The Postpartum Period - Incidence and Risk Factors of Autoimmune Diseases

Pregnancy can be one of the most exciting times in a woman’s life. It can also be one of the most stressful times, especially if the pregnancy is complicated with health issues. There are many common and familiar “side effects” of pregnancy, such as nausea, heartburn, and fatigue. However, there are also more serious conditions that can develop following pregnancy, and the symptoms should not be ignored or brushed aside, as they can potentially be signs of new disease onset, and could greatly affect long-term health. In particular, there are important changes that happen to a woman’s immune system during pregnancy. These changes are vital, as they allow the pregnant woman to maintain the pregnancy and not reject the fetus as a miscarriage.

This process is referred to as tolerance. Tolerance describes the process by which the immune system develops a state of unresponsiveness to substances that would usually elicit an immune response. In normal circumstances, the immune system has the ability to recognize “self” versus “nonself”, and it is this ability that allows our bodies to fight off infection from foreign bacteria or viruses. In the pregnant state, it is imperative that the mother’s body does not recognize the fetus as nonself and mount an immune response. The idea of fetal tolerance has mystified biologists for many years, as it is still largely unknown how the majority of women do not reject a developing fetus, as half its DNA is from the father and therefore different from the woman’s own DNA. Unfortunately, the immune system can also get mixed up and start to recognize self as nonself. When this happens, antibodies and other immune messengers, called cytokines, start to attack the body’s own tissues. This is precisely what happens in the case of autoimmune diseases, such as rheumatoid arthritis (RA), multiple sclerosis (MS), Hashimoto’s thyroiditis, and systemic lupus erythematosus (SLE). During pregnancy, the hormonal environment changes drastically, with significantly increased levels of estrogen, progesterone, and cortisol. These hormones have a strong influence on the way that immune cells behave. Because of this influence, it is well known that many autoimmune diseases can either experience a remission, such as MS and RA, or can aggravate, such as SLE, while a woman is pregnant. After child birth, serum levels of progesterone, estrogen, cortisol, and DHEAS decrease substantially, leaving behind both a deficient adrenal and gonadal hormonal environment, which theoretically could result in a diminished ability to suppress or control an inflammatory response.^[1] It is this environment in which disease can develop, and it is not uncommon for autoimmune diseases to occur postpartum. This article focuses on two such conditions, postpartum thyroiditis and RA, that can have new onset in the postpartum period.

Postpartum Thyroiditis

Postpartum thyroiditis (PPT) in its classic form presents as a transient thyrotoxic phase, with hyperthyroid symptoms such as palpitations, nervousness, sweating, and shakiness, followed by a transient hypothyroid phase, with return to a euthyroid state by the end of the first year postpartum.^[2] However, some women never return to the euthyroid state, and remain permanently hypothyroid, necessitating the need for medication for the rest of their lives. This also poses potential problems if the woman plans to have more children, as being hypothyroid can result in increased rates of miscarriage and preterm delivery. PPT is autoimmune in nature and is associated with testing positive for thyroid peroxidase antibodies (TPO‑Ab) or thyroglobulin antibodies (TG‑Ab) in the first trimester of pregnancy.^[3] Women with positive antibodies have a 33–50% chance of developing PPT, and chances are greater with higher titers.^[3] Other risk factors for developing PPT are having a previous history of PPT, higher thyroid-stimulating hormone (TSH) values, older age, having more than one child, and having a higher degree of thyroid hypoechogenicity on ultrasound.^[3] One study reported that of 54 women who developed PPT in their first pregnancy, 69% had a recurrence in their second pregnancy.^[4] The risk of becoming permanently hypothyroid due to PPT has been reported anywhere from 20 to 40% in the majority of the studies. A recent study contacted 409 women 12 years postdelivery. Of these, 71 had developed PPT, and of these 71, 38% remained permanently hypothyroid.^[5] When PPT was classified as either hypothyroid or hyperthyroid, only hypothyroid states conferred a greater risk of becoming permanently hypothyroid. In addition, TSH values at 6 months postpartum was also associated with long term hypothyroidism, with 2.6 μM/L being a positive predictive cutoff.

Screening guidelines for thyroid disorders during pregnancy, as set out by the American Thyroid Association, currently include testing TSH values and free T4. Screening for TPO‑Ab and TG‑Ab remains controversial, especially during a first pregnancy. However, following a second pregnancy, if they are known to be TPO‑Ab positive, have a previous history of PPT, or have another autoimmune disorder, it is recommended that women get screened for antibodies, TSH, and free T4 at 3, 6, and 9 months postpartum (unless they become TPO‑Ab negative at one of the testing intervals).^[6] This would allow for early intervention, such as selenium supplementation, which has been shown in many studies to reduce the levels of TPO‑Ab, TSH, and ultrasound echogenicity.^[3] As previously mentioned, screening for TPO‑Ab during pregnancy is controversial. However, it is the opinion of this author that given the high incidence rates of PPT, as well as the high rates of remaining permanently hypothyroid, screening should be commonplace. The presence of thyroid antibodies in euthyroid women doubles the miscarriage rate compared to euthyroid women who tested negative for these antibodies.^[3] As well, one study reported that 25% of women who tested positive for antibodies in a first pregnancy, but did not go on to develop PPT, developed PPT in their second pregnancy.^[7]

Rheumatoid Arthritis

Rheumatoid arthritis (RA) is an autoimmune, chronic inflammatory condition that typically affects smaller joints of the hands, but can also affect larger joints. Its peak onset is usually after age 40, and it occurs three times more often in females than males. This gender disparity, as well as the observation that RA usually subsides or remits during pregnancy, has led medical researchers to look at the relationship between sex hormones and the behaviour of this condition. A clear relationship between RA and hormones has yet to be established, although there have been a number of interesting studies. One study found that estrogen levels in rheumatoid joints were 2–2.5 times higher compared to joints affected by osteoarthritis, which is significant as estrogen stimulates monocytes, a type of white blood cell, which can contribute to synovial inflammation.^[8] With respect to the onset of RA, there are many studies reporting the overall decreased incidence during pregnancy by about 70%, but an increased incidence postpartum, particularly in the first 3 months.^[8] One British study reported that RA occurred in the first year postpartum in 19%, and in 29% during the first 2 years among all patients with RA under the age of 45.^[9] A Finnish study reported that 12.6% of all patients with RA had disease onset within one year of delivery.^[10] Interestingly, the peak incidence of RA in women is during perimenopause, a time in which sex hormones are rapidly declining, much like the postpartum period.

It has also been suggested that breast-feeding further increases the risk of developing RA, and in one study women who breast-fed were five times more likely to develop the disease compared to controls.^[11] This is thought to be due to the role of prolactin, which is proinflammatory in nature, and high levels have been implicated in other autoimmune diseases, including SLE, Sjogren’s, systemic sclerosis, Hashimoto’s, celiac disease, and MS.^[12] With respect to RA, the studies linking it to prolactin are inconsistent, but it may play a role in the severity of disease. In one study of 176 women who were classified to have severe RA (defined as greater inflammatory markers, higher RF titers, worse radiographs scores, and more than six persistently swollen joints), 46% had a total breast-feeding duration of more than 6 months, compared to 26% with mild RA.^[13] Despite these findings implying risk of pregnancy and breast-feeding for developing RA, the medical literature is extremely mixed. Results of the Nurses’ Health Study from 674 women reported that the average time between the last pregnancy and the date on which RA was diagnosed was 25 years. Additionally, lifetime breast-feeding duration of 12–23 months was associated with a 30% reduction in the risk of RA, and breastfeeding for 24 months or longer was associated with a 50% reduction.^[14] Another recent study found no risk of pregnancy on disease incidence, and a protective benefit of breast-feeding,^[15] while yet another found that pregnancy actually lowered the risk of RA by 40%.^[16]

Conclusion

Various factors, including the rapid change in the hormonal environment, can affect the development of autoimmune diseases in the postpartum period, specifically PPT and RA. It is not uncommon for women to have sore joints during and after pregnancy, which could easily be passed off as transient symptoms. Additionally, symptoms of PPT can also be common after parturition, such as fatigue, sweating, and mood changes. In women with various risk factors for these conditions, early detection is important.