Maternal intrahepatic cholestasis of pregnancy and neurodevelopmental conditions in offspring: A population-based cohort study of 2 million Swedish children

Shuyun Chen; Viktor H Ahlqvist; Hugo Sjöqvist; Olof Stephansson; Cecilia Magnusson; Christina Dalman; Håkan Karlsson; Brian K Lee; Renee M Gardner

doi:10.1371/journal.pmed.1004331

. 2024 Jan 16;21(1):e1004331. doi: 10.1371/journal.pmed.1004331

Maternal intrahepatic cholestasis of pregnancy and neurodevelopmental conditions in offspring: A population-based cohort study of 2 million Swedish children

Shuyun Chen ^1,^‡,^*, Viktor H Ahlqvist ^1,^‡,^*, Hugo Sjöqvist ¹, Olof Stephansson ^2,³, Cecilia Magnusson ^1,⁴, Christina Dalman ^1,⁴, Håkan Karlsson ⁵, Brian K Lee ^1,^6,⁷, Renee M Gardner ¹

Editor: Gordon C Smith⁸

PMCID: PMC10790993 PMID: 38227577

Abstract

Background

Intrahepatic cholestasis of pregnancy (ICP) is the most common obstetric liver disorder and is associated with an increased risk of iatrogenic preterm birth and adverse infant outcomes. Hence, there are several plausible pathways through which ICP could affect offspring neurodevelopment. However, to the best of our knowledge, no studies have investigated these associations. Thus, we aimed to determine whether ICP is associated with offspring neurodevelopmental conditions.

Methods and findings

In this Swedish register-based cohort study, we included singleton non-adopted children born in Sweden between the 1st of January 1987 and the 31st of December 2010, who were resident in Sweden >5 years, with no missing covariate information, which we followed until the 31st of December 2016. Maternal ICP diagnosis and the date of the initial diagnosis during pregnancy were obtained from the National Patient Register. Offspring diagnoses of attention deficit/hyperactivity disorder (ADHD), autism, or intellectual disability were obtained from the National Patient Register, and the dispensation of ADHD medications were obtained from the Prescribed Drug Register. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression while controlling for observed confounders and unobserved confounders shared among full siblings and maternal full cousins.

A total of 2,375,856 children were included in the study; 81.6% of them were of Nordic origin, and 51.4% were male. Of these, 10,378 (0.44%) were exposed to ICP. During a median of 18 years follow-up (interquartile range 11 to 24), 143,746 (6.05%) of children were diagnosed with a neurodevelopmental condition. After adjusting for child’s sex, birth year, birth month, maternal age, highest parental education level, maternal birth country, birth order, maternal psychiatric history, ICP was associated with increased odds of offspring neurodevelopmental conditions (OR 1.22, 95% CI 1.13 to 1.31), particularly among those exposed to early-onset ICP (OR 2.38, 95% CI 1.71 to 3.30) as compared to ICP diagnosed after reaching term (≥37 weeks of gestation) (OR 1.08, 95% CI 0.97 to 1.20). The findings of early-onset ICP were consistent in family-based analyses. Within-family comparisons of full maternal cousins yielded an OR of 2.99 (95% CI 1.48 to 6.04), and comparisons of full siblings showed an OR of 1.92 (95% CI 0.92 to 4.02), though the latter was less precise. The findings were consistent across specific neurodevelopmental conditions and different analytical approaches. The primary limitations of this study included its observational design, the absence of data on ICP therapeutics, and the lack of bile acid measures.

Conclusions

In this study, we observed that exposure to ICP during gestation is associated with an increased likelihood of neurodevelopmental conditions in offspring, particularly in cases of early-onset ICP. Further studies are warranted to better understand the role of early-ICP in offspring neurodevelopment.

In this Swedish register-based cohort study, Shuyun Chen, Viktor H. Ahlqvist and colleagues assess the association between maternal intrahepatic cholestasis of pregnancy and neurodevelopmental disorders in children exposed during gestation.

Author summary

Why was this study done?

Intrahepatic cholestasis of pregnancy (ICP) is a common liver disorder during pregnancy characterized by rising bile acid levels, and it is associated with early delivery and adverse infant outcomes.
Less is known about the long-term outcomes of children exposed to ICP. Because ICP may plausibly affect the development of the fetus either directly or via its association with adverse pregnancy outcomes, this study examined the hypothesis that ICP would be associated with an increased likelihood of neurodevelopmental conditions in children exposed during gestation.

What did the researchers do and find?

The study analyzed data from the Swedish registers including children born between 1987 and 2010, with follow-up for neurodevelopmental outcomes until the end of 2016. The study recorded cases of mothers diagnosed with ICP and documented the timing of these diagnoses during pregnancy using patient registries. Associations between these diagnoses and neurodevelopmental conditions, including attention deficit/hyperactivity disorder (ADHD), autism, or intellectual disability in children, were estimated using multiple analytical approaches.
The results suggested that children exposed to ICP during pregnancy were more likely to receive diagnoses of neurodevelopmental conditions, particularly when ICP was diagnosed early in pregnancy (before 28 weeks of gestation).
Because the associations were similar when children were compared to their maternal cousins and to their siblings, these findings do not appear to be explained by factors shared within families, such as genetics and some aspects of the early life environment, that can also influence the likelihood of neurodevelopmental conditions.

What do these findings mean?

Diagnosis of ICP during pregnancy, especially early in pregnancy, is associated with an increased likelihood of neurodevelopmental disorders in the children exposed during gestation.
Because this study is observational, it is not possible to determine whether ICP is a causative factor in the development of neurodevelopmental conditions in children born to affected mothers.
This study did not include information on bile acid concentrations among the pregnant women, and this study was conducted before treatment (using ursodeoxycholic acid) was widely used in Sweden. It will be important for future studies to consider if therapeutic modulation of bile acid levels in pregnant women affected by ICP can mitigate the associations we observe.

Introduction

Intrahepatic cholestasis of pregnancy (ICP) is the most common obstetric liver disorder, affecting 0.5% to 2% of pregnant women [1]. ICP is characterized by pruritus (itching) and liver dysfunction with elevated serum bile acid concentration and/or liver aminotransferases [1–3]. It typically occurs in the late second or third trimester of pregnancy. Though the etiology of ICP is not completely understood, it is likely caused by a combination of genetic, hormonal, and environmental factors [1]. The main treatment for ICP is ursodeoxycholic acid, which is administered to alleviate pruritus. In severe cases, early elective delivery may be necessary, especially since ICP typically resolves rapidly after delivery [2].

Although ICP can cause significant discomfort for pregnant women, it is typically not associated with severe maternal morbidity, but may increase the risk of later hepatobiliary disease [3]. However, ICP is associated with an elevated risk of adverse outcomes for infants, including stillbirth, preterm birth, and admission to neonatal care unit [4]. Despite some of these factors, such as preterm birth, being associated with adverse neonatal outcomes, including neurodevelopmental conditions, to the best of our knowledge, there have been no previous studies examining neurodevelopmental conditions among offspring exposed to ICP during pregnancy.

We addressed this knowledge gap by examining the association between ICP in offspring neurodevelopmental conditions (i.e., attention-deficit/hyperactivity disorder [ADHD], autism, and intellectual disability) in a population-based cohort using the Swedish health and administrative registries. The consecutive structural and functional growth of the fetal brain throughout gestation [5] implies that there may be critical periods of exposure during fetal brain development. We therefore also investigated whether the gestational week of ICP diagnosis differentially affects the likelihood of offspring neurodevelopmental conditions. Finally, capitalizing on the nationwide register-linkage of individuals across and within families, we explored the extent to which these associations could be explained by unmeasured factors shared between individuals of varying degrees of relatedness.

Methods

The main analysis was prospectively planned (S2 Appendix), and all sensitivity analyses were developed during the research process. Reviewers requested a crude analysis, an analysis that adjusts for gestational age and an analysis with detailed imputation of maternal pre-pregnancy body mass index (BMI); these analyses were therefore not part of our original prospective plan.

Study population

We created a population-based cohort study of mothers and offspring by linking information across nationwide registers using the unique identification number assigned to each Swedish resident at immigration or birth [6]. We included children born in Sweden between the 1st of January 1987 and the 31st of December 2010 (n = 2,545,022) and linked these children to their biological mothers, fathers, and maternal grandparents using the Total Population Register [7]. We excluded children not recorded in the Medical Birth Register (covering 97% to 99% of all children born in Sweden, depending on the year of birth) [8], children who resided less than 5 years in Sweden, children who were adopted, non-singletons and children with missing covariate information (Fig 1A). Our final analytical population included 2,375,856 children born to 1,308,096 mothers, who were followed until the 31 December 2016. Ethical approval was obtained from the Stockholm regional ethical review committee, with the need for informed consent waived (DNR 2010/1185-31/5, 2016/987-32). This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline (S1 Appendix).

Overview of the derivation of the analytical sample (A), the incidence of maternal intrahepatic cholestasis across offspring birth years (B), the gestational time of onset of intrahepatic cholestasis (C), and the age-specific incidence of offspring neurodevelopmental conditions across birth cohorts (D).^aAs each individual can have multiple cousins, we formed 134,906 1:1 matched cousin sets, where an individual could contribute to multiple sets (i.e., be the comparative cousin to different index individuals). Fig 1D was manually calculated, and for illustrative purposes, a median spline with 50 cross-median knots was fitted to the aggregate incidences. Figure created using BioRender.com, used under license/permission.

Maternal intrahepatic cholestasis of pregnancy

Maternal ICP was identified by a recorded diagnosis in the National Patient Register (ICD-9: 646.7, ICD-10: O26.6) [9], which covers all inpatient care (and specialized outpatient care after 2001) provided in Sweden [10]. ICP is not universally screened for during pregnancy; typically, patients present with symptoms of itching. Abnormalities in bile acid concentrations and liver function tests usually emerge days or weeks later, leading to a diagnosis of ICP. We retained the first diagnosis date of ICP as a proxy for the date of onset. In the main analysis, we classified the timing of ICP according to 3 categories: before the third trimester (<28 weeks), early in the third trimester (28 to 36 weeks), and late in the third trimester (≥37 weeks).

Offspring neurodevelopmental conditions

The primary outcome was neurodevelopmental conditions identified using the National Patient Register [11]. We defined a child as having a neurodevelopmental condition if they were ever diagnosed with ADHD (ICD-9: 314, ICD-10: F90), autism (ICD-9: 299, ICD-10: F84), or intellectual disability (ICD-9: 317–319, ICD-10: F70-F79). We also used the Prescribed Drug Register (from July 2005 and onwards), which records all dispensed prescription medications in Sweden, to identify ADHD based on the dispensation of commonly used ADHD medications [12]: methylphenidate [ATC: N06BA04] or atomoxetine [ATC: N06BA09]. We considered any neurodevelopmental condition as our primary outcome (diagnosed with at least one of the 3 neurodevelopmental conditions). As secondary outcomes, we also separately examined ADHD, autism, and intellectual disability.

Covariates

We collected a series of potential confounding variables (factors theorized or confirmed to have a causal impact on both the exposure and the outcome) from the Medical Birth Register, which contains detailed pregnancy and delivery information on virtually all deliveries in Sweden [13], the National Patient Register and the longitudinal integrated database for health insurance and labor market studies (LISA) [14]: the child’s sex [15–18], birth year [16,17,19], birth month [1,17], birth order [19,20], maternal age [1,17,18], birth country [1,16,17], early pregnancy body mass index [17,19] (from 1992, see “Sensitivity Analyses” below) and psychiatric history [21,22], and the highest parental education level [17,19]. We also collected information on pregnancy and fetal characteristics (when available), which we considered to occur concurrently with or after onset of ICP and therefore consider as potential mediators of the relationships examined in this study: gestational diabetes mellitus, gestational hypertensive conditions, mode of delivery, labor induction, gestational age at birth, Apgar score at 5-minutes, birth weight for gestational age, neonatal asphyxia, hypoglycemia, and jaundice (S1 Table).

Statistical analysis

To estimate the odds ratio (OR) and 95% confidence intervals (95% CI) of offspring neurodevelopmental conditions associated with maternal ICP and timing of ICP, we use logistic regression models with robust standard errors (to account for multiple children being born to the same mother). To enhance clinical interpretability, we also calculated the average absolute adjusted risk (marginal probability) of neurodevelopmental conditions based on the aforementioned models [23]. We present 3 models: one crude model without any adjustments, one model where we adjust for the child’s sex and birth year, and our main model, where we further adjust for birth month, birth order, maternal age, maternal country of birth and maternal psychiatric history, and the highest parental education level. In our main analysis, we did not adjust for gestational age, as we consider it to be a mediator or a collider (S5 Fig). However, in complementary analyses not registered in the protocol, we adjusted for gestational age using 3 different approaches: as a linear term in weeks, as a categorical term (<37, 37-, 38-, 39-, 40-, 41-, 42-), and by employing restricted cubic splines with 4 knots placed at the 5th, 35th, 65th, and 95th percentile.

Family-informed analysis

To account for unobserved genetic and environmental confounders shared between full siblings, we performed a sibling analysis of N = 185,323 full siblings using conditional logistic regression analysis with robust standard errors. Furthermore, as full siblings are often concordant on ICP status and only discordant pairs can contribute to the familial analysis, we also performed an analysis where we matched each child to a maternal full cousin. As each child can have multiple cousins, we formed K = 134,906 matched cousin pairs (1:1 matched), where an individual could contribute to multiple pairs (i.e., be the comparative cousin to different index children). Full sibling analysis accounts for, on average, 50% of the children’s genotype and maternal full cousin analysis accounts for, on average, 12.5% of the children’s genotype. Similarly, we may assume that full siblings (on average) share more environmental factors than cousins. Furthermore, as ICP is a maternal phenotype, it is also relevant to note that sibling analysis accounts for 100% of the maternal genotype and maternal full cousin analysis accounts for, on average, 50% of the maternal genotype. The family-based analysis was adjusted for all observed putative confounders which differed among relatives (e.g., not maternal education for full siblings).

Sensitivity analyses

We performed several sensitivity analyses. First, we replicated our primary analyses among participants with identifiable siblings and cousins to ensure that these individuals were not systematically different from that of the main cohort. Second, we replicated our primary analyses while excluding those with ICP diagnosed at delivery, as some of these ICP cases may have debuted sometime during pregnancy but were recorded as occurring at delivery. Third, we excluded all children born preterm to assess whether the association between ICP and neurodevelopmental conditions is fully explained by the effect of ICP on preterm birth. We used adjusted Wald tests to compare the results from these sensitivity analyses with the primary analysis. Fourth, we controlled for early pregnancy body mass index categories as defined by the World Health Organization among those born ≥ 1992, while either (i) performing complete case analysis; (ii) treating those with missing data as a separate category (“missing-as-indicator”); (iii) performing multiple imputation on categorical BMI (across 20 datasets with multinomial imputation and the exposure, outcome and covariates as auxiliary variables); or (iv) using inverse-probability weights to correct for missing patterns, since we chose not to control for it in our primary analyses due to it being poorly recorded in the Medical Birth Register (14.11% missing ≥ 1992). Fifth, we restricted the sample to those who were exposed to ICP and compared the odds of neurodevelopmental conditions between those diagnosed with ICP before 28 weeks, 28 to 36 weeks, and after 37 weeks of gestation (reference). Sixth, instead of categorizing the timing of ICP, we modeled the gestational week at diagnosis as a continuous variable using restricted cubic splines with 4 knots (placed at the 14, 28, 34, and 37 weeks of gestation) to relax the homogeneity assumption of the categorization. Seventh, we modeled the cumulative exposure to ICP as the number of weeks of fetal exposure to ICP (calculated from date of diagnosis to date of birth and categorized into <5, 5–8, 9–12, 13–16, and ≥17 weeks of exposure) and as the percentage of pregnancy exposed using restricted cubic splines models with 4 knots (placed at the 30%, 50%, 80%, and 90%).

Results

Among the 2,375,856 children included in this study, 10,378 (0.44%) were exposed to ICP (Fig 1B), which was most commonly diagnosed in the late third trimester (N = 344, 0.01%, <28 weeks of gestation; N = 3,759, 0.16%, 28 to 36 weeks of gestation and N = 6,275, 0.26%, ≥37 weeks of gestation) (Fig 1C). Children born to mothers with ICP were more often male, first-born, born in recent years and between January and March; and more often had well-educated, older mothers, born in a Nordic country, with previous psychiatric conditions, with overweight/obesity, and had more obstetric and neonatal complications (i.e., gestational diabetes mellitus, gestational hypertensive conditions, large for gestational age, cesarean section, preterm birth, low Apgar score, neonatal asphyxia-related comorbidities, neonatal hypoglycemia, and neonatal jaundice) (Table 1).

Table 1. Characteristics of the 2,375,856 children, born to 1,308,096 mothers between 1987 and 2010, who were included in the study, stratified by maternal ICP diagnosis.

	No ICP	ICP	Gestational week of ICP diagnosis
	No ICP	ICP	<28 weeks	28–36 weeks	≥37 weeks
Total N	2,365,478	10,378	344	3,759	6,275
Child’s sex
Female	1,149,882 (48.6%)	4,791 (46.2%)	172 (50.0%)	1,757 (46.7%)	2,862 (45.6%)
Birth year
1987–1992	668,473 (28.3%)	1,137 (11.0%)	34 (9.9%)	418 (11.1%)	685 (10.9%)
1993–1998	567,648 (24.0%)	2,021 (19.5%)	47 (13.7%)	578 (15.4%)	1,396 (22.2%)
1999–2004	525,904 (22.2%)	3,122 (30.1%)	102 (29.7%)	1,040 (27.7%)	1,980 (31.6%)
2005–2010	603,453 (25.5%)	4,098 (39.5%)	161 (46.8%)	1,723 (45.8%)	2,214 (35.3%)
Birth months
January–March	604,761 (25.6%)	2,799 (27.0%)	78 (22.7%)	1,035 (27.5%)	1,686 (26.9%)
April–June	632,404 (26.7%)	2,759 (26.6%)	93 (27.0%)	1,007 (26.8%)	1,659 (26.4%)
July–September	606,931 (25.7%)	2,350 (22.6%)	96 (27.9%)	824 (21.9%)	1,430 (22.8%)
October–December	521,382 (22.0%)	2,470 (23.8%)	77 (22.4%)	893 (23.8%)	1,500 (23.9%)
Maternal age
<25	448,618 (19.0%)	1,360 (13.1%)	57 (16.6%)	508 (13.5%)	795 (12.7%)
25–29	803,497 (34.0%)	3,054 (29.4%)	99 (28.8%)	1,087 (28.9%)	1,868 (29.8%)
30–34	731,623 (30.9%)	3,645 (35.1%)	105 (30.5%)	1,296 (34.5%)	2,244 (35.8%)
35–39	319,254 (13.5%)	1,891 (18.2%)	65 (18.9%)	697 (18.5%)	1,129 (18.0%)
≥40	62,486 (2.6%)	428 (4.1%)	18 (5.2%)	171 (4.5%)	239 (3.8%)
Highest parental education level
Primary school	78,200 (3.3%)	244 (2.4%)	6 (1.7%)	104 (2.8%)	134 (2.1%)
Upper secondary school	984,862 (41.6%)	3,480 (33.5%)	150 (43.6%)	1,295 (34.5%)	2,035 (32.4%)
University level	1,302,416 (55.1%)	6,654 (64.1%)	188 (54.7%)	2,360 (62.8%)	4,106 (65.4%)
Maternal birth country
Nordic	2,035,556 (86.1%)	9,108 (87.8%)	279 (81.1%)	3,236 (86.1%)	5,593 (89.1%)
Europe	100,591 (4.3%)	329 (3.2%)	11 (3.2%)	141 (3.8%)	177 (2.8%)
Africa	43,686 (1.8%)	126 (1.2%)	13 (3.8%)	41 (1.1%)	72 (1.1%)
Asia	154,686 (6.5%)	582 (5.6%)	34 (9.9%)	246 (6.5%)	302 (4.8%)
Other	30,959 (1.3%)	233 (2.2%)	7 (2.0%)	95 (2.5%)	131 (2.1%)
Maternal history of psychiatric conditions	119,450 (5.0%)	801 (7.7%)	47 (13.7%)	363 (9.7%)	391 (6.2%)
Birth order
1	1,014,257 (42.9%)	4,677 (45.1%)	143 (41.6%)	1,679 (44.7%)	2,855 (45.5%)
2	856,290 (36.2%)	3,636 (35.0%)	122 (35.5%)	1,287 (34.2%)	2,227 (35.5%)
≥3	494,931 (20.9%)	2,065 (19.9%)	79 (23.0%)	793 (21.1%)	1,193 (19.0%)
Early-pregnancy Maternal BMI ^a
Underweight (<18.5 kg/m²)	57,543 (2.4%)	246 (2.4%)	9 (2.6%)	93 (2.5%)	144 (2.3%)
Normal weight (18.5–24.9 kg/m²)	1,160,457 (49.1%)	5,469 (52.7%)	146 (42.4%)	1,860 (49.5%)	3,463 (55.2%)
Overweight (25.0–29.9 kg/m²)	398,199 (16.8%)	1,887 (18.2%)	73 (21.2%)	688 (18.3%)	1,126 (17.9%)
Obese (≥30 kg/m²)	157,579 (6.7%)	832 (8.0%)	40 (11.6%)	357 (9.5%)	435 (6.9%)
Missing	591,700 (25.0%)	1,944 (18.7%)	76 (22.1%)	761 (20.2%)	1,107 (17.6%)
Gestational hypertensive conditions ^b	100,011 (4.2%)	1,192 (11.5%)	33 (9.6%)	531 (14.1%)	628 (10.0%)
Gestational diabetes mellitus	21,112 (0.9%)	278 (2.7%)	9 (2.6%)	134 (3.6%)	135 (2.2%)
Birth weight for gestational age
Appropriate for gestational age	2,213,837 (93.6%)	9,385 (90.4%)	298 (86.6%)	3,310 (88.1%)	5,777 (92.1%)
Small for gestational age	56,558 (2.4%)	172 (1.7%)	19 (5.5%)	91 (2.4%)	62 (1.0%)
Large for gestational age	82,215 (3.5%)	739 (7.1%)	17 (4.9%)	310 (8.2%)	412 (6.6%)
Missing	12,868 (0.5%)	82 (0.8%)	10 (2.9%)	48 (1.3%)	24 (0.4%)
Mode of delivery
Vaginal non-instrumental	1,886,258 (79.7%)	7,606 (73.3%)	212 (61.6%)	2,609 (69.4%)	4,785 (76.3%)
Vaginal instrumental	162,784 (6.9%)	795 (7.7%)	21 (6.1%)	233 (6.2%)	541 (8.6%)
Cesarean section	316,436 (13.4%)	1,977 (19.1%)	111 (32.3%)	917 (24.4%)	949 (15.1%)
Induction of labor
Spontaneous onset	1,617,945 (68.4%)	4,366 (42.1%)	172 (50.0%)	1,588 (42.2%)	2,606 (41.5%)
Induced labor	183,592 (7.8%)	4,503 (43.4%)	80 (23.3%)	1,450 (38.6%)	2,973 (47.4%)
Cesarean section before labor onset	129,464 (5.5%)	831 (8.0%)	68 (19.8%)	454 (12.1%)	309 (4.9%)
Missing	434,477 (18.4%)	678 (6.5%)	24 (7.0%)	267 (7.1%)	387 (6.2%)
Gestational age at birth
Preterm (<37 weeks)	116,683 (4.9%)	1,405 (13.5%)	88 (25.6%)	1,317 (35.0%)	N/A
Term (37-<42 weeks)	2,076,269 (87.8%)	8,742 (84.2%)	249 (72.4%)	2,406 (64.0%)	6,087 (97.0%)
Post-term (≥42 weeks)	169,912 (7.2%)	222 (2.1%)	7 (2.0%)	33 (0.9%)	182 (2.9%)
Missing	2,614 (0.1%)	9 (0.1%)	0	<5	6 (0.1%)
Apgar score at 5-minutes
≥7	2,318,119 (98.0%)	10,148 (97.8%)	329 (95.6%)	3,652 (97.2%)	6,167 (98.3%)
<7	24,529 (1.0%)	153 (1.5%)	11 (3.2%)	69 (1.8%)	73 (1.2%)
Missing	22,830 (1.0%)	77 (0.7%)	<5	38 (1.0%)	35 (0.6%)
Neonatal asphyxia-related comorbidities	102,910 (4.4%)	737 (7.1%)	53 (15.4%)	404 (10.7%)	280 (4.5%)
Neonatal hypoglycemia	42,838 (1.8%)	383 (3.7%)	10 (2.9%)	221 (5.9%)	152 (2.4%)
Neonatal jaundice	107,386 (4.5%)	719 (6.9%)	49 (14.2%)	467 (12.4%)	203 (3.2%)

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All results are presented as numbers and percentages (n, %), with the denominator being the column total (Total N).

^aAvailable from 1992 onwards.

^bIncluding gestational hypertension, pre-eclampsia (mild and severe), and eclampsia.

BMI, body mass index; ICP, intrahepatic cholestasis of pregnancy.

During a median follow-up of 18 years (interquartile range 11 to 24), 143,746 (6.05%) of children were diagnosed with a neurodevelopmental condition (either ADHD, autism, or intellectual disability): 106,381 (4.48%) with ADHD, 48,363 (2.04%) with autism, and 23,933 (1.01%) with intellectual disability. These conditions increased in prevalence across birth cohorts (Fig 1D).

Primary analyses

Children born to mothers with ICP were more likely to be diagnosed with neurodevelopmental conditions (Fig 2 and Table 2). Adjusting for potential confounders (i.e., child’s sex, birth year, birth month, maternal age, highest parental education level, maternal birth country, birth order, and maternal psychiatric history) slightly attenuated these associations. Specifically, children exposed to ICP had a 7.23% (95% CI 6.73 to 7.73) absolute risk of being diagnosed with neurodevelopmental conditions while those unexposed to ICP had a 6.05% (95% CI 6.02 to 6.08) absolute risk of being diagnosed, after adjusting for putative confounders (Fig 2). That is, children exposed to ICP were 22% more likely to be diagnosed with a neurodevelopmental condition (adjusted OR 1.22, 95% CI 1.13 to 1.31, P < 0.001), after controlling for putative confounders, compared to children born to mothers without ICP. These associations were consistent after controlling for shared familial factors between maternal full cousins (adjusted OR 1.24, 95% CI 1.09 to 1.42, P = 0.001), but attenuated after further controlling for factors shared between full siblings (adjusted OR 1.04, 95% CI 0.88 to 1.24, P = 0.632).

Table 2. The association between maternal intrahepatic cholestasis and different offspring neurodevelopmental conditions, stratified by the gestational period of onset of intrahepatic cholestasis.

			Unadjusted	Sex and birth year adjusted^a				Fully adjusted model^a^,^b
	N _{ICP Unexposed}	N _{ICP Exposed}	Odds ratio (95% CI)	Absolute risk unexposed % (95% CI)	Absolute risk exposed %, (95% CI)	Odds ratio (95% CI)	P-value	Absolute risk unexposed % (95% CI)	Absolute risk exposed % (95% CI)	Odds ratio (95% CI)	P-value
Any diagnoses of ICP
Total	2,365,478	10,378
Any NDCs	143,033	713	1.15 (1.06–1.24)	6.05 (6.02–6.08)	7.14 (6.64–7.64)	1.20 (1.11–1.29)	<0.001	6.05 (6.02–6.08)	7.23 (6.73–7.73)	1.22 (1.13–1.31)	<0.001
ADHD	105,841	540	1.17 (1.08–1.28)	4.55 (4.52–4.57)	5.46 (5.01–5.91)	1.22 (1.11–1.33)	<0.001	4.54 (4.52–4.57)	5.57 (5.12–6.02)	1.25 (1.14–1.36)	<0.001
Autism	48,111	252	1.20 (1.06–1.37)	2.12 (2.10–2.14)	2.58 (2.26–2.89)	1.22 (1.08–1.39)	0.002	2.12 (2.10–2.14)	2.53 (2.22–2.83)	1.20 (1.06–1.36)	0.004
Intellectual disability	23,842	91	0.88 (0.71–1.08)	1.06 (1.05–1.07)	1.02 (0.81–1.23)	0.96 (0.78–1.18)	0.70	1.06 (1.05–1.07)	1.07 (0.85–1.29)	1.01 (0.82–1.24)	0.91
ICP diagnosed <28 weeks
Total	2,365,478	344
Any NDCs	143,033	43	2.22 (1.61–3.06)	6.05 (6.02–6.08)	13.93 (10.09–17.77)	2.55 (1.84–3.55)	<0.001	6.05 (6.02–6.08)	12.97 (9.41–16.53)	2.38 (1.71–3.30)	<0.001
ADHD	105,841	33	2.30 (1.61–3.30)	4.55 (4.52–4.57)	10.96 (7.46–14.46)	2.62 (1.82–3.79)	<0.001	4.54 (4.52–4.57)	10.21 (6.99–13.44)	2.46 (1.70–3.55)	<0.001
Autism	48,111	10	1.54 (0.82–2.88)	2.12 (2.10–2.14)	3.52 (1.38–5.65)	1.69 (0.90–3.19)	0.11	2.12 (2.10–2.14)	3.24 (1.27–5.22)	1.56 (0.82–2.94)	0.17
Intellectual disability	23,842	7	2.17 (1.03–4.59)	1.06 (1.05–1.07)	2.68 (0.73–4.63)	2.57 (1.22–5.45)	0.01	1.06 (1.05–1.07)	2.43 (0.66–4.19)	2.34 (1.10–4.96)	0.03
ICP diagnosed between 28–36 weeks
Total	2,365,478	3,759
Any NDCs	143,033	277	1.24 (1.09–1.40)	6.05 (6.02–6.08)	8.08 (7.18–8.98)	1.37 (1.21–1.55)	<0.001	6.05 (6.02–6.08)	7.99 (7.10–8.88)	1.36 (1.20–1.54)	<0.001
ADHD	105,841	204	1.23 (1.07–1.42)	4.55 (4.52–4.57)	6.07 (5.27–6.87)	1.36 (1.18–1.57)	<0.001	4.54 (4.52–4.57)	6.03 (5.25–6.82)	1.36 (1.18–1.57)	<0.001
Autism	48,111	96	1.27 (1.04–1.56)	2.12 (2.10–2.14)	2.87 (2.30–3.43)	1.37 (1.11–1.67)	0.003	2.12 (2.10–2.14)	2.77 (2.22–3.31)	1.32 (1.07–1.62)	0.008
Intellectual disability	23,842	31	0.83 (0.58–1.18)	1.06 (1.05–1.07)	1.02 (0.66–1.37)	0.96 (0.67–1.37)	0.82	1.06 (1.05–1.07)	1.03 (0.67–1.39)	0.97 (0.68–1.39)	0.88
ICP diagnosed ≥37 weeks
Total	2,365,478	6,275
Any NDCs	143,033	393	1.04 (0.94–1.15)	6.05 (6.02–6.08)	6.28 (5.68–6.88)	1.04 (0.94–1.16)	0.43	6.05 (6.02–6.08)	6.48 (5.87–7.09)	1.08 (0.97–1.20)	0.15
ADHD	105,841	303	1.08 (0.96–1.21)	4.55 (4.52–4.57)	4.86 (4.33–5.39)	1.07 (0.96–1.21)	0.23	4.54 (4.52–4.57)	5.06 (4.52–5.61)	1.12 (1.00–1.26)	0.05
Autism	48,111	146	1.15 (0.97–1.35)	2.12 (2.10–2.14)	2.38 (2.00–2.76)	1.13 (0.95–1.33)	0.16	2.12 (2.10–2.14)	2.36 (1.99–2.74)	1.12 (0.95–1.32)	0.18
Intellectual disability	23,842	53	0.84 (0.64–1.10)	1.06 (1.05–1.07)	0.94 (0.69–1.20)	0.89 (0.68–1.16)	0.39	1.06 (1.05–1.07)	1.02 (0.75–1.29)	0.96 (0.73–1.26)	0.78

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^aLogistic regression models with robust (sandwich) standard errors. P-values were derived using Wald tests.

^bAdjusted for sex, birth year, maternal age, highest parental education level, maternal birth country, birth order, maternal psychiatric history, and birth month.

ADHD, attention deficit/hyperactivity disorder; ICP, intrahepatic cholestasis of pregnancy; NDC, neurodevelopmental conditions.

The strength of the association between ICP and offspring neurodevelopmental conditions increased the earlier ICP was diagnosed (Fig 2 and Table 2). For example, children born to mothers with ICP diagnosed <28 weeks of gestation were more than 2 times more likely to be diagnosed with a neurodevelopmental condition (adjusted OR 2.38, 95% CI 1.71 to 3.30, P < 0.001; adjusted absolute risk 13.93%, 95% CI 10.09% to 17.77%), as compared to children born to mothers without ICP, while children born to mothers with ICP diagnosed ≥37 weeks of gestation had comparable risk of neurodevelopmental conditions to that of children born to mothers without ICP (adjusted OR 1.08, 95% CI 0.97 to 1.20, P = 0.15; adjusted absolute risk 6.28%, 95% CI 5.68% to 6.88%). The association between early-onset ICP and offspring neurodevelopmental conditions was largely consistent after controlling for unobserved factors shared between full maternal cousins (adjusted OR 2.99, 95% CI 1.48 to 6.04, P = 0.002) and between full siblings (adjusted OR 1.92, 95% CI 0.92 to 4.02, P = 0.082), albeit with less precision.

For specific neurodevelopmental conditions, the association between ICP and offspring autism (adjusted OR 1.20, 95% CI 1.06 to 1.36, P = 0.004) and ADHD (adjusted OR 1.25, 95% CI 1.14 to 1.36, P < 0.001) were similar. However, the association between ICP and offspring intellectual disability was weaker and not statistically significant (adjusted OR 1.01, 95% CI 0.82 to 1.24, P = 0.91). When categorizing ICP based on the time of diagnosis in gestational weeks, the associations with ICP diagnosed before 28 weeks were similar for offspring ADHD (adjusted OR 2.46, 95% CI 1.70 to 3.55, P < 0.001) and intellectual disability (adjusted OR 2.34, 95% CI 1.10 to 4.96, P = 0.03), but the association with offspring autism was not statistically significant (adjusted OR 1.56, 95% CI 0.82 to 2.94, P = 0.17). For ICP diagnosed between 28 and 36 weeks, the associations with offspring autism (adjusted OR 1.32, 95% CI 1.07 to 1.62, P = 0.008) and ADHD (adjusted OR 1.36, 95% CI 1.18 to 1.57, P < 0.001) were similar, but there was not a statistically significant association with offspring intellectual disability (adjusted OR 0.97, 95% CI 0.68 to 1.39, P = 0.88). For ICP diagnosed at ≥37 weeks of gestation, none of the associations with specific neurodevelopmental outcomes were statistically significant (ADHD adjusted OR 1.12, 95% CI 1.00 to 1.26, P = 0.05; autism adjusted OR 1.12, 95% CI 0.95 to 1.32, P = 0.18; intellectual disability adjusted OR 0.96, 95% CI 0.73 to 1.26, P = 0.78) (Fig 2 and Table 2).

Adjusting for gestational age slightly attenuated the observed associations but did not alter the qualitative conclusion; early ICP was associated with neurodevelopmental conditions irrespective of controlling for gestational age (Table 3), albeit with slightly less precision. For example, further adjusting for gestational age altered the statistical significance of the association between ICP diagnosed before 28 weeks and intellectual disability, as well as the association between ICP diagnosed between 28 and 36 weeks and autism (Table 3).

Table 3. The association between intrahepatic cholestasis of pregnancy and neurodevelopmental conditions after adjusting for gestational age.

	Adjusting for gestational age as:
	Linear term^a		Categorical term^b		Restricted cubic splines^c
	OR (95% CI)	P-value	OR (95% CI)	P-value	OR (95% CI)	P-value
Any diagnoses of ICP
Any NDCs	1.15 (1.06–1.24)	0.001	1.14 (1.05–1.23)	0.001	1.15 (1.07–1.24)	<0.001
ADHD	1.19 (1.09–1.30)	<0.001	1.18 (1.08–1.29)	<0.001	1.19 (1.09–1.30)	<0.001
Autism	1.14 (1.00–1.29)	0.045	1.13 (1.00–1.28)	0.056	1.14 (1.01–1.30)	0.037
Intellectual disability	0.88 (0.71–1.08)	0.228	0.84 (0.68–1.03)	0.099	0.89 (0.72–1.09)	0.255
Diagnosed <28 weeks
Any NDCs	2.13 (1.53–2.97)	<0.001	2.14 (1.54–2.98)	<0.001	2.09 (1.50–2.91)	<0.001
ADHD	2.27 (1.57–3.28)	<0.001	2.28 (1.58–3.30)	<0.001	2.24 (1.55–3.24)	<0.001
Autism	1.39 (0.73–2.64)	0.311	1.40 (0.74–2.66)	0.297	1.36 (0.71–2.58)	0.353
Intellectual disability	1.73 (0.81–3.70)	0.157	1.75 (0.82–3.71)	0.145	1.68 (0.78–3.60)	0.183
Diagnosed between 28–36 weeks
Any NDCs	1.20 (1.06–1.36)	0.004	1.14 (1.01–1.30)	0.034	1.19 (1.05–1.34)	0.007
ADHD	1.24 (1.07–1.43)	0.004	1.20 (1.04–1.38)	0.014	1.22 (1.06–1.41)	0.006
Autism	1.17 (0.96–1.44)	0.125	1.12 (0.92–1.38)	0.262	1.16 (0.94–1.42)	0.159
Intellectual disability	0.72 (0.51–1.03)	0.076	0.62 (0.43–0.88)	0.008	0.71 (0.50–1.02)	0.062
Diagnosed ≥37 weeks
Any NDCs	1.06 (0.96–1.18)	0.265	1.07 (0.97–1.19)	0.171	1.08 (0.97–1.19)	0.161
ADHD	1.11 (0.99–1.24)	0.086	1.11 (0.99–1.25)	0.075	1.12 (0.99–1.25)	0.067
Autism	1.10 (0.93–1.30)	0.248	1.12 (0.95–1.32)	0.178	1.12 (0.95–1.32)	0.170
Intellectual disability	0.94 (0.71–1.23)	0.637	0.97 (0.74–1.28)	0.849	0.96 (0.73–1.26)	0.785

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^aLogistic regression models with standard errors computed using the robust (sandwich) method. Adjusted for the same covariates as the main model (i.e., child’s sex, birth year, maternal age, highest parental education level, maternal birth country, birth order, maternal psychiatric history, and birth month) and gestational age in weeks as a linear term.

^bAdjusted for the same covariates as the main model and gestational age in weeks as a categorical term (<37, 37-, 38-, 39-, 40-, 41-, 42-).

^cAdjusted for the same covariates as the main model and gestational age in weeks using restricted cubic splines with 4 knots placed at the 5th, 35th, 65th, and 95th percentile.

ADHD, attention deficit/hyperactivity disorder; ICP, intrahepatic cholestasis of pregnancy; NDC, neurodevelopmental disorder.

Sensitivity analyses

Results from sensitivity analyses were consistent with those from primary analyses (S3–S4 Tables and S1–S4 Figs). That is, the associations remained consistent with the main findings after excluding individuals without identifiable maternal cousins (N = 1,584,097) or full siblings (N = 664,358) (P-values of cross-model Wald tests ≥ 0.05) (S3 Table). The associations were also consistent with the main findings when ICP cases diagnosed on the delivery date (N = 2,290) were excluded (P-values of cross-model Wald tests ≥ 0.05) (S4 Table). However, after excluding preterm births (N = 118,088), the association between ICP diagnosed before 28 weeks of gestation and offspring intellectual disability was no longer statistically significant, though other estimates remained largely in line with the main findings (S4 Table). The results were slightly attenuated after excluding individuals born before 1992 (N = 553,230). While the majority of the associations were still statistically significant, the association between ICP diagnosed before 28 weeks of gestation and offspring intellectual disability was no longer statistically significant (adjusted OR 1.85, 95% CI 0.76 to 4.52) (S5 Table). After further adjustment for maternal BMI (irrespective of via complete case analysis, “missing-as-indicator,” multiple imputation or inverse-probability weights), slight attenuations were observed in the associations between maternal ICP diagnosed before 28 weeks and between 28 and 36 weeks of gestation, and offspring neurodevelopmental conditions. Similarly, the association between ICP diagnosed before 28 weeks of gestation and offspring intellectual disability was not statistically significant (adjusted OR_{complete case analysis} 1.88, 95% CI 0.69 to 5.08; adjusted OR_{missing-as-indicator} 1.81, 95% CI 0.74 to 4.41; adjusted OR_{inverse-probability weights} 1.84, 95% CI 0.51 to 6.66; adjusted OR_{multiple imputation} 1.82, 95% CI 0.75 to 4.44) (S5 Table).

Similar to findings relating to early-onset ICP, a longer duration of exposure to maternal ICP was associated with greater odds of offspring neurodevelopmental conditions (S1 Fig). That is, children exposed to ICP for more than 16 weeks were at increased odds of being diagnosed with neurodevelopmental conditions (OR 2.90, 95% CI 1.45 to 5.80), as compared to the children who were never exposed to ICP. However, all children in this group (duration >16 weeks) were diagnosed with ICP before 28 weeks of gestation. Modeling the time of diagnosis of ICP as continuous variables with restricted cubic splines (S2 Fig), or as the completed percentage of pregnancy at ICP diagnosis (S3 Fig), among women with ICP yielded results in line with our main finding that earlier diagnosis of ICP was more strongly associated with offspring neurodevelopment. A similar pattern was also observed in the sibling analysis using continuous variables (S2 Fig). Restricting the analysis to those with ICP and contrasting the associations between categories of onset of ICP yielded the same conclusion as our main analysis (S4 Fig).

Discussion

In this Swedish nationwide cohort study, we found that children born to mothers with ICP were more likely to be diagnosed with neurodevelopmental conditions than children born to mothers without ICP. Specifically, children born to mothers diagnosed with ICP before 28 weeks of gestation were twice as likely to be diagnosed with neurodevelopmental conditions. Although we found some evidence to suggest that genetic and environmental factors shared between full siblings and full maternal cousins contribute to this relationship, these factors did not appear to fully explain the higher occurrence of neurodevelopmental conditions among children exposed to early-onset ICP.

Though it is well recognized that maternal ICP is a risk factor for obstetric and neonatal complications [4,19] and that the risk increases with the concentration of serum bile acid levels [24], we are unaware of any previous studies that have studied the long-term effects of maternal ICP on offspring neurodevelopmental conditions. Potential mechanistic pathways linking maternal ICP and offspring neurodevelopmental conditions include placental vasospasms and fetal hypoxia [25–27], oxidative stress [28–30], and chronic inflammation [31–34]. Persons with early-onset ICP had a higher proportion of SGA, cesarean section, low Apgar score at 5-minutes, neonatal asphyxia-related comorbidities, and neonatal jaundice. These factors are associated with increased risks of neurodevelopmental conditions in offspring [16–18,20]. Another potential mediator linking ICP to offspring neurodevelopment is preterm birth. However, we did not observe a higher proportion of preterm births among those diagnosed with early-onset ICP. Furthermore, excluding premature births or adjusting for gestational age at birth only had a negligible effect on most of our estimates, suggesting that preterm birth is unlikely to explain the stronger associations observed with early-onset ICP. However, adjusting for gestational age altered the statistical significance of the association between ICP diagnosed before 28 weeks and intellectual disability, as well as the association between ICP diagnosed between 28 and 36 weeks and autism. It is important to note, however, that adjusting for gestational age might introduce bias into the results, as it can act as either a mediator or a collider (refer to S5 Fig). Therefore, caution is necessary when interpreting results that have been adjusted for gestational age. It is important, however, to emphasize that preterm birth is a well-recognized risk factor for offspring neurodevelopmental conditions [16–18]. Our findings regarding the length of exposure to ICP should not be misconstrued as an encouragement for earlier deliveries of these children. In fact, although we are not powered to formally examine mediation, it seems probable that the connection between early ICP and offspring neurodevelopmental conditions may involve shorter gestation; earlier (iatrogenic) delivery is not necessarily recommended because it may partly explain the observed excess risk, and we currently do not know if treatment (i.e., ursodeoxycholic acid) might mitigate the observed risks. Further investigations are warranted to better understand the underlying etiology of early-onset ICP and the possible mechanisms that implicate it in offspring neurodevelopmental conditions.

The primary strength of this study is our large nationwide sample, which allowed us to examine a population with minimal selection bias and loss to follow-up and to utilize robust methods to mitigate unobserved genetic and environmental confounders—strengthening our causal inferences beyond that of traditional methods.

There are, however, some limitations of using Swedish health registries that should be acknowledged. First, although a longer duration of exposure (duration ≥17 weeks) to ICP was associated with higher risks of neurodevelopmental conditions, all cases with ICP exposure ≥17 weeks were diagnosed with ICP before 28 weeks of gestation. Therefore, we were not able to clearly differentiate whether this association was due to ICP exposure during a critical window in early fetal development or the consequence of greater cumulative duration of fetal exposure to ICP. Nonetheless, these analyses suggest that ICP is somehow involved in the etiology of neurodevelopmental conditions in the offspring. Second, the registers do not record any measures of bile acid concentration, so we were unable to examine the role of serum bile acid concentration—which is a strong marker for ICP severity. Third, ursodeoxycholic acid had not gained widespread use as a treatment for ICP in Sweden during our study period, and we were therefore unable to examine its potential role. We suggest that future studies examine if ursodeoxycholic acid may mitigate the role of ICP in offspring neurodevelopment. Fourth, although we were able to control for a range of both observed and unobserved confounders, our study is observational and may be subject to residual confounding. Fifth, while our study encompasses almost everyone giving birth in Sweden, it is not certain that our findings generalize to other populations with different prevalence’s of ICP and neurodevelopmental conditions. Finally, although our findings point to a role of early-onset ICP in neurodevelopment, ICP rarely presents in early gestation, with only a limited number of children exposed to ICP before 28 weeks of gestation in this study. While we have made thorough efforts to describe women with early-onset ICP and their obstetric and neonatal complications, which we attempt to control for, they may not be comparable to other women who develop ICP—differing in characteristics above and beyond what can be controlled for in register-based studies. To resolve this, we urge replication of our study, including collection of more detailed information on women experiencing early-onset ICP in future studies.

Of note, early-onset ICP only accounted for 3.3% of the ICP cases in our study sample as most ICP cases were diagnosed in the late second or third trimester [1,19]. Clinically, this means that few women and children are likely to ever experience this exposure (0.16% of the population) and that eliminating this exposure from the population would only have a small impact on the population-wide prevalence of neurodevelopmental conditions.

In this large population-based cohort study, we found evidence to suggest that offspring exposed to ICP during pregnancy are more likely to be diagnosed with neurodevelopmental conditions, especially when exposed to early-onset ICP. Further studies are warranted to replicate our findings and to explore the potential underlying mechanisms of this relationship.

Supporting information

S1 Appendix. STROBE Checklist.

Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist.

(DOCX)

Click here for additional data file.^{(44.7KB, docx)}

S2 Appendix. Protocol.

Prospectively recorded analysis plan.

(DOCX)

Click here for additional data file.^{(56.8KB, docx)}

S1 Fig. The association between duration of fetal exposure to maternal intrahepatic cholestasis and any offspring neurodevelopmental conditions, and the distribution of week of onset across duration of exposure.

(DOCX)

Click here for additional data file.^{(151.3KB, docx)}

S2 Fig. The association between gestational week of maternal intrahepatic cholestasis diagnosis and any offspring neurodevelopmental conditions, among the offspring exposed to maternal intrahepatic cholestasis (N = 10,378), separated by full-cohort analysis and full-sibling analysis.

(DOCX)

Click here for additional data file.^{(162.3KB, docx)}

S3 Fig. The association between timing at maternal intrahepatic cholestasis diagnosis, as a function of the percentage of pregnancy completed at diagnosis, and any offspring neurodevelopmental conditions among children exposed to ICP (N = 10,378).

(DOCX)

Click here for additional data file.^{(176.2KB, docx)}

S4 Fig. The association between the categorical timing of intrahepatic cholestasis of pregnancy diagnosis and any neurodevelopmental conditions in offspring among those who were born to mothers with ICP (N = 10,378).

(DOCX)

Click here for additional data file.^{(101.1KB, docx)}

S5 Fig. Directed Acyclic Graph illustrating the adjustments for gestational age.

(DOCX)

Click here for additional data file.^{(80.2KB, docx)}

S1 Table. Extended details on variable definitions and their underlying ICD/ATC codes.

(DOCX)

Click here for additional data file.^{(22.7KB, docx)}

S2 Table. Characteristics of the study sample over diagnoses of neurodevelopmental conditions in offspring.

(DOCX)

Click here for additional data file.^{(30.8KB, docx)}

S3 Table. The association between intrahepatic cholestasis of pregnancy and any neurodevelopmental conditions among those with identifiable full cousins and full siblings.

(DOCX)

Click here for additional data file.^{(25.4KB, docx)}

S4 Table. The association between intrahepatic cholestasis of pregnancy and neurodevelopmental conditions after excluding those with intrahepatic cholestasis of pregnancy diagnosed at delivery and after excluding those born prematurely.

(DOCX)

Click here for additional data file.^{(23.1KB, docx)}

S5 Table. The association between intrahepatic cholestasis of pregnancy and neurodevelopmental conditions.

The association between intrahepatic cholestasis of pregnancy and neurodevelopmental conditions while adjusting for maternal BMI.

(DOCX)

Click here for additional data file.^{(24.4KB, docx)}

Abbreviations

ADHD: attention deficit/hyperactivity disorder
BMI: body mass index
CI: confidence interval
ICP: intrahepatic cholestasis of pregnancy
NDC: neurodevelopmental conditions
OR: Odds ratio
wkGA: weeks of gestational age

Data Availability

Swedish privacy law prohibits us from making register data publicly available. The data supporting our findings were used under license and ethical approval for the current study. Readers interested in obtaining microdata or replicating our study may seek similar approvals and inquire through Statistics Sweden. For further advice see: https://www.scb.se/en/services/guidance-for-researchers-and-universities/, or contact Statistics Sweden at: mikrodata@scb.se.

Funding Statement

This work was supported by grants from the Swedish Research Council [grant numbers 2017–02900 (to R.M.G.) and 523–2010-1052 (to C.D.)], from StratNeuro [Strategic Research Area Neuroscience at the Karolinska Institutet) (to R.M.G.)] and from China Scholarship Council [grant numbers 201907930020 (to S.C.)]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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PLoS Med. doi: 10.1371/journal.pmed.1004331.r001

Decision Letter 0

Louise Gaynor-Brook

12 Jul 2023

Dear Dr Ahlqvist,

Thank you for submitting your manuscript entitled "Maternal intrahepatic cholestasis of pregnancy and neurodevelopmental conditions in offspring: a population-based cohort study of two million Swedish children" for consideration by PLOS Medicine.

Your manuscript has now been evaluated by the PLOS Medicine editorial staff with relevant expertise and I am writing to let you know that we would like to send your submission out for external peer review. Please include continuous line numbers in your revised manuscript (i.e. not starting from 1 with each new page).

However, before we can send your manuscript to reviewers, we need you to complete your submission by providing the metadata that is required for full assessment. To this end, please login to Editorial Manager where you will find the paper in the 'Submissions Needing Revisions' folder on your homepage. Please click 'Revise Submission' from the Action Links and complete all additional questions in the submission questionnaire.

Please re-submit your manuscript within two working days, i.e. by Jul 14 2023 11:59PM.

Once your full submission is complete, your paper will undergo a series of checks in preparation for peer review. Once your manuscript has passed all checks it will be sent out for review.

Feel free to email us at plosmedicine@plos.org if you have any queries relating to your submission.

Kind regards,

Louise Gaynor-Brook, MBBS PhD

Senior Editor

PLOS Medicine

PLoS Med. doi: 10.1371/journal.pmed.1004331.r002

Decision Letter 1

Louise Gaynor-Brook

28 Sep 2023

Dear Dr. Ahlqvist,

Thank you very much for submitting your manuscript "Maternal intrahepatic cholestasis of pregnancy and neurodevelopmental conditions in offspring: a population-based cohort study of two million Swedish children" (PMEDICINE-D-23-01940R1) for consideration at PLOS Medicine.

Your paper was evaluated by four independent reviewers, including a statistical reviewer, and was discussed among all the editors here and with an academic editor with relevant expertise. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:

[LINK]

In light of these reviews, I am afraid that we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to consider a revised version that addresses the reviewers' and editors' comments. Obviously we cannot make any decision about publication until we have seen the revised manuscript and your response, and we plan to seek re-review by one or more of the reviewers.

In revising the manuscript for further consideration, your revisions should address the specific points made by each reviewer and the editors. Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments, the changes you have made in the manuscript, and include either an excerpt of the revised text or the location (eg: page and line number) where each change can be found. Please submit a clean version of the paper as the main article file; a version with changes marked should be uploaded as a marked up manuscript.

In addition, we request that you upload any figures associated with your paper as individual TIF or EPS files with 300dpi resolution at resubmission; please read our figure guidelines for more information on our requirements: http://journals.plos.org/plosmedicine/s/figures. While revising your submission, please upload your figure files to the PACE digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at PLOSMedicine@plos.org.

We expect to receive your revised manuscript by Oct 19 2023 11:59PM. Please email me (lgaynor@plos.org) if you have any questions or concerns.

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

We ask every co-author listed on the manuscript to fill in a contributing author statement, making sure to declare all competing interests. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. If new competing interests are declared later in the revision process, this may also hold up the submission. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT. You can see our competing interests policy here: http://journals.plos.org/plosmedicine/s/competing-interests.

Please use the following link to submit the revised manuscript:

https://www.editorialmanager.com/pmedicine/

Your article can be found in the "Submissions Needing Revision" folder.

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

We look forward to receiving your revised manuscript.

Sincerely,

Louise Gaynor-Brook, MBBS PhD

Senior Editor, PLOS Medicine

lgaynor@plos.org

plosmedicine.org

-----------------------------------------------------------

Requests from the editors:

Thank you for your patience, and apologies for the delay in providing you with an editorial decision. As you will see from the reviewer comments, adjustment is required for gestational age in your analyses. Please respond to the reviewer and editorial comments in full before resubmitting your manuscript, which will be re-reviewed.

Comment from the Academic Editor:

The authors need to fully adjust for GA; please see e.g. PMID 20543995 which addresses the continuous relationship between GA and special educational needs.

General comments:

Throughout the paper, please adapt reference call-outs to the following style: "... every year [1,2]." (noting the absence of spaces within the square brackets).

Please define all abbreviations at first use e.g. CI, IQR, etc.

Abstract:

Please structure your abstract using the PLOS Medicine headings (Background, Methods and Findings (combined in one subsection), Conclusions). Please ensure that the Abstract is written as prose.

Abstract Background: The final sentence should clearly state the study question.

Abstract Methods and Findings:

Please provide brief demographic details of the study population (e.g. sex, ethnicity, etc)

Please include the important dependent variables that are adjusted for in the analyses.

In the last sentence of the Abstract Methods and Findings section, please describe 2-3 of the main limitations of the study's methodology.

Please define CI at first use.

Please define “term” in terms of gestational age.

Please clarify what is being compared for the ORs presented for maternal cousins and full siblings.

Abstract Conclusions:

Please begin your Abstract Conclusions with "In this study, we observed ..." or similar, to summarize the main findings from your study, without overstating your conclusions. Please emphasize what is new and address the implications of your study, being careful to avoid assertions of primacy.

Author Summary:

At this stage, we ask that you include a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract. Please see our author guidelines for more information: https://journals.plos.org/plosmedicine/s/revising-your-manuscript#loc-author-summary

In the final bullet point of ‘What Do These Findings Mean?’, please describe the main limitations of the study in non-technical language.

Introduction:

Line 77 - please temper assertions of primacy by adding ‘to the best of our knowledge’ or similar

Methods:

Did your study have a prospective protocol or analysis plan? Please state this (either way) early in the Methods section. If a prospective analysis plan (from your funding proposal, IRB or other ethics committee submission, study protocol, or other planning document written before analyzing the data) was used in designing the study, please include the relevant prospectively written document with your revised manuscript as a Supporting Information file to be published alongside your study, and cite it in the Methods section. A legend for this file should be included at the end of your manuscript. If no such document exists, please make sure that the Methods section transparently describes when analyses were planned, and if/when reported analyses differed from those that were planned. Changes in the analysis-- including those made in response to peer review comments-- should be identified as such in the Methods section of the paper, with rationale. If a reported analysis was performed based on an interesting but unanticipated pattern in the data, please be clear that the analysis was data-driven.

Please add the following statement, or similar, to the Methods: "This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline (S1 Checklist)." The STROBE guideline can be found here: http://www.equator-network.org/reporting-guidelines/strobe/

Results:

Please present numerators and denominators for percentages in the Tables.

For the adjusted analyses in Table 2, please also provide the unadjusted analyses.

Please indicate which factors are adjusted for, in the main text.

Line 209 - please revise to ‘strength of the association’

Line 221 - the results presented in this paragraph do not correspond well with the results presented in Table 2, showing that there is only an association (after full adjustment) between ICP and autism between 28-36 weeks of pregnancy (and all diagnoses of ICP); and between ICP before 28 weeks of pregnancy and intellectual disability . Please revise this paragraph to better reflect the results presented in Table 2, especially the sentence “children born to mothers with ICP diagnosed before 28 weeks of gestation were more likely to be diagnosed with.. autism (adjusted OR 1.56, 95% CI 0.82-2.94)"

Please see https://journals.plos.org/plosmedicine/s/supporting-information for our supporting information

guidelines; supplementary files should be referred to as Table S1, S2, Figure S1, S2, and so on.

Line 230 - please provide the results for the analysis excluding those without siblings (N=515 550) in eTable4

Sensitivity analyses: Please revise this paragraph to reflect that associations were not similar for ICP before 28 weeks of pregnancy and intellectual disability when excluding preterm birth, children born before 1993 and after adjustment for maternal BMI.

Discussion:

Please present and organize the Discussion as follows: a short, clear summary of the article's findings; what the study adds to existing research and where and why the results may differ from previous research; strengths and limitations of the study; implications and next steps for research, clinical practice, and/or public policy; one-paragraph conclusion.

Please remove all subheadings within your Discussion e.g. Strengths and limitations

Figures:

When a p value is given, please specify the statistical test used to determine it in the figure legend.

Please define abbreviations used in the figure legend of each figure.

Please indicate in the figure caption what is represented by the error bars.

Tables:

When a p value is given, please specify the statistical test used to determine it in the table legend.

Please define all abbreviations used in the table legend of each table.

Please provide the unadjusted comparisons as well as the adjusted comparisons in Table 2.

References:

Please ensure that journal name abbreviations match those found in the National Center for Biotechnology Information (NCBI) databases (http://www.ncbi.nlm.nih.gov/nlmcatalog/journals), and are appropriately formatted and capitalised. Six authors should be listed prior to ‘et al’.

Please also see https://journals.plos.org/plosmedicine/s/submission-guidelines#loc-references for further details on reference formatting.

Comments from the reviewers:

Reviewer #1: Review of manuscript:

"Maternal intrahepatic cholestasis of pregnancy and neurodevelopmental conditions in offspring: a population-based cohort study of two million Swedish children"

Thank you for inviting me to review this manuscript, which uses a retrospective national dataset and linked coded diagnostic terms to interrogate any associations between ICP and offspring neurodevelopmental disorders (NDD). It is a useful and important topic, which attempts to answer a question that has not previously been adequately addressed within the literature, and also addresses questions that I have heard asked by affected families within PPI engagement.

This study makes use of the excellent Swedish data collection at a population level, and is an appropriate population and study design to attempt to address this question.

It is important to recognise that, once this study is published, its simplest message will be interpreted across the patient community as being that "ICP causes NDD", which still cannot be proven by this retrospective approach demonstrating association rather than causation, and thus there is a critical importance that all co-variates are accounted for appropriately, and a very clear message is presented through from the abstract about this limitation.

The authors have taken multiple approaches to account for the impact of co-variates on their overall findings. However, the major concern that I have with their findings is that they have not appropriately accounted for gestational age at birth - excluding those babies born preterm simply does not exclude the impact of advancing gestational age at birth being inversely associated with NDD even after 37/40. There is a plethora of studies demonstrating this, and it is one of the main counselling factors underpinning recommendations regarding planned gestational age at birth; Swedish population studies have also beautifully demonstrated the shorter term impacts of early term birth on many neonatal outcomes that plausibly could affect later NDD (Mitha et al. J Pediatrics 2021; 223: 43-50.e5).

I therefore would recommend that the authors include gestational age at birth as a continuous variable in their statistical models to confirm that this does not impact their conclusion before considering accepting the manuscript. I have huge concerns that the risk of publishing this manuscript without absolute certainty of the findings will be that patients read the association between longer exposure to ICP and increased risk of NDD, and therefore request earlier birth to prevent this (which in actual fact might increase the risk of NDD and other consequences of preterm and early term iatrogenic birth). We know that patients with early onset ICP are more likely to give birth at earlier gestations, and so this finding is not unsurprising.

Similarly, it is very easy to look through the (well presented) Table 1 and Supplementary Table and come to vastly different conclusions if all of these factors are not accounted for in the final analyses: I would suggest from these data that:

1) More recent birth year

2) Caesarean birth

3) Induction of labour

4) Overweight / obesity or missing BMI data

Etc etc may be more associated with ICP and / or NDD - the authors have accounted for many of these factors in these models but it would be worth summarising in a table / figure which factors are independently associated with autism in separate models so that you are able to clearly follow why you have selected your various sensitivity analyses and confounders included. Otherwise, it may appear by chance that you have selected BMI as the factor to adjust by (supp table 4) rather than through logical selection of the most important confounding variable.

In summary, I think that this is an important and useful manuscript, but would not recommend publication in its current format without appropriate correction as described above, most importantly treating gestation of birth as a continuous variable. Once published, the manuscript risks reactionary concerns from those patients and clinicians who will read only the abstract and headline conclusion, and risk detrimental care decisions for the pregnancy which may be difficult to reverse given the relatively limited datasets with this duration of follow up that currently could be used to address this question.

Reviewer #2: Thanks for the opportunity to review your manuscript. My role is as a statistical reviewer, so my review concentrates on the study design, data, and analysis that are presented. I have put general questions first, followed by queries relevant to a specific section of the manuscript (with a page/paragraph reference).

This manuscript examines whether exposure to intrahepatic cholestasis during gestation is associated with later incidence of neurodevelopmental conditions (ADHD, autism, ID). The link between is ICP and ND is proposed based on links between ICP and other neonatal adverse events, and assuming ICP could similarly alter fetal brain development during a critical period. Data is taken from linked routinely collected healthcare data and registries from Sweden, and initially includes all children born between 1987 and 2010. Children not in the birth registry, or were not in country (and with data) for less than 5 years, non-singletons were excluded. Children with missing covariate information were also excluded (0.1 % of initial sample). ICP (exposure) was identified from inpatient data, with date of diagnosis used for date of onset (and categorised into three categories). ND conditions (outcome) were ascertained from inpatient data, and dispensing for drugs used to treat ADHD. A combined ND outcome was used, as well as specific diagnoses as secondary outcomes. A range of covariates is considered, these are sourced from several different databases and includes in maternal, gestational, and birth information. Full details (i.e. ICD-10 codes) are provided in the appendix. The main analysis uses logistic regression, one minimally adjusted with sex and year of birth, and one that also considers more potential confounders. Several sensitivity analyses of the main analysis are considered, the rationale for these is explained well. In several secondary analyses, a conditional LR analysis of siblings and cousins who were discordant for ICP status were completed.

There is a small association between ICP and ND in the main analysis, this shrinks back to no association in the full-sibling analysis. There is a 'dose-response' with period of ICP exposure, with more ND seen in those exposed to ICP from earlier in development. The association between ND and ICP seemed to be mostly driven by ADHD and Autism, with no robust association between ICP and ID. The results from the sensitivity analyses were consistent with the main analyses. Limitations of the study (e.g. limitations in the data collection) are clearly discussed. The figures presented in the manuscript are excellent - very clear and elegant.

P3, L75. I'm not sure what the right wording here is, but stillbirth can't be an intermediary between ICP and ND conditions. '

P4, L94. Why wasn't more recent data (2011-) used in the study?

P4, L96. Were the children identified but on the birth registry likely to have been born outside of Sweden? Or are these non-matches from the data linkage process?

P5, L107. Would this condition typically be diagnosed soon after onset? e.g. is it symptomatic or part of normal screening?

P5, L118. Is atomexetine used for paediatric cases of narcolepsy? i.e. would all dispensing of this drug be strictly for ADHD?

P6, L137. Were robust standard errors used to account for multiple children born to the same mother?

P6, L139. The second model uses a subset of the potential confounders detailed in the previous section. How were these particular covariates selected for the second model?

P6, L165. Missing-as-indicator assumes no correlation between the exposure and the missing variable - a more robust option here would be to repeat the analysis with something like IPW or MI that is robust for data that is missing-at-random (i.e. conditional on the observed data).

Figure 1. In D), what method was used to create the smoothed incidence curves over age?

Reviewer #3: This is a nice paper. Original research. No suggestions for improvement.

I recommend acceptance.

Jim Thornton

Nottingham. 31 July 2023

Reviewer #4: I am asked to comment on revision 1 of this article.

My main concern is the correction for the main confounder gestational age. As ICP results more often in preterm birth (as the authors acknowledge) this should be controlled for.

The authors write

"and our main model, where we further adjust for birth month, birth order, maternal age, maternal country of birth and maternal psychiatric history and the highest parental education level."

Gestational age is not mentioned here.

Gestational age is reported as <37, 37-42 and >42 weeks.

They then provide data stratified for gestational age at diagnosis, by reporting them in any, and diagnosis <28, 28-37 and > 37. The stronger effect after the earlier diagnosis is to be expected as these pregnancies will end earlier.

I am afraid the correction for gestational age (if it already takes place?) in categories <37, 37-42 and >42 weeks is insufficient as within these categories the GA of the ICP group will be younger.

After these analyses I am happy to review again, but for me at the moment this difference in gestational age might be the main explanation/confounder for what we see here.

Prof Ben W Mol

Any attachments provided with reviews can be seen via the following link:

[LINK]

PLoS Med. 2024 Jan 16;21(1):e1004331. doi: 10.1371/journal.pmed.1004331.r003

Author response to Decision Letter 1

19 Oct 2023

Attachment

Submitted filename: Author response.docx

Click here for additional data file.^{(192.5KB, docx)}

PLoS Med. doi: 10.1371/journal.pmed.1004331.r004

Decision Letter 2

Louise Gaynor-Brook

22 Nov 2023

Dear Dr. Ahlqvist,

Thank you very much for re-submitting your manuscript "Maternal intrahepatic cholestasis of pregnancy and neurodevelopmental conditions in offspring: a population-based cohort study of two million Swedish children" (PMEDICINE-D-23-01940R2) for review by PLOS Medicine.

I have discussed the paper with my colleagues and the academic editor and it was also seen again by three reviewers. I am pleased to say that provided the remaining editorial and production issues are dealt with we are planning to accept the paper for publication in the journal.

The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:

[LINK]

In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.

Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. If you haven't already, we ask that you provide a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract.

We expect to receive your revised manuscript within 1 week. Please email me(lgaynor@plos.org) if you have any questions or concerns.

We ask every co-author listed on the manuscript to fill in a contributing author statement. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT.

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript.

Please note, when your manuscript is accepted, an uncorrected proof of your manuscript will be published online ahead of the final version, unless you've already opted out via the online submission form. If, for any reason, you do not want an earlier version of your manuscript published online or are unsure if you have already indicated as such, please let the journal staff know immediately at plosmedicine@plos.org.

If you have any questions in the meantime, please contact me on lgaynor@plos.org.

We look forward to receiving the revised manuscript by Nov 29 2023 11:59PM.

Sincerely,

Louise Gaynor-Brook, MBBS PhD

Senior Editor, PLOS Medicine

plosmedicine.org

------------------------------------------------------------

Requests from Editors:

Thank you for your patience, and apologies for the delay in providing you with an editorial decision. The list below contains minor points which should not require a substantial amount of time to attend to.

After discussion among the editorial team and with the Academic Editor, and in line with Reviewer 1, we request that S6 Table (adjusting for gestational age) is incorporated into the main paper.

To help us extend the reach of your research, please provide any Twitter handle(s) that would be appropriate to tag, including your own, your co-authors', your institution, funder, etc.

Abstract:

Line 63 - In view of reviewer concerns, we suggest revising the first sentence of your Conclusions to “In this study, we observed that exposure to ICP during gestation is associated with an increased likelihood of neurodevelopmental conditions in offspring, particularly in cases of early-onset ICP” - or similar.

Author Summary:

Line 106 - We suggest revising to “Diagnosis of ICP during pregnancy, especially early in pregnancy, is associated with an increased likelihood of neurodevelopmental disorders in the children exposed during gestation” or similar

Line 109 - Please revise ‘causal relationship’. We suggest “...it is not possible to determine whether ICP is a causative factor in the development of neurodevelopmental conditions in children born to affected mothers” or similar

Introduction:

Line 133 - please revise to ‘...by examining the association between…’

Line 139 - please revise to ‘differentially affects the likelihood of’

Methods:

Please refer to your prospective analysis plan early in the Methods section.

Results:

Line 265 - please revise to Children born to mothers with ICP

Please provide p values alongside 95% CIs where available.

Line 309 - please clarify whether this is adjusted OR

Line 354 - As you have been so transparent about where results are no longer statistically significant, it is appropriate to comment that adjusting for gestational age affects the statistical significance of the association between intellectual disability and ICP diagnosed <28w, and between autism and ICP diagnosed between 28-36 weeks / any diagnoses of ICP.

Line 356 - Please incorporate S6 Table into the main paper

Discussion:

Line 379 - please revise that adjusting for gestational age had only a negligible effect on the estimates. It would be preferable to acknowledge that adjusting for gestational age affected the statistical significance of the association between intellectual disability and ICP diagnosed <28w, and between autism and ICP diagnosed between 28-36 weeks / any diagnoses of ICP; and to reiterate what is demonstrated in Figure S5.

Line 402 - please replace effect with association

Comments from Reviewers:

Reviewer #1: Thank you for inviting me to rereview this manuscript following author comments. I appreciate the depth and approach to address the comments by the authors throughout.

The authors have used arguments developed from mediation analysis to justify their approach of not including gestational age at birth within their initial protocol. I do understand that the authors propose that gestational age at birth itself is likely a mediator between the exposure (ICP) and the outcome (NCD). However, the gestation of birth is determined not only by spontaneous labour onset, but also by clinician-initiated birth; including them as a single pathway risks oversimplification of quite different events, with different relationships both to the exposure (ICP) and, potentially, the outcome (although this is more speculative). Particularly for clinician-initiated birth, the opportunity in this approach of analysis would be to identify a modifiable mediator (and potentially give evidence to support or refute early birth for affected patients). Similarly, I dispute that gestational age of birth is always determined after ICP onset - in clinical practice, iatrogenic birth (e.g. by caesarean section) may be planned before ICP diagnosis and irrespective of this (e.g. in patients with other obstetric indications for early birth) - whilst I don't think that this needs including within this study, it reflects the number of assumptions that have to be made within such a study approach, and supports my recommendation of need to adjust for this (which you have done). In reviewing the mediation analysis, I should emphasise that, whilst I am familiar with the approach, I am by no means an expert in this methodology, so my ability to review that aspect was limited. I have based my understanding upon this BMJ paper (Understanding how health interventions or exposures produce their effects using mediation analysis (bmj.com)) - the editors may wish additional expert review from an epidemiologist if they require additional insight upon this methodology.

As such, I do really appreciate the inclusion of the new supplementary table including multiple methods of analysis accounting for gestational age at birth (and would prefer it to be included in the main document - I appreciate that will be more of an editorial decision due to this being post hoc, and with the limitation of space). I still interpret the findings with demonstrated increased risk of NCD and specifically ADHD but do not agree that we can conclude increased risk of autism - I appreciate that the authors have modified their wording to reflect this (even if we disagree a little on the interpretation!).

As with all good research, I think that new evidence often raises more questions; I appreciate that the use of mediation analysis requires readers to have an understanding of epidemiological approaches with which clinicians providing direct care may be less familiar, and I anticipate that the findings may generate some useful further discussions within the field.

Reviewer #2: Thanks for the revised manuscript and responses to my original review.

I agree with the authors that gestational age is inappropriate for the main analyses as changes in gestational age are after any impact of cholestasis, so it can't really be considered a confounder. The analysis including gestational age hints that maybe this is a mediator, but I think this is appropriately left in the appendix.

The inclusion of the sensitivity analysis of different approaches to missing data strengthens the manuscript - given the results are very similar with MI and IVP weights this indicates that MNAR is a reasonable assumption in this case.

One of the reviewers has legitimate concerns around the findings of this study causing distress to parents. This revised manuscript does make the limitations of the study design clear (i.e. observational) as clear as possible.

Reviewer #4: Thank you for the response and adjustments. I have no further questions.

Any attachments provided with reviews can be seen via the following link:

[LINK]

PLoS Med. 2024 Jan 16;21(1):e1004331. doi: 10.1371/journal.pmed.1004331.r005

Author response to Decision Letter 2

29 Nov 2023

Attachment

Submitted filename: Editorial comments.docx

Click here for additional data file.^{(33.9KB, docx)}

PLoS Med. doi: 10.1371/journal.pmed.1004331.r006

Decision Letter 3

Louise Gaynor-Brook

6 Dec 2023

Dear Dr Ahlqvist,

On behalf of my colleagues and the Academic Editor, Prof. Gordon Smith, I am pleased to inform you that we have agreed to publish your manuscript "Maternal intrahepatic cholestasis of pregnancy and neurodevelopmental conditions in offspring: a population-based cohort study of two million Swedish children" (PMEDICINE-D-23-01940R3) in PLOS Medicine.

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Thank you again for submitting to PLOS Medicine. We look forward to publishing your paper.

Sincerely,

Louise Gaynor-Brook, MBBS PhD

Senior Editor, PLOS Medicine

lgaynor@plos.org

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Appendix. STROBE Checklist.

Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist.

(DOCX)

Click here for additional data file.^{(44.7KB, docx)}

S2 Appendix. Protocol.

Prospectively recorded analysis plan.

(DOCX)

Click here for additional data file.^{(56.8KB, docx)}

(DOCX)

Click here for additional data file.^{(151.3KB, docx)}

(DOCX)

Click here for additional data file.^{(162.3KB, docx)}

(DOCX)

Click here for additional data file.^{(176.2KB, docx)}

(DOCX)

Click here for additional data file.^{(101.1KB, docx)}

S5 Fig. Directed Acyclic Graph illustrating the adjustments for gestational age.

(DOCX)

Click here for additional data file.^{(80.2KB, docx)}

S1 Table. Extended details on variable definitions and their underlying ICD/ATC codes.

(DOCX)

Click here for additional data file.^{(22.7KB, docx)}

S2 Table. Characteristics of the study sample over diagnoses of neurodevelopmental conditions in offspring.

(DOCX)

Click here for additional data file.^{(30.8KB, docx)}

S3 Table. The association between intrahepatic cholestasis of pregnancy and any neurodevelopmental conditions among those with identifiable full cousins and full siblings.

(DOCX)

Click here for additional data file.^{(25.4KB, docx)}

(DOCX)

Click here for additional data file.^{(23.1KB, docx)}

S5 Table. The association between intrahepatic cholestasis of pregnancy and neurodevelopmental conditions.

The association between intrahepatic cholestasis of pregnancy and neurodevelopmental conditions while adjusting for maternal BMI.

(DOCX)

Click here for additional data file.^{(24.4KB, docx)}

Attachment

Submitted filename: Author response.docx

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Attachment

Submitted filename: Editorial comments.docx

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Data Availability Statement

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PERMALINK

Maternal intrahepatic cholestasis of pregnancy and neurodevelopmental conditions in offspring: A population-based cohort study of 2 million Swedish children

Shuyun Chen

Viktor H Ahlqvist

Hugo Sjöqvist

Olof Stephansson

Cecilia Magnusson

Christina Dalman

Håkan Karlsson

Brian K Lee

Renee M Gardner

Roles

Abstract

Background

Methods and findings

Conclusions

Author summary

Why was this study done?

What did the researchers do and find?

What do these findings mean?

Introduction

Methods

Study population

Fig 1.

Maternal intrahepatic cholestasis of pregnancy

Offspring neurodevelopmental conditions

Covariates

Statistical analysis

Family-informed analysis

Sensitivity analyses

Results

Table 1. Characteristics of the 2,375,856 children, born to 1,308,096 mothers between 1987 and 2010, who were included in the study, stratified by maternal ICP diagnosis.

Primary analyses

Fig 2. The association (and 95% CI) between maternal intrahepatic cholestasis and offspring neurodevelopmental conditions, stratified by the gestational period of onset of intrahepatic cholestasis, with and without control for factors shared between maternal full cousins and full siblings.

Table 2. The association between maternal intrahepatic cholestasis and different offspring neurodevelopmental conditions, stratified by the gestational period of onset of intrahepatic cholestasis.

Table 3. The association between intrahepatic cholestasis of pregnancy and neurodevelopmental conditions after adjusting for gestational age.

Sensitivity analyses

Discussion

Supporting information

Abbreviations

Data Availability

Funding Statement

References

Decision Letter 0

Louise Gaynor-Brook

Roles

Decision Letter 1

Louise Gaynor-Brook

Roles

Author response to Decision Letter 1

Decision Letter 2

Louise Gaynor-Brook

Roles

Author response to Decision Letter 2

Decision Letter 3

Louise Gaynor-Brook

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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