Reproductive health planning is an emerging, crucial issue for people with IMDs. Contraception limits risks to patients with IMD and their offspring, as it allows for adequate reproductive planning and early pregnancy monitoring. Contraception is therefore a necessary component of the healthcare of adults and adolescents with IMD.
Contraception counseling was most likely to occur with adult women who live independently. These women are likely to attend visits independently or with a partner, avoiding the potential discomfort of addressing sexual health in front of parents or caregivers. Adult women living independently may demonstrate higher career focus making them more likely to use contraception to delay pregnancy.18 Gynecology referral had a positive impact on contraceptive use. LARC have the lowest failure rate and were used significantly more frequently in females followed by gynecologists (with gynecology: 9/81; without gynecology: 4/121, p<0.04). Co-management with gynecology allows for a greater range of contraceptive options.
Diagnosis of ID had an equivocal effect on both contraception counseling and use of contraception. This runs counter to current literature on sexual health in women with ID, where the presence of ID decreases the likelihood of reproductive planning.19 Metabolism providers may be uniquely suited to have such conversations with patients with ID because of strong rapport with patients and their families due to longstanding patient-doctor relationships. For our cohort with ID, there was no significant benefit of gynecology consultation on contraceptive use (OR 2.45, CI 0.86-6.96, p=0.092). In contrast, metabolism provider-led counseling on contraception significantly improves actual usage among women with ID and IMD (OR 4.8, CI 1.46-15.8, p=0.01) Most women with ID in our cohort opted for daily oral contraception, such as POP or OCP (73%), and only one patient chose a LARC (IUD). We speculate that these women are already taking several daily medications and, therefore, are not burdened by adding additional daily oral medications. It is also possible that there is insufficient awareness about LARC in this population or limited options for placement.
For all cohorts, metabolism providers are well-poised to initiate conversations about reproductive health. In our clinic, engaging women even once about reproductive planning led to a 40-fold increase in contraceptive use (Fig. 1). Patients were more likely to initiate contraception on the advice of their metabolism provider compared to their gynecologist. In our clinical experience, patients with IMD frequently defer to their metabolism provider for advice on any new medication or supplement. This highlights the critical role that the metabolist plays in encouraging contraception.
Unfortunately, overall contraceptives were used only by a minority of patients across all classes of IMD, increasing the risk for unintended pregnancy (Fig. 2). This was true even in conditions where pregnancy was associated with high risk for adverse pregnancy outcomes. Only 23% of women with PKU have ever used contraception, with slightly higher percentages for female patients with organic acidemias (32%) and UCDs (35%). This resulted in an unacceptably high rate of maternal PKU syndrome (1/12 pregnancies), which causes irreversible neurologic damage to the fetus. These data are similar to those found in other studies showing that reproductive health is often omitted from healthcare transition planning 20 In general, women with chronic diseases are less likely to use contraception, despite the risks of unintended pregnancy.21,22
One barrier to universal metabolic counseling on contraception is the lack of systematic resources. In the IMD literature, most recommendations are provided on an ad hoc, case report basis. Contraception was addressed in 14.3% (12/84) of clinical practice guidelines (Table 2). The lack of expert opinion minimizes the importance of reproductive health counseling and fails to provide guidance for metabolic physicians. Misperceptions may exist about sexual activity in patients with IMD, especially those that are evaluated in a pediatric context or who still live with a caregiver, and providers may feel discomfort discussing this topic with patients whom they have known since childhood.23 Counseling through educational hand-outs or inclusion of questionnaires in the electronic health record could lead to uniform guidance on contraception. Likewise, incorporation of healthcare contracts may encourage contraceptive use prior to starting potentially teratogenic medications, such as pegvaliase and eligustat. Similar processes, for example the iPledge program for isoretinol use, have shown efficacy in preventing unintended pregnancy in analogous contexts.24
This study is limited by the setting of our cohort. CHOP is a stand-alone children’s hospital. It is not affiliated with an adult hospital. The Section of Metabolic Disease at CHOP follows all-aged patients (currently newborn to 88 years-old). Adults with disorders of intermediary metabolism continue to be admitted to CHOP for metabolic crises and other emergent care. There are six attending physicians within the section, all of whom are trained in pediatrics and clinical genetics. Adults are frequently seen by their childhood metabolism provider. Potential barriers include lack of experience in discussing or providing contraception, limited knowledge on contraceptive options, scant training on offering adult-centered care, and discomfort with shared decision-making. Our cohort, with only 30% contraceptive use, may not be generalizable to metabolism clinics specifically dedicated to adult-centered care. Metabolism providers with training in internal medicine, family medicine, or obstetrics-gynecology have a stronger background in discussing and prescribing contraception, leading to higher rates of compliance with contraceptives.
Another possibility is that reproductive healthcare is lacking throughout the practice of metabolism. Many IMD were previously thought to be life-limiting with accompanying decrease in reproductive fitness. The advent of newborn screen, novel therapeutics, and improved care has a new population of adults who require specialized management. Women with IMD require more uniformity in counseling on the adverse effects of unintended pregnancy and how contraception can ameliorate these risks. Metabolism providers can serve as leaders in this area and should not assume that discussions are better led by gynecology or primary care providers. To empower metabolism-driven discussion of contraception, we summarize important aspects of counseling on contraception for women with IMD below.
Contraceptive counseling for women with IMD
To provide optimal reproductive planning advice to women with IMD, both the efficacy of the method and the effects of sex hormones on metabolism should be considered. The WHO recommends using the contraception with the lowest failure rate in women with health risks due to unintended pregnancy (currently LARC, including the hormonal and non-hormonal IUD and the progestin implant).3,4 Estrogen and progestin, both separately and combined as CHC are responsible for several changes to metabolism in healthy women (Table 2). Patients’ PCPs or gynecologists may not consider the side effects of contraception on metabolic pathways, placing the metabolism doctor in a unique role to suggest the method most compatible with the patient’s diagnosis.
IMD patients’ comorbidities also play an important role in contraceptive choice. Use of CHC is contraindicated in women with a history of hypertension, cardiac disease, or stroke (21.5% of our patient cohort).3,4 Migraines with aura, a common manifestation of mitochondrial disease and reported in 23.1% of our entire cohort, are another contraindication for CHC use due to the risk of stroke.12 Women with a history or increased risk for venous thromboembolism due to homocystinuria, cobalaminopathies and other thrombophilic IMDs also should not receive CHC.25,26 Women with IMD may be the recipients of solid organ transplants, including liver and kidney. Most contraceptive methods are safe to use after uncomplicated organ transplant, but CHC are contraindicated in women with acute or chronic graft rejection.3,27 IUD have also been proven to be safe post-transplant, with no increased risk of developing pelvic infections.28 Depot medroxyprogesterone (DMPA) and IUD are preferred for women on anti-epileptic drugs due to potential medication interactions (29.4% of our cohort).3
Contraception may improve IMD symptoms. The guidelines for propionic acidemia/methylmalonic acidemia recommend hormonal contraception for management of perimenstrual metabolic instability.16 Several cases of catamenial hyperammonemia in UCDs have been described, which resolved with menstrual suppression using DMPA or CHCs.29–31 Hormonal contraception may also limit perimenstrual aggression in Smith-Lemli-Opitz Syndrome and catamenial porphyria crises in acute intermittent porphyria.32,33 In our cohort, 16 patients reported catamenial metabolic decompensations, of which 5 (31%) utilized hormonal contraception for management.
Discussing reproductive health with IMD patients
It is important to address surgical methods of contraception or sterilization due to its history with the eugenics movement. The United Nations convention on the rights of persons with disabilities states that “people with disabilities must have access on an equal basis to all forms of sexual and reproductive health care.”3 For women with intellectual disability, supported decision-making should occur with a trusted caregiver who will act in the best interests of the patient. Decision-makers should consider social factors, protection against sexual abuse, and support options through potential pregnancy and parenthood.34 They should also have valid grounds for desiring sterilization, such as avoidance of grave harm from pregnancy or inability to use a reversible contraceptive. For women with IMD, consideration of the metabolic risks of pregnancy and labor must also be weighed. The popularity and effectiveness of LARCs, including the IUD and the progestin implant, may make sterilization a rarer choice.35
Finally, genetic counseling should occur at least once with adolescent and adult IMD patients. Counseling should address disease inheritance, recurrence risk, and options for genetic testing during antenatal and prenatal periods. Prospective parents should also be informed that variable expressivity occurs between generations for many IMD, making disease course less predictable in offspring. Additionally, discussions about reproductive health may lead to improved care coordination with patients’ primary care and OB providers. These providers may need education about risks during and after pregnancy related to IMDs. Pediatricians of patients’ future offspring should also be involved in care, as they may be directing the initial screening or management of newborn infants.