Mixed evidence on the link between maternal influenza during pregnancy and autism spectrum disorder

Could flu during pregnancy raise risk for autism?

Researchers at the Center for Infection and Immunity (CII) at Columbia University's Mailman School of Public Health found no evidence that laboratory-diagnosis alone of maternal influenza during pregnancy is associated with risk of autism spectrum disorder (ASD) in the offspring. They did, however, find a trend toward risk in mothers with a laboratory diagnosis of influenza and self-reported symptoms of severe illness. This trend did not achieve statistical significance.

The study is the first to assess the risk for ASD based on laboratory-verified maternal influenza infection, not just survey data or medical records. Results appear in the journal mSphere. 

The researchers analyzed questionnaires and blood samples from 338 mothers of children with ASD and 348 matched controls, as part of the Autism Birth Cohort Study, a prospective birth cohort in Norway. Blood samples were collected from mothers at mid-pregnancy and after delivery. Mothers also reported on their cold and flu symptoms during pregnancy.

Positive blood tests for past influenza A or influenza B infection were not associated with increased ASD risk. However, when researchers combined reports of influenza-like illness with the blood test results, they found a substantial, albeit statistically insignificant, increased risk of ASD. While random error could be responsible for the finding, the authors caution against dismissing it outright due to the magnitude of the association: children born to mothers with laboratory-verified flu and matching symptoms had nearly double the odds of later being diagnosed with ASD compared to women without flu and symptoms.

"Symptoms are important because they may indicate the extent to which the mother's immune system is fighting the flu," says first author Milada Mahic, a post-doctoral research scientist at Center for Infection and Immunity and the Norwegian Institute of Public Health. "If infection is contributing to increased risk, it likely comes from inflammation related to maternal immune system response rather than the flu infection itself. Further research is warranted." 

The flu-ASD finding aligns with past research suggesting that admission to hospital for maternal viral infection in the first trimester and maternal bacterial infection in the second trimester is associated with increased risk of ASD. 

In other recent studies from the Autism Birth Cohort Study, researchers reported that women actively infected with genital herpes during early pregnancy had twice the odds of giving birth to a child later diagnosed with ASD. Another new study reports maternal fever during pregnancy may raise risk for the child developing ASD. 

"The fetal brain undergoes rapid changes that make it vulnerable to a robust maternal immune response," says senior author W. Ian Lipkin, director of CII and John Snow Professor of Epidemiology at the Mailman School. "That said, mothers should not conclude that having an infection during pregnancy means that their child will develop autism. It may simply be one among many risk factors."

Autism risk linked to fever during pregnancy

Fever during pregnancy may raise the risk for autism spectrum disorder (ASD) in the child, according to a study led by scientists at the Center for Infection and Immunity (CII) at Columbia University's Mailman School of Public Health. The effect was most pronounced in the second trimester, raising odds for ASD by 40 percent. Risk of an ASD was increased by over 300 percent for the children of women reporting three or more fevers after the twelfth week of pregnancy.

The study is the most robust to date to explore the risk of ASD associated with fevers across the entire span of pregnancy, and of the capacity of two different types of commonly used anti-fever medications--acetaminophen and ibuprofen--to address that risk. Risks were minimally mitigated among the children of women taking acetaminophen for fever in the second trimester. Although there were no cases of ASD among children of mothers who took ibuprofen, a nonsteroidal anti-inflammatory drug, researchers could not ascertain whether risk was mitigated due to the extremely small number of women using this particular drug for fever. Results of the study appear in the journal Molecular Psychiatry.

The researchers followed 95,754 children born between 1999 and 2009, including 583 cases of ASD identified in Norway through the Autism Birth Cohort (ABC) Study. Mothers of 15,701 children (16 percent) reported fever in one or more four-week intervals throughout pregnancy, similar to rates reported in the U.S. ASD risk was increased by 34 percent when mothers reported fever at any time during pregnancy, and by 40 percent in the second trimester. The risk increased in a dose-dependent fashion from 1.3-fold with one or two fever episodes after the twelfth prenatal week to 3.12-fold with three or more episodes.

"Our results suggest a role for gestational maternal infection and innate immune responses to infection in the onset of at least some cases of autism spectrum disorder," says first author Mady Hornig, associate professor of Epidemiology and director of Translational Research at CII.

Questionnaire analysis did not indicate an association between risk and maternally-reported symptoms of infection in individual organ systems that might implicate specific infectious agents. An ongoing study is testing blood samples collected at mid-pregnancy and at birth to explore the possible role of specific infectious agents and the contribution of distinctive patterns of immune response among mothers and children to understand the mechanisms creating vulnerability.

"Future work should focus on identifying and preventing prenatal infections and inflammatory responses that may contribute to autism spectrum disorder," says senior author W. Ian Lipkin, John Snow Professor of Epidemiology and director of CII.

How do preemies perform in school?

Parents of prematurely born babies often fear their children may go on to struggle in school, but findings from a new large-scale study from the Institute for Policy Research at Northwestern University and Northwestern Medicine should reassure parents.

The large-scale study found that two-thirds of babies born at only 23 or 24 weeks were ready for kindergarten on time. Unexpectedly, nearly two percent of them even achieved gifted status in school. While these extremely premature babies often scored low on standardized tests, preterm infants born 25 weeks or later performed only slightly lower than full-term infants. In fact, as the length of pregnancy increased after 28 weeks, the differences in test scores were negligible.

The study will be published June 12 in JAMA Pediatrics.

"What excites me about this study is that it changes the focus for the clinician and families at the bedside from just focusing on the medical outcomes of the child to what the future educational outcomes might be for a child born early," said first author Dr. Craig Garfield, associate professor of pediatrics and of medical social sciences at Northwestern University Feinberg School of Medicine.

The longitudinal study analyzed more than 1.3 million babies born in Florida from 1992 to 2002 with gestational ages of 23 to 41 weeks who later entered Florida public schools between 1995 and 2012. The scientists matched the babies' vital statistic records with their Florida public school records to examine the association between being born early and educational performance.

"Many studies look at premature babies but very few of them look at their educational outcomes into middle school in such a large population," said Garfield, who also is an attending pediatrician at Ann & Robert H. Lurie Children's Hospital of Chicago. "What's special about this study is it speaks to the importance of administrative data sets and the ability to combine different data sets in ways that allow us to ask questions and get answers about how our children are doing in the long-run."

"While some people might be troubled that very premature infants tend to score well below their full-term peers on standardized tests, I believe that the glass is more than half-full," said senior author David Figlio, director of the Institute for Policy Research at Northwestern University. "Most infants born at 23 to 24 weeks still demonstrate a high degree of cognitive functioning at the start of kindergarten and throughout school."

While this study's data is strong, it does not account for some of these infants' medical issues related to preterm birth or provide information about why these children performed well in school, such as their biological make-up or if they received extra support from family or schools, Garfield said. Nevertheless, most babies born prematurely ended up performing reasonably well on standardized tests through middle school.

"Our future work in this area will focus on what parents and service providers can do to help future premature children to achieve their full potential," Garfield said.

Common periodontal pathogen may interfere with conception in women

According to a study carried out at the University of Helsinki, Finland, a common periodontal pathogen may delay conception in young women. This finding is novel: previous studies have shown that periodontal diseases may be a risk for general health, but no data on the influence of periodontal bacteria on conception or becoming pregnant have been available.

"Our results encourage young women of fertile age to take care of their oral health and attend periodontal evaluations regularly", says periodontist and researcher Susanna Paju, University of Helsinki.

Study population comprised 256 healthy non-pregnant women (mean age 29.2 years, range 19 to 42) who had discontinued contraception in order to become pregnant. They were enrolled from the general community from Southern Finland. Clinical oral and gynecological examinations were performed. Detection of major periodontal pathogens in saliva and analysis of serum and saliva antibodies against major periodontal pathogens as well as a vaginal swab for the diagnosis of bacterial vaginosis at baseline were carried out.

Subjects were followed-up to establish whether they did or did not become pregnant during the observation period of 12 months.

Porphyromonas gingivalis, a bacterium associated with periodontal diseases, was significantly more frequently detected in the saliva among women who did not become pregnant during the one-year follow-up period than among those who did. The levels of salivary and serum antibodies against this pathogen were also significantly higher in women who did not become pregnant.

Statistical analysis showed that the finding was independent of other risk factors contributing to conception, such as age, current smoking, socioeconomic status, bacterial vaginosis, previous deliveries, or clinical periodontal disease.

Women who had P. gingivalis in the saliva and higher saliva or serum antibody concentrations against this bacterium had a 3-fold hazard for not becoming pregnant compared to their counterparts. Increased hazard was nearly to 4-fold if more than one of these qualities and clinical signs of periodontitis were present.

"Our study does not answer the question on possible reasons for infertility but it shows that periodontal bacteria may have a systemic effect even in lower amounts, and even before clear clinical signs of gum disease can be seen", says Dr. Paju. "More studies are needed to explain the mechanisms behind this association."

Infertility is a major concern, and increasing healthcare resources are needed for infertility treatments. More attention should be paid to the potential effects of common periodontal diseases on general health. Young women are encouraged to take care of their oral health and maintain good oral hygiene also when they are planning pregnancy, suggests Dr. Paju.

Medical advice from risk-averse health professionals may contribute to some women's decisions to stop cycling to work during pregnancy, meaning they miss out on the potential benefits of the active commute

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Medical advice from risk-averse health professionals may contribute to some women's decisions to stop cycling to work during pregnancy, meaning they miss out on the potential benefits of the active commute. A recent study in the Journal of Transport & Health reveals the reasons why women decide to stop or continue cycling to work when they are pregnant, including often ambiguously worded or overly-cautious advice from medical guidelines, midwives and obstetricians.

More people than ever are commuting to work by bicycle in London. According to data from the 2011 census, the city saw a 144% increase in cycle-commuting over the previous decade. This has big health benefits, for the health of the individual cyclist as well as for public health more broadly, as it helps people move more as part of their everyday activities.

Moderate intensity exercise provides benefits during pregnancy for mother and baby. In the UK, the National Institute for Clinical Excellence (NICE) and the National Health Service (NHS) both recommend pregnant women engage in daily exercise to help manage common discomforts, reduce pregnancy complications like preeclampsia, reduce discomfort and improve mood. But when it comes to cycling, the advice dries up: there are no clear recommendations women can use to decide whether to continue cycling.

"Despite the clear health benefits of cycling and the push to get more people commuting by bike, especially in cities like London, the medical advice on cycling during pregnancy remains murky," commented Davara Lee Bennett, the author of the new study. "My research aimed to explore why women do -- and don't -- cycle to work when they're pregnant, with a view to supporting informed decision-making -- including, if women so wish, rocking the rust off their chains, and bringing their bikes out from under the stairs and into the light."

Bennett conducted three individual interviews and held three focus group discussions: with a group of women who had stopped cycling early, a group that had carried on into later pregnancy and a mixed group. She recorded and transcribed all of them, and analyzed the transcripts line-by-line to develop themes. The resulting factors that affected women's decisions fell into a few main areas: physical obstacles and enablers, perceptions of risk and of pregnancy itself, and advice.

The idea of risk was a key factor in decisions about continued cycling: women adjusted their cycling practices to minimize risk, taking partners' support or concern into account. Although some women had positive encounters with health professionals, the medical advice they received was often noncommittal or risk-averse.

During pregnancy, depending on women's proportions and the type of bike, the growing belly can feel physically restrictive. Some women stopped cycling because of this, while others found comfort from their daily aches and pains when they commuted by bike. Either way, more comfortable bikes helped: women preferred Dutch-style, upright designs with a low crossbar and a wide, supportive seat.
Perceptions of pregnancy also had an impact on women's decisions: some preferred to abandon their active commute, opting for a more peaceful state, while others continued to cycle in a bid to remain connected to their authentic selves.

"Understanding the obstacles to women's cycling during pregnancy can support the development of safer cycling infrastructure and informed medical guidelines, ultimately offering more women the opportunity to benefit from an active commute," said Bennett. "By addressing some of the more socially prohibitive public discourses on the topic, I hope that my research will not just enable informed decision-making by women, but also encourage more constructive support and advice for women from health professionals."

Pregnancy after breast cancer does not increase chance of recurrence

"These data provide reassurance to breast cancer survivors that having a baby after a breast cancer diagnosis may not increase the chance of their cancer coming back. For many young women around the world who want to grow and expand their families, it's very comforting news," said Erica L. Mayer, MD, MPH, ASCO Expert.

Findings from a retrospective study of 1,200 women provide reassurance to breast cancer survivors who are contemplating pregnancy. In the study, women who became pregnant after an early breast cancer diagnosis, including those with estrogen receptor (ER)-positive tumors, did not have a higher chance of cancer recurrence and death than those who did not become pregnant.

The study will be featured in a press briefing today and presented at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting.

Breast cancer is the most common cancer in women of reproductive age. Taking into account current trends toward delaying childbearing, breast cancer in young women may occur before the completion of reproductive plans. Although half of young women with newly diagnosed breast cancer report interest in having children, less than 10% become pregnant after treatment.1 In fact, of all cancer survivors, breast cancer survivors are the least likely to have a baby after diagnosis.

Doctors and patients have long been concerned that pregnancy could increase the chance of breast cancer recurrence, particularly for women with ER-positive disease. Because ER-positive breast cancer is fueled by estrogen, the fear is that hormone levels during pregnancy could coax any occult cancer cells -- those that may remain in the body after treatment -- to grow.

Another concern regarding pregnancy in women with ER-positive cancer is the need to interrupt adjuvant (post-surgery) hormone therapy before trying to achieve a pregnancy. Such hormone therapy helps prevent cancer recurrence, and it is recommended that women receive it for at least 5 years and in some cases up to 10 years. "Our findings confirm that pregnancy after breast cancer should not be discouraged, even for women with ER-positive cancer," said lead study author Matteo Lambertini, MD, a medical oncologist and ESMO fellow at the Institut Jules Bordet in Brussels, Belgium.

"However, when deciding how long to wait before becoming pregnant, patients and doctors should consider each woman's personal risk for recurrence, particularly for women who need adjuvant hormone therapy."

With 1,207 patients, this is the largest study to investigate the safety of pregnancy after breast cancer and the only to address this question specifically in women with ER-positive breast cancer (the most common type of breast cancer), according to the authors.

This study included women who were diagnosed with non-metastatic breast cancer before 2008, under the age of 50. The majority (57%) had ER-positive cancer, and more than 40% had poor prognostic factors, such as large tumor size and cancer spread to the axillary lymph nodes. Among the 1,207 patients included in the study, 333 of the women became pregnant, and 874 did not (as per the case-control study design, researchers matched each patient who became pregnant with three patients who had similar cancer characteristics but did not become pregnant).

The median time from diagnosis to conception was 2.4 years. Women with ER-positive breast cancer tended to achieve pregnancy later than those with ER-negative disease; 23% of patients with ER-positive disease had a pregnancy beyond 5 years from diagnosis as compared to 7% in those with ER-negative tumors.

Key Findings

After a median follow-up of about 10 years from cancer diagnosis, there was no difference in disease-free survival between women who became pregnant and those who did not, irrespective of ER status. Secondary analyses showed that there was no difference in disease-free survival compared to women who did not become pregnant, irrespective of whether women completed the pregnancy or had an abortion, became pregnant less than two years or more than two years from breast cancer diagnosis, and whether patients had breastfed.

Among survivors of ER-positive cancer, there was also no difference in overall survival between women who became pregnant and those who did not. Survivors of ER-negative breast cancer who became pregnant had a 42% lower chance of dying than those who did not become pregnant.
"It's possible that pregnancy could be a protective factor for patients with ER-negative breast cancer, through either immune system mechanisms or hormonal mechanisms, but we need more research into this," said Dr. Lambertini.

Although there was limited data on breastfeeding in this study (64 patients, with 25 women who reported having breastfed their newborn), the results suggest that breastfeeding is feasible, even after breast surgery.

Next Steps

Although large, this study had limited information on the use of assisted reproductive technologies (such as in vitro fertilization) in breast cancer survivors, and HER2 status was unknown for about 80% of the women. Further research is also needed to study the effect of pregnancy on health outcomes of women with BRCA mutations, a group that generally develops breast cancer at a younger age. A large clinical trial (the POSITIVE study) is under way investigating the impact of interrupting adjuvant hormone therapy to allow for pregnancy in women with ER-positive breast cancer. This study will also provide further insight on the impact of reproductive technologies and breastfeeding.

This study was partly supported by grants from Les Amis de l'Institut Bordet (grant number 2012-09) and the European School of Oncology (ESO). The International Breast Cancer Study Group (IBCSG) study, which provided patient information for this study, was partially funded by the National Institutes of Health (grant number CA-753562).

1Letourneau JM, et al. Pretreatment fertility counseling and fertility preservation improve quality of life in reproductive age women with cancer. Cancer. 2012 Mar 15;118(6):1710-7
 

 

 

Cesarean patients sent home with more narcotic pain medications than needed

cesarean childbirth are prescribed more opioid (narcotic) pain medications than needed upon release from the hospital, a Vanderbilt University Medical Center (VUMC) study shows.

The study, published online today in Obstetrics and Gynecology and in print in July, studied 179 cesarean patients from VUMC over an eight-week period to examine the variation in opioid prescribing and consumption after cesarean delivery, the most common major surgical procedure performed in the United States.

"What we found is that prescribers, partly in order to expedite a patient's release from the hospital, have kind of a one-size-fits-all prescription model for patients when they are discharged from the hospital," said Sarah Osmundson, M.D., assistant professor of Obstetrics and Gynecology in the Division of Maternal-Fetal Medicine and the first author of the study, 'Postdischarge Opioid Use After Cesarean Delivery.' What we've learned is that this method may undertreat a few patients, but likely overtreats the vast majority of patients.

"There's so much attention around excess opioids and the growing problem with opioid addiction, and the question came up, how much are patients really using when they go home," Osmundson said. "Anecdotally, I was hearing that patients were using one to two tablets once they were home, but they went home with a prescription for 30 tablets. The big question for us is what is happening after discharge and can we modify that to reduce the amount of excess opioids prescribed."

The number of opioid overdose deaths in the United States has quadrupled in 15 years, a dramatic result of the current opioid abuse epidemic. The rise correlates with a sharp increase in the amount of legal prescription opioids dispensed. Most individuals using prescription opioids for non-medical purposes have obtained them from family members or friends who have been prescribed the medications.

For the study, starting on postoperative day 14 until they had stopped taking the medication, women were asked weekly about the number of opioid pills used, the amount remaining and their pain experience. The state's Substance Monitoring Program was used to ascertain prescription-filling details.

Michael Richardson, M.D., associate professor of Anesthesiology and a co-author, said more attention needs to be paid to patients' opioid use while they are still inpatients in the hospital to better predict their use after going home. "Our data suggest that providers are not currently considering in-hospital opioid use to determine the amount of opioid prescribed at discharge," Richardson said. "If the patient is not using very much in the hospital, why should they go home with a prescription for 30 oxycodone tablets?"

The study authors also found that many patients with a 30-day prescription believe they are supposed to take the pills until they are all gone, when in fact, they only need to take them when absolutely needed. Normally over-the-counter pain relievers such as ibuprofen or Tylenol are sufficient in controlling post cesarean pain.

The study found that most women (83 percent) used opioids after discharge for an average of eight days, and of the women who filled their prescriptions (92 percent) 74 percent had unused tablets. This amounted to about 2,540 unused 5 mg oxycodone tablets over the study period, Richardson said, and about 19,000 excess oxycodone per year from cesareans at VUMC alone.

And the majority (63 percent) stored their pills in an unlocked location in their home, which is another cause for concern, Osmundson said.

"Large studies show that the most common source for misused opioids are ones that are prescribed legally and to the appropriate person," Osmundson said. "We know that these are falling into the wrong hands and that people frequently use opioids prescribed to a friend or family member. One way to tackle the opioid epidemic is not to have excess opioids around, which is unlikely to happen, or to minimize what we're currently prescribing, which is doable," she said.

There's a balance, though, Richardson added. "You don't want to underprescribe either. In Tennessee a health care provider can't just call in a refill for opioids, so if you underprescribe when the patient is sent home from the hospital, someone has to pick up a paper prescription, and that's inconvenient for many patients.

Osmundson and Richardson say that they plan further study to determine whether in-hospital opioid use can guide postdischarge prescribing to reduce opioids without undertreating pain.

"If we can find a more nuanced way to prescribe, we can do a lot to reduce the excess opioids out there," Osmundson said.