Biologics in Pregnancy: Are They Safe?

Study shows no increased risk for preterm delivery or small for gestational age

Exposure to biologic therapies among women with autoimmune diseases was not associated with increased risks of preterm delivery or having small for gestational age babies, a population-based Canadian study found.

Among 109 women who had 120 pregnancies and who received a biologic medication during or 3 months prior to pregnancy, the odds ratio for preterm delivery after high-dimensional propensity score matching was 1.13 (95% CI 0.67-1.90), which was not significantly different from the risk seen among women not receiving biologics, according to Mary A. De Vera, PhD, of the University of British Columbia in Vancouver, and colleagues.

And also after propensity score matching, the risk of small for gestational age birth compared with nonuse of biologics was 0.91 (95% CI 0.46-1.78) among users, they reported online in Annals of the Rheumatic Diseases.

A critical component of autoimmune disease is the dysregulation of regulatory cytokines and chemokines, with tumor necrosis factor (TNF) being key.

“In pregnancy, TNF-alpha controls cyclo-oxygenases that affect blastocyst implantation, endometrial permeability and decidualization, and contributes to the process of labor. Abnormally high levels of TNF-alpha and other cytokines have been implicated in pregnancy complications including preterm delivery, fetal growth retardation, early and unexplained spontaneous abortions, and miscarriages,” De Vera’s group explained.

This suggests that these undesirable outcomes correlate with levels of disease activity, which is held in check by effective treatments such as TNF inhibitors.

To see if these two adverse outcomes associated with infant morbidity and mortality were influenced by biologic use shortly before or during pregnancy, the researchers analyzed data from Population Data British Columbia, which contains longitudinal data on health services for all residents of British Columbia.

Additional information was obtained from the Medical Services Plan database, the Discharge Abstract Database, Population Data BC, PharmaNet, and the BC Perinatal Database Registry.

The study cohort included women with recorded diagnoses of rheumatoid arthritis (RA), inflammatory bowel disease (IBD), psoriasis/psoriatic arthritis, juvenile idiopathic arthritis, systemic lupus erythematosus, and other connective tissue diseases.

Preterm delivery was birth before 37 weeks’ gestation, and small for gestational age was weight below the 10th percentile of age- and sex-specific neonatal weight.

High-dimensional propensity score matching was used to limit the likelihood of confounding by indication. This was based on an algorithm that took into account the use of multiple medications, concurrent disorders and symptoms, and previous adverse obstetric outcomes.

The analysis included 6,218 women with autoimmune disease and their 8,607 pregnancies.

Mean maternal age at delivery was 31, and the majority of women had either RA or IBD. The most commonly used biologics were infliximab (Remicade) in 37%, etanercept (Enbrel) in 31%, and adalimumab (Humira) in 26%.

A total of 21 of the 120 babies with biologic exposure (18%) were born preterm, as were 95 of 600 (16%) not exposed, for an unadjusted odds ratio of 1.64 (95% CI 1.02-2.63). Small for gestational age births were seen in 11 of 120 (9%) of babies who were biologics exposed, and in 60 of 600 (10%) of those who were unexposed, for an unadjusted OR of 1.34 (95% CI 0.72-2.51). After propensity score matching, however, neither outcome was statistically significant.

Among the small for gestational age neonates, mean Apgar scores for those who were biologics exposed were 8.1 and 9 at 1 and 5 minutes, respectively, while for the nonexposed, the corresponding scores were 7.7 and 8.7.

An important feature of this study was the use of high-dimensional propensity scoring, so that differences in baseline characteristics were taken into account. Earlier studies found odds ratios for preterm delivery of 2 to 2.71. However, those studies did not attempt to adjust for the effects of disease severity or other confounders and therefore had limited generalizability.

“Indeed, addressing confounding by indication is of utmost importance in the population of women with autoimmune disease, given the association between disease activity and adverse pregnancy outcomes,” De Vera’s group stated.

Despite being limited by relatively small numbers, the study “represents an important contribution to the accumulation of evidence on the safety of the use of biologics in pregnant women, which may lead to increased prescriber comfort and patient acceptance, decreased uncertainty, and improved maternal and neonatal outcomes in this population,” they concluded.

The dangers of being born too small or too soon.

Birth is dangerous, especially for infants born too small or too soon. Although much is known about the mortality risk for such infants in high-income countries, little is known about the risk in poorer countries. In The Lancet, Joanne Katz and colleagues begin to fill in the gap on just how dangerous it is to be born too small or too soon in a low-income or middle-income country.1 The investigators analysed more than 2 million birth outcomes from resource-poor countries in Asia, Africa, and Latin America and calculated the regional risk of neonatal and post-neonatal mortality associated with being born preterm, small-for-gestational age (SGA), or both.

Using data from 20 cohorts in 13 countries, Katz and colleagues show that being born SGA increased the risk of neonatal mortality by two to five times across the three regions, but being born preterm (<37 completed weeks of gestation) raised the risk by six to 26 times. When children were born both SGA and preterm, neonatal mortality was ten to 39 times higher than in otherwise normal neonates. These findings provide the first solid estimates of the excess risk of dying for infants in these categories of births for countries where 135 million babies are born every year.

Katz and colleagues’ findings advance our knowledge by going beyond the use of low birthweight (<2500 g) as a means of identifying infants in danger. The low birthweight category includes both premature and growth-restricted infants. It excludes newborn babies heavier than 2500 g who might also be premature or have restricted growth and therefore still have an increased risk of dying. As a result of these findings, the sources of neonatal mortality are now better known in the regions studied and appropriate interventions to prevent early deaths can be developed.

Katz and colleagues are also the first to document the high proportion of Asian and African newborn babies (21% and 16%, respectively) who are SGA (defined as the lowest tenth percentile of the growth reference) but neither preterm nor low birthweight. In view of the surprisingly high proportion of such infants, it is disappointing that the authors did not provide the associated mortality risk. Term-SGA infants had about three times higher risk of death (across all regions) during the early and late neonatal as well as the postneonatal periods, but these included a high proportion of low-birthweight (LBW) infants. The investigators state that the large group of infants who are SGA but not preterm or LBW have a higher mortality risk than term, appropriate weight-for-gestational-age infants, but we are left to wonder: how much higher?

The high prevalence of term SGA births and their excess risk of death throughout infancy suggest that there is more to know about these babies than just their weight-for-gestational age. They could also be shorter, as documented in Guatemala,2where linear growth failure was detectable as early as 15 weeks of gestation, and infants tend to be born “short and round”.3 Infants of HIV-infected mothers on antiretroviral therapy in Haiti and Zambia were also born small, largely because of shortness at birth rather than thinness.45 There has been much discussion about the causes and consequences of proportional (ie, short and round) versus disproportional (long and thin) phenotypes of SGA babies, with some evidence that thin SGA babies are at higher risk of adverse outcomes.67 Elucidation of the differences in mortality risk among types of SGA infants will require datasets that include infant length at birth, but such data are rare.

Katz and colleagues’ findings present important methodological challenges. The investigators included cohorts on the basis of completeness and quality of their data. Nonetheless, in six of the cohorts, they imputed some birthweights because some data were missing or measured too late. Some of the variability in birthweight might have resulted from the 72 h observation window used (during which breastfed neonates can lose up to 10% of their weight8). Unfortunately, the preferred reference dataset for calculating birthweight-for-gestational age (the Alexander reference9) provides data at only the tenth percentile, so the authors used a different reference dataset to identify infants below the third percentile.10 Both references are from large US populations, with data obtained in 1972—76 and 1991, respectively. The appropriateness of these reference populations, especially for the cohorts from South Asia, is unknown and might be among the factors that account for the high proportions of SGA births seen. Again, not knowing the excess mortality associated with the SGA babies who were term and not LBW, we wonder whether the use of the tenth percentile of the Alexander reference put too many babies in this risk category.

The analysis presented by Katz and colleagues is a substantial contribution, and points the way to further advances. Most of the cohort studies included were not representative of the country where they were done, and the studies included in a given region were also not representative of that region—eg, the vast majority of data from Latin America was from Chile. More representative data are surely needed. Also, many low-income or middle-income countries are in eastern Europe and central Asia, regions not represented in these analyses. The scarcity of data from these regions, however, is because of a dearth of global resources and attention rather than a product of poor study design. We hope that this important study can serve as a catalyst for the development of stronger datasets that require fewer assumptions and include additional essential information, including length at birth.

Source: Lancet


Mediators of the association between pre-eclampsia and cerebral palsy: population based cohort study.


Objective To test the hypothesis that pre-eclampsia is a risk factor for cerebral palsy mediated through preterm birth and being born small for gestational age.

Design Population based cohort study.

Setting Clinical data from the Norwegian Cerebral Palsy Registry were linked with perinatal data prospectively recorded by the Medical Birth Registry of Norway.

Participants All singleton babies who survived the neonatal period during 1996-2006 (849 children with cerebral palsy and 616 658 control children).

Main outcome measures Cerebral palsy and cerebral palsy subtypes.

Results Children exposed to pre-eclampsia had an excess risk of cerebral palsy (unadjusted odds ratio 2.5, 95% confidence interval 2.0 to 3.2) compared with unexposed children. Among children born at term (≥37 weeks), exposure to pre-eclampsia was not associated with an excess risk of cerebral palsy in babies not born small for gestational age (1.2, 0.7 to 2.0), whereas children exposed to pre-eclampsia and born small for gestational age had a significantly increased risk of cerebral palsy (3.2, 1.5 to 6.7). Non-small for gestational age babies born very preterm (<32 weeks) and exposed to pre-eclampsia had a reduced risk of cerebral palsy compared with unexposed children born at the same gestational age (0.5, 0.3 to 0.8), although the risk was not statistically significantly reduced among children exposed to pre-eclampsia and born small for gestational age (0.7, 0.4 to 1.3). Exposure to pre-eclampsia was not associated with a specific cerebral palsy subtype.

Conclusions Exposure to pre-eclampsia was associated with an increased risk of cerebral palsy, and this association was mediated through the children being born preterm or small for gestational age, or both. Among children born at term, pre-eclampsia was a risk factor for cerebral palsy only when the children were small for gestational age.


In this study we found that pre-eclampsia was associated with an increased risk of cerebral palsy and that the excess risk was mainly mediated through preterm birth, but also through being born small for gestational age. Exposed children born at term as non-small for gestational age did not have an excess risk of cerebral palsy and we did not find that a specific cerebral palsy subtype was more common in children exposed to pre-eclampsia than not exposed. Thus we were not able to find evidence for a direct effect of pre-eclampsia on the risk of cerebral palsy.

What is already known on this topic

  • Pre-eclampsia is a frequent cause of preterm birth and being born small for gestational age, both of which are known risk factors for cerebral palsy
  • Observational studies have shown conflicting results with respect to whether pre-eclampsia is a risk factor for cerebral palsy
  • Pre-eclampsia is a risk factor for cerebral palsy mainly mediated through preterm birth and being small for gestational age
  • Among term born children exposed to pre-eclampsia only those born small for gestational age had an excess risk of cerebral palsy
  • Pre-eclampsia was not associated with specific subtypes of cerebral palsy

What this study adds


Source: BMJ


Association between maternal serum 25-hydroxyvitamin D level and pregnancy and neonatal outcomes: systematic review and meta-analysis of observational studies.


Objective To assess the effect of 25-hydroxyvitamin D (25-OHD) levels on pregnancy outcomes and birth variables.

Design Systematic review and meta-analysis.

Data sources Medline (1966 to August 2012), PubMed (2008 to August 2012), Embase (1980 to August 2012), CINAHL (1981 to August 2012), the Cochrane database of systematic reviews, and the Cochrane database of registered clinical trials.

Study selection Studies reporting on the association between serum 25-OHD levels during pregnancy and the outcomes of interest (pre-eclampsia, gestational diabetes, bacterial vaginosis, caesarean section, small for gestational age infants, birth weight, birth length, and head circumference).

Data extraction Two authors independently extracted data from original research articles, including key indicators of study quality. We pooled the most adjusted odds ratios and weighted mean differences. Associations were tested in subgroups representing different patient characteristics and study quality.

Results 3357 studies were identified and reviewed for eligibility. 31 eligible studies were included in the final analysis. Insufficient serum levels of 25-OHD were associated with gestational diabetes (pooled odds ratio 1.49, 95% confidence interval 1.18 to 1.89), pre-eclampsia (1.79, 1.25 to 2.58), and small for gestational age infants (1.85, 1.52 to 2.26). Pregnant women with low serum 25-OHD levels had an increased risk of bacterial vaginosis and low birthweight infants but not delivery by caesarean section.

Conclusion Vitamin D insufficiency is associated with an increased risk of gestational diabetes, pre-eclampsia, and small for gestational age infants. Pregnant women with low 25-OHD levels had an increased risk of bacterial vaginosis and lower birth weight infants, but not delivery by caesarean section.


Source: BMJ