Maternal pruritus gravidarum and its long-term effect on dermatological morbidity in the offspring

Abstract Purpose Pruritus gravidarum is characterized by general pruritus in the absence of primary skin lesions. In this study, we sought to evaluate whether the offspring (≤ 18 years) of mothers diagnosed with pruritus gravidarum, are at increased risk of long-term dermatology-related hospitalization. Methods A population-based, retrospective cohort study of all singleton deliveries between 1991 and 2021 was conducted at a tertiary medical center. Offspring of mothers diagnosed with pruritus gravidarum were compared to offspring of non-exposed mothers. First admission involving dermatological morbidity of the offspring were analyzed using ICD-9 codes. Kaplan-Meier survival curves were used to compare the cumulative hospitalization incidence between the groups and Cox regression models were utilized to adjust for confounding variables. Results A total of 849 women out of 356,356 deliveries that fulfilled the inclusion criteria were diagnosed with pruritus gravidarum during pregnancy (0.23%). Among offspring to mothers with pruritus gravidarum versus non-pruritus gravidarum mothers, hospitalization rates involving dermatological morbidity, were higher (7.1% vs. 4.6%, p < .001) a finding that was consistent with the Kaplan-Meier survival curve (Log rank p = .002). In the Cox regression model, pruritus gravidarum was found to be a significant independent risk factor for dermatological-related hospitalizations in the offspring after controlling for gestational age, hypertensive disorders, diabetic disorders, meconium-stained amniotic fluid exposure and fertility treatments (adjusted HR = 1.44, 95% CI 1.12–1.85, p = .004). Conclusions Maternal pruritus gravidarum is an independent risk factor for long-term dermatology-related hospitalization in the offspring up to the age of 18 years.


Introduction
Pregnancy is associated with varied changes in the mother affecting all body systems, including the skin [1,2].Dermatological manifestations that occur during pregnancy arise from hormonal, immunological and metabolic changes [1].Dermatological manifestations of skin disease in pregnancy can be broadly classified into three groups: physiological skin changes including hyperpigmentation, stretch marks and others [3][4][5]; preexisting dermatoses such as psoriasis; and pregnancy-specific dermatoses such as pemphigoid gestationis, pruritic urticarial papules, plaques, and pruritus gravidarum, of which pruritus is a major and prominent symptom [6,7].
Pruritus is a symptom defined as an unpleasant sensation in the body that triggers the desire to scratch [1].The prevalence of pruritus in the general population is between 8 and 10% and is more prevalent in certain population groups, such as the elderly [8,9].Pruritus gravidarum is defined as generalized itching, appearing mostly in the third trimester of pregnancy which is not accompanied by a significant rash [10].The predominant symptom of the condition is pruritus which may or may not be associated with laboratory evidence of cholestasis [11,12].
The prevalence of pruritus gravidarum in pregnancy is not well documented in the literature [1].The percentage of pregnancies complicated by a maternal diagnosis of pruritus gravidarum is between 0.2 and 0.8%, with previous studies showing that there is an associated risk of prematurity, meconium-stained amniotic fluid (MSAF) and perinatal mortality [10,[13][14][15].Thus far, studies investigating the relationship between pruritus gravidarum, obstetric risk factors and adverse perinatal outcomes have focused only on the short-term neonatal consequences [10].
In this study, our objective was to evaluate whether pruritus gravidarum confers a long-term effect on the offspring (up to the age of 18 years).Since pruritus gravidarum is a cutaneous dermatological manifestation, we chose to focus on the long-term effect of dermatological morbidity in the offspring.

Materials and methods
All singleton deliveries recorded at Soroka University Medical Center (SUMC) between the years 1991-2021 were included in this retrospective, population-based cohort study.
The study was conducted at the single tertiary hospital in the Negev (Southern Israel) that provides healthcare services for a population of close to one million residents.SUMC is also the largest obstetric medical center in the country with approximately 16,000 births per year (2016 data).Therefore, our study is based on large nonselective population data.The study was approved by the institutional review board (SUMC IRB Committee), complying with the ethical requirements of the 1964 Helsinki Declaration and the requirements set for by the 1975 Helsinki Declaration and 2013 revision.
The exposure was defined as offspring of mothers with pruritus gravidarum (ICD-9 [International Classification of Disease 9] codes 6982 and 6989), defined as generalized itching without significant rash after dermatological consultation.
Offspring with congenital anomalies or multiple gestations were excluded from the study.
The data collected for the study was based on two large electronic databases.The first is a computerized perinatal database of the obstetrics and gynecology department, which includes general, maternal, obstetric, fetal and neonatal data documented by the obstetrician immediately after birth.The second is the computerized hospitalization database of SUMC ("Demog-ICD9") which includes demographic information and all medical diagnoses (based on ICD9 codes) documented during any hospitalization in the pediatric departments.In order to verify the information and provide assurance on data integrity, two trained medical secretaries routinely examined the information received, and only after careful review of the information, data was entered into the relevant repository.
Several clinical characteristics were evaluated in this study, including maternal age at index birth, parity, mean gestational age, birth weight and the gender of the offspring.In addition, obstetric risk factors including fertility treatments, diabetes mellitus, and hypertensive disorders of pregnancy, as well as labor characteristics and perinatal outcomes, such as perinatal mortality and meconium-stained amniotic fluid exposure were evaluated.
To evaluate the offspring's hospitalization for a dermatological condition, we defined any hospitalization in which a dermatological diagnosis was given for a child up to the age of 18.The dermatological diagnosis was not necessarily the cause of the hospitalization.The diagnoses included are based on ICD9 and are attached in Supplementary Table A.
Follow-up time ended if one of the following events occurred: the first offspring was hospitalized with a dermatological morbidity, or when censored.Censoring occurred when offspring reached the age of 18, there was a loss to follow-up, or in the case of death during hospitalization.

Statistical analysis
The SPSS package 23rd ed.(IBM/SPSS, Chicago, IL) was utilized to perform statistical analysis.Categorical data are shown in counts and rates.To evaluate the differences in categorical variables for general associations the chi-square test was used.Data on continuous variables with normal distribution are presented as mean-± standard deviation (SD) and compared using Student t-tests.Kaplan-Meier survival curves were performed to compare the cumulative dermatologyrelated hospitalization incidences over time between the two study groups, and the log-rank test was used to evaluate the differences between the curves.Finally, Cox regression models were used to adjust for confounders and clinically significant variables.These included birth weight, diabetes mellitus, hypertensive disorders, gestational age, meconium-stained amniotic fluid, and fertility treatments.A two-sided p-value of .05 was considered statistically significant.

Results
There were 356,356 singleton deliveries after initial analysis, disregarding those patients with incomplete inclusion criteria.Of these, 849 mothers were diagnosed with pruritus gravidarum (0.23%).Maternal characteristics and delivery outcomes for both groups are shown in Table 1.Several significant differences between exposed and non-exposed group were found: mothers with pruritus gravidarum were more likely to be diagnosed with diabetes mellitus and hypertensive disorders, and they were more likely to be nulliparous and to conceive following fertility treatments.Mean gestational age was significantly lower and the rate of neonates of male gender was significantly higher in the exposed group compared with the non-exposed group.
Table 2 shows the rates and the long-term dermatological morbidities in hospitalized offspring of mothers with and without pruritus gravidarum.Several dermatological illnesses and conditions, including allergies, dermatitis and psoriasis were found to be more common in the offspring of women with pruritus gravidarum in pregnancy, although none reached statistical significance.Total dermatology-related hospitalizations rate was significantly higher in the exposed group versus the nonexposed group (7.1% vs. 4.6%; OR ¼ 1.60, 95% CI 1.23-2.08,p-value <.001).
A Kaplan-Meier survival curve (Figure 1) demonstrated a significantly higher cumulative incidence of dermatology-related hospitalizations of the offspring in the pruritus-exposed group as compared to the unexposed group (log-rank p ¼ .002).
The results from several Cox regression model are presented in Table 3, showing the association between maternal pruritus gravidarum and the longterm risk of dermatology-related hospitalizations in the offspring (up to the age of 18 years).Maternal pruritus gravidarum was found to be a significant independent risk factor for dermatology-related hospitalizations in the offspring after controlling for Gestational age in weeks, Diabetes mellitus, hypertensive disorders, MSAF exposure and fertility treatment (adjusted HR 1.44, 95% CI 1.12-1.85,p ¼ .004).

Discussion
In this large retrospective, population-based cohort with a long-term follow-up, maternal pruritus gravidarum was shown to be an independent risk factor for long-term dermatology-related hospitalizations of the offspring (18 years).This association remained significant after controlling for several confounding variables.
In our study, a number of different illnesses, including allergies, dermatitis and psoriasis, were found to be more common in the offspring of women with pruritus gravidarum, although none were found to be statistically significant.This lack of statistical significance may be related to the relatively low number of cases in our study.This is because a large proportion of dermatological conditions were treated in the  community setting and were thus excluded from our analysis which included only eruptive skin disorders associated with hospitalization.However, the total dermatology-related hospitalizations in the offspring of the group of maternal pruritus gravidarum was significantly higher (7.1%) compared to the comparator group (4.6%).In a similar manner, analysis of the cumulative hospitalizations over time for dermatologyrelated hospitalizations demonstrated that offspring born to the maternal pruritus gravidarum group had a significantly higher incidence of hospitalization for dermatological morbidity (Kaplan-Meier, log-rank p ¼ .002).It is noteworthy that recently, in another study, pruritus was also noted as an independent risk factor with long-term neuropsychiatric hospitalizations of the offspring [16].Our study did not find higher rates of perinatal mortality in the exposed group.This is in contrast to other studies' results.For example, a study by Shanmugam et al. [15], reported an increased rate of perinatal mortality among mothers with a diagnosis of pruritus gravidarum.This difference might be related to their small sample study in comparison to ours; they included just 23 patients with only 1 case of mortality.Perinatal mortality is a cause for great concern in the field of obstetrics.Accordingly, there are ongoing efforts to proactively detect antecedent risk factors for mortality in order to better identify populations at risk [17,18].The lack of association between pruritus gravidarum and perinatal mortality found in this study is reassuring, since fear of such an association leads to increased induction of labor in affected women [10].
In keeping with our study results, the study by Shanmugam et al. [15], also demonstrated that pruritus gravidarum was significantly more common in nulliparous women.The association between pruritus gravidarum and nulliparity, or actually the lower occurrence in multiparous women, may suggest a pathogenetic immunological reaction.Such a reaction may be directed toward paternal antigens, with a tolerance developed in subsequent pregnancies [19].
Our study found diabetes mellitus (DM) to be a significant risk factor for pruritus gravidarum.This finding corresponds to a study previously conducted at our institution that found a 1.4-fold increased risk for pruritus gravidarum in patients with DM (OR ¼ 1.4, 95% CI 1.05-1.9,p ¼ .024)[10].Chronic pruritus is a common skin manifestation of DM with a prevalence of itching ranging from 3 to 49% [20].The pathophysiology may be related to diabetic polyneuropathy and impairment of the sympathetic nervous system [21].Dermatological adverse events may also be triggered by pharmacological treatment for DM [22].This higher dermatological sensitivity may play a role in the tendency of women with DM to be diagnosed with pruritus gravidarum after conception.Given the lack of extensive literature on the topic and to verify that this variable does not obscure the association between pruritus gravidarum and dermatological hospitalizations for children of exposed mothers, we performed a further analysis to exclude a possible confounder.
The possible role of estrogens in the pathogenesis of pruritus gravidarum was examined by Kreek et al. [23] This hypothesis was further supported by the fact that pruritus gravidarum usually appears during the third trimester of pregnancy when estrogen levels are maximal [10,24].In addition, women with a history of pruritus gravidarum, that were challenged with a synthetic estrogen several months after delivery, showed clinical findings of generalized itching and biochemical abnormalities in liver function resulting from a decline in hepatic clearance.These findings matched those of the same women during pregnancy [23,25].
There are no reports in the literature suggesting that sex hormones act as pruritogens [26].However, estradiol and progesterone were found to directly and indirectly induce T helper 2 cell (TH2)-related cytokine secretion, including IL-4, IL-13, IL-31 and IL-33.These cytokines bind to corresponding receptors on C-type sensory neurons leading to the sensation of itching [27].In addition, estrogen is known to act, inter alia, on mast cells and induce IgE-mediated degranulation, reinforcing the stimulatory effect of this hormone on allergic diseases [28,29].It is therefore believed that women with pruritus gravidarum develop the condition from having higher estrogen levels; a hypersensitivity to estrogen receptors; or an abnormal estrogen metabolism [23].
Estrogen and progesterone increase TH2/regulatory T cell activity and suppress TH1/TH17 activity, allowing acceptance of the allogeneic fetus during pregnancy [26].It is also known that allergic diseases including asthma and atopic dermatitis (AD) are characterized by an immune tendency toward TH2 [26,30].AD is a chronic inflammatory skin disease and the main representative of allergic eruptions.It is characterized by TH2-shifted immune abnormality, skin barrier impairment and pruritus [26,31].Kanda et al. [26], hypothesized that sex hormones might modulate the course of AD in the context of the features we described earlier.This hypothesis was based on two facts.Firstly, the permeability of the skin barrier is impaired by progesterone [26].Secondly, that estradiol levels produced during pregnancy may worsen the progesterone-induced skin barrier impairment resulting in a further detrimental effect on the skin [32].
Changes in estrogen metabolism during pregnancy among women with pruritus gravidarum, and the varied effects of estrogen on the mother as previously described, may have a similar effect on the fetus.Accordingly, the effect on the fetus' developing immune system and skin barrier may be related to the higher risk of dermatology-related hospitalizations later in life.
An alternative explanation for the dermatological hypersensitivity in the offspring may be linked to higher levels of alkaline phosphatase and serum glutamic pyruvic transaminase in women with pruritus gravidarum [12].During the course of a normal pregnancy, there is a nonspecific increase in serum alkaline phosphatase which is largely associated with an increase in release of these enzymes from the placenta, but also partly due to a decrease in maternal liver function and impaired hepatic clearance [23].Various studies have shown a link between maternal serum alkaline phosphatase (specifically heat stable alkaline phosphatase) and fetal maturity [33], and have described its important physiological role in the skin regarding morphogenesis, differentiation of the pilary system, and the keratinization of the epidermis and nail plate of the fetus [34].These findings raise an interesting question as to whether changes in alkaline phosphatase levels in women with pruritus gravidarum affect enzyme function in fetal tissues.
Our study had several limitations.Firstly, our study analysis only included eruptive skin disorders associated with hospitalization, while an extensive percentage of dermatological conditions are treated in the community.Secondly, our study had an inherent weakness resulting from the lack of information regarding biological, endocrine, and chemical changes.Lastly, due to the retrospective nature of our study, we were unable to demonstrate evidence of causation, only association.
The main strength of our study is due to the fact that it was conducted at SUMC which is the only tertiary center in the south of the country and allows for continuous monitoring of the same population over time with minimal loss to follow up.In addition, this was a non-selected cohort study based on a large subject population.These parameters give our research a significant advantage by enabling us to obtain reliable results that can reflect the true situation of the population.
Pruritus gravidarum is a complex symptom affecting the wellbeing of the mother, the fetus and, as our research suggests, also the offspring in terms of longterm dermatological morbidity later in life.Further research on the impact of these associated factors on long-term dermatological morbidity is needed.

Figure 1 .
Figure 1.Kaplan-Meier hazard function curve demonstrating the cumulative incidence of hospitalizations involving dermatological morbidity in the offspring of exposed and non-exposed groups (Log rank p value ¼ .002).

Table 1 .
Maternal characteristics and delivery outcomes based on study group.

Table 2 .
Selected long-term dermatological morbidities in the offspring (up to the age of 18 years) based on study group.

Table 3 .
Cox regression model Demonstrates the association between pruritus gravidarum and long-term dermatological morbidity in the offspring.