Studies - PreTerm Delivery / Premature Birth / Prematurity Complications

Harvard University Study Links Prior Abortion, Diabetes in Pregnancy, to Autism Risk (2011,AR)

Study Links Autism, Diabetes in Pregnancy

Though progress is being made, scientists still know relatively little about what causes autism, or why rates of the disorder seem to be increasing.

A new Harvard University study, not reported on until now, offers an intriguing clue, suggesting that women who have had gestational diabetes – diabetes that crops up during pregnancy – are twice as likely to have an autistic child.

Other “complications” of pregnancy, from having had an abortion to the mother being at a sub-optimal age for bearing children, also increased the odds they would give birth to a child with autism-spectrum disorder. The results were reported by Kristen Lyall and other scientists from the Harvard School of Public Health recently in the journal Autism Research.

The researchers looked at data from Nurses Health Study in the U.S., which is tracking various health issues for a group of about 116,000 nurses. The women were asked in 2005 whether they had had an autistic child. Of about 66,000 pregnancies, there were 793 cases of ASD. Then the study looked at pregnancy-related factors that could be connected.

Jumping out was gestational diabetes; after filtering out age-related and other factors that could skew results, women who had had the condition during a pregnancy were 75% more likely to have an ASD child, as were those who gave birth when less than 20 or more than 30. The more pregnancy complications, the more likely they were to have an autistic child.

The links found by the researchers are just statistical, so do not prove a cause-and-effect relationship. But the authors theorize that nutritional intake or hormone levels associated with gestational diabetes could interect with a genetic predisposition to make autism more likely. They call for more research into the gestational-diabetes angle.
[27 Oct 2011, Tom Blackwell,]

Harvard University Study Links Prior Abortions to Autism Risk

[Comment: The 2011 Kristen Lyall (PhD, Harvard U.) study finds that women with an IA (Induced Abortion) of a 1st pregnancy elevate relative odds of a later newborn later diagnosed with Autism by 26%
In the first paragraph of the     RESULTS    section of the Lyall (Harvard U.) it is stated that mothers with abortions, miscarriages etc. were more likely to report children with ASD.  The quantification of the   ASD/IA  (Autism Spectrum Disorders / Induced Abortions) risk is only presented in a table of the 'Lyall' study.
— Brent Rooney (MSc), Research Director, Reduce Preterm Risk Coalition,]

Pregnancy Complications and Obstetric Sub-optimality in Association With Autism Spectrum Disorders [ASD] in Children of the Nurses’ Health Study II
Autism Research 2011, International Society for Autism Research (INSAR)
Kristen Lyall, David L. Pauls, Donna Spiegelman, Alberto Ascherio, and Susan L. Santangelo

The authors examined pregnancy and obstetric complications in association with autism spectrum disorders (ASD) in children of participants from the Nurses’ Health Study II, a prospective national cohort with information collected through biennial mailed questionnaires since 1989. Logistic regression was used to obtain crude and adjusted odds ratios for ASD, and by diagnostic subgroup.

Seven hundred and ninety-three cases were reported among 66,445 pregnancies.

Pregnancy complications and obstetric sub-optimality factors were assessed by maternal report of occurrence in first birth and, in secondary analyses, in any birth. Complications and a sub-optimality score were significantly associated with having a child with ASD (OR 1.49, 95% CI 1.26, 1.77, Po0.0001 for pregnancy complications in first birth and 2.76, 95% CI 2.04, 3.74, Po0.0001 comparing individuals with four or more obstetric sub-optimality factors in first birth to those with none; results similar when assessed in any birth).

In particular, gestational diabetes was associated with a significantly increased risk of ASD in results of primary and sensitivity analyses (OR in primary analysis51.76, 95% CI 1.34, 2.32, Po0.0001); suboptimal parity and suboptimal age-at-first-birth were also individual factors associated with ASD.

Associations were similar by diagnostic subgroup, suggesting autism, Asperger syndrome, and other Pervasive Developmental Disorders are all associated with pregnancy complications.

Consistent with previous research, the general class of pregnancy complications was associated with ASD as a whole. Additional work will be required to more fully assess the role of gestational diabetes. Autism Res 2011,4:xxx–xxx. & 2011 International Society for Autism Research, Wiley Periodicals, Inc.

Keywords: autism spectrum disorders; gestational diabetes; obstetric complications; pregnancy complications

The results of numerous case–control [Burd, Severud, Kerbeshian, & Klug, 1999; Glasson et al., 2004; Hultman, Sparen, & Cnattingius, 2002; Juul-Dam, Townsend, & Courchesne, 2001; Maimburg & Vaeth, 2006] and cohort studies [Croen, Grether, & Selvin, 2002; Eaton, Mortensen, Thomsen, & Frydenberg, 2001; Lauritsen, Pedersen, & Mortensen, 2005] suggest that obstetric complications may be associated with autism spectrum disorders (ASD).

A recent meta analysis, which examined 40 studies of prenatal factors in association with ASD, found evidence for association with parental age and gestational diabetes, as well as a few other prenatal factors, but noted the inconsistency in results across studies [Gardener et al., 2009b].

Further, the authors highlighted the fact that few factors have been examined in multiple rigorous studies, demonstrating the need for replication. Questions remain, including the mechanisms underlying these associations, whether associations differ by diagnostic subgroup, and whether certain obstetric complications confer a higher risk than others [Bolton et al., 1997; Gardener et al., 2009b; Gillberg & Cederlund, 2005].

Further, the majority of the larger studies examining these factors have been conducted in other countries [Glasson et al., 2004; Hultman et al., 2002; Larsson et al., 2005; Lauritsen et al., 2005], suggesting a need for large cohort studies in the USA.

We sought to replicate previous results and provide additional data on these issues in a large United States cohort, the Nurses’ Health Study II. We hypothesized that we would find similar associations across diagnostic subgroups, and that our results would be consistent with previous research demonstrating a significant association between ASD and the general category of pregnancy and obstetric complications, rather than specific factors.

Materials and Methods
Study Population
The Nurses’ Health Study II (NHS II) is a prospective cohort of 116,608 female nurses aged 25–42 years when recruited in 1989, who have been followed by biennial mailed quest

ionnaires to assess the incidence of cancer and other chronic diseases. The Partners Health Care Institutional Review Board has reviewed and approved the methods of this study, and completion and return of questionnaires sent by U.S. mail constitutes implied consent.

The 2005 questionnaire included an item asking women if they had a child diagnosed with autism, Asperger syndrome, or ‘‘other ASD.’’ Only parous women with at least one birth before the end of 2003 (to allow time for report of diagnosis by 2005) who also returned the 2005 questionnaire when the outcome was assessed were included; this provided a primary study population of 66,445 women. Among those women, 9,477 had their first birth in 1989 or later and were included in our prospective subgroup sensitivity analysis, while 11,287 women had only one pregnancy and were included in our uniparous sensitivity analysis.

Figure 1 summarizes the groups, exposures, and outcomes used in this study.
Outcome Information
Cases were defined as those women meeting inclusion criteria and reporting having had a child with autism, Asperger syndrome, or other autism spectrum, as reported on the 2005 questionnaire. While it is expected that the "other autism spectrum" category includes pervasive-developmental disorder not-otherwise specified (PDD-NOS), this disorder was not specified on the questionnaire. If the ASD question was left blank but the rest of the questionnaire was completed, it was assumed that the mother had no ASD-affected children.

No further information on the affected child was available. Two Center for Disease Control and Prevention (CDC) studies have utilized parental report of ASD, and a high concordance in estimated prevalence of ASD between the two studies was seen, as was a strong correlation between report of diagnosis and developmental and behavioral problems as measured on screening items [Center for Disease Control and Prevention, 2006].

Exposure Information
A history of past pregnancies, miscarriages, gestational diabetes, toxemia, and preeclampsia was assessed at baseline and updated every 2 years.

Occurrence of induced abortions was assessed beginning in 1993 (with age ranges) and every questionnaire year thereafter.

Pregnancy-related high blood pressure was assessed on the 1993, 1995, and 1997 questionnaires. All NHS Figure 1. Summary of study groups, exposures, and outcome definitions used in primary and sensitivity analyses. NHS II, Nurses Health Study II. Owing to the way in which the NHS II question was asked, we did not know year of birth for the ASD children, except for those women with one child (uniparous group); however, using information on age-at–first- and last-birth when available (for most women) identified a known period of time in which the child was born, which for most women was within 5 years, and was similar in cases and
controls. 2 Lyall et al./

Pregnancy complications and autism INSAR questionnaires are available online at

In order to ensure exposure occurrence before a woman’s first delivery, and thus before the birth of the affected child (since for women with multiple children we do not have information on which of the nurses’ children may be affected), exposures and other covariates were considered when reported before first birth or during first pregnancy, as appropriate (before first birth for miscarriages, abortions, and infertility; during first pregnancy for toxemia, gestational diabetes, pregnancy-related high blood pressure and twin birth at first birth). In secondary analyses, we considered classification of these variables as ‘‘ever reported’’ in any birth/pregnancy through 2003.

Exposures of interest in this analysis may therefore have occurred before or after the birth of the child diagnosed with autism, but may be considered useful in determining overall differences between women who have a child with ASD and those who do not, and in comparison with the primary analyses.

Statistical Analyses
Univariate relationships and basic characteristics of exposures and covariates were assessed by descriptive statistics, w2 tests, and t-tests. Relationships between ASD and reproductive and obstetric complications (as both individual factors and summarized in a suboptimality score) under study were assessed by multivariate logistic regression, with and without adjustment for potential confounders. Potential confounders were considered on the basis of a priori associations with exposures and outcome, and included age-at-first-birth (in years), nurses’ age at baseline (in years), race (as binary white/other), marital status (as married, past married, or never married as of first birth), income (in five levels of household income), spouse education (in four categories: high school or less, 2 or 4 year college, and graduate), and parity (as a continuous variable).

When assessing risk of individual complications, the other reproductive factors under study were also considered in multivariate models (for example, when assessing risk of gestational diabetes, adjustment for history of miscarriages, previous abortions, and pregnancy-related high blood pressure, etc, was considered).

Gestational diabetes, toxemia/ preeclampsia, and pregnancy-related hypertension were considered individually, and, to address potential metabolic syndrome, were also assessed as a single "pregnancy complications" variable (1 if reported any and 0, otherwise).

We also created an obstetric suboptimality score (OSS) similar to those used in previous studies for the purposes of comparison with previous work, and to assess the risk associated with increasing number of suboptimality factors [Bolton et al., 1997; Gillberg & Gillberg, 1983;
Lord et al., 1991; Piven et al., 1993]. Owing to limited availability of information, this score was a modified, reduced version of the Gillberg score, although other scores were considered in selecting OSS factors [Gardener et al., 2009a; Glasson et al., 2004; Stein et al., 2006].

Our OSS is a sum of the following items (defined to be consistent with the Gillberg and other scores, which were designed to assess optimal birth and pregnancy conditions): suboptimal age-at-first-birth [defined as o20 or 430, Gillberg & Gillberg, 1983], suboptimal parity [defined as 42, Gillberg & Gillberg, 1983], history of induced abortion, previous miscarriage, history of infertility, pregnancy-related high blood pressure, gestational diabetes, toxemia, twin births, epilepsy, and autoimmune diseases.

This score gives an equal weight to each factor, with a possible total score of 11. A second OSS was created which did not include suboptimal age-at-first-birth, for purposes of comparison with subgroups used in sensitivity analyses (due to older age-at-first-birth in these subgroups, which are described below). Many studies have found that a higher number of suboptimal factors is associated with increased risk of ASDs [Brimacombe et al., 2007; Gillberg & Gillberg, 1983], suggesting that the OSS is a useful complement to analyses of individual items. Individuals with one, two, three, and four or more factors were compared with those with none, using indicator variables in regression mod


The ordinal score test was used to assess evidence for a trend of the OSS. We also examined the potential for a nonlinear relationship between the OSS and ASD non-parametrically using cubic splines [Durrleman & Simon, 1989; Govindarajulu et al., 2007].

For all analyses, crude, age-adjusted, age and age-at first-birth adjusted, and multivariate models were compared.

Analyses were also conducted by diagnostic subgroup. Missingness was low (o5%) for race and o10% for marital status and paternal education, although income was missing in approximately 20%; the missing indicator method was used to handle the missing covariate data [Miettinen, 1985].

Sensitivity Analyses
A number of sensitivity analyses were utilized to test the robustness of results. As we currently have no information on which child is the affected child (the 2005 question asked only whether women had any affected children), analyses were repeated among women who had only one pregnancy (the "uniparous group"). For these women, we know the year of birth of the reported child with ASD, and whether any reported complication refers to the child with ASD.

As our primary study population included women with children born before 1989, for any exposures reported at baseline which occurred in the past, reporting was retrospective even though we only scored it if it was before first birth/during first pregnancy.

In order to assess the possibility of recall bias, we created a prospective subgroup and excluded the 56,968 women with any children born before 1989 to ensure that exposures not only occurred before first birth/during first pregnancy but were also measured before the first birth (and therefore the outcome).

A total of 793 mothers reported having had a child with an ASD among 66,445 pregnancies through the end of the study period (representing 1.2% of the study group).

ASD mothers were, on average, significantly younger at baseline than non-ASD mothers, but had a later age-at  first-birth (AFB) (Table I).

Crude comparisons demonstrated differences between cases (mothers who reported having a child with ASD) and noncases (mothers who did not report having a child with ASD) with regard to a number of reproductive factors (Table I).

ASD mothers were more likely to have reported abortions, miscarriages, toxemia, gestational diabetes, pregnancy-related high blood pressure, and to have higher OSS scores. These differences were observed whether exposures were classified as occurring before the first birth or at any time.

Frequencies of obstetric complications among the non-case pregnancies were consistent with those in the general US population [Hunt & Schuller, 2007; Weinberg & Wilcox, 1998].

In the primary analysis, pregnancy complications and OSSs were significantly associated with ASD (Table II), as were the following individual factors: suboptimal age-at first birth, suboptimal parity, abortions, and autoimmune disease in the mother. When exposures were assessed in secondary analyses as ever reported in any birth, results were similar in both magnitude and direction (Supplementary data).

Specifically, pregnancy complications were associated with an approximately 50% increased odds of ASD (both first pregnancy and ever), and this association was similar and remained significant in the prospective and uniparous groups (Table III).

For individual complications, toxemia and gestational diabetes were each significantly associated with an increased risk of ASD, whether assessed during first pregnancy or ever. However, only gestational diabetes remained significantly associated with ASD in the prospective group (OR 1.59, 95% CI 1.05, 2.41, P50.03).

None of the three individual complications assessed was associated with ASD in the uniparous group, although the point estimate for gestational diabetes was similar to that of the prospective group. There were also fewer exposed cases in the prospective subgroup, which negatively affected our power to detect associations by these factors.

The OSS was significantly associated with ASD in the primary analysis, with a significant dose–response type increase in risk of ASD with increase in OSS, and a nearly tripling of risk with four or more obstetric suboptimality factors (Table II); associations were slightly stronger for ever reported exposures (supplementary data).

Although the ordinal trend test was significant (Po0.0001), the relationship between the OSS and ASD was nonlinear (P50.007 for the nonlinearity test; Fig. 2).

The OSS was significantly associated with an increased risk of ASD in both the prospective and uniparous subgroups for OSS Z4; the association was weaker for OSS of 1–3 in these groups, although numbers and power were reduced (Table III).

Although suboptimal AFB and parity, induced abortion, and autoimmune disease were significantly associated with ASD in the primary analysis, only suboptimal AFB remained significantly associated with ASD in the uniparous group (OR52.56, 95% CI 1.59, 4.14); none of these individual items were associated in the prospective group. Ever report of a twin birth was the only additional factor associated with an increased risk of ASD in the secondary analysis of factors occurring in any births (supplementary data).

Results by Diagnostic Subgroup
Results by diagnostic subgroup in the full study population are shown in Table IV. Overall, autism, Asperger syndrome, and "other ASD" cases had a similar profile of obstetric complications, with OSS of two or more factors, suboptimal AFB, and parity being the factors most consistently significantly associated with increased risk. In the prospective sensitivity analyses of diagnostic subgroups (supplementary data), OSS of Z4 was significantly associated for all diagnostic subgroups, with a similar magnitude and strength as the primary
analyses, while the indicator for general pregnancy complications was significantly associated with only ‘‘other ASD.’’

Gestational diabetes was the only individual pregnancy complication that was significantly associated with ASD in this analysis, and only for autism cases. Case numbers by exposure category were small in this prospective sensitivity analysis.


In this large cohort of nurses, we found that women with a history of pregnancy and obstetric complications were more likely to have a child with an ASD than women with a normal obstetric history, consistent with previous findings [Bolton et al., 1997; Brimacombe et al., 2007; Gardener et al., 2009b; Juul-Dam et al., 2001].

This association was independent of maternal age. The individual pregnancy complication that was most consistently significantly associated across the full study group and subgroups was a history of gestational diabetes, indicating as much as a doubling of the risk of having a child with ASD.

This study has a number of strengths, including a large sample size, a national coho

rt of women with a high level of health education and good access to health care, detailed and prospectively collected obstetric history, and information on potential confounding variables. However, a number of limitations should be noted. We reliedon maternal report of ASD status. Results from a pilot study among these women including Autism Diagnostic Interview-Revised (ADI-R) validation of maternal report of ASD, however, suggests very high accuracy of reported diagnoses; 10 of 11 individuals deemed affected bymaternal report met full criteria according to ADI-R.

Further, maternally reported ASD and developmental disorders have been demonstrated to be reliable in previous reports in other populations [Center for Disease Control and Prevention, 2006; Faraone et al., 1995]. To the extent that diagnostic misclassification may have led to the inclusion of some borderline ASD cases, this would tend to weaken rather than strengthen the observed associations. Another related limitation is that we did not have data on the child’s date of birth, which could improve information on timing of exposures, and, for multiparous women, we did not have the ability to determine which child carried the ASD diagnosis. However, the main results were confirmed in sensitivity analyses restricted to women with only one pregnancy, which are not affected by this limitation. It should also be noted that the magnitude of associations that we found are consistent with those of investigations with more complete data on the affected children [Eaton et al., 2001; Glasson et al., 2004].

All data in this study were self-reported via mailed questionnaires; mis-categorization of pregnancy complications, obstetrical history, and other model covariates is therefore possible. However, validation studies conducted within this population of nurses have repeatedly demonstrated reliability of self-reported health information [Colditz et al., 1997], including pregnancy-specific information [Tomeo et al., 1999]. As results of the prospective sensitivity analyses that excluded women with births before exposure reporting were similar to those of the primary analysis, recall bias is not likely to have occurred.

The possible exception is for history of induced abortion in the full study population, as this factor did not remain significantly associated with risk of ASD in the prospective subgroup analysis.
We did not have information on paternal age, which has been reported as a risk factor for ASD in a number of
studies [Kolevzon et al., 2007; Lauritsen et al., 2005; Reichenberg et al., 2006; Sasanfar et al., 2010].
However, paternal age does not appear to be associated with obstetric complications [Tarı´n et al., 1998] and it is therefore unlikely that paternal age would affect results after adjustment for maternal age. We did not have information on birth order, though we did account for parity; in addition, our uniparous group cannot be confounded by birth order. The role of genetic factors cannot be ruled out and would need to be addressed in a separate study. Although we adjusted for race and income, our study population is composed primarily of well-educated, mid- to high-SES Caucasian women. Thus, it is uncertain to what extent the results of this study can be generalized to different social and ethnic groups.

General pregnancy and obstetric complications have been implicated in a number of other studies, but results
have been inconsistent for specific factors [Gillberg & Gillberg, 1983; Glasson et al., 2004; Kolevzon et al., 2007; Stein et al., 2006; Wallace et al., 2008].

In our study, gestational diabetes was consistently associated with risk of ASD, and, in particular, for autism even in the smaller prospective group. A recent meta-analysis pooling available data from six studies with data on gestational diabetes found this to be one of the few significantly associated prenatal factors, with a summary estimate indicating a doubling in risk of autism [Gardener et al., 2009b].

Our results are consistent with these findings. It is possible that nutritional factors or elevated hormone levels associated with gestational diabetes could interact with a genetic predisposition for ASD. Future studies should assess gestational diabetes individually and with adequate control for potential confounders. Given the robustness of our gestational diabetes finding across the multiple analyses, one possible preventative measure might be to target women at risk for gestational diabetes in order to intervene early.

Our results confirm previous findings of no relationship between ASD and pregnancy-related high blood pressure and toxemia [Eaton et al., 2001; Gardener et al., 2009b; Glasson et al., 2004; Hultman et al., 2002; Stein et al., 2006; Wallace et al., 2008].

Our OSS was significantly associated with ASD in all analyses for four or more factors and, in the primary analyses, for two or more factors. Our results demonstrated a significant dose–response relationship between the OSS and ASD, suggesting that a greater number of complications is associated with greater risk for ASD (though the increase in risk appeared to attenuate with very large OSS), a trend which has been found in other studies [Gardener et al., 2009b; Gillberg & Gillberg, 1983; Lord et al., 1991].

 Although our score did not include information on birth weight, APGAR scores, and other factors often assessed in optimality or suboptimality scores, many of the previous studies either did not separately assess the effect of the individual factors that make up the score [Bolton et al., 1997; Piven et al., 1993; Zwaigenbaum et al., 2002], provide estimates adjusted for a host of potential confounders [Piven et al., 1993; Stein et al., 2006], or consider a potential nonlinear relationship between ASD and OSS [Zwaigenbaum et al., 2002], which could lead to model misspecification and invalid estimates.

In assessing individual suboptimality factors, a fairly consistent association between increased maternal age and ASD has been noted; our finding in the primary analysis of an approximate doubling of odds with suboptimal AFB (which was primarily AFB430) is consistent with those reports [Bhasin & Schendel, 2006;
Croen et al., 2002; Glasson et al., 2004; Maimburg & Vaeth, 2006]. In our score, we defined suboptimal AFB as o20 or 430 in order to be consistent with the previously utilized suboptimality scores and reports of increased risk associated with both younger [Larsson et al., 2005] and older mothers [Croen et al., 2002; Eaton et al., 2001; Glasson et al., 2004]; however, defining this item in the score as only AFB430, which has been more consistently associated with increased risk of autism, did not materially alter results.

Further, when excluding "suboptimal" parity from the OSS [as both higher and lower parity and birth order have been inconsistently associated with ASD; Gardener et al., 2009b], results were slightly attenuated but remained significant. Although history of infertility was included in our OSS, these results are not presented here as they have been reported in a separate article (Lyall et al., submitted manuscript).

Maternal autoimmune disease has also been suggested to be associated with autism in previous work, though findings are not consistent [Atlado´ ttir et al., 2009; Croen et al., 2005].
Our results suggested a moderate but significant association in primary analyses, but no association was seen in the sensitivity analyses of prospective or uniparous subgroups.

Few studies have assessed pregnancy and obstetric complications by diagnostic subgroup; those that have tend to have small sample sizes or focus on one diagnostic subgroup rather than comparing the full spectrum of ASD within one study [Ghaziuddin et al., 1995; Gillberg, 1989]. Because our ques

tionnaire asked for autism, Asperger syndrome, and ‘‘other autism spectrum,’’ it is possible that the latter category included not only PDD-NOS but also other non-ASD conditions.

However, such miscategorization is expected to be relatively low in this study of medically trained nurses, who are less likely to confuse other disorders with ASD. A few previous reports have suggested a relationship between severity of ASD and number of obstetric complications [Glasson et al., 2004; Wallace et al.,
2008]. Although results for our OSS were somewhat weaker in our ‘‘other ASD’’ group, we did not note such a clear relationship between ASD severity and complications, assuming reported diagnosis of autism versus Asperger’s or other autism spectrum correlates with severity.

In general, our results seem to support the suggestion of Eaton et al. of overall similarity rather than differences by diagnostic groups [Eaton et al., 2001]. In our study, the mothers of children with ASD were more likely to have reported pregnancy complications and obstetric suboptimality factors in first pregnancy, or in any pregnancy as assessed over multiple questionnaire years, than were comparison mothers. These results are consistent with a previous observation that both ASD cases and their unaffected siblings had more obstetric complications than unaffected controls [Zwaigenbaum et al., 2002].
However, confounding by genetic factors that may predispose to both ASD and obstetric suboptimality,
cannot be ruled out. Additional work is needed to tease apart the underlying reasons for associations between pregnancy complications and obstetric suboptimality factors and ASD.
Future studies could benefit from taking into account obstetric complications in order to learn more about potential subgroups within the autism spectrum.

In summary, in this large cohort of US nurses, we found that women with a history of pregnancy complications were significantly more likely to have a child diagnosed with ASD than women with uncomplicated pregnancies.

Our results by diagnostic subgroup suggest that this association holds regardless of the type of autism spectrum diagnosis. Future work assessing gestational diabetes in particular is warranted given its strength and consistency as an individual risk factor in these analyses.

The authors would like to thank the participants of the NHS II, as well as the funding organizations for their support. Funding organizations have reviewed and approved the design and conduct of the overall NHS II,
but were not involved in the collection, management, analysis, or interpretation of the data; nor were they involved in the preparation, review, or approval of this manuscript.


INSAR Autism Research 4: 1–10, 2011   1
Received October 9, 2010; accepted for publication July 20, 2011
Published online in Wiley Online Library (
DOI: 10.1002/aur.228 & 2011 International Society for Autism Research, Wiley Periodicals, Inc.
Additional Supporting Information may be found in the online version of this article.
From the Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts (K.L., D.L.P., D.S., A.A., S.L.S.); Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts (K.L., A.A.); Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts (D.S.); Department of Psychiatry, Harvard Medical School, Boston, Massachusetts (D.L.P., S.L.S.); Massachusetts General Hospital Psychiatric and
Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Simches Research Building, Boston, Massachusetts (D.L.P., S.L.S.); Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School Channing Laboratory, Boston, Massachusetts (A.A.)

Dr. Lyall is currently affiliated with the Department of Nutrition, Harvard School of Public Health, and the U.C. Davis MIND Institute, Sacramento, CA.

Grant sponsor: NIH; Grant number: R01-CA50385; Grant sponsor: Autism Speaks; Grant numbers: 1788; 2210; Grant sponsor: United States
Department of Defense (DOD) and Army Medical Research and Material Command (USAMRMC); Grant number: A-14917.

Table I. Reproductive Factors and Characteristics of the Study
[Table not available]
All variables are self-reported.

4 Lyall et al./Pregnancy complications and autism INSAR

Table II. Pregnancy Complications and Obstetric Suboptimality Factors During or Before First Pregnancy in Relation to ASD Risk in the Study Group (N566,445)
AFB, age-at-first-birth; HBP, high blood pressure; OSS, obstetric suboptimality score. OSS and variables above are reported at or before first pregnancy.
Values shown are odds ratios, with 95% confidence intervals in parentheses for fully adjusted estimates. Pregnancy complications and obstetric suboptimality factors assessed here were considered if reported during first pregnancy or before first birth as applicable.
A For individual complications, fully adjusted models include the following demographic variables: race, marital status, income, and spouse education, as well as age, AFB, and parity, and, when not being assessed as the complication of interest, twin births, pregnancy complications, induced abortions, and miscarriages. When omitting adjustment for twin births, results were slightly stronger but did not change overall significance. The fully adjusted OSS models included adjustment for demographic factors as well as age and AFB; additional adjustment for parity as a continuous variable slightly attenuated, but did not alter significance of, results.
B OSS included the following items, defined in the text and in Table I: suboptimal AFB and parity, maternal epilepsy, maternal autoimmune disease, twin birth, gestational diabetes, toxemia, pregnancy-related HBP, history of infertility, abortion before first birth, and miscarriage before first birth.
C OSS-2 does not include the item suboptimal age at first birth; shown for comparison with Table III and supplementary data. Case n for this OSS-2 as follows, from 0 to 41factors: 129, 253, 221, 113, 77.

INSAR Lyall et al./Pregnancy complications and autism 5

Table III. Pregnancy Complications and Obstetric Suboptimality Factors During or Before First Pregnancy in Relation to ASD Risk
in the Prospective and Uniparous Subgroups
Prospective (N59,477)a Uniparous (N511,287)b
Variable n OR (95% CI) P-value n OR (95% CI) P-value
Miscarriage 88 0.82 (0.59, 1.14) 0.23 36 0.72 (0.43, 1.19) 0.20
Abortion 22 0.90 (0.51, 1.58) 0.70 23 1.30 (0.73, 2.29) 0.37
61 1.50 (1.11, 2.01) 0.008 30 1.71 (1.11, 2.65) 0.02
Toxemia 17 1.22 (0.68, 2.18) 0.50 14 1.47 (0.72, 2.99) 0.29
Gestational diabetes 26 1.59 (1.05, 2.41) 0.03 8 1.51 (0.73, 3.16) 0.27
Pregnancy-related HBP 23 1.62 (0.95, 2.77) 0.08 17 1.09 (0.56, 2.10) 0.80
0 49 1.0 — 22 1.0 –
1 62 0.95 (0.65, 1.39) 0.79 23 0.96 (0.53, 1.73) 0.87
2 66 1.24 (0.85, 1.80) 0.27 27 1.28 (0.72, 2.27) 0.41
3 33 1.11 (0.71, 1.74) 0.66 15 1.20 (0.61, 2.35) 0.60
41 33 2.24 (1.42, 3.53) 0.005 15 2.43 (1.23, 4.83) 0.01
Suboptimal AFB 172 1.02 (0.72, 1.45) 0.91 77 2.56 (1.59, 4.14) 0.0001
Suboptimal parity 50 1.09 (0.78, 1.53) 0.61 NA – –
Epilepsy 9 1.97 (0.99, 3.92) 0.05 3 1.34 (0.41, 4.30) 0.63

Autoimmune disease 52 1.03 (0.75, 1.41) 0.88 31 1.21 (0.79, 1.88) 0.38
Twin birth- first pregnancy 19 1.37 (0.84, 2.24) 0.20 11 1.73 (0.90, 3.34) 0.10
Abbreviations and notes as in Table II. Fully adjusted as in Table II with the exception of no adjustment for parity in the uniparous subgroup.
aThe prospective subgroup includes 243 cases and 9,234 noncases with first births by 1989 or later. Due to differing year of first report, prospective
analyses for pregnancy-related HBP and abortion includes 111 cases and 3,874 noncases (first report in 1993).
bThe uniparous subgroup includes 102 cases and 11,185 noncases reporting only one pregnancy.
cDue to age distribution in these groups, OSS-2 does not include AFB.
6 Lyall et al./Pregnancy complications and autism INSAR

Figure 2. The graph [not available here] shows the odds of ASD (Y axis) associated with value of OSS (X axis). ORs on the Y axis represent values from fully adjusted models, as in Tables III and IV. The horizontal dotted line represents the null OR value of no association, whereas dashed lines flanking the solid line indicate 95% confidence intervals. OSS, obstetric suboptimality score.

Table IV. Pregnancy Complications and Obstetric Suboptimality Factors During or Before First Pregnancy in Relation to Risk of Diagnostic Subgroups: Autism, Asperger Syndrome, and Other ASDa

[Data graph not available]

Abbreviations and notes as in Table II.
A All comparison mothers (n 565,652) were used for these analyses; case group n varied by diagnostic subgroup. Case numbers for diagnostic subgroups add up to greater than the total 793 cases due to 53 women reporting in multiple categories (seven women reported in all three diagnostic groups).
Results were overall similar when mutually exclusive case groups were utilized.
Epilepsy and twin births were the two individual factors not assessed by diagnostic subgroup due to small n.

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