A systematic review of reproductive technologies for shared conception in same-sex female couples.

Once publication titles were identified, two independent researchers screened titles and abstracts for relevance, with ties broken by a third researcher. Full texts were then reviewed by two independent researchers to identify all aspects of the inclusion criteria including population, intervention, and outcomes, as outlined above. Conflicts of full texts reviews were resolved by a third researcher. Excluded articles were labeled by their specific exclusion criterion, such as outcomes outside the scope of this review or for not being a full-length research article ( Figure 1 ). Data extraction was conducted using the Covidence software by one researcher and reviewed for accuracy by a second researcher. This study did not attempt to further analyze or pool results.

The search strategy identified 1634 unique studies for potential inclusion. Of those, 1573 studies were excluded for being unrelated to either reciprocal IVF or IVC. Many of the excluded studies were of adjacent topics: 454 articles related to LGBTQIA+ (lesbian, gay, bisexual, transgender, intersex, asexual, and other sexual or gender minorities) fertility generally, with 286 of those articles focusing on transgender fertility, 17 articles on clinical outcomes of SSFC undergoing MAR other than IVF or IVC, 26 articles on non-clinical aspects of IVF in SSFCs (such as attitudes, opinions or ethics), and 125 articles on non-clinical outcomes of SSFC or LGBTQIA+ fertility more broadly ( Figure 1 ). A total of 62 studies were assessed via full text review after title and abstract screening. Of those, 44 were excluded due to either having incorrect outcomes (3 articles), lacking the intervention of reciprocal IVF or IVC (2 articles), taking place before 1995 (7 articles), or not being original research articles (32 articles) ( Figure 1 ). With the addition of one IVC study identified through citation review ( 14 ), a total of 18 studies that evaluated clinical cycle or pregnancy outcomes including embryo quality, positive pregnancy test rate, clinical pregnancy rate, live birth rate, or perinatal outcomes were included in this review. Eight articles relating to reciprocal IVF and ten articles relating to IVC met inclusion criteria ( Figure 1 ). The study designs of the eight reciprocal IVF articles that qualified for review were as follows: four case series (with no comparison group included) and four retrospective studies ( Table 1 ). Of the four retrospective studies, reciprocal IVF outcomes were compared to IUI outcomes in one study and autologous IVF outcomes in three studies. Data collection for these publications occurred between November 2002 and January 2021. Six out of the eight studies were conducted in Spain ( 5 , 15 – 19 ), one in the United Kingdom ( 6 ), and one in the United States ( 20 ). The eight studies described a total of 1405 reciprocal IVF cycles, including more than 595 couples (ranging from 14 to 281 couples in any individual study). The cycle total includes cycles from Matorras et al., which described 660 reciprocal IVF cycles but did not specify the number of couples ( 19 ). The most commonly reported findings were clinical pregnancy rate and live birth rate. Three studies reported on neonatal outcomes ( 5 , 19 , 20 ). Among the four comparative studies, three compared reciprocal IVF cycles to other SSFCs using autologous IVF or IUI ( 15 , 18 , 19 ), and one compared them to both heterosexual couples and single patients who utilized autologous oocytes with donor sperm and had no known fertility disorder ( 16 ). Exclusion criteria differed amongst the studies, especially concerning the diagnosis of infertility. Matorras et al. excluded patients who were previously pregnant by IUI or reciprocal IVF or those with a need for IVF due to infertility or genetics ( 19 ). Brandão et al. 2022b excluded any patients with a disorder that could impact fertility ( 16 ). Four studies explicitly mentioned the inclusion of patients with conditions impacting fertility, with overall incidence reported between 40% and 60% of reciprocal IVF couples ( 5 , 6 , 15 , 20 ). Of the 172 cycles analyzed in Bodri et al., 40% had a medical indication for IVF such as failed IUI/IVF, diminished ovarian reserve (DOR), or parental age >40 years ( 6 ). In Brandão et al. 2023, infertility factors were present in 54% of the 356 reciprocal IVF cycles reported ( 5 ). These included DOR (7%), endometriosis (3%), polycystic ovarian syndrome (2%), and parental age >38 years ( 5 ). Yeshua et al. found that 65% of couples undergoing reciprocal IVF had infertility factors such as failed IVF/IUI or DOR ( 20 ). Brandão et al. 2022a found that >60% of included couples had at least one infertility factor or advanced parental age ( 15 ). The average age of oocyte donors in reciprocal IVF cycles ranged from 32-36 years while the average age of the oocyte recipients (gestational carriers) ranged from 33-38 years. Of the seven studies that reported both partners’ ages, four reported the average age of oocyte donors was lower than the average age of oocyte recipients (gestational carriers) ( 5 , 6 , 19 , 20 ). Among the five studies that reported population body mass index (BMI), all found the average BMI did not differ between oocyte donors and gestational carriers ( 5 , 6 , 16 , 18 , 19 ). One study found that oocyte donors had a significantly higher anti-müllerian hormone (AMH) compared to gestational carriers (25 vs. 19 pmol/L, p=0.002) ( 6 ). The two other studies reporting on AMH did not report a difference between oocyte donors and gestational carriers ( 5 , 15 ). Six studies reported positive pregnancy test rates as the following: 69% (5), 61% (6), 70% (18), 44% (19), 60% (16), and 63% (20). Of the two studies that compared positive pregnancy test rates of reciprocal IVF and autologous IVF with intracytoplasmic sperm injection (ICSI), Núñez et al. reported rates to be significantly higher than autologous IVF/ICSI after first fresh embryo transfer (ET) (70% vs. 48%, p=0.004), while Brandão et al. 2022b reported no difference (63% vs. 58%, p= 0.3) ( 16 , 18 ). Matorras et al. reported a significantly higher positive pregnancy test rate when compared to IUI (45% vs. 22%, p<0.001) amongst SSFCs ( 19 ). Six studies reported on clinical pregnancy rate per ET. For reciprocal IVF cycles, the reported rates were: 52% (6), 57% (16), 54% (5), 46% (17), 60% (18), and 56% (20). Of the two studies that compared clinical pregnancy rates between reciprocal IVF and autologous IVF, Núñez et al. reported a significantly higher clinical pregnancy rate for reciprocal IVF when compared to autologous IVF/ICSI (60% vs. 40%, p=0.01) ( 18 ), though Brandão et al. 2022b found no difference IVF (57% vs. 50%, p=0.2) ( 16 ) after each patien’s first fresh ET. The live birth rates per ET were as follows: 42% (6), 36% (16), 45% (5), 29% (19), and 57% (18). Marina et al. and Yeshua et al. reported an ongoing pregnancy or live birth rate of 31% (17) and 39% (20), respectively. When comparing reciprocal IVF to autologous IVF, Núñez et al. reported an increase in LBR per ET (57% vs. 30%, p=0.001) ( 18 ), while Brandão et al. 2022b found no difference (36% vs. 41%, p=0.1) ( 16 ). When comparing reciprocal IVF to IUI, Matorras et al. found reciprocal IVF to have a 30% higher odds of live birth (OR=1.3, 95% Confidence lnterval=1.0-1.7) ( 19 ). Cumulative LBR per couple were reported in three studies. In their two studies, Brandão et al. identified a 79% and 78% cumulative LBR in couples undergoing reciprocal IVF ( 15 , 16 ). In a much smaller study, Yeshua et al. reported a cumulative LBR per couple of 43%, with another 24% of couples reporting an ongoing pregnancy at time of publication ( 20 ). Matorras et al. compared the incidence of perinatal complications in pregnancies resulting from reciprocal IVF and IUI amongst SSFCs ( 19 ). They reported no difference in the following outcomes: gestational age at delivery or preterm birth, neonatal weight, incidence of birth defects, cesarean delivery rate, and perinatal morbidity ( 19 ). The study reported a non-significant increase in the primary outcome of preeclampsia or gestational hypertension in reciprocal IVF pregnancies as compared to IUI pregnancies (aOR=1.9, CI = 0.7-5.2) ( 19 ). In twin pregnancies (n=9 reciprocal IVF, n=46 IUI), there was a significantly higher odds of preeclampsia or gestational hypertension among reciprocal IVF pregnancies (aOR = 21.7, CI= 2.8-289.4) ( 19 ). Bodri et al. reported a preterm delivery rate of 10% and a low birth weight rate of 7% in reciprocal IVF singleton pregnancies ( 6 ). For twins, the rates of these complications were significantly higher (60% and 30% respectively, p=0.006) ( 6 ). The study also reported a singleton cesarean delivery rate of 40% with 64% documented as emergent ( 6 ). One newborn out of 72 had a congenital anomaly ( 6 ). Yeshua et al. reported no birth defects from all reciprocal IVF live births (n=9) ( 20 ). The ten IVC studies that qualified for data extraction included three case series, two retrospective studies, one prospective cohort study, and four randomized trials ( Table 2 ). These studies, in total, reported outcomes of 776 intravaginal culture cycles, with another study reporting on perinatal outcomes of 66 pregnancies resulting from IVC. Data collection for these publications occurred between June 2009 and August 2022. Four of the ten studies were conducted in the United States, two in Brazil, and the remainder were from Columbia, Peru, Canada, or Malaysia. The primary outcomes reported in most studies were percentage of quality embryos, positive pregnancy test rate, clinical pregnancy rate, and live birth rate. One study focused on perinatal outcomes for pregnancies resulting from IVC ( 21 ). Most studies included only patients with a diagnosis of infertility, defined as one of more years of inability to conceive ( 22 – 24 ). Patients’ ages ranged between 18 to 44 years in all reported studies, though some excluded patients over the age of 38 years. Patients with DOR, endometriosis, male factor infertility, history of recurrent failed IVF cycles, and BMI >35 kg/m 2 were most commonly excluded from the studies. Two studies explicitly excluded patients utilizing donor sperm ( 22 , 23 ). Coelho et al. and Garcia-Ferreyra et al. compared patients undergoing IVC to patients undergoing autologous IVF/ICSI, reporting 95 total IVF/ICSI cycles ( 25 , 26 ). Doody et al. and Cedars et al. compared patients undergoing IVC to patients undergoing autologous IVF ( 23 , 24 ), while Mitri et al., Mohsin et al., and Freitas Aguiar et al. compared outcomes between sibling oocytes that were assigned to IVC or autologous IVF ( 22 , 27 , 28 ). Five studies reported on the rate of “good quality embryos” produced. Mohsin et al. considered good embryo quality as those reaching a Gardner scoring grade of 4BB and above, with trophectoderm grades of A or B ( 27 , 29 ). Doody et al. used a modified Gardner scoring method to define good quality as a grade of 2BB or greater, with trophectoderm grades of A or B ( 23 , 30 ). Garcia-Ferreya et al. defined good quality as day 3 embryos with 6-8 cells, no multinucleation, ≥10% fragmentation, and a type A or B inner cell mass and trophectoderm ( 26 ). Cedars et al. defined embryo grade by the simplified Society for Assisted Reproductive Technology (SART) embryo scoring system ( 24 ). Freitas Aguiar et al. compared embryo quality between a 3 or 5 day intravaginal culture protocol to autologous IVF; defining “high quality” for day 3 embryos as having 8-12 cells and for day 5 embryos as expanded blastocysts ( 28 ). Two cohort studies found no difference in good quality embryo rate per retrieved oocyte between IVC and autologous IVF or ICSI embryos: Garcia-Ferreyra et al. reported good quality embryo rate of 77% vs. 87% (p>0.05) ( 26 ), and Mohsin et al. reported 11% vs. 26% (p=0.6) ( 27 ). In contrast, two randomized controlled trials reported a lower good quality embryo rate for IVC compared to autologous IVF: Doody et al. reported 31% vs. 51% (p<0.001) ( 23 ) and Freitas Aguiar et al. reported 3 day culture: 60% vs. 100%, p<0.001; 5 Day culture: 28% vs. 66%, p<0.001 ( 28 ). Cedars et al. did not calculate statistical difference but reported a lower good quality embryo rate between IVC and autologous IVF: 76% vs. 83% ( 24 ). Clinical pregnancy rate was reported in seven studies. The clinical pregnancy rates reported were as follows (per ET if differentiated in publication): 33% (25), 65% (23), 54% (26), 47% (31), 43% (22), 13% (24), and 46% (14). In studies where clinical pregnancy rate was compared between IVC and autologous IVF/ICSI, similar rates were reported (54% vs. 58%; 33% vs. 25%) ( 25 , 26 ). When IVC was compared to autologous IVF, Doody et al. reported no difference (65% vs. 65%) and Cedars et al. reported the IVC rate to be 13% and autologous IVF rate to be 46% of all embryo transfers without statistical testing ( 23 , 24 ). Live birth rates, defined as the number of live births per ET, were reported in four studies. All studies used a fresh ET protocol directly after culturing the embryo in the intravaginal device. Jellerette-Nolan et al. reported the largest cohort of IVC cycles to date, with 526 fresh ETs resulting in a LBR of 51% (31). Smaller studies reported LBR of 55% (23), 31% (14), and 13% (24). Two studies compared LBR between IVC and autologous IVF, though neither conducted statistical testing ( 23 , 24 ). Doody et al. found a similar LBR between IVC and autologous IVF (55% vs. 60%) ( 23 ), and Cedars et al. reported LBRs of 13% and 38% respectively ( 24 ). The only study to investigate perinatal outcomes was Kaye et al., who studied 74 infants from 50 singleton and 16 twin pregnancies resulting from IVC ( 21 ). Overall reassuring outcomes were demonstrated in their findings. Among singletons, four infants were born with low birth weight (mean birth weight: 3195 grams), three were born preterm (mean gestational age at delivery: 38 weeks and 4 days), and one was macrosomic ( 21 ). Among twins, most had low birth weight (mean birth weight: 1992 grams) and were preterm (mean gestational age at delivery: 33 weeks 4 days). They did not report any adverse parental outcomes of pregnancies resulting from IVC ( 21 ).

The use of MAR has increased significantly amongst SSFCs building their families in the past decade ( 32 ). Treatment options include IUI, autologous IVF, reciprocal IVF, and IVC. These methods offer patients different success rates, costs, and experiences, but only reciprocal IVF and IVC offer couples the ability to jointly contribute to biological parenthood. This review summarized the clinical outcomes of reciprocal IVF and IVC. The available literature demonstrates that reciprocal IVF is an effective strategy resulting in live birth rates between 29% and 57%, and with similar or improved cycle and pregnancy outcomes when compared to autologous IVF ( 15 , 16 , 18 ). One study found no difference in positive pregnancy test, clinical pregnancy, and live birth rates between reciprocal IVF and autologous IVF ( 16 ), and another found significantly higher positive pregnancy test, clinical pregnancy, and live birth rates in reciprocal IVF when compared to autologous IVF/ICSI ( 18 ). Only one study was designed with perinatal complications as the primary outcome and found that reciprocal IVF was not associated with increased incidence of preterm birth or hypertensive disease of pregnancy when compared to pregnancies conceived via IUI ( 19 ). This finding differs from the sufficiently established increased risk of these outcomes associated with donor IVF pregnancies when compared to autologous IVF pregnancies ( 19 ). This finding is likely due to differing baseline health and fertility factors between SSFCs and patients requiring donor oocytes. However, these conclusions are limited as they are drawn from a single retrospective study which compared different fertility treatment methods. Overall, studies of IVC showed good clinical cycle and pregnancy outcomes, though rates of good quality embryo creation may be lower than autologous IVF. Live birth rates varied between studies, ranging from 13% to 55%, which is likely due to varying inclusion criteria, patient characteristics, and sample sizes between studies ( 14 , 23 , 24 , 31 ). When compared, live birth rate did not differ between IVC and autologous IVF ( 23 , 24 ). Clinical pregnancy rates ranged from 13% to 65% and were similar in all studies that compared IVC to IVF/ICSI ( 23 – 26 ). Lastly, while two retrospective studies reported no difference when comparing IVC to autologous IVF or ICSI ( 26 , 27 ), two randomized controlled trials found that quality embryo rate in IVC was lower than autologous IVF ( 23 , 28 ). With the FDA approval of the INVOcell ® device in 2016, IVC provides a more affordable option to shared biological contribution to conception as compared to reciprocal IVF, due to decreased embryology lab costs. IVC also offers an opportunity for patients of diverse sexual and gender identities, with many variations of reproductive anatomy, a new way to biologically contribute to a pregnancy beyond genetics or gestation. However, no studies have explicitly evaluated IVC in the SSFC or LGBTQIA+ population. Some studies on IVC mentioned its potential for utilization within the SSFC population, but only two studies reported included any SSFCs in their cohort ( 21 , 31 ). Additionally, there is a need for studies evaluating the acceptability and the desirability of IVC amongst the SSFC and LGBTQIA+ population. Both the literature on reciprocal IVF and IVC are limited by small sample sizes, primarily retrospective study design, and lack of patient diversity. At present, only eight studies on reciprocal IVF in SSFCs have been published, with 80% of them originating from Spain. Additionally, only four of these studies have comparison groups and all are retrospective studies, limiting the quality of the data. Future work analyzing both reciprocal IVF and IVC should include diverse populations, strive for prospective data collection, and aim to understand how social determinants of health and baseline fertility and health factors affect success rates. While three reciprocal IVF studies report on couples’ cumulative pregnancy rate ( 15 , 16 , 20 ), future work should continue to characterize the pathways and outcomes of couples that utilize multiple MAR treatments. For example, Carpinello et al. reported an increased cumulative pregnancy rate when both partners (compared to just one) participated in MAR, though their data was limited by a lack of reciprocal IVF cycles ( 33 ). This data has the potential to help counsel couples, as survey studies show that cost, success, and possibility of shared biological contribution are all important factors for SSFCs choosing between MAR options for family building ( 5 , 34 ). This review is the first study to systematically analyze all published data on reciprocal IVF and IVC pregnancy-related outcomes. The analysis is limited by the fact that all reciprocal IVF and many of the IVC studies were retrospective in design. Additionally, with a lack of consistent covariate data reported and with comparative studies evaluating different populations, pooled analysis of available data would have little utility and, thus, was not included in the present study. As with many review studies of MAR, different articles had different definitions of outcomes such as “high quality embryo,” “clinical pregnancy,” and “positive pregnancy test.” The strengths of this study included the systematic approach to searching the literature, double reviewer methodology at each step, and the novel inclusion of data on IVC cycles. In conclusion, while the initial data on MAR methods that allow for shared biological contribution to conception for SSFCs are promising and offer good options for this marginalized population, there is still significant need for high quality, prospective research evaluating cycle outcomes, pregnancy outcomes, and perinatal complications. As a field, reproductive endocrinology relies on strong and reliable data to counsel patients on family building strategies that align with their goals and desires. The SSFC and LGBTQIA+ population deserves parity to the cisgender, heterosexual population seeking MAR. With further research focused specifically on this demographic, equitable access to care will be achievable for all patients who wish to build a family regardless of sexual orientation and gender identity.

Research articles or case series were eligible for inclusion if published after 1995. This date range was chosen to limit the included studies to modern MAR methods. Articles studying reciprocal IVF were eligible if they explicitly included and reported on SSFCs, even if they were a subgroup of the total population. SSFCs are often part of heterogenous study populations or are compared to other populations of patients. Articles studying IVC were eligible if they included any population because there is limited data on this newer technology, and unlike reciprocal IVF, IVC does not require two female participants. Population baseline health and fertility characteristics were not part of this review’s inclusion or exclusion criteria. Inclusion criteria required all articles to have at least one of the following clinical outcomes: embryo quality, positive pregnancy test rate, clinical pregnancy rate, live birth rate, miscarriage rate, pregnancy complications, or neonatal outcomes. As case series were included in this review, selected publications were not required to have a comparison group. Articles from any country of origin were included if there was a manuscript publicly available in English. Studies were excluded for the following reasons: publication prior to 1995, manuscript text not published in English, or only reporting qualitative outcomes. Abstracts, reviews, opinions, commentaries, case reports, and articles in other disciplines (e.g., sociology or ethics) were excluded. Articles were identified via title search of “Reciprocal IVF” and “INVOcell” search terms of the PubMed ® , Scopus ® , Embase ® , and ClinicalTrials.gov databases on July 30, 2024. The “Reciprocal IVF” search term was (“LGBTQ” OR “LGBT” OR “LGBTQIA” OR “LGBTQI” OR “Queer” OR “Lesbian” OR “Bisexual” OR “homosexual” OR “Gay” OR “trans” OR “Transgender” OR “Nonbinary” OR “Non-binary” OR “Orientation” OR “gender” OR “Same sex” OR “same-sex” OR “Same-sex female” OR “Same-sex couple” OR “Same gender” OR “Female couple” OR “SSFC” OR “SSF”) AND (“IVF” OR “In vitro fertilization” OR “In vitro fertilisation” OR “Co-IVF” OR “Co IVF” OR “Reciprocal IVF” OR “Shared Motherhood IVF” OR “ROPA” OR “Intrauterine insemination” OR “IUI” OR “Artificial insemination” OR “Intra-partner oocyte donation” OR “Intra partner oocyte donation” OR “shared IVF” OR “partner IVF”) OR (“Fertility” OR “Infertility” OR “Family building” OR “Pregnancy” OR “Motherhood”). The INVOcell ® search term was (“INVOcell” OR “Intravaginal culture”).

Medically assisted reproduction (MAR) offers same sex female couples (SSFCs) numerous options for biological family building. Intrauterine insemination (IUI) and in vitro fertilization (IVF) have been documented to be safe and effective in this population ( 1 – 4 ), but many SSFCs desire joint biological contribution to a pregnancy ( 5 ). Currently, two fertility interventions exist that can offer two female partners shared methods of conception: reciprocal IVF and intravaginal culture (IVC). Reciprocal IVF [also known as ROPA (Reception of Oocytes from PArtner IVF), co-IVF, or shared motherhood IVF] allows one partner to act as an oocyte source while the other partner undergoes subsequent embryo transfer to act as the gestational carrier for a pregnancy. Recent data shows this method is safe and effective ( 6 ). Intravaginal culture with the INVOcell ® device offers a lower cost option for shared conception by minimizing embryology lab involvement and expenses. IVC places retrieved oocytes and sperm in an INVOcell ® device which is then placed vaginally in either the oocyte source or their partner. Fertilization occurs within the vaginal device and subsequently developed embryos are then utilized for embryo transfer to either partner in a process similar to IVF. While recent literature evaluating these MAR innovations amongst SSFCs have been promising, many of the current studies are limited to small retrospective cohorts with variations in study design and comparator groups. Some may argue that SSFCs interested in technologies like reciprocal IVF can refer to literature describing outcomes in IVF cycles with donor oocytes. These donor oocyte studies have demonstrated increased complications such as hypertensive disease of pregnancy, preterm birth, and low neonatal birth weight when compared to autologous IVF ( 7 – 10 ). However, SSFCs undergoing IVF differ from heterosexual couples and single females utilizing donor oocytes for many reasons, including differing baseline reproductive health status, indication for use of non-autologous oocytes, and unique social determinants of health ( 6 – 8 ). Similarly, SSFCs utilizing IVC differ from heterosexual patients experiencing infertility due to differing baseline health factors and different distributions of infertility diagnoses ( 11 – 13 ). Thus, there is a need to gather data specifically from the SSFC population on the outcomes and complications of these technologies. This review aimed to synthesize the available literature on reciprocal IVF and IVC, and also identify areas for future research. The primary outcome was live birth rate (LBR). Additional cycle and pregnancy outcomes were reported, if available.