Before I get into details regarding specific abnormalities of the maternal immune system and clotting system that appear to be related to recurrent early pregnancy loss, let me tell you a story about one of those ‘special patients’ in my life who changed forever the way I practice medicine…
I remember being fascinated with patients who had recurrent pregnancy loss from early on in my training. The prototype patients for this problem were those with known autoimmune disorders, specifically, systemic lupus erythematosus (SLE). The curious thing about that was not all patients who had SLE had difficulty with pregnancies. The ones who seemed to be at the greatest risk were those who had lupus nephritis (kidney damage) or a history of blood clotting complications (deep venous thrombosis, arterial thrombosis, strokes, and pulmonary emboli). Many of these patients were also found to have false-positive RPRs (a test for syphilis) and later, as laboratory evaluation evolved, positive ‘lupus anticoagulants’ (in some ways a misnomer, because these actually increased the risk for persistence of blood clots).
In the early 1980’s, I took care of a woman who had history of recurrent early pregnancy losses who also happened to be the wife of the director of our Coagulation Laboratory. She was a ‘healthy’ woman who had no known medical problems. I first saw her on referral early in another pregnancy and during the routine evaluation, found that she too had a false-positive RPR. Out of curiosity (and with her husband’s blessing) we also screened for and found that she had a ‘lupus anticoagulant.’ She had no physical, symptomatic, or laboratory evidence of SLE, so by definition, she did not have this condition. She lost that pregnancy shortly after her first visit with me before any medical intervention could be tried. When I saw her back between pregnancies, her ‘lupus anticoagulant’ was no longer detectable! Regardless, I told her to start taking a baby aspirin (80 mg) daily (because of its known benefits in preventing clotting initiated by platelets on one side of the coagulation cascade) and to contact me the “minute you think you’re pregnant again.”
About 3 months later, she presented at about 5-6 weeks, still taking her baby aspirin. The RPR came back ‘false-positive’ again, and the ‘lupus anticoagulant’ had returned! At this point, I added high-dose prednisone to her treatment regimen ('immunosuppression' was one empiric approach to management of patients with lupus anticoagulants at that time). Her pregnancy survived the first trimester, so rather than arguing with success, we continued her on this regimen. Indeed, at many institutions back then, she would not have even been started on the prednisone until the pregnancy had gotten through the first trimester. At about 26 weeks, she was found to have developed ‘gestational diabetes’ probably as much the result of the prednisone therapy as any predisposition for this she might have brought to the pregnancy. We admitted her to the hospital to begin insulin therapy for the diabetes and during the course of her routine evaluation, an ultrasound was performed and the baby was found to be severely growth restricted. Within two weeks, she developed severe preeclampsia (HELLP syndrome) and needed to be delivered by cesarean section. Although small, that baby did just fine, but did require a long stay in the neonatal intensive care unit, and my friends had their first baby. When she returned for her postpartum examination, the lupus anticoagulant was gone again!
A year or so later, she again began taking the aspirin and conceived shortly thereafter. This time her RPR returned ‘negative’ and no lupus anticoagulant was detected either. Not knowing what to do with this information, but also with the history of her previous complicated obstetrical history fresh in our minds, we compromised on a plan. We started the prednisone again in early pregnancy, decided to follow the growth of the baby, and if that was normal, planned to begin tapering the prednisone at 24 weeks and to discontinue it completely by about 26 weeks, just before we ordinarily did our diabetes screening. The growth of the baby was normal, the lupus anticoagulant was never detected, and so we followed through on the plan. Stopping the prednisone when we did prevented the onset of gestational diabetes. The fetal growth continued to be normal, the patient never developed preeclampsia, and she was delivered close to term by repeat cesarean section, having a bouncing 8 pound+ baby. She subsequently conceived one more time, never redeveloped a lupus anticoagulant, and again carried to term with no therapy other than the baby aspirin (and who knows if that was even necessary at this point!).
This patient taught me several things: 1) ‘Healthy’ people can have abnormalities of their coagulation system that either are associated with early pregnancy loss, or are ‘markers’ for an abnormal immune response for pregnancy; 2) These ‘markers’ may only be apparent during a pregnancy in some cases; 3) Treatment may help, but it might not completely prevent an ‘abnormality of placentation’ that can still result in severe fetal growth restriction and maternal preeclampsia; 4) Resolution of a ‘marker’ (in this case a ‘lupus anticoagulant’) might also reflect having overcome an abnormal immune response to pregnancy (finally successfully immunized???) and should remind us to be flexible in designing empiric management strategies for these difficult patients.
Keeping this patient in mind, let’s now look at specific abnormalities of the immune and clotting systems that may be associated with recurrent early pregnancy losses….