Wednesday, October 20, 2021

Individuals Treated for Gender Dysphoria with Medical and/or Surgical Transition Who Subsequently Detransitioned: A Survey of 100 Detransitioners

Individuals Treated for Gender Dysphoria with Medical and/or Surgical Transition Who Subsequently Detransitioned: A Survey of 100 Detransitioners. Lisa Littman. Archives of Sexual Behavior, Oct 19 2021.

Abstract: The study’s purpose was to describe a population of individuals who experienced gender dysphoria, chose to undergo medical and/or surgical transition and then detransitioned by discontinuing medications, having surgery to reverse the effects of transition, or both. Recruitment information with a link to an anonymous survey was shared on social media, professional listservs, and via snowball sampling. Sixty-nine percent of the 100 participants were natal female and 31.0% were natal male. Reasons for detransitioning were varied and included: experiencing discrimination (23.0%); becoming more comfortable identifying as their natal sex (60.0%); having concerns about potential medical complications from transitioning (49.0%); and coming to the view that their gender dysphoria was caused by something specific such as trauma, abuse, or a mental health condition (38.0%). Homophobia or difficulty accepting themselves as lesbian, gay, or bisexual was expressed by 23.0% as a reason for transition and subsequent detransition. The majority (55.0%) felt that they did not receive an adequate evaluation from a doctor or mental health professional before starting transition and only 24.0% of respondents informed their clinicians that they had detransitioned. There are many different reasons and experiences leading to detransition. More research is needed to understand this population, determine the prevalence of detransition as an outcome of transition, meet the medical and psychological needs of this population, and better inform the process of evaluation and counseling prior to transition.


This study was designed to explore the experiences of individuals who obtained medical and surgical treatment for gender dysphoria and then detransitioned by discontinuing the medications or having surgery to reverse the changes from transition. The findings of this study, however, should not be assumed to be representative of all individuals who detransition. Although this study further documents that detransitioners exist, the prevalence of detransition as an outcome of transition is unknown. Only a small percentage of detransitioners (24.0%) informed the clinicians and clinics that facilitated their transitions that they had detransitioned. Therefore, clinic rates of detransition are likely to be underestimated and gender transition specialists may be unaware of how many of their own patients have detransitioned, particularly for patients who are no longer under their care.

This research demonstrates that the experiences of individuals who detransition are varied and the reasons for detransition are complex. Nearly all participants identified as transgender or nonbinary at the start of their transition and most sought transition because they did not want to be associated with their natal sex, their bodies felt wrong the way they were, and they believed that transition was the only option to relieve their distress. Some were helped by transition and only detransitioned because they were pressured to do so by people in their lives, society, or because they had medical complications. Some were harmed by transition and detransitioned because they concluded that their gender dysphoria was caused by trauma, a mental health condition, internalized homophobia, or misogyny—conditions that are not likely to be resolved with transition. These findings highlight the complexity of gender dysphoria and suggest that, in some cases, failure to explore co-morbidities and the context in which the gender dysphoria emerged can lead to misdiagnosis, missed diagnoses, and inappropriate gender transition. Some individuals detransitioned because their gender dysphoria resolved, because they found better ways to address their symptoms, or because their personal definitions of male and female changed and they became comfortable identifying as their natal sex.

The study sample was predominantly young natal females, many of whom experienced late-onset gender dysphoria which mirrors the recent, striking changes in the demographics of gender dysphoric youth seeking care as well as the youth described by their parents in Littman (2018) (see also Aitken et al., 2015; de Graaf et al., 2018; Zucker, 2019). Concerns have been raised that this new cohort of gender dysphoric individuals is unlike previous cohorts. Professionals have started to call for caution before treating this cohort with interventions with permanent effects because the etiologies, desistance and persistence rates, expected duration of symptoms, and whether this new population is helped or harmed by gender transition is still unknown (D’Angelo et al., 2021; Kaltiala-Heino et al., 2018). The natal females and natal males in this sample differed on several dimensions, including that natal females were younger than natal males when they sought transition, when they decided to detransition, and at the time of survey completion. Natal females were more likely than natal males to have experienced a trauma less than one year before the onset of their gender dysphoria and were more likely to have felt pressured to transition. Compared to natal males, natal females remained transitioned for a shorter duration of time before deciding to detransition. Additionally, natal females transitioned more recently than natal males, so their experiences may vary due to changing trends in the clinical management of gender dysphoria and the cultural settings in which they became gender dysphoric.

The study findings covered a wide range of detransition experiences that are consistent with the diversity of experiences described in previously published clinical case reports and case series. Overlap of findings include: transition regret; absence of transition regret; re-identification with birth sex; continued identification as transgender; improvement or worsening of well-being with transition; retransitioning; detransitioning due to external social pressures; nonbinary identification; and recognizing and accepting oneself as homosexual or bisexual (D’Angelo, 2018; Djordjevic et al., 2016; Levine, 2018; Pazos Guerra et al., 2020; Turban & Keuroghlian, 2018; Turban et al., 2021; Vandenbussche, 2021). The population in this study is similar to the population in Vandenbussche in that both were predominantly natal females in their mid-20s. Because the current study recruited in 2016–2017 and Vandenbussche recruited in 2019, the similar mean age of participants may reflect the age of individuals who can be reached in online detransitioner communities. Several findings in this study were consistent with Vandenbussche’s findings, including similar reasons for detransition (realizing that their gender dysphoria was related to other issues, finding alternatives to address gender dysphoria, gender dysphoria resolved, etc.). Although these two studies were recruited in different years, had different eligibility criteria, and included participants from several countries, it is possible that there may be some overlap of study populations.

The current study findings provide additional insight into the complex relationships between internalized homophobia, gender dysphoria, and desire to transition. Contrary to arguments against the potential role of homophobia in gender transitions (Ashley, 2020), participants reported that their own gender dysphoria and desire to transition stemmed from the discomfort they felt about being same-sex attracted, their desire to not be gay, and the difficulties that they had accepting themselves as lesbian, gay or bisexual. For these individuals, exploring their distress and discomfort around sexual orientation issues may have been more helpful to them than medical and surgical transition or at least an important part of exploration before making the decision to transition. This research adds to the existing evidence that gender dysphoria can be temporary (Ristori & Steensma, 2016; Singh et al., 2021; Zucker, 2018). It has been established that the most likely outcome for prepubertal youth with gender dysphoria is to develop into lesbian, gay, bisexual (LGB) (non-transgender) adults (Ristori & Steensma, 2016; Singh et al., 2021; Wallien & Cohen-Kettenis, 2008; Zucker, 2018). And, temporary gender dysphoria may be a common part of LGB identity development (Korte et al., 2008; Patterson, 2018). Therefore, intervening too soon to medicalize gender dysphoric youth risks iatrogenically derailing the development of youth who would otherwise grow up to be LGB non-transgender adults. Participants who detransitioned because they became comfortable identifying as their natal sex and because their gender dysphoria resolved further support that gender dysphoria is not always permanent.

The data in this study strengthen, with first-hand accounts, the rapid-onset gender dysphoria (ROGD) hypotheses which, briefly stated, are that psychosocial factors (such as trauma, mental health conditions, maladaptive coping mechanisms, internalized homophobia, and social influence) can cause or contribute to the development of gender dysphoria in some individuals (Littman, 2018). Littman also postulated that certain beliefs could be spread by peer contagion, including the belief that a wide range of symptoms should be interpreted as gender dysphoria (and proof of being transgender) and the belief that transition is the only solution to relieve distress. The current study supports the potential role of psychosocial factors in the development of gender dysphoria and further suggests, by participant responses that transitioning prevented or delayed them from addressing their underlying conditions, that maladaptive coping mechanisms may be relevant for some individuals. The potential role of social influence is demonstrated as well. First, when respondents were asked to describe how they currently feel about having identified as transgender in the past, more than a third endorsed the option, “Someone told me that the feelings I was having meant that I was transgender, and I believed them.” Second, a subset of participants experienced the unique friendship group dynamics reported in Littman where peer groups mocked people who were not transgender and popularity within the friend group increased when respondents announced their plan to transition. Additionally, respondents identified several social sources that encouraged them to believe that transitioning would help them including: YouTube transition videos, blogs, Tumblr, and online communities. And finally, 20.0% of participants felt pressured to transition by social sources that included friends, partners, and society. More research is needed to further explore these hypotheses.

The current study and the Turban et al. (2021) analysis of the USTS data share some similarities and differences. Similarities include the use of convenience samples, targeted recruitment, and anonymous data collection. The findings of Turban et al. (including external pressures to detransition and transgender identification after detransition) are a subset of the array of experiences described in the current study. The current study differed from James et al. (2016) and Turban et al. in that it enrolled participants based on the criterion of detransition after medical or surgical transition regardless of how they currently identified, recruited from communities with diverse perspectives about transition and detransition, used a precise definition for detransition that specifies the use of medication or surgery, and included answer options that were relevant to many different types of detransition experiences. In contrast, the USTS only enrolled transgender-identifying individuals regardless of whether they medically or surgically transitioned, recruited from communities likely to have similar perspectives about transition and detransition, and provided multiple choice answer options that were relevant to a narrower range of detransition experiences (James et al., 2016). Further, the definition used by the USTS for “detransitioned” (having “gone back to living as [their] sex assigned as birth, at least for a while”) is quite vague. Although Turban et al. provide valuable information about the subset of transgender-identifying people who may have detransitioned, the current study provides a more comprehensive view of individuals who detransition after medical or surgical transition.

Over the past 15 years, there have been substantial changes in the clinical approach to gender dysphoric patients notable for a shift from approaches that employ thorough evaluations and judicious use of medical and surgical transition (the watchful waiting or Dutch approach, the developmentally informed approach, and the medical model of care) to approaches with minimized or eliminated evaluation and liberal use of transition interventions (the affirmative approach and the informed consent model of care) (Cavanaugh et al., 2016; de Vries & Cohen-Kettenis, 2012; Meyer et al., 2002; Rafferty et al., 2018; Schulz, 2018; Zucker et al., 2012b). This trend is prominent in the U.S. where the American Academy of Pediatrics endorsed the affirmative approach in 2018 and Planned Parenthood currently uses the informed consent model to provide medical transition in more than 200 clinics in 35 states (Planned Parenthood, 2021; Rafferty et al., 2018). It is plausible that an unintended consequence of these clinical shifts may be an increase in people who detransition. Many participants in this study believe that they did not receive an adequate evaluation by a clinician before transition. The definition of “adequate evaluation” was not provided in the survey and may be open to respondent interpretation. But given the complexities of the gender dysphoria described in the current study, one might consider a low bar of “adequate” to be the exploration of factors that could be misinterpreted as non-temporary gender dysphoria as well as factors that could be underlying causes for gender dysphoria. The most recently emerging approach to gender dysphoria is called the “exploratory approach” which is a neutral psychotherapeutic approach to help individuals gain a deeper understanding of their gender distress and the factors contributing to their dysphoria (Churcher Clarke & Spiliadis, 2019; Spiliadis, 2019). The study’s findings suggest that an exploratory type of approach may have been beneficial to some of the respondents. Future research is needed to determine which patients are best treated by which approaches long term.

Patients considering medical and surgical interventions deserve accurate information about the risks, benefits, and alternatives to that treatment. In this sample, nearly half of the participants reported that the counseling they received about transition was overly positive about the benefits of transition and more than a quarter reported that the counseling was not negative enough about the risks. Several participants felt pressured to transition by their doctors and therapists. If these types of clinical interactions are verified, exploration is needed to determine the extent to which this situation occurs and what measures might be taken to ensure that clinicians provide patients with their options accurately and dispassionately.

There are several obstacles to obtaining accurate rates of detransition and desistance, including stigma and the low numbers of detransitioners who inform their clinicians that they detransitioned. One approach to bypass some of these barriers would be to incorporate non-judgmental questions about detransition and desistance into nationally representative surveys that collect health data. For example, the Behavioral Risk Factor Surveillance System contains an optional module about sexual orientation and gender identity that includes two questions to explore gender issues (Downing & Przedworski, 2018). By changing one existing question, “Do you consider yourself to be transgender?” into two questions, “Have you ever, at any point in your life, considered yourself to be transgender?” and “Do you currently consider yourself to be transgender?” and by adding a follow-up question if answers indicate past but not current transgender identification, “Did you ever take puberty blockers, cross-sex hormones, anti-androgens, or have any surgery as part of your transition?”, valuable information about desistance, detransition, and current transgender identification could be obtained. These types of questions may also be of use in clinical practice and electronic medical records. The information gained about rates of detransition and desistance would enhance transgender healthcare by aiding informed consent processes at the start of any medical or surgical transition.

One of the strengths of this study is that it is one of the largest samples of detransitioners to date. Other strengths include the use of a precise definition for detransition, enrollment of detransitioners regardless of their post-detransition gender identification, recruitment from communities with likely divergent views about transition and detransition, and collaboration with two individuals who had detransitioned which helped to create a survey instrument with questions relevant to a variety of detransition experiences and enhanced the recruitment efforts.

There are several limitations to this study that should be considered when interpreting the findings. Like Vandenbussche (2021), James et al. (2016), and Turban et al. (2021), this study used a cross-sectional design, anonymous surveying, and a convenience sample and therefore shares the same limitations that are inherent to these methodologies. These limitations include that conclusions about causation cannot be determined, identities of participants cannot be verified, and the findings of this study may not be generalizable to the entire population of people who detransition or to people outside of the countries where participants were from. Although this study reached out to communities with differing perspectives about transition and detransition, targeted recruitment and convenience samples always introduce the limitations associated with selection biases which should be addressed in future research. Finally, many of the participants in this study had less than ideal outcomes to their medical and surgical transitions, and it is possible that these experiences may have colored some of the responses.

Additional research is needed to determine the prevalence of detransition as an outcome of transition and to identify and meet the psychological and medical needs of the emerging detransitioned population. Because many individuals who detransition re-identify with their birth sex, are no longer connected to LGBT communities, and don’t return to gender clinics, future research about detransition needs to expand recruitment efforts beyond gender clinics and transgender communities. The development and testing of non-medical interventions for gender dysphoria could provide valuable options to be used as alternatives or in conjunction with medical and surgical treatments. Because of the potential for some to experience trauma, mental health conditions, internalized homophobia, and misogyny as gender dysphoria, research needs to be conducted on the evaluation process before transition to find approaches that respectfully and collaboratively explore factors that might contribute to gender-related distress. There continues to be an absence of long-term outcomes evidence for youth treated with medical and surgical transition and a lack of information about the trajectories of youth experiencing late-onset gender dysphoria–research is needed to address these gaps. Continued work is needed to reduce rigid gender roles, increase representation of gender stereotype nonconformity, and to address discrimination and social pressures exerted against people who are transgender, lesbian, gay, bisexual, and gender stereotype non-conforming.

Greater Internet access predicts a larger gender news gap, while female representation in politics interacts with political freedom and press freedom to influence the size of the gap

Explaining the Gender Gap in News Access Across Thirty Countries: Resources, Gender-Bias Signals, and Societal Development. Macau K. F. Mak. The International Journal of Press/Politics, October 19, 2021.

Abstract: The gender gap in news access affects the opportunities available for a particular gender to advocate politically, as news consumption contributes to citizens’ understanding of politics and their political participation. Given the significance of the issue, this study uses multilevel modelling and investigates how resources (Internet, education, household income), gender-bias signals (female political representation and economic participation), and societal development (press freedom, political freedom, and economic development) influence the size of the gender news gap. The analysis of multinational cross-sectional survey data (N = 61,677) shows that greater Internet access predicts a larger gender news gap, while female representation in politics interacts with political freedom and press freedom to influence the size of the gap. This study does not only advance the understanding about the individual and societal factors influencing the gender news gap, but also provides insights into solutions to alleviate the gap.

Keywords: gender news gap, gender inequality, news access, multilevel modelling, Internet access, gender-bias signals, press freedom, political freedom

Male and female fetuses respond differently to COVID-19 virus

Maternal SARS-CoV-2 infection elicits sexually dimorphic placental immune responses. Evan A Bordt et al. Sciece Translational Medicine, Oct 19 2021. DOI: 10.1126/scitranslmed.abi7428

Abstract: There is a persistent bias toward higher prevalence and increased severity of coronavirus disease 2019 (COVID-19) in males. Underlying mechanisms accounting for this sex difference remain incompletely understood. Interferon responses have been implicated as a modulator of COVID-19 disease in adults, and play a key role in the placental antiviral response. Moreover, the interferon response has been shown to alter Fc receptor expression, and therefore may impact placental antibody transfer. Here we examined the intersection of maternal-fetal antibody transfer, viral-induced placental interferon responses, and fetal sex in pregnant women infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Placental Fc receptor abundance, interferon stimulated gene (ISG) expression, and SARS-CoV-2 antibody transfer were interrogated in 68 human pregnancies. Sexually dimorphic expression of placental Fc receptors, ISGs and proteins, and interleukin-10 was observed following maternal SARS-CoV-2 infection, with up-regulation of these features in placental tissue of pregnant individuals with male fetuses. Reduced maternal SARS-CoV-2-specific antibody titers and impaired placental antibody transfer were also observed in pregnancies with a male fetus. These results demonstrate fetal sex-specific maternal and placental adaptive and innate immune responses to SARS-CoV-2.

Popular version:


Our results demonstrate the impact of fetal sex on the maternal and placental immune response to SARS-CoV-2, and the potential consequences for neonatal antibody-mediated immunity. We show that maternal SARS-CoV-2 infection is associated with reduced maternal SARS-CoV-2-specific IgG titers in the setting of a male fetus. SARS-CoV-2-specific placental antibody transfer to the male fetus was reduced despite up-regulation of placental Fc receptors in SARS-CoV-2-exposed male placentas; males were unable to overcome the reduced maternal titers and the highly fucosylated glycan profile of the spike protein-specific antibodies. Mirroring Fc receptor expression, placental expression of interferon stimulated genes and proteins was also sexually dimorphic, with notable up-regulation noted in male placentas in the setting of maternal SARS-CoV-2 infection. Collectively these findings provide evidence of maternal-placental-fetal immune crosstalk in the setting of maternal viral infection, with fetal sex playing a key role in modifying maternal humoral responses and placental innate and adaptive immune responses.
Epidemiologic data point to a persistent male bias in the development and severity of COVID-19 disease in adults, children, and infants (6898283). Male COVID-19 patients are three times as likely to require admission to intensive care units and have higher odds of death than females (84). This male-biased vulnerability to maternal SARS-CoV-2 infection mirrors the male-biased risk of mortality and morbidity across the perinatal period (13). Our findings of sexually dimorphic placental innate immune responses to infection, coupled with sex differences in transfer of maternal humoral immunity, may provide insight into increased vulnerability of male infants to morbidity and mortality.
Although the impact of fetal sex is not consistently evaluated in studies of placental function (85), sex-specific alterations in the placental transcriptome have been described in both normal and pathologic pregnancies (8689). Sex differences in the placental immune response to prenatal infections and other immune stressors have been described in human and animal models (549093), but have not been examined in SARS-CoV-2 infection. Here we report that maternal SARS-CoV-2 infection induces a sexually dimorphic placental antiviral innate immune response, with up-regulation of ISGs in male, but not female, placentas. Male-specific stimulation of placental ISGs following SARS-CoV-2 exposure is consistent with the heightened male immune responses reported in SARS-CoV-2-infected adult and pediatric cohorts (568104294). Interestingly, although we did not see evidence of maternal viremia nor placental, cord blood, or neonatal SARS-CoV-2 infection (2895), and the majority of maternal infections represent mild or moderate disease, there is still evidence of altered placental gene expression and an antiviral response in the placentas of male pregnancies. This indicates that even a mild maternal infection in the absence of placental or fetal infection has the potential to affect placental function and fetal development.
Due to their immature immune system, newborns rely on the passive transplacental transfer of maternal antibodies for initial protection against infectious pathogens (151896). Although previous reports in adults have noted sex differences in the production of SARS-CoV-2-specific antibodies (4297), sex-biased maternal production and transplacental transfer of SARS-CoV-2-specific antibodies has not been well-described. We previously reported impaired placental transfer of maternal SARS-CoV-2-specific antibodies in the setting of maternal COVID-19 (2829). Although there are known sex differences in adult antibody production in response to SARS-CoV-2 infection (4294), little is known about sex differences in maternal titers or transplacental antibody transfer (9899) in the setting of maternal SARS-CoV-2 infection. Our finding of decreased maternal antibody titers against all measured SARS-CoV-2-specific antigens (S, S1, S2, RBD, N) when the fetus was male versus female was a difference not observed for influenza or pertussis-specific antibodies. Reduced maternal SARS-CoV-2-specific IgG titer in male pregnancies was undoubtedly a driver of the reduced transplacental transfer noted in male fetuses (15). This finding of impaired placental transfer of SARS-CoV-2-specific antibodies, more pronounced in males, is consistent with the male-specific reduction of placental transfer of maternal IgG reported in a non-human primate model of maternal stress (98). Reduced maternal antibody titers in the setting of a male fetus were likely attributable to suppressed maternal pro-inflammatory responses in the setting of a male fetus, which have been described in prior studies and may function to improve tolerance of the fetal allograft (1314). The direct correlation between pro-inflammatory response and increased antibody production noted in COVID-19 infection (6667) suggests that blunted maternal inflammatory responses in the setting of a male fetus may limit maternal antibody production in the setting of acute infection. Whether the male-biased impairment in placental SARS-CoV-2-specific antibody transfer renders male infants more vulnerable to early-life SARS-CoV-2 infection remains unclear, as the amount of antibody necessary for protection against SARS-CoV-2 infection is unknown and there are few sex-disaggregated reports of neonatal (100101) or infant infection (8).
Although the up-regulation of Fc receptor expression in male placentas may represent a compensatory placental response driven by reduced maternal antibody titer and transplacental transfer of SARS-CoV-2 antibodies (22102103), this response was likely reinforced by the increased IFN signaling in males versus females. IFN-stimulated signaling may impact placental antibody transfer via alteration in Fc receptor expression and function (104106); for example, Type I IFN signaling is known to up-regulate Fcγ receptor expression on monocytes (107). Hofbauer cells, tissue-resident macrophages of the placenta, express FcγRI, II and III (23). The male-specific Hofbauer cell hyperplasia in placentas exposed to maternal SARS-CoV-2 infection could therefore also be contributing to increased placental FcγRI and FcγRIII expression in males.
Although the low maternal antibody titers in male pregnancies may have driven a compensatory up-regulation of Fc receptors in the male placenta, the up-regulation of FcγRIII and co-localization of FcγRIII with FcRn in the male placenta likely impeded placental transfer of SARS-CoV-2-specific antibodies, given their distinct Fc-glycan profile. Our Fc-glycan analysis demonstrated that SARS-CoV-2-specific antibodies were highly fucosylated in both male and female pregnancies, a post-translational modification that lowers antibody affinity for FcγRIII (6971). The male-specific placental increase in FcγRIII expression and co-localization of FcγRIII with FcRn might therefore present an additional impediment to transferring the already-low maternal titers of SARS-CoV-2-specific antibodies to the fetus. Males instead preferentially transferred bisected (afucosylated) and agalactosylated (G0), afucosylated spike protein-specific antibodies, as afucosylated antibodies are more easily transferred by FcγRIII. Given the inflammatory nature of G0 and B antibodies (72108109), their preferential transfer might promote a more inflammatory immune response in male fetuses.
Innate immune sensing of SARS-CoV-2 involves the activation of type I and type III interferons and up-regulation of ISGs in target cells (110). Given the relative paucity of SARS-CoV-2 placental infection (28) in comparison to other pandemic infections such as Zika virus (ZIKV) (111), the increased ISG production and up-regulated IL10 expression in exposed male placentas may be a protective mechanism to prevent direct placental infection and pathology. Indeed, high IFN concentrations during pregnancy have proven protective against placental herpes simplex virus infection (112) and type III IFNs impair ZIKV transplacental transmission (113). Induction of ISGs is likely not universally protective, however. Whereas type III IFNs primarily serve a barrier defense role, type I and type II IFNs can serve a more classical immune activating or inflammatory role (3145). Animal models of viral infection in pregnancy implicate type I and type II interferons and ISGs in impaired placental development and fetal growth restriction (465051114), conditions which can have both short- and long-term impact on fetal and offspring health. We demonstrated increased expression of IFN-γ, initiator of Type II interferon signaling, in male SARS-CoV-2-exposed placentas. IFN-γ and the Type II IFN response have been implicated in placental spiral artery remodeling, and may mediate fetal growth restriction and fetal demise in malarial and Toxoplasma gondii infection in pregnancy (5051115116). A transcriptomic analysis of SARS-CoV-2 response genes demonstrated that IFN-γ was an upstream regulator of host viral response in the setting of SARS-CoV-2 infection (117), with higher IFN-γ abundance associated with increased risk for SARS-CoV-2 viral entry (52) and increased mortality in moderate and severe COVID-19 illness (53). Thus, it remains unclear if the male-specific up-regulation of ISGs described here is potentially beneficial (protection from viral infection) versus harmful (increased placental inflammation, increased risk for fetal growth restriction or poor placental function). It was noteworthy that female placentas from SARS-CoV-2-negative control pregnancies generally had higher expression of interferon-stimulated genes and proteins than did male SARS-CoV-2-negative placentas. The potential for a baseline female “antiviral placental advantage” is consistent with the established increased vulnerability of the male fetus to in utero insults, including viral and bacterial infection (92118), and observed sex differences in baseline innate immunity described in non-placental cells and tissues (12119). These findings highlight the necessity of future studies assessing baseline differences in male and female placental immune responses. The long-term consequences of SARS-CoV-2-associated placental induction of Type I, II, and III IFN responses for fetal development and in utero programming of later life metabolic and neurodevelopmental outcomes remains to be determined.
A limitation of our study is the infection of participants primarily in the third trimester, because these samples were collected during the initial wave of the SARS-CoV-2 pandemic in Boston. Whether maternal SARS-CoV-2 infection in the first and second trimester alters ISG and Fc receptor expression, and how such altered expression might durably impact placental immune function, is a question that remains to be answered in future studies. It remains unclear whether the reduced SARS-CoV-2-specific maternal antibody titers, highly fucosylated glycan profile of spike protein-specific antibodies, and attenuated male-specific transplacental antibody transfer are unique to SARS-CoV-2 biology, or whether these phenomena instead reflect a common response to de novo infection during pregnancy. Future studies should assess the effect of fetal sex on maternal SARS-CoV-2 antibody titers and transplacental transfer in women infected prior to pregnancy, and the effect of fetal sex on maternal antibody responses to other de novo infections during pregnancy. In addition, although we found no association between disease severity and placental gene expression or antibody transfer, such examinations were limited by the relatively small number of women with severe or critical illness. Although our results demonstrate male-specific up-regulation of Type I and II IFNs (IFN-α and IFN-γ), and interferon-stimulated genes and proteins downstream of Type I-III signaling cascades, this study did not assess protein expression of Type III IFN-λ. Finally, although our regression models did not find time from infection to delivery to be a substantial contributor to the antibody transfer ratios, we cannot entirely rule out any contribution of timing of maternal infection to the reduced antibody transfer noted in males. However, our robust sexually dimorphic gene and protein expression results, with up-regulation of both placental ISGs and Fc receptors in males, demonstrate placental factors are a stronger driver of antibody transfer than any time-from-infection effect.
In conclusion, our comprehensive evaluation of the impact of fetal sex on placental gene expression and transplacental antibody transfer in maternal SARS-CoV-2 infection provides insight into sexually dimorphic or sex-specific placental innate and adaptive immune responses to maternal SARS-CoV-2 infection. The increased impact of maternal SARS-CoV-2 infection on male placental and neonatal immunity highlights the importance of evaluating fetal sex in future studies of placental pathology and infant outcomes in SARS-CoV-2, as well as the critical importance of disaggregating sex data in follow-up studies of offspring neurodevelopmental and metabolic outcomes. These findings may have broader implications for understanding placental immune response, male vulnerability, and passive transfer of maternal antibody in other viral infections. Studies investigating SARS-CoV-2 vaccine safety and efficacy in pregnant women should also evaluate placental immune response and antibody-transfer effects, in addition to neonatal infection rates, and report these data in a sex-disaggregated fashion (120).