased slightly from 13.1% in cycle 2 to 9.6% in cycle 13.

In general, 27.2% of patch users experienced a study-related AE, most reported as mild to moderate. Nausea (4.1%) and headaches (3.6%) were the most common hormone-related AE. Importantly, 4 obese users experienced 5 VTEs (deep vein thrombosis, n = 2; pulmonary embolism, n = 3) between cycle 5 and 13. Three of these users had additional VTE risk factors, such as air travel and a family history of clots. No users who were of normal weight or overweight experienced VTE.

Continue to: Novel vaginal pH buffering spermicide is a new Rx-only option...

Novel vaginal pH buffering spermicide is a new Rx-only option

Thomas MA, Chappell BT, Maximos B, et al. A novel vaginal pH regulator: results from the phase 3 AMPOWER contraception clinical trial. Contracept X. 2020;2:100031.

In an open-label phase 3 study, Thomas and colleagues enrolled 1,384 participants aged 18 to 35 with regular cycles at 112 sites in the United States to assess the contraceptive efficacy, safety, and acceptability of Phexxi vaginal gel (lactic acid, citric acid, and potassium bitartrate) over 7 cycles (6 months). Participants were required to have at least 3 episodes of heterosexual vaginal intercourse per cycle and return throughout the treatment duration for study visits. Fifty-three percent of participants did not complete the study, most frequently due to loss to follow-up (18.1%) and participant withdrawal (12.3%). Most participants were White (69%) and had an average (SD) age of 27.7 (4.5) years.

Efficacy and AE rates

The investigators reported a cumulative pregnancy rate of 13.7% over 7 cycles (6 months). In this study, 45.2% of women experienced 1 AE, and most were noted to be mild (23.9%) to moderate (18.7%). The most reported AE was vulvovaginal burning (20.0%), followed by vulvovaginal pruritus (11.2%), urinary tract infection (5.7%), and vulvovaginal pain (3.8%). Less than 2% of participants discontinued the study due to an AE. Burning and itching decreased with time and with decreased frequency of use. When used twice per day compared with once per day, burning rates decreased from 4.6% to 2.1%, and itching rates decreased from 1.0% to 0.7%. Serious AEs were uncommon, occurring in 1.3% of users; only 1, cystitis, was noted to be “probably” related to the treatment. ●

CASE 1st prenatal appointment for young, pregnant migrant

A 21-year-old primigravid woman at 12 weeks’ gestation recently immigrated to the United States from an impoverished rural area of Southeast Asia. On the first prenatal appointment, she is noted to have no evidence of immunity to rubella, measles, or varicella. Her hepatitis B surface antigen and hepatitis C antibody tests are negative. She also has negative test results for gonorrhea, chlamydia, syphilis, and HIV infection. Her pap test is negative.

• What vaccinations should this patient receive during her pregnancy?
• What additional vaccinations are indicated postpartum?

Preventive vaccinations: What to know

As ObGyns, we serve as the primary care physician for many women throughout their early and middle decades of life. Accordingly, we have an obligation to be well informed about preventive health services such as vaccinations. The purpose of this article is to review the principal vaccines with which ObGyns should be familiar. I will discuss the vaccines in alphabetical order and then focus on the indications and timing for each vaccine and the relative cost of each immunization. Key points are summarized in the TABLE.

COVID-19 vaccine

In the latter part of 2020 and early part of 2021, three COVID-19 vaccines received emergency use authorization (EUA) from the US Food and Drug Administration (FDA) for individuals 16 years of age and older (Pfizer-BioNTech) and 18 years of age and older (Moderna and Johnson & Johnson).¹ The cost of their administration is borne by the federal government. Two of the vaccines are mRNA agents—Moderna and Pfizer-BioNTech. Both are administered in a 2-dose series, separated by 4 and 3 weeks, respectively. The efficacy of these vaccines in preventing serious or critical illness approaches 95%. The Pfizer-BioNTech vaccine has now been fully FDA approved for administration to individuals older than age 16, with EUA for those down to age 12. Full approval of the Moderna vaccine will not be far behind. Because of some evidence suggesting waning immunity over time and because of growing concerns about the increased transmissibility of the delta variant of the virus, the FDA has been strongly considering a recommendation for a third (booster) dose of each of these vaccines, administered 8 months after the second dose for all eligible Americans. On September 17, 2021, the FDA advisory committee recommended a booster for the Pfizer-BioNTech vaccine for people older than age 65 and for those over the age of 16 at high risk for severe COVID-19. Several days later, full FDA approval was granted for this recommendation. Subsequently, the Director of the Centers for Disease Control and Prevention (CDC) included health care workers and pregnant women in the group for whom the booster is recommended.

The third vaccine formulation is the Johnson & Johnson DNA vaccine, which is prepared with a human adenovirus vector. This vaccine is administered in a single intramuscular dose and has a reported efficacy of 66% to 85%, though it may approach 95% in preventing critical illness. The FDA is expected to announce decisions about booster doses for the Johnson & Johnson and Moderna vaccines in the coming weeks.

Although initial trials of the COVID-19vaccines excluded pregnant and lactating women, the vaccines are safe in pregnancy or postpartum. In fact the vaccines do not contain either a killed or attenuated viral particle that is capable of transmitting infection. Therefore, both the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine now support routine immunization during pregnancy.

A recent report by Shimabukuro and colleagues² demonstrated that the risk of vaccine-related complications in pregnant women receiving the Pfizer-BioNTech or Moderna vaccines was no different than in nonpregnant patients and that there was no evidence of teratogenic effects. The trial included more than 35,000 pregnant women; 2.3% were vaccinated in the periconception period, 28.6% in the first trimester, 43.3% in the second trimester, and 25.7% in the third trimester. Given this, and in light of isolated reports of unusual thromboembolic complications associated with the Johnson & Johnson vaccine, I strongly recommend use of either the Moderna or Pfizer-BioNTech vaccine in our prenatal and postpartum patients.

Continue to: Hepatitis A vaccine...

The hepatitis A vaccine is an inactivated vaccine and is safe for use in pregnancy. It is available in two monovalent preparations—Havrix (GlaxoSmithKline) and Vaqta (Merck & Co.) and is administered in a 2-dose intramuscular injection at time zero and 6 to 12 months later.³ The vaccine is also available in a bivalent form with recombinant hepatitis B vaccine—Twinrix (GlaxoSmithKline). When administered in this form, the vaccine should be given at time zero, 1 month, and 6 months. The wholesale cost of the monovalent vaccine is $66 to $119, depending upon whether the provider uses a multi-dose or a single-dose vial. The cost of Twinrix is $149.

The hepatitis A vaccine is indicated for select pregnant and nonpregnant patients:

• international travelers
• intravenous drug users
• those with occupational exposure (eg, individuals who work in a primate laboratory)
• residents and staff in chronic care facilities
• individuals with chronic liver disease
• individuals with clotting factor disorders
• residents in endemic areas.

Hepatitis B vaccine

The hepatitis B vaccine is a recombinant vaccine that contains an inactivated portion of the hepatitis B surface antigen. It was originally produced in two monovalent formulations: Engerix B (GlaxoSmithKline) and Recombivax-HB (Merck & Co.). These original formulations are given in a 3-dose series at time zero, 1 month, and 6 months. Recently, a new and more potent formulation was introduced into clinical practice. Heplisav-B (Dynavax Technologies Co.) is also a recombinant vaccine that contains a boosting adjuvant. It is programed to be administered in a 2-dose series at time zero and 1 month.^4-6

The wholesale cost of the monovalent vaccines varies from $60 to $173, depending upon use of a multi-dose vial versus a single-use vial. The cost of Heplisav-B varies from $146 to $173, depending upon use of a prefilled syringe versus a single-dose vial.

Although the hepatitis B vaccine should be part of the childhood immunization series, it also should be administered to any pregnant woman who has not been vaccinated previously or who does not already have evidence of immunity as a result of natural infection.

Continue to: Herpes zoster vaccine...

Herpes zoster infection (shingles) can be a particularly disabling condition in older patients and results from reactivation of a latent varicella-zoster infection. Shingles can cause extremely painful skin lesions, threaten the patient’s vision, and result in long-lasting postherpetic neuralgia. Both cellular and hormonal immunity are essential to protect against recurrent infection.

The original herpes zoster vaccine (Zoster Vaccine Live; ZVL, Zostavax) is no longer produced in the United States because it is not as effective as the newer vaccine—Recombinant Zoster Vaccine (Shingrix, GlaxoSmithKline).^7,8 The antigen in the new vaccine is a component of the surface glycoprotein E, and it is combined with an adjuvant to enhance immunoreactivity. The vaccine is given intramuscularly in two doses at time zero and again at 2 to 6 months and is indicated for all individuals >50 years, including those who may have had an episode of shingles. This newer vaccine is 97% effective in patients >50 years and 90% effective in patients >70. The wholesale cost of each injection is about $160.

Human papillomavirus vaccine

The HPV vaccine (Gardasil-9, Merck & Co.) is a recombinant 9-valent vaccine directed against the human papillomavirus. It induces immunity to serotypes 6 and 11 (which cause 90% of genital warts), 16 and 18 (which cause 80% of genital cancers), and 31, 33, 45, 52, and 58 (viral strains that are responsible for both genital and oropharyngeal cancers). The vaccine is administered intramuscularly in a 3-dose series at time zero, 1-2 months, and 6 months. The principal target groups for the vaccine are males and females, ages 9 to 45 years. Ideally, children of both sexes should receive this vaccine prior to the onset of sexual activity. The wholesale cost of each vaccine injection is approximately $222.⁹

Influenza vaccine

The inactivated, intramuscular flu vaccine is recommended for anyone over age 2, including pregnant women. Although pregnant women are not more likely to acquire flu compared with those who are not pregnant, if they do become infected, they are likely to become more seriously ill, with higher mortality. Accordingly, all pregnant women should receive, in any trimester, the inactivated flu vaccine beginning in the late summer and early fall of each year and extending through March of the next year.^10,11

Multiple formulations of the inactivated vaccine are marketed, all targeting two strains of influenza A and two strains of influenza B. The components of the vaccine vary each year as scientists try to match the new vaccine with the most highly prevalent strains in the previous flu season. The vaccine should be administered in a single intramuscular dose. The cost varies from approximately $20 to $70.

The intranasal influenza vaccine is a live virus vaccine that is intended primarily for children and should not be administered in pregnancy. In addition, there is a higher dose of the inactivated quadrivalent vaccine that is available for administration to patients over age 65. This higher dose is more likely to cause adverse effects and is not indicated in pregnancy.

Continue to: Measles, mumps, rubella vaccine (MMR)...

Measles, mumps, rubella vaccine (MMR)

The MMR is a standard component of the childhood vaccination series. The trivalent preparation is a live, attenuated vaccine that is typically given subcutaneously in a 2-dose series. The first dose is administered at age 12-15 months, and the second dose at age 4-6 years. The vaccine is highly immunogenic, with vaccine-induced immunity usually life-long. In some patients, however, immunity wanes over time. Accordingly, all pregnant women should be screened for immunity to rubella since, of the 3, this infection poses the greatest risk to the fetus. Women who do not have evidence of immunity should be advised to avoid contact with children who may have a viral exanthem. They should then receive a booster dose of the vaccine immediately postpartum and should practice secure contraception for 1 month. The vaccine cost is approximately $60.

Pneumococcal vaccine

The inactivated pneumococcal vaccine is produced in two forms, both of which are safe for administration in pregnancy.¹² The original vaccine, introduced in 1983, was PPSV23 (Pneumovax 23, Merck & Co), a 23-serovalent vaccine that was intended primarily for adults. This vaccine is administered in a single subcutaneous or intramuscular dose. The newest vaccine, introduced in 2010, is PCV13 (Prevnar 13, Pfizer Inc), a 13-serovalent vaccine. It was intended primarily for children, in whom it is administered in a 4-dose series beginning at 6 to 8 weeks of age. The cost of the former is approximately $98 to $120; the cost of the latter is $228.

Vaccination against pneumococcal infection is routinely indicated for those older than the age of 65 and for the following at-risk patients, including those who are pregnant¹¹:

• individuals who have had a splenectomy or who have a medical illness that produces functional asplenia (eg, sickle cell anemia)
• individuals with chronic cardiac, pulmonic, hepatic, or renal disease
• individuals with immunosuppressive conditions such as HIV infection or a disseminated malignancy
• individuals who have a cochlear implant
• individuals who have a chronic leak of cerebrospinal fluid.

The recommendations for timing of these 2 vaccines in adults can initially appear confusing. Put most simply, if a high-risk patient first receives the PCV13 vaccine, she should receive the PPSV23 vaccine in about 8 weeks. The PPSV23 vaccine should be repeated in 5 years. If an at-risk patient initially receives the PPSV23 vaccine, the PCV13 vaccine should be given 1 year later.¹²

Tdap vaccine

The Tdap vaccine contains tetanus toxoid, reduced diptheria toxoid, and an acellular component of the pertussis bacterium. Although it has long been part of the childhood vaccinations series, immunity to each component, particularly pertussis, tends to wane over time.

Pertussis poses a serious risk to the health of the pregnant woman and the newborn infant. Accordingly, the Advisory Committee on Immunization Practices (ACIP), CDC, and the ACOG now advise administration of a booster dose of this vaccine in the early third trimester of each pregnancy.^13-15 The vaccine should be administered as a single intramuscular injection. The approximate cost of the vaccine is $64 to $71, depending upon whether the provider uses a single-dose vial or a single-dose prefilled syringe. In nonpregnant patients, the ACIP currently recommends administration of a booster dose of the vaccine every 10 years, primarily to provide durable protection against tetanus.

Continue to: Varicella vaccine...

Varicella vaccine

The varicella vaccine is also one of the main components of the childhood immunization series. This live virus vaccine can be administered subcutaneously as a monovalent agent or as a quadrivalent agent in association with the MMR vaccine.

Pregnant women who do not have a well-documented history of natural infection should be tested for IgG antibody to the varicella-zoster virus at the time of their first prenatal appointment. Interestingly, approximately 70% of patients with an uncertain history actually have immunity when tested. If the patient lacks immunity, she should be vaccinated immediately postpartum.^16,17 The vaccine should be administered in a 2-dose series at time zero and then 4 to 8 weeks later. Patients should adhere to secure contraception from the time of the first dose until 1 month after the second dose. The cost of each dose of the vaccine is approximately $145.

Adverse effects of vaccination

All vaccines have many of the same side effects. The most common is simply a reaction at the site of injection, characterized by pain, increased warmth, erythema, swelling, and tenderness. Other common side effects include systemic manifestations, such as low-grade fever, nausea and vomiting, malaise, fatigue, headache, lymphadenopathy, myalgias, and arthralgias. Some vaccines, notably varicella, herpes zoster, measles, and rubella may cause a disseminated rash. Most of these minor side effects are easily managed by rest, hydration, and administration of an analgesic such as acetaminophen or ibuprofen. More serious side effects include rare complications such as anaphylaxis, Bell palsy, Guillain-Barre syndrome, and venous thromboembolism (Johnson & Johnson COVID-19 vaccine). Any of the vaccines discussed above should not be given, or given only with extreme caution, to an individual who has experienced any of these reactions with a previous vaccine.

Barriers to vaccination

Although the vaccines reviewed above are highly effective in preventing serious illness in recipients, the medical profession’s “report card” in ensuring adherence with vaccine protocols is not optimal. In fact, it probably merits a grade no higher than C+, with vaccination rates in the range of 50% to 70%.

One of the major barriers to vaccination is lack of detailed information about vaccine efficacy and safety on the part of both provider and patient. Another is the problem of misinformation (eg, the persistent belief on the part of some individuals that vaccines may cause a serious problem, such as autism).^18,19 Another important barrier to widespread vaccination is the logistical problem associated with proper scheduling of multidose regimens (such as those for hepatitis A and B, varicella, and COVID-19). A final barrier, and in my own university-based practice, the most important obstacle is the expense of vaccination. Most, but not all, private insurance companies provide coverage for vaccines approved by the Centers for Disease Control and Prevention and the US Preventive Services Task Force. However, public insurance agencies often provide disappointingly inconsistent coverage for essential vaccines.

By keeping well informed about the most recent public health recommendations for vaccinations for adults and by leading important initiatives within our own practices, we should be able to overcome the first 3 barriers listed above. For example, Morgan and colleagues²⁰ recently achieved a 97% success rate with Tdap administration in pregnancy by placing a best-practice alert in the patients’ electronic medical records. Surmounting the final barrier will require intense effort on the part of individual practitioners and professional organizations to advocate for coverage for essential vaccinations for our patients.

CASE Resolved

This patient was raised in an area of the world where her family did not have easy access to medical care. Accordingly, she did not receive the usual childhood vaccines, such as measles, mumps, rubella, varicella, hepatitis B, and almost certainly, tetanus, diphtheria, and pertussis (Tdap), and the HPV vaccine. The MMR vaccine and the varicella vaccine are live virus vaccines and should not be given during pregnancy. However, these vaccines should be administered postpartum, and the patient should be instructed to practice secure contraception for a minimum of 1 month following vaccination. She also should be offered the HPV vaccine postpartum. During pregnancy, she definitely should receive the COVID-19 vaccine, the 3-dose hepatitis B vaccine series, the influenza vaccine, and Tdap. If her present living conditions place her at risk for hepatitis A, she also should be vaccinated against this illness. ●

CASE 1st prenatal appointment for young, pregnant migrant

A 21-year-old primigravid woman at 12 weeks’ gestation recently immigrated to the United States from an impoverished rural area of Southeast Asia. On the first prenatal appointment, she is noted to have no evidence of immunity to rubella, measles, or varicella. Her hepatitis B surface antigen and hepatitis C antibody tests are negative. She also has negative test results for gonorrhea, chlamydia, syphilis, and HIV infection. Her pap test is negative.

• What vaccinations should this patient receive during her pregnancy?
• What additional vaccinations are indicated postpartum?

Preventive vaccinations: What to know

As ObGyns, we serve as the primary care physician for many women throughout their early and middle decades of life. Accordingly, we have an obligation to be well informed about preventive health services such as vaccinations. The purpose of this article is to review the principal vaccines with which ObGyns should be familiar. I will discuss the vaccines in alphabetical order and then focus on the indications and timing for each vaccine and the relative cost of each immunization. Key points are summarized in the TABLE.

COVID-19 vaccine

In the latter part of 2020 and early part of 2021, three COVID-19 vaccines received emergency use authorization (EUA) from the US Food and Drug Administration (FDA) for individuals 16 years of age and older (Pfizer-BioNTech) and 18 years of age and older (Moderna and Johnson & Johnson).¹ The cost of their administration is borne by the federal government. Two of the vaccines are mRNA agents—Moderna and Pfizer-BioNTech. Both are administered in a 2-dose series, separated by 4 and 3 weeks, respectively. The efficacy of these vaccines in preventing serious or critical illness approaches 95%. The Pfizer-BioNTech vaccine has now been fully FDA approved for administration to individuals older than age 16, with EUA for those down to age 12. Full approval of the Moderna vaccine will not be far behind. Because of some evidence suggesting waning immunity over time and because of growing concerns about the increased transmissibility of the delta variant of the virus, the FDA has been strongly considering a recommendation for a third (booster) dose of each of these vaccines, administered 8 months after the second dose for all eligible Americans. On September 17, 2021, the FDA advisory committee recommended a booster for the Pfizer-BioNTech vaccine for people older than age 65 and for those over the age of 16 at high risk for severe COVID-19. Several days later, full FDA approval was granted for this recommendation. Subsequently, the Director of the Centers for Disease Control and Prevention (CDC) included health care workers and pregnant women in the group for whom the booster is recommended.

The third vaccine formulation is the Johnson & Johnson DNA vaccine, which is prepared with a human adenovirus vector. This vaccine is administered in a single intramuscular dose and has a reported efficacy of 66% to 85%, though it may approach 95% in preventing critical illness. The FDA is expected to announce decisions about booster doses for the Johnson & Johnson and Moderna vaccines in the coming weeks.

Although initial trials of the COVID-19vaccines excluded pregnant and lactating women, the vaccines are safe in pregnancy or postpartum. In fact the vaccines do not contain either a killed or attenuated viral particle that is capable of transmitting infection. Therefore, both the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine now support routine immunization during pregnancy.

A recent report by Shimabukuro and colleagues² demonstrated that the risk of vaccine-related complications in pregnant women receiving the Pfizer-BioNTech or Moderna vaccines was no different than in nonpregnant patients and that there was no evidence of teratogenic effects. The trial included more than 35,000 pregnant women; 2.3% were vaccinated in the periconception period, 28.6% in the first trimester, 43.3% in the second trimester, and 25.7% in the third trimester. Given this, and in light of isolated reports of unusual thromboembolic complications associated with the Johnson & Johnson vaccine, I strongly recommend use of either the Moderna or Pfizer-BioNTech vaccine in our prenatal and postpartum patients.

Continue to: Hepatitis A vaccine...

The hepatitis A vaccine is an inactivated vaccine and is safe for use in pregnancy. It is available in two monovalent preparations—Havrix (GlaxoSmithKline) and Vaqta (Merck & Co.) and is administered in a 2-dose intramuscular injection at time zero and 6 to 12 months later.³ The vaccine is also available in a bivalent form with recombinant hepatitis B vaccine—Twinrix (GlaxoSmithKline). When administered in this form, the vaccine should be given at time zero, 1 month, and 6 months. The wholesale cost of the monovalent vaccine is $66 to $119, depending upon whether the provider uses a multi-dose or a single-dose vial. The cost of Twinrix is $149.

The hepatitis A vaccine is indicated for select pregnant and nonpregnant patients:

• international travelers
• intravenous drug users
• those with occupational exposure (eg, individuals who work in a primate laboratory)
• residents and staff in chronic care facilities
• individuals with chronic liver disease
• individuals with clotting factor disorders
• residents in endemic areas.

Hepatitis B vaccine

The hepatitis B vaccine is a recombinant vaccine that contains an inactivated portion of the hepatitis B surface antigen. It was originally produced in two monovalent formulations: Engerix B (GlaxoSmithKline) and Recombivax-HB (Merck & Co.). These original formulations are given in a 3-dose series at time zero, 1 month, and 6 months. Recently, a new and more potent formulation was introduced into clinical practice. Heplisav-B (Dynavax Technologies Co.) is also a recombinant vaccine that contains a boosting adjuvant. It is programed to be administered in a 2-dose series at time zero and 1 month.^4-6

The wholesale cost of the monovalent vaccines varies from $60 to $173, depending upon use of a multi-dose vial versus a single-use vial. The cost of Heplisav-B varies from $146 to $173, depending upon use of a prefilled syringe versus a single-dose vial.

Although the hepatitis B vaccine should be part of the childhood immunization series, it also should be administered to any pregnant woman who has not been vaccinated previously or who does not already have evidence of immunity as a result of natural infection.

Continue to: Herpes zoster vaccine...

Herpes zoster infection (shingles) can be a particularly disabling condition in older patients and results from reactivation of a latent varicella-zoster infection. Shingles can cause extremely painful skin lesions, threaten the patient’s vision, and result in long-lasting postherpetic neuralgia. Both cellular and hormonal immunity are essential to protect against recurrent infection.

The original herpes zoster vaccine (Zoster Vaccine Live; ZVL, Zostavax) is no longer produced in the United States because it is not as effective as the newer vaccine—Recombinant Zoster Vaccine (Shingrix, GlaxoSmithKline).^7,8 The antigen in the new vaccine is a component of the surface glycoprotein E, and it is combined with an adjuvant to enhance immunoreactivity. The vaccine is given intramuscularly in two doses at time zero and again at 2 to 6 months and is indicated for all individuals >50 years, including those who may have had an episode of shingles. This newer vaccine is 97% effective in patients >50 years and 90% effective in patients >70. The wholesale cost of each injection is about $160.

Human papillomavirus vaccine

The HPV vaccine (Gardasil-9, Merck & Co.) is a recombinant 9-valent vaccine directed against the human papillomavirus. It induces immunity to serotypes 6 and 11 (which cause 90% of genital warts), 16 and 18 (which cause 80% of genital cancers), and 31, 33, 45, 52, and 58 (viral strains that are responsible for both genital and oropharyngeal cancers). The vaccine is administered intramuscularly in a 3-dose series at time zero, 1-2 months, and 6 months. The principal target groups for the vaccine are males and females, ages 9 to 45 years. Ideally, children of both sexes should receive this vaccine prior to the onset of sexual activity. The wholesale cost of each vaccine injection is approximately $222.⁹

Influenza vaccine

The inactivated, intramuscular flu vaccine is recommended for anyone over age 2, including pregnant women. Although pregnant women are not more likely to acquire flu compared with those who are not pregnant, if they do become infected, they are likely to become more seriously ill, with higher mortality. Accordingly, all pregnant women should receive, in any trimester, the inactivated flu vaccine beginning in the late summer and early fall of each year and extending through March of the next year.^10,11

Multiple formulations of the inactivated vaccine are marketed, all targeting two strains of influenza A and two strains of influenza B. The components of the vaccine vary each year as scientists try to match the new vaccine with the most highly prevalent strains in the previous flu season. The vaccine should be administered in a single intramuscular dose. The cost varies from approximately $20 to $70.

The intranasal influenza vaccine is a live virus vaccine that is intended primarily for children and should not be administered in pregnancy. In addition, there is a higher dose of the inactivated quadrivalent vaccine that is available for administration to patients over age 65. This higher dose is more likely to cause adverse effects and is not indicated in pregnancy.

Continue to: Measles, mumps, rubella vaccine (MMR)...

Measles, mumps, rubella vaccine (MMR)

The MMR is a standard component of the childhood vaccination series. The trivalent preparation is a live, attenuated vaccine that is typically given subcutaneously in a 2-dose series. The first dose is administered at age 12-15 months, and the second dose at age 4-6 years. The vaccine is highly immunogenic, with vaccine-induced immunity usually life-long. In some patients, however, immunity wanes over time. Accordingly, all pregnant women should be screened for immunity to rubella since, of the 3, this infection poses the greatest risk to the fetus. Women who do not have evidence of immunity should be advised to avoid contact with children who may have a viral exanthem. They should then receive a booster dose of the vaccine immediately postpartum and should practice secure contraception for 1 month. The vaccine cost is approximately $60.

Pneumococcal vaccine

The inactivated pneumococcal vaccine is produced in two forms, both of which are safe for administration in pregnancy.¹² The original vaccine, introduced in 1983, was PPSV23 (Pneumovax 23, Merck & Co), a 23-serovalent vaccine that was intended primarily for adults. This vaccine is administered in a single subcutaneous or intramuscular dose. The newest vaccine, introduced in 2010, is PCV13 (Prevnar 13, Pfizer Inc), a 13-serovalent vaccine. It was intended primarily for children, in whom it is administered in a 4-dose series beginning at 6 to 8 weeks of age. The cost of the former is approximately $98 to $120; the cost of the latter is $228.

Vaccination against pneumococcal infection is routinely indicated for those older than the age of 65 and for the following at-risk patients, including those who are pregnant¹¹:

• individuals who have had a splenectomy or who have a medical illness that produces functional asplenia (eg, sickle cell anemia)
• individuals with chronic cardiac, pulmonic, hepatic, or renal disease
• individuals with immunosuppressive conditions such as HIV infection or a disseminated malignancy
• individuals who have a cochlear implant
• individuals who have a chronic leak of cerebrospinal fluid.

The recommendations for timing of these 2 vaccines in adults can initially appear confusing. Put most simply, if a high-risk patient first receives the PCV13 vaccine, she should receive the PPSV23 vaccine in about 8 weeks. The PPSV23 vaccine should be repeated in 5 years. If an at-risk patient initially receives the PPSV23 vaccine, the PCV13 vaccine should be given 1 year later.¹²

Tdap vaccine

The Tdap vaccine contains tetanus toxoid, reduced diptheria toxoid, and an acellular component of the pertussis bacterium. Although it has long been part of the childhood vaccinations series, immunity to each component, particularly pertussis, tends to wane over time.

Pertussis poses a serious risk to the health of the pregnant woman and the newborn infant. Accordingly, the Advisory Committee on Immunization Practices (ACIP), CDC, and the ACOG now advise administration of a booster dose of this vaccine in the early third trimester of each pregnancy.^13-15 The vaccine should be administered as a single intramuscular injection. The approximate cost of the vaccine is $64 to $71, depending upon whether the provider uses a single-dose vial or a single-dose prefilled syringe. In nonpregnant patients, the ACIP currently recommends administration of a booster dose of the vaccine every 10 years, primarily to provide durable protection against tetanus.

Continue to: Varicella vaccine...

Varicella vaccine

The varicella vaccine is also one of the main components of the childhood immunization series. This live virus vaccine can be administered subcutaneously as a monovalent agent or as a quadrivalent agent in association with the MMR vaccine.

Pregnant women who do not have a well-documented history of natural infection should be tested for IgG antibody to the varicella-zoster virus at the time of their first prenatal appointment. Interestingly, approximately 70% of patients with an uncertain history actually have immunity when tested. If the patient lacks immunity, she should be vaccinated immediately postpartum.^16,17 The vaccine should be administered in a 2-dose series at time zero and then 4 to 8 weeks later. Patients should adhere to secure contraception from the time of the first dose until 1 month after the second dose. The cost of each dose of the vaccine is approximately $145.

Adverse effects of vaccination

All vaccines have many of the same side effects. The most common is simply a reaction at the site of injection, characterized by pain, increased warmth, erythema, swelling, and tenderness. Other common side effects include systemic manifestations, such as low-grade fever, nausea and vomiting, malaise, fatigue, headache, lymphadenopathy, myalgias, and arthralgias. Some vaccines, notably varicella, herpes zoster, measles, and rubella may cause a disseminated rash. Most of these minor side effects are easily managed by rest, hydration, and administration of an analgesic such as acetaminophen or ibuprofen. More serious side effects include rare complications such as anaphylaxis, Bell palsy, Guillain-Barre syndrome, and venous thromboembolism (Johnson & Johnson COVID-19 vaccine). Any of the vaccines discussed above should not be given, or given only with extreme caution, to an individual who has experienced any of these reactions with a previous vaccine.

Barriers to vaccination

Although the vaccines reviewed above are highly effective in preventing serious illness in recipients, the medical profession’s “report card” in ensuring adherence with vaccine protocols is not optimal. In fact, it probably merits a grade no higher than C+, with vaccination rates in the range of 50% to 70%.

One of the major barriers to vaccination is lack of detailed information about vaccine efficacy and safety on the part of both provider and patient. Another is the problem of misinformation (eg, the persistent belief on the part of some individuals that vaccines may cause a serious problem, such as autism).^18,19 Another important barrier to widespread vaccination is the logistical problem associated with proper scheduling of multidose regimens (such as those for hepatitis A and B, varicella, and COVID-19). A final barrier, and in my own university-based practice, the most important obstacle is the expense of vaccination. Most, but not all, private insurance companies provide coverage for vaccines approved by the Centers for Disease Control and Prevention and the US Preventive Services Task Force. However, public insurance agencies often provide disappointingly inconsistent coverage for essential vaccines.

By keeping well informed about the most recent public health recommendations for vaccinations for adults and by leading important initiatives within our own practices, we should be able to overcome the first 3 barriers listed above. For example, Morgan and colleagues²⁰ recently achieved a 97% success rate with Tdap administration in pregnancy by placing a best-practice alert in the patients’ electronic medical records. Surmounting the final barrier will require intense effort on the part of individual practitioners and professional organizations to advocate for coverage for essential vaccinations for our patients.

CASE Resolved

This patient was raised in an area of the world where her family did not have easy access to medical care. Accordingly, she did not receive the usual childhood vaccines, such as measles, mumps, rubella, varicella, hepatitis B, and almost certainly, tetanus, diphtheria, and pertussis (Tdap), and the HPV vaccine. The MMR vaccine and the varicella vaccine are live virus vaccines and should not be given during pregnancy. However, these vaccines should be administered postpartum, and the patient should be instructed to practice secure contraception for a minimum of 1 month following vaccination. She also should be offered the HPV vaccine postpartum. During pregnancy, she definitely should receive the COVID-19 vaccine, the 3-dose hepatitis B vaccine series, the influenza vaccine, and Tdap. If her present living conditions place her at risk for hepatitis A, she also should be vaccinated against this illness. ●

CASE 1st prenatal appointment for young, pregnant migrant

A 21-year-old primigravid woman at 12 weeks’ gestation recently immigrated to the United States from an impoverished rural area of Southeast Asia. On the first prenatal appointment, she is noted to have no evidence of immunity to rubella, measles, or varicella. Her hepatitis B surface antigen and hepatitis C antibody tests are negative. She also has negative test results for gonorrhea, chlamydia, syphilis, and HIV infection. Her pap test is negative.

• What vaccinations should this patient receive during her pregnancy?
• What additional vaccinations are indicated postpartum?

Preventive vaccinations: What to know

As ObGyns, we serve as the primary care physician for many women throughout their early and middle decades of life. Accordingly, we have an obligation to be well informed about preventive health services such as vaccinations. The purpose of this article is to review the principal vaccines with which ObGyns should be familiar. I will discuss the vaccines in alphabetical order and then focus on the indications and timing for each vaccine and the relative cost of each immunization. Key points are summarized in the TABLE.

COVID-19 vaccine

In the latter part of 2020 and early part of 2021, three COVID-19 vaccines received emergency use authorization (EUA) from the US Food and Drug Administration (FDA) for individuals 16 years of age and older (Pfizer-BioNTech) and 18 years of age and older (Moderna and Johnson & Johnson).¹ The cost of their administration is borne by the federal government. Two of the vaccines are mRNA agents—Moderna and Pfizer-BioNTech. Both are administered in a 2-dose series, separated by 4 and 3 weeks, respectively. The efficacy of these vaccines in preventing serious or critical illness approaches 95%. The Pfizer-BioNTech vaccine has now been fully FDA approved for administration to individuals older than age 16, with EUA for those down to age 12. Full approval of the Moderna vaccine will not be far behind. Because of some evidence suggesting waning immunity over time and because of growing concerns about the increased transmissibility of the delta variant of the virus, the FDA has been strongly considering a recommendation for a third (booster) dose of each of these vaccines, administered 8 months after the second dose for all eligible Americans. On September 17, 2021, the FDA advisory committee recommended a booster for the Pfizer-BioNTech vaccine for people older than age 65 and for those over the age of 16 at high risk for severe COVID-19. Several days later, full FDA approval was granted for this recommendation. Subsequently, the Director of the Centers for Disease Control and Prevention (CDC) included health care workers and pregnant women in the group for whom the booster is recommended.

The third vaccine formulation is the Johnson & Johnson DNA vaccine, which is prepared with a human adenovirus vector. This vaccine is administered in a single intramuscular dose and has a reported efficacy of 66% to 85%, though it may approach 95% in preventing critical illness. The FDA is expected to announce decisions about booster doses for the Johnson & Johnson and Moderna vaccines in the coming weeks.

Although initial trials of the COVID-19vaccines excluded pregnant and lactating women, the vaccines are safe in pregnancy or postpartum. In fact the vaccines do not contain either a killed or attenuated viral particle that is capable of transmitting infection. Therefore, both the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine now support routine immunization during pregnancy.

A recent report by Shimabukuro and colleagues² demonstrated that the risk of vaccine-related complications in pregnant women receiving the Pfizer-BioNTech or Moderna vaccines was no different than in nonpregnant patients and that there was no evidence of teratogenic effects. The trial included more than 35,000 pregnant women; 2.3% were vaccinated in the periconception period, 28.6% in the first trimester, 43.3% in the second trimester, and 25.7% in the third trimester. Given this, and in light of isolated reports of unusual thromboembolic complications associated with the Johnson & Johnson vaccine, I strongly recommend use of either the Moderna or Pfizer-BioNTech vaccine in our prenatal and postpartum patients.

Continue to: Hepatitis A vaccine...

The hepatitis A vaccine is an inactivated vaccine and is safe for use in pregnancy. It is available in two monovalent preparations—Havrix (GlaxoSmithKline) and Vaqta (Merck & Co.) and is administered in a 2-dose intramuscular injection at time zero and 6 to 12 months later.³ The vaccine is also available in a bivalent form with recombinant hepatitis B vaccine—Twinrix (GlaxoSmithKline). When administered in this form, the vaccine should be given at time zero, 1 month, and 6 months. The wholesale cost of the monovalent vaccine is $66 to $119, depending upon whether the provider uses a multi-dose or a single-dose vial. The cost of Twinrix is $149.

The hepatitis A vaccine is indicated for select pregnant and nonpregnant patients:

• international travelers
• intravenous drug users
• those with occupational exposure (eg, individuals who work in a primate laboratory)
• residents and staff in chronic care facilities
• individuals with chronic liver disease
• individuals with clotting factor disorders
• residents in endemic areas.

Hepatitis B vaccine

The hepatitis B vaccine is a recombinant vaccine that contains an inactivated portion of the hepatitis B surface antigen. It was originally produced in two monovalent formulations: Engerix B (GlaxoSmithKline) and Recombivax-HB (Merck & Co.). These original formulations are given in a 3-dose series at time zero, 1 month, and 6 months. Recently, a new and more potent formulation was introduced into clinical practice. Heplisav-B (Dynavax Technologies Co.) is also a recombinant vaccine that contains a boosting adjuvant. It is programed to be administered in a 2-dose series at time zero and 1 month.^4-6

The wholesale cost of the monovalent vaccines varies from $60 to $173, depending upon use of a multi-dose vial versus a single-use vial. The cost of Heplisav-B varies from $146 to $173, depending upon use of a prefilled syringe versus a single-dose vial.

Although the hepatitis B vaccine should be part of the childhood immunization series, it also should be administered to any pregnant woman who has not been vaccinated previously or who does not already have evidence of immunity as a result of natural infection.

Continue to: Herpes zoster vaccine...

Herpes zoster infection (shingles) can be a particularly disabling condition in older patients and results from reactivation of a latent varicella-zoster infection. Shingles can cause extremely painful skin lesions, threaten the patient’s vision, and result in long-lasting postherpetic neuralgia. Both cellular and hormonal immunity are essential to protect against recurrent infection.

The original herpes zoster vaccine (Zoster Vaccine Live; ZVL, Zostavax) is no longer produced in the United States because it is not as effective as the newer vaccine—Recombinant Zoster Vaccine (Shingrix, GlaxoSmithKline).^7,8 The antigen in the new vaccine is a component of the surface glycoprotein E, and it is combined with an adjuvant to enhance immunoreactivity. The vaccine is given intramuscularly in two doses at time zero and again at 2 to 6 months and is indicated for all individuals >50 years, including those who may have had an episode of shingles. This newer vaccine is 97% effective in patients >50 years and 90% effective in patients >70. The wholesale cost of each injection is about $160.

Human papillomavirus vaccine

The HPV vaccine (Gardasil-9, Merck & Co.) is a recombinant 9-valent vaccine directed against the human papillomavirus. It induces immunity to serotypes 6 and 11 (which cause 90% of genital warts), 16 and 18 (which cause 80% of genital cancers), and 31, 33, 45, 52, and 58 (viral strains that are responsible for both genital and oropharyngeal cancers). The vaccine is administered intramuscularly in a 3-dose series at time zero, 1-2 months, and 6 months. The principal target groups for the vaccine are males and females, ages 9 to 45 years. Ideally, children of both sexes should receive this vaccine prior to the onset of sexual activity. The wholesale cost of each vaccine injection is approximately $222.⁹

Influenza vaccine

The inactivated, intramuscular flu vaccine is recommended for anyone over age 2, including pregnant women. Although pregnant women are not more likely to acquire flu compared with those who are not pregnant, if they do become infected, they are likely to become more seriously ill, with higher mortality. Accordingly, all pregnant women should receive, in any trimester, the inactivated flu vaccine beginning in the late summer and early fall of each year and extending through March of the next year.^10,11

Multiple formulations of the inactivated vaccine are marketed, all targeting two strains of influenza A and two strains of influenza B. The components of the vaccine vary each year as scientists try to match the new vaccine with the most highly prevalent strains in the previous flu season. The vaccine should be administered in a single intramuscular dose. The cost varies from approximately $20 to $70.

The intranasal influenza vaccine is a live virus vaccine that is intended primarily for children and should not be administered in pregnancy. In addition, there is a higher dose of the inactivated quadrivalent vaccine that is available for administration to patients over age 65. This higher dose is more likely to cause adverse effects and is not indicated in pregnancy.

Continue to: Measles, mumps, rubella vaccine (MMR)...

Measles, mumps, rubella vaccine (MMR)

The MMR is a standard component of the childhood vaccination series. The trivalent preparation is a live, attenuated vaccine that is typically given subcutaneously in a 2-dose series. The first dose is administered at age 12-15 months, and the second dose at age 4-6 years. The vaccine is highly immunogenic, with vaccine-induced immunity usually life-long. In some patients, however, immunity wanes over time. Accordingly, all pregnant women should be screened for immunity to rubella since, of the 3, this infection poses the greatest risk to the fetus. Women who do not have evidence of immunity should be advised to avoid contact with children who may have a viral exanthem. They should then receive a booster dose of the vaccine immediately postpartum and should practice secure contraception for 1 month. The vaccine cost is approximately $60.

Pneumococcal vaccine

The inactivated pneumococcal vaccine is produced in two forms, both of which are safe for administration in pregnancy.¹² The original vaccine, introduced in 1983, was PPSV23 (Pneumovax 23, Merck & Co), a 23-serovalent vaccine that was intended primarily for adults. This vaccine is administered in a single subcutaneous or intramuscular dose. The newest vaccine, introduced in 2010, is PCV13 (Prevnar 13, Pfizer Inc), a 13-serovalent vaccine. It was intended primarily for children, in whom it is administered in a 4-dose series beginning at 6 to 8 weeks of age. The cost of the former is approximately $98 to $120; the cost of the latter is $228.

Vaccination against pneumococcal infection is routinely indicated for those older than the age of 65 and for the following at-risk patients, including those who are pregnant¹¹:

• individuals who have had a splenectomy or who have a medical illness that produces functional asplenia (eg, sickle cell anemia)
• individuals with chronic cardiac, pulmonic, hepatic, or renal disease
• individuals with immunosuppressive conditions such as HIV infection or a disseminated malignancy
• individuals who have a cochlear implant
• individuals who have a chronic leak of cerebrospinal fluid.

The recommendations for timing of these 2 vaccines in adults can initially appear confusing. Put most simply, if a high-risk patient first receives the PCV13 vaccine, she should receive the PPSV23 vaccine in about 8 weeks. The PPSV23 vaccine should be repeated in 5 years. If an at-risk patient initially receives the PPSV23 vaccine, the PCV13 vaccine should be given 1 year later.¹²

Tdap vaccine

The Tdap vaccine contains tetanus toxoid, reduced diptheria toxoid, and an acellular component of the pertussis bacterium. Although it has long been part of the childhood vaccinations series, immunity to each component, particularly pertussis, tends to wane over time.

Pertussis poses a serious risk to the health of the pregnant woman and the newborn infant. Accordingly, the Advisory Committee on Immunization Practices (ACIP), CDC, and the ACOG now advise administration of a booster dose of this vaccine in the early third trimester of each pregnancy.^13-15 The vaccine should be administered as a single intramuscular injection. The approximate cost of the vaccine is $64 to $71, depending upon whether the provider uses a single-dose vial or a single-dose prefilled syringe. In nonpregnant patients, the ACIP currently recommends administration of a booster dose of the vaccine every 10 years, primarily to provide durable protection against tetanus.

Continue to: Varicella vaccine...

Varicella vaccine

The varicella vaccine is also one of the main components of the childhood immunization series. This live virus vaccine can be administered subcutaneously as a monovalent agent or as a quadrivalent agent in association with the MMR vaccine.

Pregnant women who do not have a well-documented history of natural infection should be tested for IgG antibody to the varicella-zoster virus at the time of their first prenatal appointment. Interestingly, approximately 70% of patients with an uncertain history actually have immunity when tested. If the patient lacks immunity, she should be vaccinated immediately postpartum.^16,17 The vaccine should be administered in a 2-dose series at time zero and then 4 to 8 weeks later. Patients should adhere to secure contraception from the time of the first dose until 1 month after the second dose. The cost of each dose of the vaccine is approximately $145.

Adverse effects of vaccination

All vaccines have many of the same side effects. The most common is simply a reaction at the site of injection, characterized by pain, increased warmth, erythema, swelling, and tenderness. Other common side effects include systemic manifestations, such as low-grade fever, nausea and vomiting, malaise, fatigue, headache, lymphadenopathy, myalgias, and arthralgias. Some vaccines, notably varicella, herpes zoster, measles, and rubella may cause a disseminated rash. Most of these minor side effects are easily managed by rest, hydration, and administration of an analgesic such as acetaminophen or ibuprofen. More serious side effects include rare complications such as anaphylaxis, Bell palsy, Guillain-Barre syndrome, and venous thromboembolism (Johnson & Johnson COVID-19 vaccine). Any of the vaccines discussed above should not be given, or given only with extreme caution, to an individual who has experienced any of these reactions with a previous vaccine.

Barriers to vaccination

Although the vaccines reviewed above are highly effective in preventing serious illness in recipients, the medical profession’s “report card” in ensuring adherence with vaccine protocols is not optimal. In fact, it probably merits a grade no higher than C+, with vaccination rates in the range of 50% to 70%.

One of the major barriers to vaccination is lack of detailed information about vaccine efficacy and safety on the part of both provider and patient. Another is the problem of misinformation (eg, the persistent belief on the part of some individuals that vaccines may cause a serious problem, such as autism).^18,19 Another important barrier to widespread vaccination is the logistical problem associated with proper scheduling of multidose regimens (such as those for hepatitis A and B, varicella, and COVID-19). A final barrier, and in my own university-based practice, the most important obstacle is the expense of vaccination. Most, but not all, private insurance companies provide coverage for vaccines approved by the Centers for Disease Control and Prevention and the US Preventive Services Task Force. However, public insurance agencies often provide disappointingly inconsistent coverage for essential vaccines.

By keeping well informed about the most recent public health recommendations for vaccinations for adults and by leading important initiatives within our own practices, we should be able to overcome the first 3 barriers listed above. For example, Morgan and colleagues²⁰ recently achieved a 97% success rate with Tdap administration in pregnancy by placing a best-practice alert in the patients’ electronic medical records. Surmounting the final barrier will require intense effort on the part of individual practitioners and professional organizations to advocate for coverage for essential vaccinations for our patients.

CASE Resolved

This patient was raised in an area of the world where her family did not have easy access to medical care. Accordingly, she did not receive the usual childhood vaccines, such as measles, mumps, rubella, varicella, hepatitis B, and almost certainly, tetanus, diphtheria, and pertussis (Tdap), and the HPV vaccine. The MMR vaccine and the varicella vaccine are live virus vaccines and should not be given during pregnancy. However, these vaccines should be administered postpartum, and the patient should be instructed to practice secure contraception for a minimum of 1 month following vaccination. She also should be offered the HPV vaccine postpartum. During pregnancy, she definitely should receive the COVID-19 vaccine, the 3-dose hepatitis B vaccine series, the influenza vaccine, and Tdap. If her present living conditions place her at risk for hepatitis A, she also should be vaccinated against this illness. ●

The first transdermal contraceptive patch was approved by the US Food and Drug Administration (FDA) in 2001.¹ A 2018 survey revealed that 5% of women in the United States between the ages of 15 and 49 years reported the use of a short-acting hormonal contraceptive method (ie, vaginal ring, transdermal patch, injectable) within the past month, with just 0.3% reporting the use of a transdermal patch.² Transdermal contraceptive patches are an effective form of birth control that may be a convenient option for patients who do not want to take a daily oral contraceptive pill but want similar efficacy and tolerability. Typical failure rates of patches are similar to that of combined oral contraceptives (COCs).^1,3

While transdermal hormone delivery results in less peaks and troughs of estrogen compared with COCs, the total estrogen exposure is higher than with COCs; therefore, the risk for venous thromboembolism (VTE) with previously available patches is about twice as high.¹ Twirla (Agile), an ethinyl estradiol (EE)/levonorgestrel (LNG) patch, delivers a low and consistent daily dose of hormones over 3 patches replaced once weekly, with no patch on the fourth week.³ Twirla contains 120 μg/day LNG and 30 μg/day EE. OrthoEvra, FDA approved in 2001 as mentioned, contains 150 μg/day norelgestromin and 35 μg/day EE.¹ A reduction of the EE dose in COCs has been associated with lower risk for VTE.⁴

The addition of Twirla to the market offers another contraceptive option for patients who opt for a weekly, self-administered method.

How much lower is the VTE risk?

OBG Management: Can you define what is the reduction in VTE risk for the EE dose in Twirla versus Ortho Evra (a norelgestromin/EE patch) and similar contraceptive patches already available?

Barbara Levy, MD: The reality is we can’t designate a reduction of risk, except, in general, when the dose of ethinyl estradiol is lower, we think that the VTE risk is lower. There has not been a head-to-head comparison in a large enough population to be able to say that the risk is reduced by a certain factor. We just look at the overall exposure to estrogen and say, “In general, for VTE risk, a lower dose is a better thing for women.”

That being said, look at birth control pills, like COCs. We don’t have actual numbers to say that a 30-μg pill is this much less risky than a 35-μg pill. We just put it into a hierarchy, and that’s what we can do with the patch. We can say that, in general, lower is better for VTE risk, but no one can provide absolute numbers.

Continue to: Efficacy...

Efficacy

OBG Management: What is Twirla’s efficacy in preventing pregnancy, and how does this compare to previous patches and other types of hormonal birth control?

Dr. Levy: You have to look at the pivotal trials and look at what the efficacy was in a trial setting. In the real-world setting, the effectiveness is never quite as good as it is in a clinical trial. I think the bottom line for all of us is that combined oral contraception, meaning estrogen with progestin, is equivalently effective across the different options that are available for women. Efficacy really isn’t the factor to use to distinguish which one I’m going to pick. It is about the patient’s convenience and many other factors. But in terms of its clinical effectiveness in preventing pregnancy, from a very practical standpoint, I think we consider them all the same.

Considering route of administration

OBG Management: Are there benefits associated with transdermal birth control vs other contraceptive options, and are women interested in transdermal contraception?

Dr. Levy: I think there’s always a benefit in having lots of choices. And for some women, being able to put a patch on once a week is much more convenient, easier to remember, and delivers a very consistent dose of hormone absorbed through the skin, which is different than taking a pill in the morning when your levels go up quickly then diminish over the day. The hormones are higher at a certain time, and then they drop off, so there might be some advantages for people who are very sensitive to swings in hormonal levels. There’s also a convenience factor, where for some people they will choose that. Other people might really dislike having a relatively large patch on their skin somewhere, or they may have skin sensitivity to the adhesive. Overall, I always think that having more options is better and individual girls/women will choose what works best for them.

Counseling tips

OBG Management: What are the instructions for patients to effectively use Twirla, and how should they be counseled regarding the expectations for their menstrual cycle?

Dr. Levy: Like other patches that are available on the market, these are a once-a-week patch. The patch should be placed on clean, dry skin. No lotions, perfumes, or anything on the skin because you really want them to stick for the whole week, and it’s not going to stick if there’s anything oily on the skin. The first patch is placed on day 1 of a menstrual cycle, the first day of bleeding, and then changed weekly for 3 weeks. Then there’s a 7-day patch-free time in which one would expect to have a period.

In general, breakthrough bleeding was not a significant problem with the patch, but some women will have some irregular spotting and bleeding with any sort of hormonal treatment; some women may have no periods at all. In other words, the estrogen dose and progestin may be of a balance that allows the patient not to have periods. But, in general, most of the women in the trial had regular light menstrual flow during the week when their patch was not on.⁵

Continue to: Pricing...

Pricing

OBG Management: Are you aware of the current payment options for Twirla? Is it covered by any insurance plans right now?

Dr. Levy: That’s a tricky question. Insurance plans through Obamacare, the Affordable Care Act, are required to cover every form of contraception. That means they must cover a patch. It doesn’t mean that they have to cover this patch. And because there are generics available of the other patch formulation, it is likely that this would be a higher tier, meaning that there may be a higher copay for someone who wanted to use Twirla versus one of the generic patches.

I can’t say that that’s universally the case, but my experience with most of the health insurance plans is that they tend to put barriers in the way for any of us to prescribe, and for women to use, brand-name products. So Twirla is new on the market; it’s a brand-name product. It may work much better for some people; and in those cases, the health care provider might have to send a letter to the insurance company saying why this one is medically necessary for a patient. There probably will be some hoops to go through for coverage without a copay. I think coverage will be there, but there may be a substantial copay because of the tier level.

OBG Management: Do you think that there would be a challenge for someone trying to get a prescription for a patient saying that there is a need because it is a lower dose of estrogen?

Dr. Levy: I don’t think that the payer is going to buy that argument unless the requirement is to use a patch. If the patient, for example, has some sort of gastrointestinal disease where they don’t absorb things well, so pills don’t work well, we might get to the place where they have to have a patch. If the patient has a lot of breast tenderness or has symptoms on the generic patch that delivers a higher level of estrogen, then we would have to document those symptoms to say, “She’s not tolerating this one and, therefore, we need to go to that one.” So, I think as prescribers we would have to justify not only the lower dose but also the form.

As a clinician, I would always like to put somebody on the lower dose. We do think lower is better, but we have to be sensitive to the costs of all of these things too. I’m very sensitive to my patients’ out-of-pocket costs because, in the end, if the costs are a lot of money or she can only afford one month at a time, then she may miss a window where she may not have the money to buy next month’s supply when it’s due, and get pregnant. We have to balance all of those things as we’re thinking through the best option for an individual.

We have more to learn

OBG Management: Is there anything else you would like to add?

Dr. Levy: I think it’s always exciting when we have new products available, and there’s a lot more we’ll learn as Twirla comes into commercial use and millions instead of thousands of people are using it. Overall, I think it’s fantastic that there’s ongoing research and that there are new products out there. And kudos to the company for doing the research and for getting approval, and I’m looking forward to learning more about it.
 

The first transdermal contraceptive patch was approved by the US Food and Drug Administration (FDA) in 2001.¹ A 2018 survey revealed that 5% of women in the United States between the ages of 15 and 49 years reported the use of a short-acting hormonal contraceptive method (ie, vaginal ring, transdermal patch, injectable) within the past month, with just 0.3% reporting the use of a transdermal patch.² Transdermal contraceptive patches are an effective form of birth control that may be a convenient option for patients who do not want to take a daily oral contraceptive pill but want similar efficacy and tolerability. Typical failure rates of patches are similar to that of combined oral contraceptives (COCs).^1,3

While transdermal hormone delivery results in less peaks and troughs of estrogen compared with COCs, the total estrogen exposure is higher than with COCs; therefore, the risk for venous thromboembolism (VTE) with previously available patches is about twice as high.¹ Twirla (Agile), an ethinyl estradiol (EE)/levonorgestrel (LNG) patch, delivers a low and consistent daily dose of hormones over 3 patches replaced once weekly, with no patch on the fourth week.³ Twirla contains 120 μg/day LNG and 30 μg/day EE. OrthoEvra, FDA approved in 2001 as mentioned, contains 150 μg/day norelgestromin and 35 μg/day EE.¹ A reduction of the EE dose in COCs has been associated with lower risk for VTE.⁴

The addition of Twirla to the market offers another contraceptive option for patients who opt for a weekly, self-administered method.

How much lower is the VTE risk?

OBG Management: Can you define what is the reduction in VTE risk for the EE dose in Twirla versus Ortho Evra (a norelgestromin/EE patch) and similar contraceptive patches already available?

Barbara Levy, MD: The reality is we can’t designate a reduction of risk, except, in general, when the dose of ethinyl estradiol is lower, we think that the VTE risk is lower. There has not been a head-to-head comparison in a large enough population to be able to say that the risk is reduced by a certain factor. We just look at the overall exposure to estrogen and say, “In general, for VTE risk, a lower dose is a better thing for women.”

That being said, look at birth control pills, like COCs. We don’t have actual numbers to say that a 30-μg pill is this much less risky than a 35-μg pill. We just put it into a hierarchy, and that’s what we can do with the patch. We can say that, in general, lower is better for VTE risk, but no one can provide absolute numbers.

Continue to: Efficacy...

Efficacy

OBG Management: What is Twirla’s efficacy in preventing pregnancy, and how does this compare to previous patches and other types of hormonal birth control?

Dr. Levy: You have to look at the pivotal trials and look at what the efficacy was in a trial setting. In the real-world setting, the effectiveness is never quite as good as it is in a clinical trial. I think the bottom line for all of us is that combined oral contraception, meaning estrogen with progestin, is equivalently effective across the different options that are available for women. Efficacy really isn’t the factor to use to distinguish which one I’m going to pick. It is about the patient’s convenience and many other factors. But in terms of its clinical effectiveness in preventing pregnancy, from a very practical standpoint, I think we consider them all the same.

Considering route of administration

OBG Management: Are there benefits associated with transdermal birth control vs other contraceptive options, and are women interested in transdermal contraception?

Dr. Levy: I think there’s always a benefit in having lots of choices. And for some women, being able to put a patch on once a week is much more convenient, easier to remember, and delivers a very consistent dose of hormone absorbed through the skin, which is different than taking a pill in the morning when your levels go up quickly then diminish over the day. The hormones are higher at a certain time, and then they drop off, so there might be some advantages for people who are very sensitive to swings in hormonal levels. There’s also a convenience factor, where for some people they will choose that. Other people might really dislike having a relatively large patch on their skin somewhere, or they may have skin sensitivity to the adhesive. Overall, I always think that having more options is better and individual girls/women will choose what works best for them.

Counseling tips

OBG Management: What are the instructions for patients to effectively use Twirla, and how should they be counseled regarding the expectations for their menstrual cycle?

Dr. Levy: Like other patches that are available on the market, these are a once-a-week patch. The patch should be placed on clean, dry skin. No lotions, perfumes, or anything on the skin because you really want them to stick for the whole week, and it’s not going to stick if there’s anything oily on the skin. The first patch is placed on day 1 of a menstrual cycle, the first day of bleeding, and then changed weekly for 3 weeks. Then there’s a 7-day patch-free time in which one would expect to have a period.

In general, breakthrough bleeding was not a significant problem with the patch, but some women will have some irregular spotting and bleeding with any sort of hormonal treatment; some women may have no periods at all. In other words, the estrogen dose and progestin may be of a balance that allows the patient not to have periods. But, in general, most of the women in the trial had regular light menstrual flow during the week when their patch was not on.⁵

Continue to: Pricing...

Pricing

OBG Management: Are you aware of the current payment options for Twirla? Is it covered by any insurance plans right now?

Dr. Levy: That’s a tricky question. Insurance plans through Obamacare, the Affordable Care Act, are required to cover every form of contraception. That means they must cover a patch. It doesn’t mean that they have to cover this patch. And because there are generics available of the other patch formulation, it is likely that this would be a higher tier, meaning that there may be a higher copay for someone who wanted to use Twirla versus one of the generic patches.

I can’t say that that’s universally the case, but my experience with most of the health insurance plans is that they tend to put barriers in the way for any of us to prescribe, and for women to use, brand-name products. So Twirla is new on the market; it’s a brand-name product. It may work much better for some people; and in those cases, the health care provider might have to send a letter to the insurance company saying why this one is medically necessary for a patient. There probably will be some hoops to go through for coverage without a copay. I think coverage will be there, but there may be a substantial copay because of the tier level.

OBG Management: Do you think that there would be a challenge for someone trying to get a prescription for a patient saying that there is a need because it is a lower dose of estrogen?

Dr. Levy: I don’t think that the payer is going to buy that argument unless the requirement is to use a patch. If the patient, for example, has some sort of gastrointestinal disease where they don’t absorb things well, so pills don’t work well, we might get to the place where they have to have a patch. If the patient has a lot of breast tenderness or has symptoms on the generic patch that delivers a higher level of estrogen, then we would have to document those symptoms to say, “She’s not tolerating this one and, therefore, we need to go to that one.” So, I think as prescribers we would have to justify not only the lower dose but also the form.

As a clinician, I would always like to put somebody on the lower dose. We do think lower is better, but we have to be sensitive to the costs of all of these things too. I’m very sensitive to my patients’ out-of-pocket costs because, in the end, if the costs are a lot of money or she can only afford one month at a time, then she may miss a window where she may not have the money to buy next month’s supply when it’s due, and get pregnant. We have to balance all of those things as we’re thinking through the best option for an individual.

We have more to learn

OBG Management: Is there anything else you would like to add?

Dr. Levy: I think it’s always exciting when we have new products available, and there’s a lot more we’ll learn as Twirla comes into commercial use and millions instead of thousands of people are using it. Overall, I think it’s fantastic that there’s ongoing research and that there are new products out there. And kudos to the company for doing the research and for getting approval, and I’m looking forward to learning more about it.
 

The first transdermal contraceptive patch was approved by the US Food and Drug Administration (FDA) in 2001.¹ A 2018 survey revealed that 5% of women in the United States between the ages of 15 and 49 years reported the use of a short-acting hormonal contraceptive method (ie, vaginal ring, transdermal patch, injectable) within the past month, with just 0.3% reporting the use of a transdermal patch.² Transdermal contraceptive patches are an effective form of birth control that may be a convenient option for patients who do not want to take a daily oral contraceptive pill but want similar efficacy and tolerability. Typical failure rates of patches are similar to that of combined oral contraceptives (COCs).^1,3

While transdermal hormone delivery results in less peaks and troughs of estrogen compared with COCs, the total estrogen exposure is higher than with COCs; therefore, the risk for venous thromboembolism (VTE) with previously available patches is about twice as high.¹ Twirla (Agile), an ethinyl estradiol (EE)/levonorgestrel (LNG) patch, delivers a low and consistent daily dose of hormones over 3 patches replaced once weekly, with no patch on the fourth week.³ Twirla contains 120 μg/day LNG and 30 μg/day EE. OrthoEvra, FDA approved in 2001 as mentioned, contains 150 μg/day norelgestromin and 35 μg/day EE.¹ A reduction of the EE dose in COCs has been associated with lower risk for VTE.⁴

The addition of Twirla to the market offers another contraceptive option for patients who opt for a weekly, self-administered method.

How much lower is the VTE risk?

OBG Management: Can you define what is the reduction in VTE risk for the EE dose in Twirla versus Ortho Evra (a norelgestromin/EE patch) and similar contraceptive patches already available?

Barbara Levy, MD: The reality is we can’t designate a reduction of risk, except, in general, when the dose of ethinyl estradiol is lower, we think that the VTE risk is lower. There has not been a head-to-head comparison in a large enough population to be able to say that the risk is reduced by a certain factor. We just look at the overall exposure to estrogen and say, “In general, for VTE risk, a lower dose is a better thing for women.”

That being said, look at birth control pills, like COCs. We don’t have actual numbers to say that a 30-μg pill is this much less risky than a 35-μg pill. We just put it into a hierarchy, and that’s what we can do with the patch. We can say that, in general, lower is better for VTE risk, but no one can provide absolute numbers.

Continue to: Efficacy...

Efficacy

OBG Management: What is Twirla’s efficacy in preventing pregnancy, and how does this compare to previous patches and other types of hormonal birth control?

Dr. Levy: You have to look at the pivotal trials and look at what the efficacy was in a trial setting. In the real-world setting, the effectiveness is never quite as good as it is in a clinical trial. I think the bottom line for all of us is that combined oral contraception, meaning estrogen with progestin, is equivalently effective across the different options that are available for women. Efficacy really isn’t the factor to use to distinguish which one I’m going to pick. It is about the patient’s convenience and many other factors. But in terms of its clinical effectiveness in preventing pregnancy, from a very practical standpoint, I think we consider them all the same.

Considering route of administration

OBG Management: Are there benefits associated with transdermal birth control vs other contraceptive options, and are women interested in transdermal contraception?

Dr. Levy: I think there’s always a benefit in having lots of choices. And for some women, being able to put a patch on once a week is much more convenient, easier to remember, and delivers a very consistent dose of hormone absorbed through the skin, which is different than taking a pill in the morning when your levels go up quickly then diminish over the day. The hormones are higher at a certain time, and then they drop off, so there might be some advantages for people who are very sensitive to swings in hormonal levels. There’s also a convenience factor, where for some people they will choose that. Other people might really dislike having a relatively large patch on their skin somewhere, or they may have skin sensitivity to the adhesive. Overall, I always think that having more options is better and individual girls/women will choose what works best for them.

Counseling tips

OBG Management: What are the instructions for patients to effectively use Twirla, and how should they be counseled regarding the expectations for their menstrual cycle?

Dr. Levy: Like other patches that are available on the market, these are a once-a-week patch. The patch should be placed on clean, dry skin. No lotions, perfumes, or anything on the skin because you really want them to stick for the whole week, and it’s not going to stick if there’s anything oily on the skin. The first patch is placed on day 1 of a menstrual cycle, the first day of bleeding, and then changed weekly for 3 weeks. Then there’s a 7-day patch-free time in which one would expect to have a period.

In general, breakthrough bleeding was not a significant problem with the patch, but some women will have some irregular spotting and bleeding with any sort of hormonal treatment; some women may have no periods at all. In other words, the estrogen dose and progestin may be of a balance that allows the patient not to have periods. But, in general, most of the women in the trial had regular light menstrual flow during the week when their patch was not on.⁵

Continue to: Pricing...

Pricing

OBG Management: Are you aware of the current payment options for Twirla? Is it covered by any insurance plans right now?

Dr. Levy: That’s a tricky question. Insurance plans through Obamacare, the Affordable Care Act, are required to cover every form of contraception. That means they must cover a patch. It doesn’t mean that they have to cover this patch. And because there are generics available of the other patch formulation, it is likely that this would be a higher tier, meaning that there may be a higher copay for someone who wanted to use Twirla versus one of the generic patches.

I can’t say that that’s universally the case, but my experience with most of the health insurance plans is that they tend to put barriers in the way for any of us to prescribe, and for women to use, brand-name products. So Twirla is new on the market; it’s a brand-name product. It may work much better for some people; and in those cases, the health care provider might have to send a letter to the insurance company saying why this one is medically necessary for a patient. There probably will be some hoops to go through for coverage without a copay. I think coverage will be there, but there may be a substantial copay because of the tier level.

OBG Management: Do you think that there would be a challenge for someone trying to get a prescription for a patient saying that there is a need because it is a lower dose of estrogen?

Dr. Levy: I don’t think that the payer is going to buy that argument unless the requirement is to use a patch. If the patient, for example, has some sort of gastrointestinal disease where they don’t absorb things well, so pills don’t work well, we might get to the place where they have to have a patch. If the patient has a lot of breast tenderness or has symptoms on the generic patch that delivers a higher level of estrogen, then we would have to document those symptoms to say, “She’s not tolerating this one and, therefore, we need to go to that one.” So, I think as prescribers we would have to justify not only the lower dose but also the form.

As a clinician, I would always like to put somebody on the lower dose. We do think lower is better, but we have to be sensitive to the costs of all of these things too. I’m very sensitive to my patients’ out-of-pocket costs because, in the end, if the costs are a lot of money or she can only afford one month at a time, then she may miss a window where she may not have the money to buy next month’s supply when it’s due, and get pregnant. We have to balance all of those things as we’re thinking through the best option for an individual.

We have more to learn

OBG Management: Is there anything else you would like to add?

Dr. Levy: I think it’s always exciting when we have new products available, and there’s a lot more we’ll learn as Twirla comes into commercial use and millions instead of thousands of people are using it. Overall, I think it’s fantastic that there’s ongoing research and that there are new products out there. And kudos to the company for doing the research and for getting approval, and I’m looking forward to learning more about it.