Discussion

Within this large, well-characterized, nationwide cohort of postmenopausal women, we found that higher birthweight was associated with a higher risk for prevalent underactive thyroid and a lower risk for prevalent overactive thyroid. Further, women born in the highest birthweight category had a significantly higher risk for developing incident lupus compared to women born at a normal birthweight.

Previous studies examining the relationship between an individual’s birthweight and risk for thyroid function and/or conditions are sparse. An infant’s birthweight is related to their thyroid stimulating hormone levels at birth, ^{Reference Korada, Pearce, Avis, Turner and Cheetham33,Reference Korevaar, Chaker, Jaddoe, Visser, Medici and Peeters34} but this association does not appear to persist into childhood or adulthood. ^{Reference Korevaar, Chaker, Jaddoe, Visser, Medici and Peeters34,Reference Frost, Petersen, Hegedüs, Christiansen, Brix and Christensen35} Birthweight has also demonstrated inverse associations with free thyroxine (FT4) and triiodothyronine (T3) in older adult twin pairs, ^{Reference Frost, Petersen, Hegedüs, Christiansen, Brix and Christensen35} as well as subclinical thyroid dysfunction and both thyroglobulin (TgAb) and thyroid peroxidase (TPOAb) autoantibodies, ^{Reference Phillips, Barker and Osmond36,Reference Phillips, Cooper and Fall37} although a separate study found no association between birthweight and TgAB or TPOAb. ^{Reference Brix, Hansen and Rudbeck38} No associations were observed between birthweight and autoimmune (i.e., Grave’s disease or Hashimoto’s thyroiditis) or nonautoimmune (i.e., simple and toxic nodular goiter) thyroid diseases, ^{Reference Brix, Kyvik and Hegedüs18} however lower birthweights were shown to increase the risk for spontaneous hypothyroidism in older adults. ^{Reference Kajantie, Phillips, Osmond, Barker, Forsén and Eriksson19} Moreover, low birthweight has consistently been associated with risk for congenital hypothyroidism, ^{Reference Hashemipour, Hovsepian, Ansari, Keikha, Khalighinejad and Niknam39,Reference Zhou, Luo and Lin40} particularly transient congenital hypothyroidism. ^{Reference Zhou, Luo and Lin40} Further, gestational diabetes, one of the leading causes of macrosomia (i.e., high birthweight), is an established risk factor for congenital hypothyroidism. ^{Reference Zhou, Luo and Lin40,Reference Franco, Laura, Sara and Salvatore41} Consistent with the existing body of literature, results from our cross-sectional analysis indicate both low and high birthweights are associated with higher risk for underactive thyroid.

A small number of prior studies have considered the potential association between birthweight and each of the autoimmune conditions examined in this study. Among four studies considering birthweight as a risk factor for RA, one cohort study found no association ^{Reference Mandl, Costenbader, Simard and Karlson20} while three additional case-control and cross-sectional studies observed positive associations with birthweight. ^{Reference Carlens, Jacobsson, Brandt, Cnattingius, Stephansson and Askling42-Reference Svendsen, Kyvik and Houen44} Similarly for MS, one case-control and one cohort study found no association with birthweight ^{Reference Gardener, Munger, Chitnis, Michels, Spiegelman and Ascherio45,Reference Ramagopalan, Valdar and Dyment46} while a second case-control study found individuals born weighing ≥4 kg were at increased odds for MS. ^{Reference Luetic, Menichini and Deri47} Results among studies examining risk factors for lupus are inconsistent with two case-control studies observing no association with birthweight, ^{Reference Arkema and Simard48,Reference Coleman, Naleway, Davis, Greenlee, Wilson and McCarty49} while a cohort study found a positive association ^{Reference Simard, Karlson and Costenbader50} and a cross-sectional study found an inverse association with birthweight. ^{Reference Parks, DʼAloisio and Sandler21} Lastly, two cohort studies found no associations between birthweight and either UC or CD. ^{Reference Khalili, Ananthakrishnan, Higuchi, Richter, Fuchs and Chan51,Reference Mendall, Jensen, Ängquist, Baker and Jess52} Compared to our analyses, many of the aforementioned studies were conducted in populations of similarly aged or slightly younger women, ^{Reference Mandl, Costenbader, Simard and Karlson20,Reference Parks, DʼAloisio and DeRoo43,Reference Gardener, Munger, Chitnis, Michels, Spiegelman and Ascherio45,Reference Simard, Karlson and Costenbader50,Reference Khalili, Ananthakrishnan, Higuchi, Richter, Fuchs and Chan51} including several from the Nurse’s Health Study I and/or II. ^{Reference Mandl, Costenbader, Simard and Karlson20,Reference Gardener, Munger, Chitnis, Michels, Spiegelman and Ascherio45,Reference Simard, Karlson and Costenbader50,Reference Khalili, Ananthakrishnan, Higuchi, Richter, Fuchs and Chan51} While our cross-sectional results are consistent with those studies that found no association between birthweight and the various autoimmune conditions, our analyses are underpowered to find an association given the magnitude of association observed.

Because an individual’s birthweight may be a marker for a variety of in utero exposures, determining the biological mechanism(s) by which birthweight influences the risk for thyroid and autoimmune conditions is complex. ^{Reference Class, Rickert, Lichtenstein and DʼOnofrio53} Infants born at lower birthweights are at a higher risk for intrauterine growth restriction, resulting in hypothalamic-pituitary-thyroid axis dysfunction. ^{Reference Ward, Syddall, Wood, Chrousos and Phillips54} Additional studies have suggested that fetal programming of the hypothalamic-pituitary-adrenal (HPA) axis may be one of the long-term changes that link low birthweight to adult disease, impacting cortisol responsiveness and, thus, chronic inflammation and autoimmunity. ^{Reference Ward, Syddall, Wood, Chrousos and Phillips54} In fact, adults with RA, ^{Reference Imrich55} lupus, ^{Reference Gutiérrez, Garcia, Rodriguez, Rivero and Jacobelli56} and other autoimmune conditions ^{Reference Gold, Mohr, Huitinga, Flachenecker, Sternberg and Heesen57,Reference Stasi and Orlandelli58} are known to have dysregulation of the HPA axis. At the other end of the growth spectrum, babies born weighing ≥10 lbs. (i.e., fetal macrosomia) are more likely to be delivered by women who are obese, gain too much weight during pregnancy, or diagnosed with type 2 or gestational diabetes. ^{Reference Kc, Shakya and Zhang59} In conditions of fetal overnutrition, an imbalance of the appropriate set of nutrients needed for proper organ development results in the inability of the fetus to properly regulate its nutrient excess, ^{Reference Regnault, Nijland, Budge and Morrison60} potentially resulting in altered endocrine programming that could influence thyroid function. ^{Reference Phillips61}

Strengths of our study include its large sample size with extensive phenotypic data collection at baseline. The prospective design of the WHI also allowed us to consider incident cases for four of our outcomes with up to 8 years of follow-up data available. We were also able to evaluate a broad spectrum of potential confounders that may account for the underlying association between birthweight and autoimmune or thyroid conditions.

Our study was limited to evaluating categories of birthweight based on self-report. While the most ideal birth data collection method would have been a quantitative measure obtained through medical records or birth certificates, self-reported birthweight by category has been shown to correlate with medical record data in validity studies (58%–87% correctly reported birthweight category). ^{Reference Jaworowicz, Nie and Bonner62,Reference Wodskou, Hundrup, Obel and Jorgensen63} Further, we hypothesize that any exposure misclassification would be nondifferential. Additionally, it is possible that women born within the normal birthweight range also experienced intrauterine growth restriction, a key event of fetal programming, which we would expect would bias our results toward the null.

There are also potential limitations related to our outcomes data. All of the outcomes evaluated in this study were self-reported without confirmation or adjudication, which would result in at least some misclassification. For example, the American Thyroid Association suggests that up to 60% of individuals with thyroid disease are unaware of their condition, ⁶⁴ which could result in a nontrivial number of women in our analyses being misclassified as controls. However, we would expect this to underestimate the association and bias our results toward the null. Despite the large sample size of the WHI, the number of participants diagnosed with most of the rare autoimmune conditions was comparatively small, resulting in a lack of power, particularly for the lowest and highest birthweight categories. We were also unable to distinguish between clinically overt and subclinical under- and overactive thyroid, or between autoimmune or nonautoimmune causes, so our results may not generalize to all thyroid conditions.

Another limitation of our study was our inability to adjust for all of the covariates that may be particularly important in the pathophysiology of our examined conditions. For example, the WHI did not collect information related to iodine levels or iodine consumption in the OS participants, and iodine deficiency is a well-known risk factor for thyroid dysfunction. ^{Reference Leung and Braverman65} We also did not have data on other in utero pregnancy exposures, such as in utero tobacco smoking exposure, or other conditions relating to the pregnancy or mother’s reproductive health, such as polycystic ovarian syndrome, preeclampsia, or gestational diabetes. Further, data on the participant’s family history were only available for cardiovascular disease and related outcomes, cancer, and fracture history; no family history information was available for autoimmune or thyroid conditions.

In conclusion, we demonstrate that low birthweight (<6 lbs.) may be associated with higher risk for underactive thyroid and higher birthweights (≥10 lbs.) are associated with (1) higher risk for underactive thyroid and incident lupus and (2) lower risk for overactive thyroid. To our knowledge, this is the first study evaluating the association between birthweight and overactive thyroid, as well as the largest study conducted on the association between birthweight and underactive thyroid in adults. Our research provides additional evidence of the role of early developmental phenotypes in the development of later-life conditions, further illustrating the importance of targeted interventions during preconception and prenatal care aimed at reducing both high and low birthweights and, thus, the burden of thyroid and autoimmune conditions.