key: cord-1012120-div9rzax
authors: Singh, Bhuchitra; Gornet, Megan; Sims, Holly; Kisanga, Edwina; Knight, Zachary; Segars, James
title: Severe Acute Respiratory Syndrome‐Corona Virus‐2 (SARS‐CoV‐2) and its Effect on Gametogenesis and Early Pregnancy
date: 2020-09-23
journal: Am J Reprod Immunol
DOI: 10.1111/aji.13351
sha: e7522e92592115608aff54f550548798daa57720
doc_id: 1012120
cord_uid: div9rzax

SARS‐CoV‐2 infection and pregnancy has been the topic of hundreds of publications over the last several months, however, few studies have focused on the implications of infection in early pregnancy and reproductive tissues. Here we analyzed available evidence pertaining to SARS‐CoV‐2 infection, early pregnancy, and reproductive tissues. We searched PubMed and Embase databases in accordance with guidelines of Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) for publications from inception to June 4, 2020. Four reviewers screened titles and abstracts, and obtained full text articles for analysis. 62 studies were included in the review. Biological plausibility for infection with SARS‐CoV‐2 exists in testis, ovaries, and placenta as they express ACE2 receptor activity. In males, SARS‐CoV‐2 infection could lead to functional abnormalities leading to spermatogenic failure and male infertility. In females, an alteration of the ACE2 cascade via SARS‐CoV‐2 infection could lead to impairment in important follicular and luteal processes. There is also evidence of significant placental pathology in SARS‐CoV‐2 infection, but it is unclear what effects there may be for early pregnancy, though available data suggest less severe effects compared to other respiratory virus outbreaks. Further investigation is needed regarding SARS‐CoV‐2 in reproductive function and early pregnancy.

Pregnant women and their fetuses may be impacted disproportionally by emerging infections [1] as exemplified by the 2009 H1N1 influenza pandemic [2] and the severe fetal complications of Zika virus [3, 4] . The novel coronavirus infection, Severe Acute Respiratory Coronavirus 2 (SARS-CoV-2),

This article is protected by copyright. All rights reserved was first reported in Wuhan, China, on Dec 31, 2019 and was declared a pandemic by the WHO on March 11, 2020 [5] . Since then, the number of worldwide reported cases of COVID-19 has increased to 6.11 million and 370,000 deaths as of May 31, 2020. [6] To combat the rapidly spreading virus, nations have implemented strategies to suppress and mitigate the community acquired infections such as social distancing, availability of rapid testing, contact tracing, and vaccine development [7, 8] .

Coronaviruses are single-stranded RNA, enveloped, non-segmented viruses which cause complications ranging from common cold to pneumonia and death [9] . Common symptoms of SARS-CoV-2 infection include fever, cough, myalgia, headache, and diarrhea [10] . Highly infective, the virus is transmitted to 2-3 people for every infected person, with a reproduction number (R0) of 2.2 [11] . While an estimated 80% of COVID-19 cases are mild and can be managed with home-care, 15-20% require hospitalization, with 5% of cases severe enough to require mechanical ventilation [6] .

The total mortality rate, including those from asymptomatic and mild cases, seems to be approximately 1% [12] . The primary mode of transmission occurs similarly to that of other respiratory infections; droplet particles are inhaled through close physical contact with an infected person when coughing or sneezing [13] . It does not appear that vertical transmission from pregnant women to fetuses occurs [14] , however, this has not been determined conclusively. Other coronaviruses of the previous two decades, Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome Coronavirus (MERS-CoV), have caused severe respiratory infections in humans. The novel SARS-CoV-2 shares 82% of the genome of the virus that causes SARS-CoV [15] . Since its first identification, more cases of COVID-19 have been counted than that of MERS and SARS combined. Limited studies on SARS-CoV-1 reported increased morbidity and mortality in pregnant women, while some recent studies have shown women with SARS-CoV-2 are less likely to have complications comparatively [16, 17] . However, very little data are available regarding the effects of coronaviruses in early pregnancy.

Much of the available data focuses solely on COVID-19 infections in the third trimester and the possibility of vertical transmission. Though there is a lack of concrete data, SARS-CoV-2 does have the potential to cause pregnancy complications in the first trimester including miscarriage and

This article is protected by copyright. All rights reserved congenital abnormalities [18] . In this paper, we aimed to summarize the available data related to the effects of SARS-CoV-2 infection on the ovaries, testicles, gametes, and early pregnancy. In addition to current SARS-CoV-2 literature, we also investigate the potential effects of COVID-19 in early pregnancy using published data and outcomes from the SARS-CoV and MERS-CoV pandemics.

A systematic search in the literature published in the PubMed and Embase databases was conducted in accordance with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Additional citations were identified from the reviewed literature. An academic data specialist developed the search strategy and searched the databases of PubMed and Embase from inception to June 4, 2020. We searched for articles that contained information related to SARS-CoV-2 and reproductive tissues (ovaries, testes), gametes, placentation, and early pregnancy in humans. Our search phrases included: "severe acute respiratory syndrome coronavirus 2", "2019 ncov", "sarscov 2", "SARS-Cov-2", "pregnancy", "gravidity", "abortion", "germ cells", "oocytes", "gametes", "embryonic structures", "embryo", "fertility", "testes", "miscarriage"(See Appendix 1 for completed list of databases search strategy and Figure 1 for PRISMA table). Due to limited number of publications available we did not consider a sample size as an eligibility criterion.

Majority of the literature composed of case reports, guidelines, and editorials. We did not use the Cochrane RoB 2.0 tool due to absence of randomized clinical trials. Similarly, due to lack of cohort studies, we did not use the Newcastle-Ottawa Scale to rate the studies.

Using a standardized form, 4 reviewers (HS, MG, EK, and BS) screened titles, abstracts, and full-text articles reporting potentially eligible studies. Any disagreements were resolved with a third reviewer (J.S.). We acknowledge the possibility of bias in this literature review due to inclusion of the limited research data available. SARS-CoV-2 related reporting is increasing exponentially and this review is limited to the date of the literature search was conducted. The search strategy described above identified 2,828 articles, of which 131 were considered for full review. 62 articles met the inclusion criteria and were used to support this review. Table 1 summarizes case series and studies of SARS-CoV-2 infection within various reproductive tissues in patients who tested positive for SARS-CoV-2.

Spermatogonia, Sertoli, and Leydig cells are predominantly enriched in ACE2 (19, 20) . SARS-CoV-2 and MERS-CoV use ACE2 receptors to gain entry into host cells [21] . Wang et al. [19] performed uniform manifold approximation and projection (UMAP) and marker gene analyses to identify nine major cell cluster in testicular cells. ACE2 expression was determined by analyzing the RNA expression profile of ACE2 at single-cell resolution. Spermatogonia and spermatids showed concentrated expression of transmembrane serine protease 2 (TMPRSS2) for viral spike (S) protein priming. Both Zhao and Wang [19, 20] also reported almost 3-fold higher percentage expression of ACE2 in Leydig and Sertoli cells compared to spermatogonia (4.25% vs. 1.40%). SARS-CoV-2 uses TMPRSS2 and SARS-CoV-2 ACE2 receptors to gain entry into host cells [22] . Therefore, there is a high potential for SARS-CoV-2 infection in human testes. In situ hybridization, morphological, and immunohistochemical analysis were performed on 6 testis obtained at autopsy from confirmed SARS-CoV-2 infected males and from 4 non-SARS autopsy control testis samples [23] . All control testis had normal morphology, whereas the SARS-CoV-2 infected testis showed peritubular fibrosis and vascular congestion along with extensive germ cell destruction. There were significantly more CD 3 + T lymphocytes and CD68+ macrophages (0.65% and 2.11% in control vs. 4.49% and 11.72%) infected. However, the virus did not affect the testis directly since in situ hybridization, using both sense and antisense RNA probes, showed no staining [23] . A cohort study by Li enrolled 38 SARS-CoV-2 patients for semen testing using RT-PCR and found 6 patients had positive results for SARS-CoV-2 (4 in acute stage of the disease and 2 in recovery. However, no information is known about virus shedding, survival time, and concentration in semen [24] . A cross-sectional observational study by Pan et al. identified presence of SARS-CoV-2 by qRT-PCR in a single ejaculated sample of 34 confirmed cases of SARS-CoV-2 in China. SARS-CoV-2 was not detected in the semen 1 month after diagnosis. They also reported sparse expression of ACE2 and TMPRSS 2 using single-cell transcriptome analysis, with almost no overlapping gene expression [25] .

This article is protected by copyright. All rights reserved Both Jung and Carlsen reported that male fertility may be diminished due to fever associated with the SARS-CoV-2 infection for up to 72-90 days following infection as fever can lead to decreased sperm concentration and motility [26, 27] . In addition, SARS-CoV-2 patients may develop cytokines storm syndrome (hemophagocytic lymphohistiocytosis), which can impact testicular function and maintenance, as cytokines microenvironment is critical to testicular function, and alterations may be tumorigenic [28, 29] .

As stated earlier, SARS-CoV-2 uses TMPRSS2 and SARS-CoV-2 ACE2 receptor to gain entry into host cells [21] . Both reproductive-age women and post-menopausal women have ACE2 mRNA transcripts expressed abundantly in the ovary [30] . Therefore, the female reproductive system is potentially at a high risk of SARS-CoV-2 infection. There are no studies that evaluate SARS-CoV-2 infection inhuman ovarian tissue and cells.

The ACE2 receptor is widely expressed in the placenta [31] . Overall, there is limited evidence regarding SARS-CoV-2 and transplacental transmission, though most reviews and the American College of Obstetrics and Gynecology have stated there is no conclusive evidence of transplacental transfer of SARS-CoV-2 from infected mothers [32, 33] . Comparable to other more well-known transplacental infections, which are known to have hematogenous infectivity, SARS-CoV-2 has been shown to produce RNAemia, and therefore plausibly could be transmitted via a transplacental route [34] . At present, the literature regarding vertical transmission is mixed; several recent studies have concluded there is no definitive evidence of vertical transmission [35, 36, 37] , while others have findings that suggest in utero transmission may occur, as evidenced by presence of neonatal IgM antibodies (which cannot otherwise be transferred transplacentally) [38, 39, 40] and neonatal nasopharyngeal and anal SARS CoV-2 RNA isolation [41] . While this evidence of transplacental transmission is compelling, dedicated study of placental histopathology and PCR as it relates to SARS-CoV-2 is needed to better distinguish transplacental versus intrapartum versus postpartum vertical transmission.

This article is protected by copyright. All rights reserved Our review identified two dedicated studies of placental histopathology in SARS-CoV-2. In one study investigating placentas of SARS-CoV-2 positive mothers, 45% showed low grade fetal vascular malperfusion, though notably all infants tested negative [42] . Interestingly, Shanes et al. [43] noted higher rates of arteriopathy and maternal vascular malperfusion than controls, whereas findings of fetal malperfusion was nonsignificant compared to controls. Both studies noted significant increase in intervillous thrombi, which may be a direct correlate to the thromboembolic disorders believed to occur in SARS-CoV-2. Data regarding placental viral isolates in specifically SARS-CoV-2 is scarce, and with mixed results. To date, there are few published reports of presence of SARS-CoV-2 RNA in placenta or membrane samples [44, 45] . In the study by Penfield et al. [44] 3 of 11 placental or membrane swabs were positive within 30 minutes of delivery in women with severe to critical COVID-19 at time of delivery. Notably, there were no signs of vertical transmission, and all infants were negative, raising the distinct possibility of contamination. A study by Patane et al. [45] is the first to specifically describe SARS-CoV-2 RNA on the fetal side of the placenta. In two other published reports, viral PCR was performed on placental tissue and/or all products of conception in mothers diagnosed with symptomatic SARS-CoV-2 infection following third trimester delivery. All samples were negative [36, 46] . To date, there appears to be a single study directed at investigating the intrauterine environment of early pregnancy and SARS-CoV-2 with several limitations [47] .

Specifically, the study retrospectively reviewed records and labs results for two symptomatic women with COVID-19 in the first trimester. The first woman, at 8 weeks gestation, was given a clinical diagnosis given husband's diagnosis at home as well as radiologic findings. The second woman was diagnosed at 10 weeks gestation via nasopharyngeal test. On the day of amniocentesis, both patients were negative for SARS-CoV-2 RNA via throat swabs, but positive for SARS-CoV-2 IgG antibodies in serum (the first woman also had IgM antibodies). SARS-CoV-2 RNA was not isolated in the amniotic fluid, though notably amniotic samples were collected over a month after symptom resolution and testing positive. However, according to Center for Disease Control, it is anticipated that SARS-CoV-2 infection will affect fetal development like other respiratory coronaviruses.

This article is protected by copyright. All rights reserved

The status of SARS COV-2 within the vaginal environment is currently unknown. Many viruses have been previously isolated within vaginal fluid, such as Hepatitis C virus and Zika virus, which are both RNA viruses. At present, it is not believed that SARS-CoV-2 is able to be sexually transmitted, which is consistent with other historical coronaviruses. However, inability for sexual transmission does not preclude SARS-CoV-2 from having a significant clinical impact. To our knowledge, there is one study investigating the presence of SARS-CoV-2 in the vaginal fluid of women with severe SARS-CoV-2.

Other studies that tested vaginal swabs were tested in the peripartum period, and were negative [36, 46] . Specifically, 10 women with severe COVID-19 were tested or SARS-CoV-2 in vaginal fluid, with all samples negative for virus [48] . Notably, these women were postmenopausal and swabs were taken 17 or more days after onset of disease. 

Animal studies have demonstrated that ACE2 is present within murine, leporine, bovine, and equine ovarian tissue (including but not limited to stromal cells, granulosa cells, and oocytes). Furthermore, in these studies, ACE2 is known to be an essential protein involved in multiple cascades responsible for steroid secretion [49, 50] , oocyte maturation and ovulation, and resumption of meiosis in the Accepted Article oocyte [51, 52] through its interplay with Ang II and Ang-(1-7). Most importantly, in regards to early pregnancy, Ang-II and Ang-I (and by extension ACE2) have been shown to be key proteins involved in formation, maintenance, and regression of corpus luteum [53] . Alterations in this cascade of proteins responsible for normal development of the corpus luteum may explain how SARS-CoV-2 can negatively impact early pregnancy. In the human ovary, there is evidence that folliculogenesis, oocyte maturation, and ovulation involve the renin-angiotensin aldosterone (RAS) system, an important component which involves ACE2 enzyme expression [49] . Therefore, SARS-CoV-2 could theoretically damage ovarian tissue, and decrease ovarian function and oocyte quality, resulting in female infertility or even miscarriage. The role of ACE2 with Ang-II and Ang- (1-7) , and their demonstrated importance in the formation and maintenance of corpus luteum, could explain how alterations in ACE2 may negatively impact early pregnancy [24, 53] . Specifically, the impact of SARS-CoV-2 may be two-fold: the effects of SARS-CoV-2 viral infection and local immune reaction itself, as well as the downstream consequences of altering the essential ACE2 and ACE2 receptor mechanism.

Specifically, as the ACE2 and ACE2 receptor cascades are involved in multiple basic ovarian processes, it may be reasonable to infer that their normal function and availability could be altered due to SARS-CoV-2 use for entry.

Notably, placental pathology in the setting of respiratory illness is difficult to interpret, as protracted 

This article is protected by copyright. All rights reserved

The effect of SARS-CoV-2 on early pregnancy is still unknown, and any potential effects are extrapolations from cell-level plausibility and experiences from other recent viral respiratory syndromes, such as SARS and MERS. Very limited data may suggest that there are higher miscarriage rates with SARS and MERS versus COVID-19 [35] . fluid were all negative [55] .

While the relationship between SARS-CoV, SAR-CoV-2, and third trimester placental tissues has been investigated, it is unclear what the implications may be for infection of early placental tissue and early pregnancy, and furthermore the specific consequences related to gestational age at time of infection. One study investigating ACE2 expression in human placental tissue, which is a known main protein for SARS-CoV and SARS-CoV-2 viral transmission [31] , showed differential expression of ACE2 based on gestational age. For example, the expression of ACE2 was at very low levels in placental trophoblastic cells in the first trimester, with increased expression at 24 weeks gestational age. This lower level ACE2 expression in the first trimester could suggest a decreased vulnerability to transplacental infection in early pregnancy. In comparison to Zika virus (ZIKV), which is known to be transmitted transplacentally and cause significant adverse pregnancy outcomes, AXL (an essential ZIKV entry cofactor) is more concentrated in the early maternal-fetal interface. This may explain how ZIKV is more readily transmitted in early pregnancy [56] . Interestingly, although SARS-CoV-2

and SARS-CoV seem to share this same pathogenic receptor, and additionally have up to 85% sequence similarity [57, 58] , by all published reports the effect on early pregnancy appears very different between the two infections. While a study by Ng. et al. [54] described normal placental pathology findings in women convalescent from SARS-CoV who had spontaneous miscarriage in the first trimester, the miscarriage rate overall with SARS-CoV infection appears more severe.

Specifically, data regarding miscarriage rate in SARS and MERS outbreaks may suggest a more severe effect on early pregnancy physiology, e.g. higher spontaneous pregnancy loss, than in SARS-COV-2 infection. One study demonstrated a 2% miscarriage/stillbirth rate for SARS-COV-2 versus 18% and

This article is protected by copyright. All rights reserved 25% for MERS-CoV and SARS-CoV, respectively [35] . Another study performed during the 2002-2003 SARS pandemic showed that 4 of 7 (57%) pregnant women infected with SARS-CoV had a spontaneous miscarriage in the first trimester of pregnancy [55] , though notably no viral inclusion bodies or particles were detected in the products of conception. Additional biochemical studies do not aid in further clinical understanding, as biophysical and structural evidence show that SARS-CoV-2 actually binds ACE2 with higher affinity than SARS-CoV, and therefore could plausibly transmit to placenta to a greater degree than SARS-CoV [59] . This does not appear to be consistent with the better outcomes seen with SARS-CoV-2 infection and pregnancy, and it is clear that further investigation is needed.

Notably, only transient positive results in amniocentesis have been reported for other RNA virus infections (Zika), and these patients were outside of the standard gestational age range for traditional amniocentesis.

In the event it is discovered that SARS-CoV-2 may be isolated in vaginal secretions, the implications, though unknown, could represent a mechanism for ascending infection. Interestingly, an animal study investigating rat coronavirus (RCV) found that in addition to infecting respiratory epithelium, it also infects the genital tract of females, reportedly causing perturbations of the hormonal cycle and miscarriage [60, 61] . Isolation of virus within vaginal fluid could also theoretically represent a disruption of a microbiome or "virome", of which the consequences of disruption may be reproductive failure, predisposition to other infection, and pregnancy complications. One study showed that higher viral diversity in the vagina was significantly associated with preterm birth [62] .

Notably, viruses isolated in this study included adenoviruses, which are an important cause of respiratory illness globally. As such, it is important to understand the relationship of SARS-CoV-2 within vaginal fluid, as understanding implications of SARS-CoV-2 in early pregnancy may alter counseling, work up, and approach to pre-pregnancy counseling and intervention.

The COVID-19 outbreak continues to increase in the number of cases, deaths, and countries affected. Current data regarding reproductive tissues and early pregnancy in SARS-CoV-2 infection

This article is protected by copyright. All rights reserved are limited. This may be a result of restricted capabilities of research institutions in time of pandemic, decreased patient interaction within hospitals and institutions due to social reasons and policy, and absolute gestational age relative to time and testing abilities within the pandemic, as many women are just now completing their first trimester.

In light of the currently available evidence, specific recommendations beyond standard personal protective equipment, social distancing accommodations, and hygienic practices can be made.

Specifically, it can be suggested that clinicians practicing assisted reproductive technology should be particularly cautious, as SARS CoV-2 infection and systemic effects may impact testicular tissues, ovarian tissue, and granulosa cells and therefore testicular and ovarian function, spermatozoa, oocyte quality, and pregnancy outcomes [24] . As standard reproductive health, pre-pregnancy, and pregnancy patient care resumes, surveillance 

Qiu et al. [56] Yes No Ten non-pregnant women swabbed

Liu et al. [53] Yes No Three vaginal swabs tested (peripartum).

Fan et al. [41] Yes No Two vaginal swabs tested (peripartum)

This article is protected by copyright. All rights reserved 

Accepted Article

Public health approach to emerging infections among pregnant women

Pandemic 2009 influenza A (H1N1) virus illness among pregnant women in the United States

Characterizing the pattern of anomalies in congenital Zika syndrome for pediatric clinicians

Zika vrus and birth defectsreviewing the evidence for causality

WHO Declares COVID-19 a Pandemic

World Health Organization

Accessed 31

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Coronavirus pathogenesis and the emerging pathogen severe acute respiratory syndrome coronavirus

Genetic Recombination, and Pathogenesis of Coronaviruses

pregnancy : what obstetricians need to know

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Report 4: Severity of 2019-novel coronavirus (nCoV) WHO Collaborating Centre for Infectious Disease Modelling MRC Centre for Global Infectious Accepted Article This article is protected by copyright

Disease Analysis Abdul Latif Jameel Institute for Disease and Emergency Analytics

First Case of 2019 Novel Coronavirus in the United States

Global interim guidance on coronavirus disease 2019 (COVID-19) during pregnancy and puerperium from FIGO and allied partners: Information for healthcare professionals

Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan

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What are the risks of COVID-19 infection in pregnant women?

Classification system and case definition for SARS-CoV-2 infection in pregnant women, fetuses, and neonates

scRNA-seq Profiling of Human Testes Reveals the Presence of the ACE2

A Target for SARS-CoV-2 Infection in Spermatogonia

Single-Cell Rna Expression Profiling of Ace2, the Receptor of SARS-CoV-2

CE2 Receptor Expression in Testes: Implications in COVID-19 Pathogenesis

Accepted Article This article is protected by copyright

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Orchitis: a complication of severe acute respiratory syndrome (SARS)

Clinical Characteristics and Results of Semen Tests Among Men With Coronavirus Disease

No evidence of severe acute respiratory syndrome-coronavirus 2 in semen of males recovering from coronavirus disease 2019

Influence of genital heat stress on semen quality in humans

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COVID-19: consider cytokine storm syndromes and immunosuppression

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Coronavirus disease 2019 (COVID-19) pandemic and pregnancy

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Placental Pathology in COVID-19

Detection of SARS-COV-2 in Placental and Fetal Membrane Samples

Vertical transmission of COVID-19: SARS-CoV-2 RNA on the fetal side of the placenta in pregnancies with COVID-19 positive mothers and neonates at birth

Accepted Article This article is protected by copyright. All rights reserved

Coronavirus Disease 2019 (COVID-19) During Pregnancy: A Case Series

No SARS-CoV-2 detected in amniotic fluid in midpregnancy

SARS-CoV-2 is not detectable in the vaginal fluid of women with severe COVID-19 infection

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Angiotensin II signaling promotes follicle growth and dominance in cattle

Angiotensin-(1-7) induces ovulation and steroidogenesis in perfused rabbit ovaries

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All rights reserved 57. Zhang YZ. Novel 2019 coronavirus genome

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Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation

Encyclopedia of Virology

Reproductive abnormalities associated with a coronavirus infection in rats

The vaginal eukaryotic DNA virome and preterm birth

ncov' OR 'sars cov 2' OR 'corona virus'/exp OR 'corona virus' OR (corona AND ('virus'/exp OR virus)) OR 'coronavirus'/exp OR coronavirus OR 'covid 19' OR covid19) AND (pregnant OR 'pregnancy'/exp OR pregnancy OR 'live birth'/exp OR 'live birth' OR (live AND ('birth'/exp OR birth)) OR 'miscarriage'/exp OR miscarriage OR 'abortion'/exp OR abortion OR 'birth'/exp OR birth OR 'ivf'/exp OR ivf OR iui OR 'sex'/exp OR sex OR 'fertility'/exp OR fertility OR 'infertility'/exp OR infertility OR 'gamete'/exp OR gamete OR 'oocyte'/exp OR oocyte