Varshni Nandakumar

Background: Miscarriages are defined as the spontaneous loss of a pregnancy before 20 weeks of gestation and affect around 10% of all clinically-recognized pregnancies in the USA1. Moreover, there is a clear link between autoimmune conditions and higher incidences of miscarriage. Patients with autoimmune conditions can develop antiphospholipid syndrome (APS), a disease that results in the production of antiphospholipid antibodies (APL).

Research Objective: In this review, we explored the major mechanisms by which APS may induce miscarriage.

Search Methods: A literature review was conducted on pubmed using the search terms “APS complications”, “autoimmune conditions and fertility”, and “negative pregnancy outcomes and APS”.

Results: In pregnant patients, APS can cause vascular abnormalities and inflammation in placenta tissue and subsequently lead to miscarriage. To explore the connection of APS and vascular abnormalities in miscarriage, investigators measured the levels of exosomal apolipoprotein H (APOH), a protein involved in lipid metabolism, in the serum of pregnant patients with APS. Results demonstrated that pregnant patients with APS had higher levels of exosomal APOH than in control patients without APS3. Moreover, in vitro studies revealed that APOH-exosomes caused significantly decreased cell migration due to a down-regulation of P-ERK1/2 expression, a member of the MAPK signaling pathway crucial for cell growth, migration, and angiogenesis. Ultimately, this down-regulation leads to vascular abnormalities3. Vascular abnormalities in the placenta can also be caused by activation of the APOER2 receptor, a protein involved in lipid metabolism and abundantly expressed on placental cells4.  By injecting APL antibodies to both an APOER2 knock out (K/O) and WT mice, investigators measured PP2A activity to monitor changes in cell proliferation and angiogenesis. APOER2 K/O mice had much higher PP2a activity compared to WT mice. PP2A activity has been correlated to suppression of cell growth, migration, and angiogenesis. When PP2a activation was suppressed in this group of mice, there was a reduction in endoglins, a marker of preeclampsia, indicating a role for APOER2-activated PP2A in this disorder4. APS can also lead to miscarriage by inducing placental inflammation due to loss of anti-inflammatory signaling molecules such as CD39 and CD735. In one study, researchers compared three groups of mice, WT, CD39 K/O, or CD73 K/O and injected them with either IgG or APL antibodies. Mice with CD39 or CD73 knockout had much higher rates of inflammatory TNF-alpha in placental tissue, indicating increased inflammation5.

Conclusions: These studies indicate that vascular abnormalities and inflammation in placental tissue in pregnant patients with APS are potentially large contributors in causing miscarriage. Further research into these mechanisms may provide opportunities for therapies to prevent miscarriages in patients with autoimmune conditions.

Works Cited:

1. Dugas C, Slane VH. Miscarriage. [Updated 2022 Jun 27]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK532992/
2. Quenby S, Gallos ID, Dhillon-Smith RK, et al. Miscarriage matters: the epidemiological, physical, psychological, and economic costs of early pregnancy loss. Lancet. 2021;397(10285):1658-1667. doi:10.1016/S0140-6736(21)00682-6
3. Tan Y, Bian Y, Song Y, Zhang Q, Wan X. Exosome-Contained APOH Associated With Antiphospholipid Syndrome. Front Immunol. 2021;12:604222. Published 2021 May 4. doi:10.3389/fimmu.2021.604222
4. Chu H, Sacharidou A, Nguyen A, et al. Protein Phosphatase 2A Activation Via ApoER2 in Trophoblasts Drives Preeclampsia in a Mouse Model of the Antiphospholipid Syndrome. Circ Res. 2021;129(7):735-750. doi:10.1161/CIRCRESAHA.120.318941
5. Samudra AN, Dwyer KM, Selan C, et al. CD39 and CD73 activity are protective in a mouse model of antiphospholipid antibody-induced miscarriages. J Autoimmun. 2018;88:131-138. doi:10.1016/j.jaut.2017.10.009