Background Spontaneous abortions, intrauterine growth restriction, and preeclampsia are thought to be caused by defective placentation and are associated with increased risk of adverse outcomes in subsequent pregnancies. However, it is not known whether the recurrence of adverse outcomes is associated with the recurrence of placental pathology. We hypothesized that recurrent maternal vascular malperfusion (MVM) underlies the recurrence of adverse outcomes. Methods Using data from the National Collaborative Perinatal Project, we assessed the recurrence of pregnancy complications and MVM lesions (N = 3865), associations between a history of spontaneous abortions and MVM lesions or adverse outcomes in subsequent pregnancies (N = 8312), and whether the recurrence of pregnancy complications occurred independently of the presence of MVM lesions. Results The odds of an MVM lesion were higher for a woman who had had an MVM lesion in a previous pregnancy (aOR = 1.6; 95% CI 1.3–1.9), although this was marginally non-significant after adjusting for covariates such as gestational age, race and BMI. The odds of preeclampsia, a small-for-gestational-age infant, premature delivery and early pregnancy loss were 2.7–5.0 times higher if there had been that same adverse outcome in a previous pregnancy. A history of spontaneous abortions was associated with higher risk of a small-for-gestational-age baby (aOR = 2.4; 95% CI 1.7–3.4) and prematurity (aOR = 5.1; 95% CI 2.3–11.5 for extremely preterm), but not preeclampsia. The recurrence of adverse outcomes was significant when restricting analyses to women without MVM lesions. Similarly, associations between adverse outcomes and previous spontaneous abortions were significant when statistically controlling for the presence of MVM lesions, or excluding pregnancies with MVM lesions. Conclusions Women with adverse outcomes in one pregnancy are at higher risk of complications in subsequent pregnancies. However, there is significant recurrenc ✉ * E-mail: julian_christians@sfu.ca 6 2 2020 15 2 e0228664 e0228664 19 2 2020 © 2020 Christians, Huicochea Munoz This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract Background Spontaneous abortions, intrauterine growth restriction, and preeclampsia are thought to be caused by defective placentation and are associated with increased risk of adverse outcomes in subsequent pregnancies. The recurrence of adverse outcomes was significant when restricting analyses to women without MVM lesions. Similarly, associations between adverse outcomes and previous spontaneous abortions were significant when statistically controlling for the presence of MVM lesions, or excluding pregnancies with MVM lesions. Conclusions Women with adverse outcomes in one pregnancy are at higher risk of complications in subsequent pregnancies. However, there is significant recurrence of adverse outcomes even in the absence of MVM. status released display-pdf yes is-olf no is-manuscript no is-preprint no is-journal-matter no is-scanned no is-retracted no Received 2019 Nov 25; Accepted 2020 Jan 20; Collection date 2020. Introduction Placental dysfunction is thought to underlie diverse adverse pregnancy outcomes, including spontaneous abortions, intrauterine growth restriction, and preeclampsia [ 1 ], with However, the association between MVM in one pregnancy and spontaneous abortion in another has not been investigated. Furthermore, it has not been shown that the recurrence of adverse outcomes in different pregnancies is associated with recurrent MVM pathology. We hypothesized that certain factors predispose women to recurrent MVM, which increases the risk of spontaneous abortions, preeclampsia, intrauterine growth restriction, and prematurity, and that this mechanism underlies the previously observed associations between spontaneous abortions in one pregnancy and adverse outcomes in another. Analyses of prematurity did not include gestational age. Discussion MVM lesions are thought to reflect placental dysfunction that may underlie spontaneous abortions, preeclampsia and intrauterine growth restriction. We examined whether recurrence of pathology might underlie the recurrence of adverse outcomes. The odds of an MVM lesion were 1.6 times higher for a woman who had had an MVM lesion in a previous pregnancy, using our broad definition of MVM lesions, although this was marginally non-significant after adjustment for covariates. The odds of an adverse outcome were 2.7–4.9 times higher if there had been that adverse outcome in a previous pregnancy. Lines 332-333: There are actually many papers documenting specific patterns of placental pathology in women with recurrent adverse outcomes ( "multiple complicated pregnancies"). 9. Lines 347-351: In this section I actually believe that the authors are underestimating the quality of the original data. I have discussed at length the histopathologic coding of the Collaborative Project with its main study pathologist and I would argue that very little has changed since that time. Differences would be changes in terminology, as the authors discuss, and probably some increased sensitivity for detecting mild lesions. Should be "recurrent MVM" since there are many other placental pathologies, such as VUE, fetal vascular malperfusion, and others, that cause the same outcomes, can recur, and are associated with small placentas. Text revised. 7. Lines 326-327: Reference 50 addresses recurrent preeclampsia, not adverse outcomes. This sentence has been removed (please see response to following comments). 8. Lines 332-333: There are actually many papers documenting specific patterns of placental pathology in women with recurrent adverse outcomes ( "multiple complicated pregnancies"). We agree, and have removed this paragraph.

BACKGROUND Chronic intervillositis (CI) is a rare placental condition involving diffuse infiltration of intervillous spaces by CD68- or CD45-positive maternal mononuclear inflammatory cells. Because no validated clinical or biochemical markers are specific to CI, the diagnosis is purely histopathological and is made postpartum. CASE This report describes a case of recurrent CI associated with adverse complications in two successive pregnancies. Both pregnancies were complicated by intrauterine growth restriction. Coexistent massive perivillous fibrin deposition was present in the first placenta. This case highlights the importance of CI in explaining and predicting adverse perinatal outcomes. CONCLUSION CI is associated with adverse pregnancy outcomes and a high risk of recurrence, and it can coexist with massive perivillous fibrin deposition. Pathologists must ensure that the significance of these diagnoses is adequately conveyed to clinicians, to optimize management of subsequent pregnancies.