Recurrent Pregnancy Loss. Aspects of Epidemiology, Immunology, Treatment and Obstetric Outcomes

Abstract: Aims: Recurrent pregnancy loss (RPL), defined as three consecutive miscarriages, is a multifaceted problem whose resolution needs a broad approach. In this thesis, epidemiology, immunology, treatment and obstetrical outcomes are explored. The aims are as follows: To establish the incidence of the diagnosis of RPL in the National Patient Register (NPR) in Sweden from 2003 to 2012 (Paper I). To evaluate the validity of the ICD-10 diagnosis codes of RPL registered in the NPR (Paper II). To systematically review the evidence for different treatments' efficiency at improving live birth rate (LBR) in women with idiopathic RPL (Paper III). To determine whether treatment with low-molecularweight heparin (LMWH) exerts immunological effects during pregnancy in women with a history of idiopathic RPL (Paper IV). To study if women with a subsequent pregnancy after the diagnoses of RPL are associated with adverse obstetrical outcomes (Paper V). Methods: Papers I, II and V were register-based studies and used nation-wide data on women with RPL diagnosis registered in the NPR, as well as data from the Medical Birth Register (MBR) in Paper V. In Paper I an incidence of women diagnosed with RPL in pregnant women and in women 18-42 years of age was calculated for a 10-year period. In Paper II medical records were reviewed to validate the diagnosis codes of RPL in the NPR and a positive predictive value (PPV) was estimated. Paper III was a systematic review of 21 RCTs regarding acetylsalicylic acid (ASA), LMWH, progesterone, intravenous immunoglobulin (IvIg) or leukocyte immune therapy (LIT). Meta-analyses on treatment efficiency regarding live birth rate (LBR) in women with idiopathic RPL were conducted. Paper IV was an open randomised trial, including women with idiopathic RPL in which the immunological effect of LMWH was measured by assessing cytokine/chemokine levels during pregnancy. Paper V was a retrospective cohort study in which placenta-associated complications such as preeclampsia, small for gestation infant, preterm birth, stillbirth and placental abruption, were evaluated in women with a first subsequent pregnancy after the diagnosis of RPL compared with outcomes of pregnancies of women without RPL. Results: In Paper I, the incidence of RPL diagnosis was increased from 478 to 875/100 000 pregnant women and from 39 to 73/100 000 women aged 18-42 years in the study period, 2003-2012. In Paper II, 202 out of 238 medical records had correct diagnoses of RPL, resulting in a PPV of 85% (95%CI 78–89%). In Paper III, meta-analyses showed no increase in LBR when treated with LMWH (RR 1.47, 95% CI 0.83–2.61) or IvIg (RR 1.07, 95% CI 0.91–1.26) but an increase in LBR with LIT (RR 1.8, 95% CI 1.34–2.41). No meta-analyses were possible for ASA and progesterone, although two large RCTs on the latter have shown higher LBR in treated women compared with placebo. In Paper IV, the Th1-associated chemokines CXCL10, CXCL11 were significantly higher (p=0.01 and <0.001) in LMWH treated women compared to untreated women. In Paper V women with RPL showed a higher risk of placenta-associated disorders: preeclampsia (OR 1.45 95% CI:1.24-1.69), stillbirth <37 gestational weeks (GWs) (OR 1.92 95% CI:1.22-3.02), SGA birth (OR 1.97 95%CI:1.42-2.74), preterm birth (OR 1.46 95% CI:1.20-1.77), and placental abruption <37 GWS. (OR 2.47 95% CI:1.62-3.76). Conclusion: The incidence of RPL diagnoses increased over the study period, although further studies are needed to obtain causative explanations. The diagnosis of RPL in the NPR is acceptably accurate and can be used for studies in this field. Because of low study quality, large diversity in the study groups and treatment start no recommendation can be given of one particular treatment to improve LBR in women with idiopathic RPL. Treatment with LMWH does not modulate the immune response in a favourable direction during pregnancy and is not recommended for women with idiopathic RPL. Women with RPL are at higher risk for developing placenta-associated disorders; therefore antenatal surveillance ought to be intensified for this group.