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1.  Paternal therapy with disease modifying drugs in multiple sclerosis and pregnancy outcomes: a prospective observational multicentric study 
BMC Neurology  2014;14:114.
Background
Most of Multiple Sclerosis (MS) patients undergo disease modifying drug (DMD) therapy at childbearing age. The objective of this prospective, collaborative study, was to assess outcomes of pregnancies fathered by MS patients undergoing DMD.
Methods
Structured interviews on pregnancies fathered by MS patients gathered in the Italian Pregnancy Dataset were collected; pregnancies were divided according to father exposure or unexposure to DMD at time of procreation. Treatment were compared with multivariable logistic and linear models.
Results
Seventy-eight pregnancies fathered by MS patients were tracked. Forty-five patients were taking DMD at time of conception (39 beta-interferons, 6 glatiramer acetate), while 33 pregnancies were unexposed to DMD. Seventy-five pregnancies ended in live-births, 44 in the exposed and 31 in the unexposed group. No significant differences between the two groups were found in the risk of spontaneous abortion or malformations (p > 0.454), mean gestational age (p = 0.513), frequency of cesarean delivery (p = 0.644), birth weight (p = 0.821) and birth length (p = 0.649). In comparison with data of the Italian general population, the proportion of spontaneous abortion and caesarean delivery in exposed pregnancies fell within the estimates, while the proportion of pre-term delivery in the exposed group was higher than expected.
Conclusions
Our data indicate no association between paternal DMD exposure at time of conception and risk of spontaneous abortion, adverse fetal outcomes and congenital malformations. Further studies clarifying the role of DMD fathers intake prior and during pregnancy are desirable, to supply guidelines for clinical practice.
doi:10.1186/1471-2377-14-114
PMCID: PMC4059028  PMID: 24884599
Multiple sclerosis; Paternity; Pregnancy; Interferon beta; Glatiramer acetate
2.  Pregnancy and Infant Outcomes among HIV-Infected Women Taking Long-Term ART with and without Tenofovir in the DART Trial 
PLoS Medicine  2012;9(5):e1001217.
Diana Gibb and colleagues investigate the effect of in utero tenofovir exposure by analyzing the pregnancy and infant outcomes of HIV-infected women enrolled in the DART trial.
Background
Few data have described long-term outcomes for infants born to HIV-infected African women taking antiretroviral therapy (ART) in pregnancy. This is particularly true for World Health Organization (WHO)–recommended tenofovir-containing first-line regimens, which are increasingly used and known to cause renal and bone toxicities; concerns have been raised about potential toxicity in babies due to in utero tenofovir exposure.
Methods and Findings
Pregnancy outcome and maternal/infant ART were collected in Ugandan/Zimbabwean HIV-infected women initiating ART during The Development of AntiRetroviral Therapy in Africa (DART) trial, which compared routine laboratory monitoring (CD4; toxicity) versus clinically driven monitoring. Women were followed 15 January 2003 to 28 September 2009. Infant feeding, clinical status, and biochemistry/haematology results were collected in a separate infant study. Effect of in utero ART exposure on infant growth was analysed using random effects models.
382 pregnancies occurred in 302/1,867 (16%) women (4.4/100 woman-years [95% CI 4.0–4.9]). 226/390 (58%) outcomes were live-births, 27 (7%) stillbirths (≥22 wk), and 137 (35%) terminations/miscarriages (<22 wk). Of 226 live-births, seven (3%) infants died <2 wk from perinatal causes and there were seven (3%) congenital abnormalities, with no effect of in utero tenofovir exposure (p>0.4). Of 219 surviving infants, 182 (83%) enrolled in the follow-up study; median (interquartile range [IQR]) age at last visit was 25 (12–38) months. From mothers' ART, 62/9/111 infants had no/20%–89%/≥90% in utero tenofovir exposure; most were also zidovudine/lamivudine exposed. All 172 infants tested were HIV-negative (ten untested). Only 73/182(40%) infants were breast-fed for median 94 (IQR 75–212) days. Overall, 14 infants died at median (IQR) age 9 (3–23) months, giving 5% 12-month mortality; six of 14 were HIV-uninfected; eight untested infants died of respiratory infection (three), sepsis (two), burns (one), measles (one), unknown (one). During follow-up, no bone fractures were reported to have occurred; 12/368 creatinines and seven out of 305 phosphates were grade one (16) or two (three) in 14 children with no effect of in utero tenofovir (p>0.1). There was no evidence that in utero tenofovir affected growth after 2 years (p = 0.38). Attained height- and weight for age were similar to general (HIV-uninfected) Ugandan populations. Study limitations included relatively small size and lack of randomisation to maternal ART regimens.
Conclusions
Overall 1-year 5% infant mortality was similar to the 2%–4% post-neonatal mortality observed in this region. No increase in congenital, renal, or growth abnormalities was observed with in utero tenofovir exposure. Although some infants died untested, absence of recorded HIV infection with combination ART in pregnancy is encouraging. Detailed safety of tenofovir for pre-exposure prophylaxis will need confirmation from longer term follow-up of larger numbers of exposed children.
Trial registration
www.controlled-trials.com ISRCTN13968779
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Currently, about 34 million people (mostly in low- and middle-income countries) are infected with HIV, the virus that causes AIDS. At the beginning of the epidemic, more men than women were infected with HIV but now about half of all people living with HIV/AIDS are women, most of who became infected through unprotected sex with an infected partner. In sub-Saharan Africa alone, 12 million women are HIV-positive. Worldwide, HIV/AIDS is the leading cause of death among women of child-bearing age. Moreover, most of the 400,000 children who become infected with HIV every year acquire the virus from their mother during pregnancy or birth, or through breastfeeding, so-called mother-to-child transmission (MTCT). Combination antiretroviral therapy (ART)—treatment with cocktails of powerful antiretroviral drugs—reduces HIV-related illness and death among women, and ART given to HIV-positive mothers during pregnancy and delivery and to their newborn babies greatly reduces MTCT.
Why Was This Study Done?
Because of ongoing international efforts to increase ART coverage, more HIV-positive women in Africa have access to ART now than ever before. However, little is known about pregnancy outcomes among HIV-infected African women taking ART throughout pregnancy for their own health or about the long-term outcomes of their offspring. In particular, few studies have examined the effect of taking tenofovir (an antiretroviral drug that is now recommended as part of first-line ART) throughout pregnancy. Tenofovir readily crosses from mother to child during pregnancy and, in animal experiments, high doses of tenofovir given during pregnancy caused bone demineralization (which weakens bones), kidney problems, and impaired growth among offspring. In this study, the researchers analyze data collected on pregnancy and infant outcomes among Ugandan and Zimbabwean HIV-positive women who took ART throughout pregnancy in the Development of AntiRetroviral Therapy in Africa (DART) trial. This trial was designed to test whether ART could be safely and effectively delivered in Africa without access to the expensive laboratory tests that are routinely used to monitor ART toxicity and efficacy in developed countries.
What Did the Researchers Do and Find?
The pregnancy outcomes of 302 women who became pregnant during the DART trial and information on birth defects among their babies were collected as part of the DART protocol; information on the survival, growth, and development of the infants born to these women was collected in a separate infant study. Most of the women who became pregnant were taking tenofovir-containing ART before and throughout their pregnancies. 58% of the pregnancies resulted in a live birth, 7% resulted in a stillbirth (birth of a dead baby at any time from 22 weeks gestation to the end of pregnancy), and 35% resulted in a termination or miscarriage (before 22 weeks gestation). Of the 226 live births, seven infants died within 2 weeks and seven had birth defects. Similar proportions of the infants exposed and not exposed to tenofovir during pregnancy died soon after birth or had birth defects. Of the 182 surviving infants who were enrolled in the infant study, 14 subsequently died at an average age of 9 months, giving a 1-year mortality of 5%. None of the surviving children who were tested (172 infants) were HIV infected. No bone fractures or major kidney problems occurred during follow-up and prebirth exposure to tenofovir in utero had no effect on growth or weight gain at 2 years (in contrast to a previous US study).
What Do These Findings Mean?
By showing that prebirth tenofovir exposure does not affect pregnancy outcomes or increase birth defects, growth abnormalities, or kidney problems, these findings support the use of tenofovir-containing ART during pregnancy among HIV-positive African women, and suggest that it could also be used to prevent women of child-bearing age acquiring HIV-infection heterosexually. Notably, the observed 5% 1-year infant mortality is similar to the 2%–4% infant mortality normally seen in the region. The absence of HIV infection among the infants born to the DART participants is also encouraging. However, this is a small study (only 111 infants were exposed to tenofovir throughout pregnancy) and women were not randomly assigned to receive tenofovir-containing ART. Consequently, more studies are needed to confirm that tenofovir exposure during pregnancy does not affect pregnancy outcomes or have any long-term effects on infants. Such studies are essential because the use of tenofovir as a treatment for women who are HIV-positive is likely to increase and tenofovir may also be used in the future to prevent HIV acquisition in HIV-uninfected women.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001217.
Information is available from the US National Institute of Allergy and infectious diseases on all aspects of HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS, and summaries of recent research findings on HIV care and treatment (in several languages)
Information is available from Avert, an international AIDS nonprofit on many aspects of HIV/AIDS, including detailed information on HIV/AIDS treatment and care, women, HIV and AIDS, children, HIV and AIDS, and on HIV/AIDS and pregnancy (some information in English and Spanish); personal stories of women living with HIV are available
More information about the DART trial is available
Additional patient stories about living with HIV/AIDS are available through the nonprofit website Healthtalkonline
doi:10.1371/journal.pmed.1001217
PMCID: PMC3352861  PMID: 22615543
3.  Disease-modifying drugs for multiple sclerosis in pregnancy 
Neurology  2012;79(11):1130-1135.
Objective:
To systematically review the literature regarding safety of disease-modifying drug (DMD) use during pregnancy on perinatal and developmental outcomes in offspring of patients with multiple sclerosis (MS).
Methods:
A PubMed and EMBASE search up to February 2012 was conducted with a manual search of references from relevant articles. Selected studies were evaluated using internationally accepted criteria.
Results:
Fifteen studies identified 761 interferon β-, 97 glatiramer acetate-, and 35 natalizumab-exposed pregnancies. Study quality ranged from poor to good; no study was rated excellent. Small sample sizes limited most studies. Compared with data for unexposed pregnancies, fair- to good-quality prospective cohort studies reported that interferon β exposure was associated with lower mean birth weight, shorter mean birth length, and preterm birth (<37 weeks), but not low birth weight (<2,500 g), cesarean delivery, congenital anomaly (including malformation), or spontaneous abortion. Fewer studies of fair quality were available for glatiramer acetate and natalizumab. Glatiramer acetate exposure was not associated with lower mean birth weight, congenital anomaly, preterm birth, or spontaneous abortion. Natalizumab exposure did not appear to be associated with shorter mean birth length, lower mean birth weight, or lower mean gestational age. No studies examined mitoxantrone or fingolimod exposure. One study of paternal DMD use during conception found no effect on gestational age or birth weight. Few studies examined longer-term developmental outcomes.
Conclusion:
Further studies are needed to determine the potential risks associated with preconceptional and in utero DMD exposure in patients with MS. Discontinuation of DMDs before conception is still recommended.
doi:10.1212/WNL.0b013e3182698c64
PMCID: PMC3525300  PMID: 22933738
4.  Association between Prenatal Exposure to Antiretroviral Therapy and Birth Defects: An Analysis of the French Perinatal Cohort Study (ANRS CO1/CO11) 
PLoS Medicine  2014;11(4):e1001635.
Jeanne Sibiude and colleagues use the French Perinatal Cohort to estimate the prevalence of birth defects in children born to HIV-infected women receiving antiretroviral therapy during pregnancy.
Please see later in the article for the Editors' Summary
Background
Antiretroviral therapy (ART) has major benefits during pregnancy, both for maternal health and to prevent mother-to-child transmission of HIV. Safety issues, including teratogenic risk, need to be evaluated. We estimated the prevalence of birth defects in children born to HIV-infected women receiving ART during pregnancy, and assessed the independent association of birth defects with each antiretroviral (ARV) drug used.
Methods and Findings
The French Perinatal Cohort prospectively enrolls HIV-infected women delivering in 90 centers throughout France. Children are followed by pediatricians until 2 y of age according to national guidelines.
We included 13,124 live births between 1994 and 2010, among which, 42% (n = 5,388) were exposed to ART in the first trimester of pregnancy. Birth defects were studied using both European Surveillance of Congenital Anomalies (EUROCAT) and Metropolitan Atlanta Congenital Defects Program (MACDP) classifications; associations with ART were evaluated using univariate and multivariate logistic regressions. Correction for multiple comparisons was not performed because the analyses were based on hypotheses emanating from previous findings in the literature and the robustness of the findings of the current study. The prevalence of birth defects was 4.4% (95% CI 4.0%–4.7%), according to the EUROCAT classification. In multivariate analysis adjusting for other ARV drugs, maternal age, geographical origin, intravenous drug use, and type of maternity center, a significant association was found between exposure to zidovudine in the first trimester and congenital heart defects: 2.3% (74/3,267), adjusted odds ratio (AOR) = 2.2 (95% CI 1.3–3.7), p = 0.003, absolute risk difference attributed to zidovudine +1.2% (95% CI +0.5; +1.9%). Didanosine and indinavir were associated with head and neck defects, respectively: 0.5%, AOR = 3.4 (95% CI 1.1–10.4), p = 0.04; 0.9%, AOR = 3.8 (95% CI 1.1–13.8), p = 0.04. We found a significant association between efavirenz and neurological defects (n = 4) using the MACDP classification: AOR = 3.0 (95% CI 1.1–8.5), p = 0.04, absolute risk +0.7% (95% CI +0.07%; +1.3%). But the association was not significant using the less inclusive EUROCAT classification: AOR = 2.1 (95% CI 0.7–5.9), p = 0.16. No association was found between birth defects and lopinavir or ritonavir with a power >85% for an odds ratio of 1.5, nor for nevirapine, tenofovir, stavudine, or abacavir with a power >70%. Limitations of the present study were the absence of data on termination of pregnancy, stillbirths, tobacco and alcohol intake, and concomitant medication.
Conclusions
We found a specific association between in utero exposure to zidovudine and heart defects; the mechanisms need to be elucidated. The association between efavirenz and neurological defects must be interpreted with caution. For the other drugs not associated with birth defects, the results were reassuring. Finally, whatever the impact that some ARV drugs may have on birth defects, it is surpassed by the major role of ART in the successful prevention of mother-to-child transmission of HIV.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
AIDS and HIV infection are commonly treated with antiretroviral therapy (ART), a combination of individual drugs that work together to prevent the replication of the virus and further spread of the infection. Starting in the 1990s, studies have shown that ART of HIV-infected women can substantially reduce transmission of the virus to the child during pregnancy and birth. Based on these results, ART was subsequently recommended for pregnant women. Since 2004, ART has been standard therapy for pregnant women with HIV/AIDS in high-income countries, and it is now recommended for all HIV-infected women worldwide. Several different antiviral drug combinations have been shown to be effective and are used to prevent mother-to-infant transmission. However, as with any other drugs taken during pregnancy, there is concern that ART can harm the developing fetus.
Why Was This Study Done?
Several previous studies have assessed the risk that ART taken by a pregnant woman might pose to her developing fetus, but the results have been inconsistent. Animal studies suggested an elevated risk for some drugs but not others. While some clinical studies have reported increases in birth defects in children born to mothers on ART, others have shown no such increase.
The discrepancy may be due to differences between the populations included in the studies and the different methods used to diagnose birth defects. Additional large studies are therefore necessary to obtain more and better evidence on the potential harm of individual anti-HIV drugs to children exposed during pregnancy. So in this study, the authors conducted a large cohort study in France to assess the relationship between different antiretroviral drugs and specific birth defects.
What Did the Researchers Do and Find?
The researchers used a large national health database known as the French Perinatal Cohort that contains information on HIV-infected mothers who delivered infants in 90 centers throughout France. Pediatricians follow all children, whatever their HIV status, to two years of age, and health statistics are collected according to national health-care guidelines. Analyzing the records, the researchers estimated the rate at which birth defects occurred in children exposed to antiretroviral drugs during pregnancy.
The researchers included 13,124 children who were born alive between 1994 and 2010 and had been exposed to ART during pregnancy. Children exposed in the first trimester of pregnancy, and those exposed during the second or third trimester, were compared to a control group (children not exposed to the drug during the whole pregnancy). Using two birth defect classification systems (EUROCAT and MACDP—MACDP collects more details on disease classification than EUROCAT), the researchers sought to detect a link between the occurrence of birth defects and exposure to individual antiretroviral drugs.
They found a small increase in the risk for heart defects in children with exposure to zidovudine. They also found an association between efavirenz exposure and a small increase in neurological defects, but only when using the MACDP classification system. The authors found no association between other antiretroviral drugs, including nevirapine (acting similar to efavirenz); tenofovir, stavudine, and abacavir (all three acting similar to zidovudine); and lopinavir and ritonavir (proteinase inhibitors) and any type of birth defect.
What Do These Findings Mean?
These findings show that, overall, the risks of birth defects in children exposed to antiretroviral drugs in utero are small when considering the clear benefit of preventing mother-to-child transmission of HIV. However, where there are safe and effective alternatives, it might be appropriate to avoid use by pregnant women of those drugs that are associated with elevated risks of birth defects.
Worldwide, a large number of children are exposed to zidovudine in utero, and these results suggest (though cannot prove) that these children may be at a slightly higher risk of heart defects. Current World Health Organization (WHO) guidelines for the prevention of mother-to-child transmission no longer recommend zidovudine for first-line therapy.
The implications of the higher rate of neurological birth defects observed in infants exposed to efavirenz in the first trimester are less clear. The EUROCAT classification excludes minor neurological abnormalities without serious medical consequences, and so the WHO guidelines that stress the importance of careful clinical follow-up of children with exposure to efavirenz seem adequate, based on the findings of this study. The study is limited by the lack of data on the use of additional medication and alcohol and tobacco use, which could have a direct impact on fetal development, and by the absence of data on birth defects and antiretroviral drug exposure from low-income countries. However, the findings of this study overall are reassuring and suggest that apart from zidovudine and possibly efavirenz, other antiretroviral drugs are not associated with birth defects, and their use during pregnancy does not pose a risk to the infant.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001635.
This study is further discussed in a PLOS Medicine Perspective by Mofenson and Watts
The World Health Organization has a webpage on mother-to-child transmission of HIV
The US National Institutes of Health provides links to additional information on mother-to-child transmission of HIV
The Elizabeth Glaser Pediatric AIDS Foundation also has a webpage on mother-to-child transmission
The French Perinatal Cohort has a webpage describing the cohort and its main publications (in French, with a summary in English)
doi:10.1371/journal.pmed.1001635
PMCID: PMC4004551  PMID: 24781315
5.  Quantifying the Number of Pregnancies at Risk of Malaria in 2007: A Demographic Study 
PLoS Medicine  2010;7(1):e1000221.
By combining data from the Malaria Atlas Project with country-specific data, Feiko ter Kuile and colleagues provide the first contemporary global estimates of the annual number of pregnancies at risk of malaria.
Background
Comprehensive and contemporary estimates of the number of pregnancies at risk of malaria are not currently available, particularly for endemic areas outside of Africa. We derived global estimates of the number of women who became pregnant in 2007 in areas with Plasmodium falciparum and P. vivax transmission.
Methods and Findings
A recently published map of the global limits of P. falciparum transmission and an updated map of the limits of P. vivax transmission were combined with gridded population data and growth rates to estimate total populations at risk of malaria in 2007. Country-specific demographic data from the United Nations on age, sex, and total fertility rates were used to estimate the number of women of child-bearing age and the annual rate of live births. Subregional estimates of the number of induced abortions and country-specific stillbirths rates were obtained from recently published reviews. The number of miscarriages was estimated from the number of live births and corrected for induced abortion rates. The number of clinically recognised pregnancies at risk was then calculated as the sum of the number of live births, induced abortions, spontaneous miscarriages, and stillbirths among the population at risk in 2007. In 2007, 125.2 million pregnancies occurred in areas with P. falciparum and/or P. vivax transmission resulting in 82.6 million live births. This included 77.4, 30.3, 13.1, and 4.3 million pregnancies in the countries falling under the World Health Organization (WHO) regional offices for South-East-Asia (SEARO) and the Western-Pacific (WPRO) combined, Africa (AFRO), Europe and the Eastern Mediterranean (EURO/EMRO), and the Americas (AMRO), respectively. Of 85.3 million pregnancies in areas with P. falciparum transmission, 54.7 million occurred in areas with stable transmission and 30.6 million in areas with unstable transmission (clinical incidence <1 per 10,000 population/year); 92.9 million occurred in areas with P. vivax transmission, 53.0 million of which occurred in areas in which P. falciparum and P. vivax co-exist and 39.9 million in temperate regions with P. vivax transmission only.
Conclusions
In 2007, 54.7 million pregnancies occurred in areas with stable P. falciparum malaria and a further 70.5 million in areas with exceptionally low malaria transmission or with P. vivax only. These represent the first contemporary estimates of the global distribution of the number of pregnancies at risk of P. falciparum and P. vivax malaria and provide a first step towards a more informed estimate of the geographical distribution of infection rates and the corresponding disease burden of malaria in pregnancy.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Malaria, a mosquito-borne parasitic disease, is a major global public-health problem. About half of the world's population is at risk of malaria, which kills about one million people every year. Most of these deaths are caused by Plasmodium falciparum, which thrives in tropical and subtropical regions. However, the most widely distributed type of malaria is P. vivax malaria, which also occurs in temperate regions. Most malaria deaths are among young children in sub-Saharan Africa, but pregnant women and their unborn babies are also very vulnerable to malaria. About 10,000 women and 200,000 babies die annually because of malaria in pregnancy, which can cause miscarriages, preterm births, and low-birth-weight births. Over the past decade, a three-pronged approach has been developed to prevent and control malaria in pregnancy. This approach consists of intermittent preventative treatment of pregnant women with antimalarial drugs, the use of insecticide-treated bed nets to protect pregnant women from the bites of infected mosquitoes, and management of malarial illness among pregnant women.
Why Was This Study Done?
This strategy has begun to reduce the burden of malaria among pregnant women and their babies but the resources available for its introduction are very limited in many of the developing countries where malaria is endemic (always present). Policy makers in these countries need to know the number of pregnancies at risk of malaria so that they can use their resources wisely. However, although the World Health Organization recently estimated that more than 30 million African women living in malaria endemic areas become pregnant and are at risk for malaria each year, there are no comprehensive and contemporary estimates of the number of pregnancies at risk of malaria for endemic areas outside Africa. In this study, the researchers derive global estimates of the number of women who became pregnant in 2007 in areas with P. falciparum and P. vivax transmission.
What Did the Researchers Do and Find?
The researchers estimated the sizes of populations at risk of malaria in 2007 by combining maps of the global limits of P. vivax and P. falciparum transmission with data on population densities. They used data from various sources to calculate the annual number of pregnancies (the sum of live births, induced abortions, miscarriages, and still births) in each country. Finally, they calculated the annual number of pregnancies at risk of malaria in each country by multiplying the number of pregnancies in the entire country by the fraction of the population living within the spatial limits of malaria transmission in that country. In 2007, they calculate, 125.2 million pregnancies occurred in areas with P. falciparum and/or P. vivax transmission. These pregnancies—60% of all pregnancies globally—resulted in 82.6 million live births. 77.4 million at-risk pregnancies occurred in Southeast Asia and the Western Pacific (India had the most pregnancies at risk of both P. falciparum and P. vivax malaria), 30.3 million in Africa, 13.1 million in Europe and the Eastern Mediterranean, and 4.3 million in the Americas. 54.7 million at-risk pregnancies occurred in regions with stable P. falciparum transmission (more than one case of malaria per 10,000 people per year), whereas 70.5 million occurred in areas with low malaria transmission or P. vivax transmission only.
What Do These Findings Mean?
These findings are the first contemporary estimates of the global distribution of the number of pregnancies at risk of P. falciparum and P. vivax malaria. They do not provide any information on the actual incidence of malaria during pregnancy or the health burden on mothers and unborn babies. They simply represent “any risk” of exposure. So, for example, the researchers calculate that only about 5,000 actual malaria infections may occur annually among the 70.5 million at-risk pregnancies in areas with very low malaria transmission or with P. vivax transmission only. Furthermore, these findings do not allow for the seasonality of malaria—pregnancies that occur outside of the transmission season may be at no or very low risk of malaria. Nevertheless, the estimates reported in this study are an important first step towards a spatial map of the burden of malaria in pregnancy and should help policy makers allocate resources for research into and control of this important public-health problem.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000221.
Information is available from the World Health Organization on malaria and on malaria in pregnancy (in several languages)
The US Centers for Disease Control and Prevention also provides information on malaria and on malaria in pregnancy (in English and Spanish)
Information is available from the Roll Back Malaria Partnership on all aspects of global malaria control, including information on malaria in pregnancy
The Malaria in Pregnancy Consortium is undertaking research into the prevention and treatment of malaria in pregnancy and also provides a comprehensive bibliographic database of published and unpublished literature relating to malaria in pregnancy
The Malaria Atlas Project provides maps of malaria transmission around the world
MedlinePlus provides links to additional information on malaria (in English and Spanish)
doi:10.1371/journal.pmed.1000221
PMCID: PMC2811150  PMID: 20126256
6.  Reproductive Outcomes Following Ectopic Pregnancy: Register-Based Retrospective Cohort Study 
PLoS Medicine  2012;9(6):e1001243.
Using Scottish national registry data, Sohinee Bhattacharya and colleagues investigate pregnancy outcomes following ectopic pregnancy in comparison to livebirth, miscarriage, or termination in a first pregnancy.
Background
We aimed to compare reproductive outcomes following ectopic pregnancy (EP) versus livebirth, miscarriage, or termination in a first pregnancy.
Methods And Findings
A retrospective cohort study design was used. Scottish national data on all women whose first pregnancy occurred between 1981 and 2000 were linked to records of a subsequent pregnancy. The exposed cohort comprised women with an EP in their first pregnancy. There were three unexposed cohorts: women with livebirth, miscarriage, and termination of their first pregnancies. Any differences in rates of second pregnancy, livebirth, EP, miscarriage, or terminations and complications of a second ongoing pregnancy and delivery were assessed among the different exposure groups. A total of 2,969 women had an initial EP; 667,299 had a livebirth, 39,705 women miscarried, and 78,697 terminated their first pregnancies. Women with an initial EP had an increased chance of another pregnancy within 2 years (adjusted hazard ratio (AHR) 2.76 [95% CI 2.58–2.95]) or after 6 years (AHR 1.57 [95% CI 1.29–1.91]) compared to women with a livebirth. In comparison with women with an initial miscarriage, women who had an EP had a lower chance of a second pregnancy (AHR 0.53 [95% CI 0.50–0.56]). Compared to women with an initial termination, women with an EP had an increased chance of a second pregnancy (AHR 2.38 [95% CI 2.23–2.55]) within 2 years. Women with an initial EP suffered an increased risk of another EP compared to women with a livebirth (AHR 13.0 [95% CI 11.63–16.86]), miscarriage (AHR 6.07 [95% CI 4.83–7.62]), or termination (AHR 12.84 [95% CI 10.07–16.37]). Perinatal complications in a pregnancy following EP were not significantly higher than those in primigravidae or in women with a previous miscarriage or termination.
Conclusion
Women with an initial EP have a lower chance of conception than those who miscarry but an increased risk of a repeat EP in comparison with all three comparison groups. A major limitation of this study was the inability to separate women using contraception from those who were intending to conceive.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
An ectopic pregnancy occurs when the embryo (fertilized egg) implants outside the uterine cavity, usually in the fallopian tubes but sometimes in the cervix, ovaries, or abdomen. The prevalence for this condition is between 1%–2% of all pregnancies, and risk factors are thought to include pelvic infection, smoking, previous pelvic surgery, and use of certain types of intrauterine contraceptive devices. Ectopic pregnancies are potentially life threatening because as the fetus grows, it can lead to tubal rupture and abdominal bleeding—for example, in the UK, ectopic pregnancies are responsible for almost three-quarters of early pregnancy-related deaths. However, due to improvements in early diagnosis, in high income countries, deaths from ectopic pregnancies have become increasingly rare.
Why Was This Study Done?
Having an ectopic pregnancy can have serious implications for future fertility and subsequent pregnancies but to date, there is little information on reproductive outcomes in women who have had an ectopic pregnancy. So in this study, the researchers used a population-based cohort of women in Scotland to examine future reproductive outcomes in women who had an initial ectopic pregnancy and then compare these outcomes to those in women following a successful (live birth) or unsuccessful (miscarriage or termination) intrauterine pregnancy.
What Did The Researchers Do And Find?
The researchers used a national database (The Scottish Morbidity Record) and hospital discharge information to identify women who had ectopic pregnancies, miscarriages, terminations, or on-going pregnancies between 1981–2000. Then, using unique linking identifiers, they were able to examine the outcomes of subsequent pregnancies and conducted a statistical analysis to investigate whether the first pregnancy outcome had any effect on second pregnancy outcomes.
 The researchers found that during the time period studied, in their first pregnancy, 2,969 women had an ectopic pregnancy, 39,705 women miscarried, 78,697 women underwent termination, and the majority, 667,299, gave birth to a live infant. The researchers then found that compared to women with an initial live birth, women with an ectopic pregnancy were 2.76 times more likely to conceive a second pregnancy within two years. However, compared to women whose first pregnancies ended in miscarriage, women with an initial ectopic pregnancy were significantly less likely to conceive a second time but had an increased chance of a second pregnancy within two years compared to women who terminated their first pregnancy. Importantly, the researchers found that women with an initial ectopic pregnancy had a higher risk of a further ectopic pregnancy compared to all the other groups of women. Furthermore, these women had a significantly higher risk of preeclampsia, preterm delivery, and emergency cesarean delivery in their next continuing pregnancy compared to women who had a previous live birth. However, these risks were not significantly higher than women who had an early loss in a first pregnancy.
What Do These Findings Mean?
These findings suggest that women with an initial ectopic pregnancy have a lower chance of conception than those who miscarry and also have an increased risk of a repeat ectopic pregnancy compared to women who experience miscarriage, termination, or a live birth in their first pregnancy. However, as the researchers did not have any information on contraception use, a major limitation of this study is the inability to separate women using contraception from those who were intending to conceive—women who experienced an ectopic pregnancy may not want to conceive again after a traumatic experience rather than being unable to conceive because of tubal damage. However, the results of this study may help doctors to counsel women with an ectopic pregnancy at the time of initial diagnosis and treatment, and in those willing to conceive again, offer follow-up to discuss future fertility and possible risks of subsequent pregnancy. Further research will help to investigate whether the site of ectopic pregnancy affects future reproductive outcomes.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001243.
The American Pregnancy Association and the UK National Health Service (NHS) Choices give information on ectopic pregnancy
The UK nonprofit organization Ectopic Pregnancy Trust provides support for individuals affected by ectopic pregnancy
doi:10.1371/journal.pmed.1001243
PMCID: PMC3378618  PMID: 22723747
7.  Fetal Safety of Macrolides 
Macrolide antibiotics are largely used in pregnancy for different bacterial infections. Their fetal safety has been studied by several groups, yielding opposing results. In particular, there have been studies claiming an association between macrolides and cardiovascular malformations. Exposure in early infancy has been associated with pyloric stenosis and intussusception. This has led to an avoidance in prescribing macrolides to pregnant women in several Scandinavian countries. The Objectives of the present study was to investigate the fetal safety of this class of drug by linking a large administrative database of drug dispensing and pregnancy outcome in Southern Israel. A computerized database of medications dispensed from 1999 to 2009 to all women registered in the Clalit health maintenance organization in southern Israel was linked with two computerized databases containing maternal and infant hospitalization records. Also, medical pregnancy termination data were analyzed. The following confounders were controlled for: maternal age, ethnicity, maternal pregestational diabetes, parity, and the year the mother gave birth or went through medical pregnancy termination. First- and third-trimester exposures to macrolide antibiotics as a group and to individual drugs were analyzed. During the study period there were 105,492 pregnancies among Clalit women that met the inclusion criteria. Of these, 104,380 ended in live births or dead fetuses and 1,112 in abortion due to medical reasons. In the first trimester of pregnancy, 1,033 women were exposed to macrolides. There was no association between macrolides and either major malformations [odds ratio (OR), 1.08; 95% confidence interval (CI), 0.84 to 1.38)] or specific malformations, after accounting for maternal age, parity, ethnicity, prepregnancy diabetes, and year of exposure. During the third trimester of pregnancy, 959 women were exposed to macrolides. There was no association between such exposure and perinatal mortality, low birth weight, low Apgar score, or preterm delivery. Similarly, no associations were demonstrated with pyloric stenosis or intussusception. Use of macrolides in the first trimester of pregnancy is not associated with an increased risk of major malformations. Exposure in the third trimester is not likely to increase neonatal risks for pyloric stenosis or intussusception in a clinically meaningful manner.
doi:10.1128/AAC.01691-12
PMCID: PMC3697347  PMID: 23650169
8.  Pregnancy Outcome Following Gestational Exposure to Fluoroquinolones: a Multicenter Prospective Controlled Study 
Concerns regarding the teratogenicity of fluoroquinolones have resulted in their restricted use during gestation. This is despite an increasing need for their use due to emerging bacterial resistance. The objectives of the present investigation were to evaluate pregnancy and fetal outcomes following maternal exposure to fluoroquinolones and to examine whether in utero exposure to quinolones is associated with clinically significant musculoskeletal dysfunctions. We prospectively enrolled and followed up 200 women exposed to fluoroquinolones (norfloxacin, ciprofloxacin, ofloxacin) during gestation. Pregnancy outcome was compared with that for 200 controls matched for age and for smoking and alcohol consumption habits. Controls were exposed to nonteratogenic, nonembryotoxic antimicrobial agents matched by indication, duration of therapy (±3 days), and trimester of exposure. Rates of major congenital malformations did not differ between the group exposed to quinolones in the first trimester (2.2%) and the control group (2.6%) (relative risk, 0.85; 95% confidence interval, 0.21 to 3.49). Women treated with quinolones had a tendency for an increased rate of therapeutic abortions compared with the rate among women exposed to nonteratogens (relative risk, 4.50; 95% confidence interval, 0.98 to 20.57), resulting in lower live-birth rates (86 versus 94%; P = 0.02). The rates of spontaneous abortions, fetal distress, and prematurity and the birth weight did not differ between the groups. Gross motor developmental milestone achievements did not differ between the children of the mothers in the two groups. We concluded that the use of fluoroquinolones during embryogenesis is not associated with an increased risk of major malformations. There were no clinically significant musculoskeletal dysfunctions in children exposed to fluoroquinolones in utero. The higher rate of therapeutic abortions observed in quinolone-exposed women compared to that for their controls may be secondary to the misperception of a major risk related to quinolone use during pregnancy.
PMCID: PMC105599  PMID: 9624471
9.  Duloxetine and Pregnancy Outcomes: Safety Surveillance Findings 
Background: Duloxetine hydrochloride is approved for the treatment or management of major depressive disorder, generalized anxiety disorder, diabetic peripheral neuropathic pain, chronic musculoskeletal pain, and fibromyalgia in the United States. These conditions affect millions of women, including those of childbearing potential. In pregnancy, pharmacological treatment is justified only if the potential benefits outweigh potential risks to mother and fetus, neonate or infant. There are no adequate and well-controlled studies in pregnant women treated with duloxetine. Post-marketing surveillance is an important tool for the assessment of drug safety in pregnancy in a naturalistic setting.
Objective: Using safety surveillance and spontaneous adverse events reporting databases, to provide pregnancy outcomes statistics as they relate to duloxetine exposure.
Study design and Setting: This was an analysis of pregnancy outcome data captured in Lilly Safety System (LSS) (a safety database for the collection, storage, and reporting of adverse events involving Lilly Products), through October 31 2011 and the FDA Adverse Events Reporting System (AERS) database through September 30 2011. Both databases provided spontaneous reporting data from the time of first duloxetine marketing authorization in 2004; in addition, the LSS Database includes serious adverse event and pregnancy data from clinical trials since the creation of the database in 1983.
Patients: Patients who had received duloxetine during pregnancy and reported pregnancy outcomes.
Main outcome measures: Normal and abnormal pregnancy outcomes. Abnormal outcomes comprised spontaneous abortion, premature/post-term birth, congenital anomaly, perinatal/post-perinatal complication, still birth, and ectopic pregnancy. Descriptive statistics are provided for LSS data. A disproportionality analysis was performed using the Empirical Bayes Geometric Mean (EBGM) for the AERS data. The lower bound of the 90% confidence interval of EBGM (EB05) ≥1 was used as the threshold to determine disproportionality.
Results: In the LSS analysis, 400 pregnancy cases with a known pregnancy outcome were identified. Of the 233 prospectively reported cases, 170 (73%) were spontaneous reports; the remainder were reported from clinical trials (58 [25%]) or post-marketing studies (5 [2%]). In most of these cases (74%), patients received duloxetine for the treatment of depression. Pregnancy outcomes were normal in 143 cases, and abnormal in 90 cases. Abnormal pregnancy outcomes were mainly spontaneous abortions (n=41), post/perinatal conditions (n=25) or premature births (n=19). In patients with abnormal pregnancy outcomes, relevant concomitant medication use and relevant medical history were more frequently reported, compared to those with normal pregnancy outcomes (p<0.05). For the AERS database analysis, EB05 was less than one for all clusters of abnormal pregnancy outcomes; there was no disproportionality of reporting adverse pregnancy outcomes for patients treated with duloxetine versus all other drugs or selected antidepressants.
Conclusion: While limitations of these data are recognized, the information available to date from these two data sources suggest that the frequency of abnormal outcomes reported in duloxetine pregnancy cases is generally consistent with the historic control rates in the general population.
doi:10.7150/ijms.5213
PMCID: PMC3590601  PMID: 23471302
safety surveillance; pregnancy outcomes; birth defects; antidepressants; duloxetine.
10.  Major Radiodiagnostic Imaging in Pregnancy and the Risk of Childhood Malignancy: A Population-Based Cohort Study in Ontario 
PLoS Medicine  2010;7(9):e1000337.
In a record-linkage study, Joel Ray and colleagues examine the association between diagnostic imaging during pregnancy and later childhood cancers.
Background
The association between fetal exposure to major radiodiagnostic testing in pregnancy—computed tomography (CT) and radionuclide imaging—and the risk of childhood cancer is not established.
Methods and Findings
We completed a population-based study of 1.8 million maternal-child pairs in the province of Ontario, from 1991 to 2008. We used Ontario's universal health care–linked administrative databases to identify all term obstetrical deliveries and newborn records, inpatient and outpatient major radiodiagnostic services, as well as all children with a malignancy after birth. There were 5,590 mothers exposed to major radiodiagnostic testing in pregnancy (3.0 per 1,000) and 1,829,927 mothers not exposed. The rate of radiodiagnostic testing increased from 1.1 to 6.3 per 1,000 pregnancies over the study period; about 73% of tests were CT scans. After a median duration of follow-up of 8.9 years, four childhood cancers arose in the exposed group (1.13 per 10,000 person-years) and 2,539 cancers in the unexposed group (1.56 per 10,000 person-years), a crude hazard ratio of 0.69 (95% confidence interval 0.26–1.82). After adjusting for maternal age, income quintile, urban status, and maternal cancer, as well as infant sex, chromosomal or congenital anomalies, and major radiodiagnostic test exposure after birth, the risk was essentially unchanged (hazard ratio 0.68, 95% confidence interval 0.25–1.80).
Conclusions
Although major radiodiagnostic testing is now performed in about 1 in 160 pregnancies in Ontario, the absolute annual risk of childhood malignancy following exposure in utero remains about 1 in 10,000. Since the upper confidence limit of the relative risk of malignancy may be as high as 1.8 times that of an unexposed pregnancy, we cannot exclude the possibility that fetal exposure to CT or radionuclide imaging is carcinogenic.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In industrialized countries, childhood cancer (any form of cancer in a child aged 14 years or under) remains a major cause of death. With the exception of a few known risk factors, such as acquired genetic predisposition to cancer, which accounts for about 10% of all childhood cancers, the etiology of most childhood cancer remains unknown. There is thought to be an association between exposure to ionizing radiation in pregnancy and the subsequent risk of development of cancer in the exposed mother's child, but the evidence base to support this association is conflicting. For example, studies examining maternal exposure to plain radiographs in pregnancy and subsequent childhood cancer are inconsistent. Furthermore, although their use has dramatically increased over the past two decades, little is known about the cancer risk related to certain types of radiodiagnostic tests, such as CT and radionuclide imaging, both of which expose the fetus to considerably higher doses of radiation than plain radiographs administered at the same anatomical level.
Why Was This Study Done?
Many women could be exposed to major radiodiagnostic tests, such as those used in emergency situations, before they are aware that they are pregnant, as almost 50% of pregnancies are unplanned. This situation means that it is important to determine the subsequent cancer risk to any child exposed to maternal radiodiagnostic tests before birth.
What Did the Researchers Do and Find?
The researchers conducted a retrospective population-based cohort study of women who delivered a live infant in Ontario, Canada between April 1, 1992 and March 31, 2008. The basis of the research was an anonymized database for the whole province of Ontario, where universal health care, including prenatal care and radiodiagnostic testing, is available to all residents. Database characteristics allowed the researchers to link maternal radiation exposure (a major radiodiagnostic test performed on the mother up to one day before her delivery date) in a specific (index) pregnancy to a subsequent malignancy in the child. After birth, maternal-infant pairs were only followed up if the infant was delivered at term, weighed 2,500 g or more, and survived for at least 30 days.
The researchers were able to follow up 1,835,517 maternal-child pairs. The overall rate of exposure to major radiodiagnostic testing in pregnancy was 3.0 per 1,000 and occurred at an estimated mean gestational age of 15.7 weeks. A total of four childhood cancers occurred in the exposed group and 2,539 cancers in the unexposed group corresponding to a crude hazard ratio of 0.69, which did not significantly change after adjustments were made for potential confounding factors, such as maternal age, sex, and the presence of any chromosomal or congenital anomalies in the infant. The overall prevalence of childhood cancer following exposure to CT or radionuclide imaging in pregnancy is under 0.07%, giving an incidence rate of 1.13 per 10,000 person-years.
What Do These Findings Mean?
These findings can help inform clinicians and mothers about the risk of childhood malignancy following major radiodiagnostic testing in pregnancy. The absolute risk appears to be low, while the relative risk is not materially higher than that of unexposed controls. However, as the upper confidence limit of the relative risk of malignancy may be a maximum of 1.8 times that of an unexposed pregnancy, the possibility that fetal exposure to CT or radionuclide imaging is carcinogenic cannot be excluded. Because this finding means that a very slight risk may exist, beta hCG testing should continue to be done in all potentially pregnant women before undergoing major radiodiagnostic testing, and lead apron shielding used in all women of reproductive age, whether or not known to be pregnant. In addition, nonradiation-emitting imaging, such as MRI and ultrasonography, should be considered first, when clinically appropriate. However, some pregnant women will still be faced with the decision to undergo CT or nuclear imaging because the test is clinically warranted. The findings of this study suggest that when clinically indicated, major radiodiagnostic testing in pregnancy should be performed, along with brief counseling to help lessen the anxiety experienced by an expectant mother before and after the birth of her child.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000337.
For information for patients and caregivers on radiodiagnostic testing, see The Royal College of Radiologists
The National Cancer Institute provides information about childhood cancer
CureSearch for Children's Cancer provides additional information about research into childhood cancer
doi:10.1371/journal.pmed.1000337
PMCID: PMC2935460  PMID: 20838660
11.  Anti-TNF therapies and pregnancy: outcome of 130 pregnancies in the British Society for Rheumatology Biologics Register 
Annals of the Rheumatic Diseases  2011;70(5):823-826.
Objective
The British Society for Rheumatology Biologics Register (BSRBR) has collected data on adverse events including pregnancies in patients with rheumatoid arthritis treated with anti-tumour necrosis factor (anti-TNF) therapy. The purpose of this report is to summarise the pregnancy outcomes in women treated with anti-TNF in the BSRBR.
Methods
Patients were categorised according to anti-TNF exposure as follows: (1) exposure to anti-TNF and to methotrexate (MTX) and/or leflunomide (LEF) at conception (n=21 pregnancies); (2) exposure to anti-TNF at conception (n=50); (3) exposure to anti-TNF prior to conception (n=59); (4) no exposure to anti-TNF (control group; n=10).
Results
Eighty-eight live births in a total of 130 pregnancies were reported in patients who received anti-TNF before or during pregnancy. The rate of spontaneous abortion was highest among patients exposed to anti-TNF at the time of conception (with MTX/LEF 33% and without MTX/LEF 24%). This compared with 17% spontaneous abortions in those with prior exposure to anti-TNF and 10% spontaneous abortions in the control group. Ten terminations were performed.
Conclusion
Although the results to date have been promising, no firm conclusions can be drawn about the safety of anti-TNF during pregnancy and, without further evidence, guidelines which suggest these drugs should be avoided at the time of conception cannot yet be changed.
doi:10.1136/ard.2010.140822
PMCID: PMC3070273  PMID: 21362710
12.  Observational Cohort Study of Pregnancy Outcome after First-Trimester Exposure to Fluoroquinolones 
Fluoroquinolones are avoided during pregnancy due to developmental toxicity in animals. The aim of this study was to assess the fetal risk after intrauterine fluoroquinolone exposure. We performed an observational study of a prospectively ascertained cohort of pregnant women exposed to a fluoroquinolone during the first trimester. Pregnancy outcomes were compared to those of a cohort exposed to neither fluoroquinolones nor teratogenic or fetotoxic drugs. The outcomes evaluated were major birth defects (structural abnormalities of medical, surgical, or cosmetic relevance), spontaneous abortion, and elective termination of pregnancy. Pregnancy outcomes of 949 women with fluoroquinolone treatment were compared with those of 3,796 nonexposed controls. Neither the rate of major birth defects (2.4%; adjusted odds ratio [ORadj], 0.91; 95% confidence interval [CI], 0.6 to 1.5) nor the risk of spontaneous abortion (adjusted hazard ratio [HRadj], 1.01; 95% CI, 0.8 to 1.3) was increased. However, there was a nonsignificant increase in major birth defects after exposure to moxifloxacin (6/93, 6.5%; crude odds ratio [ORcrude], 2.40; 95% CI, 0.8 to 5.6). Neither a critical exposure time window within the first trimester nor a specific pattern of birth defects was demonstrated for any of the fluoroquinolones. The rate of electively terminated pregnancies was increased among the fluoroquinolone-exposed women (HRadj, 1.32; 95% CI, 1.03 to 1.7). The gestational ages at delivery and birth weights did not differ between groups. Our study did not detect an increased risk of spontaneous abortion or major birth defects. These reassuring findings support the recommendation to allow fluoroquinolone use in early pregnancy in selected cases. After the use of moxifloxacin, a detailed fetal ultrasound examination should be considered.
doi:10.1128/AAC.02413-14
PMCID: PMC4136025  PMID: 24841264
13.  Pregnancy and Fetal Outcomes After Exposure to Mefloquine in the Pre- and Periconception Period and During Pregnancy 
Pregnant women who travel to malarious areas and their clinicians need data on the safety of malaria chemoprophylaxis. The drug safety database analysis of mefloquine exposure in pregnancy showed that the birth defect prevalence and fetal loss in maternal, prospectively-monitored cases were comparable to background rates.
Background. Pregnant women who travel to malarious areas and their clinicians need data on the safety of malaria chemoprophylaxis.
Methods. The effect of exposure to mefloquine on pregnancy and offspring outcomes was evaluated using the F. Hoffmann–La Roche global drug safety database for the time frame 31 January 1986 through 26 October 2010. We investigated pregnancy and fetal outcomes in maternal, paternal, and both-parent exposure cases with a focus on congenital malformations and fetal loss. The main outcome measures were birth defect prevalence and types of malformations.
Results. A total of 2506 cases of mefloquine exposure during pregnancy or in the pre- and periconception period were evaluated. Most cases were maternal prospective (outcome of the pregnancy unknown at the time of reporting; n = 2246 [89.6%]) followed by maternal retrospective cases (outcome of the pregnancy known at the time of reporting; n = 227 [9.0%]), with small numbers of paternal and both-parent exposure cases. Of the total 2246 mefloquine maternal prospective exposures (95.2%), 2139 occurred before conception and/or during the first trimester. Of 1383 maternal prospective cases with known outcome, 978 (70.7%) resulted in delivery, 405 (29.3%) resulted in abortion (112 spontaneous, 293 therapeutic), and 43 resulted in birth defects, corresponding to a birth defect prevalence of 4.39% (43 of 978). Prospective cases overall showed no specific pattern of birth malformations.
Conclusions. The drug safety database analysis of mefloquine exposure in pregnancy showed that the birth defect prevalence and fetal loss in maternal, prospectively monitored cases were comparable to background rates.
doi:10.1093/cid/cis215
PMCID: PMC3348951  PMID: 22495078
14.  A Randomised Controlled Trial of Artemether-Lumefantrine Versus Artesunate for Uncomplicated Plasmodium falciparum Treatment in Pregnancy 
PLoS Medicine  2008;5(12):e253.
Background
To date no comparative trials have been done, to our knowledge, of fixed-dose artemisinin combination therapies (ACTs) for the treatment of Plasmodium falciparum malaria in pregnancy. Evidence on the safety and efficacy of ACTs in pregnancy is needed as these drugs are being used increasingly throughout the malaria-affected world. The objective of this study was to compare the efficacy, tolerability, and safety of artemether-lumefantrine, the most widely used fixed ACT, with 7 d artesunate monotherapy in the second and third trimesters of pregnancy.
Methods and Findings
An open-label randomised controlled trial comparing directly observed treatment with artemether-lumefantrine 3 d (AL) or artesunate monotherapy 7 d (AS7) was conducted in Karen women in the border area of northwestern Thailand who had uncomplicated P. falciparum malaria in the second and third trimesters of pregnancy. The primary endpoint was efficacy defined as the P. falciparum PCR-adjusted cure rates assessed at delivery or by day 42 if this occurred later than delivery, as estimated by Kaplan-Meier survival analysis. Infants were assessed at birth and followed until 1 y of life. Blood sampling was performed to characterise the pharmacokinetics of lumefantrine in pregnancy. Both regimens were very well tolerated. The cure rates (95% confidence interval) for the intention to treat (ITT) population were: AS7 89.2% (82.3%–96.1%) and AL 82.0% (74.8%–89.3%), p = 0.054 (ITT); and AS7 89.7% (82.6%–96.8%) and AL 81.2% (73.6%–88.8%), p = 0.031 (per-protocol population). One-third of the PCR-confirmed recrudescent cases occurred after 42 d of follow-up. Birth outcomes and infant (up to age 1 y) outcomes did not differ significantly between the two groups. The pharmacokinetic study indicated that low concentrations of artemether and lumefantrine were the main contributors to the poor efficacy of AL.
Conclusion
The current standard six-dose artemether-lumefantrine regimen was well tolerated and safe in pregnant Karen women with uncomplicated falciparum malaria, but efficacy was inferior to 7 d artesunate monotherapy and was unsatisfactory for general deployment in this geographic area. Reduced efficacy probably results from low drug concentrations in later pregnancy. A longer or more frequent AL dose regimen may be needed to treat pregnant women effectively and should now be evaluated. Parasitological endpoints in clinical trials of any antimalarial drug treatment in pregnancy should be extended to delivery or day 42 if it comes later.
Trial Registration: Current Controlled Trials ISRCTN86353884
Rose McGready and colleagues show that an artemether-lumefantrine regimen is well tolerated and safe in pregnant Karen women with uncomplicated falciparum malaria, but efficacy is inferior to artesunate, probably because of low drug concentrations in later pregnancy.
Editors' Summary
Background.
Plasmodium falciparum, a mosquito-borne parasite that causes malaria, kills nearly one million people every year. Although most deaths occur among young children, malaria during pregnancy is also an important public-health problem. In areas where malaria transmission is high (stable transmission), women acquire a degree of immunity. Although less symptomatic than women who lack natural protection, their babies are often small and sickly because malaria-related anemia (lack of red blood cells) and parasites in the placenta limit the nutrients supplied to the baby before birth. By contrast, in areas where malaria transmission is low (unstable transmission or sporadic outbreaks), women have little immunity to P. falciparum. If these women become infected during pregnancy, “uncomplicated” malaria (fever, chills, and anemia) can rapidly progress to “severe” malaria (in which vital organs are damaged), which can be fatal to the mother and/or her unborn child unless prompt and effective treatment is given.
Why Was This Study Done?
Malaria parasites are now resistant to many of the older antimalarial drugs (for example, quinine). So, since 2006, the World Health Organization (WHO) has recommended that uncomplicated malaria during the second and third trimester of pregnancy is treated with short course (3 d) fixed-dose artemisinin combination therapy (ACT; quinine is still used in early pregnancy because it is not known whether ACT damages fetal development, which mainly occurs during the first 3 mo of pregnancy). Artemisinin derivatives are fast-acting antimalarial agents that are used in combination with another antimalarial drug to reduce the chances of P. falciparum becoming resistant to either drug. The most widely used fixed-dose ACT is artemether–lumefantrine (AL) but, although several trials have examined the safety and efficacy of this treatment in non-pregnant women, little is known about how well it works in pregnant women. In this study, the researchers compare the efficacy, tolerability, and safety of AL with a 7-d course of artesunate monotherapy (AS7; another artemisinin derivative) in the treatment of uncomplicated malaria in pregnancy in northwest Thailand, an area with unstable but highly drug resistant malaria transmission.
What Did the Researchers Do and Find?
The researchers enrolled 253 women with uncomplicated malaria during the second and third trimesters of pregnancy into their open-label trial (a trial in which the patients and their health-care workers know who is receiving which drug regimen). Half the women received each type of treatment. The trial's main outcome was the “PCR-adjusted cure rate” at delivery or 42 d after treatment if this occurred after delivery. This cure rate was assessed by examining blood smears for parasites and then using a technique called PCR to determine which cases of malaria were new infections (classified as treatment successes along with negative blood smears) and which were recurrences of an old infection (classified as treatment failures). The PCR-adjusted cure rates were 89.7% and 81.2% for AS7 and AL, respectively. Both treatments were well tolerated, few side effects were seen with either treatment, and infant health and development at birth and up to 1 y old were similar with both regimens. Finally, an analysis of blood samples taken 7 d after treatment with AL showed that blood levels of lumefantrine were below those previously associated with treatment failure in about a third of the women tested.
What Do These Findings Mean?
Although these findings indicate that the AL regimen is a well tolerated and safe treatment for uncomplicated malaria in pregnant women living in northwest Thailand, the efficacy of this treatment was lower than that of artesunate monotherapy. In fact, neither treatment reached the 90% cure rate recommended by WHO for ACTs and it is likely that cure rates in a more realistic situation (that is, not in a trial where efforts are made to make sure everyone completes their treatment) would be even lower. The findings also suggest that the reduced efficacy of the AL regimen in pregnant women compared to the efficacy previously seen in non-pregnant women may be caused by lower drug blood levels during pregnancy. Thus, a higher-dose AL regimen (or an alternative ACT) may be needed to successfully treat uncomplicated malaria during pregnancy.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050253.
The MedlinePlus encyclopedia contains a page on malaria (in English and Spanish)
Information is available from the World Health Organization on malaria (in several languages), and their 2006 Guidelines for the Treatment of Malaria includes specific recommendations for the treatment of pregnant women
The US Centers for Disease Control and Prevention provide information on malaria and on malaria during pregnancy (in English and Spanish)
Information is available from the Roll Back Malaria Partnership on malaria during pregnancy, on artemisinin-based combination therapies, and on malaria in Thailand
doi:10.1371/journal.pmed.0050253
PMCID: PMC2605900  PMID: 19265453
15.  In Vitro Fertilization and Multiple Pregnancies 
Executive Summary
Objective
The objective of this health technology policy assessment was to determine the clinical effectiveness and cost-effectiveness of IVF for infertility treatment, as well as the role of IVF in reducing the rate of multiple pregnancies.
Clinical Need: Target Population and Condition
Typically defined as a failure to conceive after a year of regular unprotected intercourse, infertility affects 8% to 16% of reproductive age couples. The condition can be caused by disruptions at various steps of the reproductive process. Major causes of infertility include abnormalities of sperm, tubal obstruction, endometriosis, ovulatory disorder, and idiopathic infertility. Depending on the cause and patient characteristics, management options range from pharmacologic treatment to more advanced techniques referred to as assisted reproductive technologies (ART). ART include IVF and IVF-related procedures such as intra-cytoplasmic sperm injection (ICSI) and, according to some definitions, intra-uterine insemination (IUI), also known as artificial insemination. Almost invariably, an initial step in ART is controlled ovarian stimulation (COS), which leads to a significantly higher rate of multiple pregnancies after ART compared with that following natural conception. Multiple pregnancies are associated with a broad range of negative consequences for both mother and fetuses. Maternal complications include increased risk of pregnancy-induced hypertension, pre-eclampsia, polyhydramnios, gestational diabetes, fetal malpresentation requiring Caesarean section, postpartum haemorrhage, and postpartum depression. Babies from multiple pregnancies are at a significantly higher risk of early death, prematurity, and low birth weight, as well as mental and physical disabilities related to prematurity. Increased maternal and fetal morbidity leads to higher perinatal and neonatal costs of multiple pregnancies, as well as subsequent lifelong costs due to disabilities and an increased need for medical and social support.
The Technology Being Reviewed
IVF was first developed as a method to overcome bilateral Fallopian tube obstruction. The procedure includes several steps: (1) the woman’s egg is retrieved from the ovaries; (2) exposed to sperm outside the body and fertilized; (3) the embryo(s) is cultured for 3 to 5 days; and (4) is transferred back to the uterus. IFV is considered to be one of the most effective treatments for infertility today. According to data from the Canadian Assisted Reproductive Technology Registry, the average live birth rate after IVF in Canada is around 30%, but there is considerable variation in the age of the mother and primary cause of infertility.
An important advantage of IVF is that it allows for the control of the number of embryos transferred. An elective single embryo transfer in IVF cycles adopted in many European countries was shown to significantly reduce the risk of multiple pregnancies while maintaining acceptable birth rates. However, when number of embryos transferred is not limited, the rate of IVF-associated multiple pregnancies is similar to that of other treatments involving ovarian stimulation. The practice of multiple embryo transfer in IVF is often the result of pressures to increase success rates due to the high costs of the procedure. The average rate of multiple pregnancies resulting from IVF in Canada is currently around 30%.
An alternative to IVF is IUI. In spite of reported lower success rates of IUI (pregnancy rates per cycle range from 8.7% to 17.1%) it is generally attempted before IVF due to its lower invasiveness and cost.
Two major drawbacks of IUI are that it cannot be used in cases of bilateral tubal obstruction and it does not allow much control over the risk of multiple pregnancies compared with IVF. The rate of multiple pregnancies after IUI with COS is estimated to be about 21% to 29%.
Ontario Health Insurance Plan Coverage
Currently, the Ontario Health Insurance Plan covers the cost of IVF for women with bilaterally blocked Fallopian tubes only, in which case it is funded for 3 cycles, excluding the cost of drugs. The cost of IUI is covered except for preparation of the sperm and drugs used for COS.
Diffusion of Technology
According to Canadian Assisted Reproductive Technology Registry data, in 2004 there were 25 infertility clinics across Canada offering IVF and 7,619 IVF cycles performed. In Ontario, there are 13 infertility clinics with about 4,300 IVF cycles performed annually.
Literature Review
Royal Commission Report on Reproductive Technologies
The 1993 release of the Royal Commission report on reproductive technologies, Proceed With Care, resulted in the withdrawal of most IVF funding in Ontario, where prior to 1994 IVF was fully funded. Recommendations of the Commission to withdraw IVF funding were largely based on findings of the systematic review of randomized controlled trials (RCTs) published before 1990. The review showed IVF effectiveness only in cases of bilateral tubal obstruction. As for nontubal causes of infertility, there was not enough evidence to establish whether IVF was effective or not.
Since the field of reproductive technology is constantly evolving, there have been several changes since the publication of the Royal Commission report. These changes include: increased success rates of IVF; introduction of ICSI in the early 1990’s as a treatment for male factor infertility; and improved embryo implantation rates allowing for the transfer of a single embryo to avoid multiple pregnancies after IVF.
Studies After the Royal Commission Report: Review Strategy
Three separate literature reviews were conducted in the following areas: clinical effectiveness of IVF, cost-effectiveness of IVF, and outcomes of single embryo transfer (SET) in IVF cycles.
Clinical effectiveness of IVF: RCTs or meta-analyses of RCTs that compared live birth rates after IVF versus alternative treatments, where the cause of infertility was clearly stated or it was possible to stratify the outcome by the cause of infertility.
Cost effectiveness of IVF: All relevant economic studies comparing IVF to alternative methods of treatment were reviewed
Outcomes of IVF with SET: RCTs or meta-analyses of RCTs that compared live birth rates and multiple birth rates associated with transfer of single versus double embryos.
OVID MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Cochrane Library, the International Agency for Health Technology Assessment database, and websites of other health technology assessment agencies were searched using specific subject headings and keywords to identify relevant studies.
Summary of Findings
Comparative Clinical Effectiveness of IVF
Overall, there is a lack of well composed RCTs in this area and considerable diversity in both definition and measurement of outcomes exists between trials. Many studies used fertility or pregnancy rates instead of live birth rates. Moreover, the denominator for rate calculation varied from study to study (e.g. rates were calculated per cycle started, per cycle completed, per couple, etc...).
Nevertheless, few studies of sufficient quality were identified and categorized by the cause of infertility and existing alternatives to IVF. The following are the key findings:
A 2005 meta-analysis demonstrated that, in patients with idiopathic infertility, IVF was clearly superior to expectant management, but there were no statistically significant differences in live birth rates between IVF and IUI, nor between IVF and gamete-intra-Fallopian transfer.
A subset of data from a 2000 study showed no significant differences in pregnancy rates between IVF and IUI for moderate male factor infertility.
In patients with moderate male factor infertility, standard IVF was also compared with ICSI in a 2002 meta-analysis. All studies included in the meta-analysis showed superior fertilization rates with ICSI, and the pooled risk ratio for oocyte fertilization was 1.9 (95% Confidence Interval 1.4-2.5) in favour of ICSI. Two other RCTs in this area published after the 2002 meta-analysis had similar results and further confirmed these findings. There were no RCTs comparing IVF with ICSI in patients with severe male factor infertility, mainly because based on the expert opinion, ICSI might only be an effective treatment for severe male factor infertility.
Cost-Effectiveness of IVF
Five economic evaluations of IVF were found, including one comprehensive systematic review of 57 health economic studies. The studies compared cost-effectiveness of IVF with a number of alternatives such as observation, ovarian stimulation, IUI, tubal surgery, varicocelectomy, etc... The cost-effectiveness of IVF was analyzed separately for different types of infertility. Most of the reviewed studies concluded that due to the high cost, IVF has a less favourable cost-effectiveness profile compared with alternative treatment options. Therefore, IVF was not recommended as the first line of treatment in the majority of cases. The only two exceptions were bilateral tubal obstruction and severe male factor infertility, where an immediate offer of IVF/ICSI might the most cost-effective option.
Clinical Outcomes After Single Versus Double Embryo Transfer Strategies of IVF
Since the SET strategy has been more widely adopted in Europe, all RCT outcomes of SET were conducted in European countries. The major study in this area was a large 2005 meta-analysis, followed by two other published RCTs.
All of these studies reached similar conclusions:
Although a single SET cycle results in lower birth rates than a single double embryo transfer (DET) cycle, the cumulative birth rate after 2 cycles of SET (fresh + frozen-thawed embryos) was comparable to the birth rate after a single DET cycle (~40%).
SET was associated with a significant reduction in multiple births compared with DET (0.8% vs. 33.1% respectively in the largest RCT).
Most trials on SET included women younger than 36 years old with a sufficient number of embryos available for transfer that allowed for selection of the top quality embryo(s). A 2006 RCT, however, compared SET and DET strategies in an unselected group of patients without restrictions on the woman’s age or embryo quality. This study demonstrated that SET could be applied to older women.
Estimate of the Target Population
Based on results of the literature review and consultations with experts, four categories of infertile patients who may benefit from increased access to IVF/ICSI were identified:
Patients with severe male factor infertility, where IVF should be offered in conjunction with ICSI;
Infertile women with serious medical contraindications to multiple pregnancy, who should be offered IVF-SET;
Infertile patients who want to avoid the risk of multiple pregnancy and thus opt for IVF-SET; and
Patients who failed treatment with IUI and wish to try IVF.
Since, however, the latter indication does not reflect any new advances in IVF technology that would alter existing policy, it was not considered in this analysis.
Economic Analysis
Economic Review: Cost–Effectiveness of SET Versus DET
Conclusions of published studies on cost-effectiveness of SET versus DET were not consistent. While some studies found that SET strategy is more cost-effective due to avoidance of multiple pregnancies, other studies either did not find any significant differences in cost per birth between SET and DET, or favoured DET as a more cost-effective option.
Ontario-Based Economic Analysis
An Ontario-based economic analysis compared cost per birth using three treatment strategies: IUI, IVF-SET, and IVF-DET. A decision-tree model assumed three cycles for each treatment option. Two separate models were considered; the first included only fresh cycles of IVF, while the second had a combination of fresh and frozen cycles. Even after accounting for cost-savings due to avoidance of multiple pregnancies (only short-term complications), IVF-SET was still associated with a highest cost per birth. The approximate budget impact to cover the first three indications for IVF listed above (severe male factor infertility, women with medical contraindications to multiple pregnancy, and couples who wish to avoid the risk of multiple pregnancy) is estimated at $9.8 to $12.8 million (Cdn). Coverage of only first two indications, namely, ICSI in patients with severe male factor infertility and infertile women with serious medical contraindications to multiple pregnancy, is estimated at $3.8 to $5.5 million Cdn.
Other Considerations
International data shows that both IVF utilization and the average number of embryos transferred in IVF cycles are influenced by IVF funding policy. The success of the SET strategy in European countries is largely due to the fact that IVF treatment is subsidized by governments.
Surveys of patients with infertility demonstrated that a significant proportion (~40%) of patients not only do not mind having multiple babies, but consider twins being an ideal outcome of infertility treatment.
A women’s age may impose some restrictions on the implementation of a SET strategy.
Conclusions and Recommendations
A review of published studies has demonstrated that IVF-SET is an effective treatment for infertility that avoids multiple pregnancies.
However, results of an Ontario-based economic analysis shows that cost savings associated with a reduction in multiple pregnancies after IVF-SET does not justify the cost of universal IVF-SET coverage by the province. Moreover, the province currently funds IUI, which has been shown to be as effective as IVF for certain types of infertility and is significantly less expensive.
In patients with severe male factor infertility, IVF in conjunction with ICSI may be the only effective treatment.
Thus, 2 indications where additional IVF access should be considered include:
IVF/ICSI for patients with severe male factor infertility
IVF-SET in infertile women with serious medical contraindications to multiple pregnancy
PMCID: PMC3379537  PMID: 23074488
16.  Final results from the Betaseron (interferon β-1b) Pregnancy Registry: a prospective observational study of birth defects and pregnancy-related adverse events 
BMJ Open  2014;4(5):e004536.
Objective
Women with multiple sclerosis are often diagnosed and treated during their reproductive years. Limited data are available on the safety of treatment during pregnancy. The Betaseron Pregnancy Registry prospectively monitored women exposed to interferon β-1b (IFNβ-1b) during pregnancy to estimate the rates of birth defects, spontaneous abortions (SABs) and other negative outcomes in this population.
Design
From 2006 to 2011, this observational registry enrolled women exposed prior to conception or during pregnancy (but prior to or without abnormalities on prenatal screening). Follow-up continued from enrolment through the 4-month paediatric visit.
Setting
Patients in the USA who met these criteria were enrolled in the registry.
Results
The registry enrolled 99 pregnant women; 3 were lost to follow-up. The earliest exposure to IFNβ-1b occurred during the first trimester for 95 pregnancies and in the third trimester for 1 pregnancy. There were 99 birth outcomes (3 twins), including 86 (86.9%) live births, 11 (11.1%) SABs and 2 (2%) stillbirths. Birth defects were reported in five (5.1%) cases. Rates of birth defects and SAB were not significantly different from population comparators. No developmental concerns were identified at the 4-month paediatric visit.
Conclusions
The small sample size limits the ability to draw definitive conclusions; however, there was no pattern to suggest increased negative outcomes with IFNβ-1b.
Clinical trials registration number
NCT00317564.
doi:10.1136/bmjopen-2013-004536
PMCID: PMC4025462  PMID: 24821713
interferon beta-1b; pediatrics; pregnancy; congenital abnormalities
17.  Use of Tamoxifen Before and During Pregnancy 
The Oncologist  2011;16(11):1547-1551.
The outcomes of pregnancies in women taking tamoxifen before conception and during pregnancy are reviewed. Because of potential confounding, a causal relationship between treatment with tamoxifen and adverse pregnancy outcome cannot be established. However, the high frequency of severe congenital abnormalities indicates that reliable birth control during tamoxifen therapy is mandatory.
For premenopausal patients with receptor-positive early breast cancer, administration of tamoxifen for 5 years constitutes the main adjuvant endocrine therapy. During pregnancy, tamoxifen and its metabolites interact with rapidly growing and developing embryonic or fetal tissues.
Information about tamoxifen and pregnancy was gathered by searching PubMed. In addition, we had access to the records of the pharmaceutical company AstraZeneca. Because these observations are retrospective and other therapies and diagnostic measures are possible confounders, a causal relationship was not established between tamoxifen treatment and pregnancy outcome.
The records from AstraZeneca documented three live births with congenital anomalies and four live births without congenital anomalies related to tamoxifen treatment before pregnancy. Tamoxifen therapy during pregnancy resulted in 16 live births with congenital malformations and a total of 122 live births without malformations. The 122 live births without malformations included 85 patients from a prevention trial that did not record a single anomaly, whereas the AstraZeneca Safety Database alone reported 11 babies with congenital malformations of 44 live births. Additionally, there were: 12 spontaneous abortions, 17 terminations of pregnancy without known fetal defects, six terminations of pregnancy with fetal defects, one stillbirth without fetal defects, two stillbirths with fetal defects, and 57 unknown outcomes.
The relatively high frequency of severe congenital abnormalities indicates that reliable birth control during tamoxifen treatment is mandatory. After tamoxifen use, a washout period of 2 months is advisable based on the known half-life of tamoxifen. In case of an inadvertent pregnancy, risks and options should be discussed.
doi:10.1634/theoncologist.2011-0121
PMCID: PMC3233288  PMID: 22020212
18.  Pregnancy Outcomes in HIV-Infected Women Receiving Long-Term Isoniazid Prophylaxis for Tuberculosis and Antiretroviral Therapy 
Objective. While 6- to 12-month courses of isoniazid for tuberculosis prevention are considered safe in pregnant women, the effects of longer-term isoniazid prophylaxis or isoniazid in combination with antiretroviral therapy (ART) are not established in human-immunodeficiency-virus-(HIV-) infected women who experience pregnancy during the course of therapy. Design. Nested study of pregnancy outcomes among HIV-infected women participating in a placebo-controlled, TB-prevention trial using 36 months daily isoniazid. Pregnancy outcomes were collected by interview and record review. Results. Among 196 pregnant women, 103 (52.6%) were exposed to isoniazid during pregnancy; all were exposed to antiretroviral drugs. Prior to pregnancy they had received a median of 341 days (range 1–1095) of isoniazid. We observed no isoniazid-associated hepatitis or other severe isoniazid-associated adverse events in the 103 women. Pregnancy outcomes were 132 term live births, 42 premature births, 11 stillbirths, 8 low birth weight, 6 spontaneous abortions, 4 neonatal deaths, and 1 congenital abnormality. In a multivariable model, neither isoniazid nor ART exposure during pregnancy was significantly associated with adverse pregnancy outcome (adjusted odds ratios 0.6, 95% CI: 0.3–1.1 and 1.8, 95% CI 0.9–3.6, resp.). Conclusions. Long-term isoniazid prophylaxis was not associated with adverse pregnancy outcomes, such as preterm delivery, even in the context of ART exposure.
doi:10.1155/2013/195637
PMCID: PMC3606726  PMID: 23533318
19.  Cesarean Section and Rate of Subsequent Stillbirth, Miscarriage, and Ectopic Pregnancy: A Danish Register-Based Cohort Study 
PLoS Medicine  2014;11(7):e1001670.
Louise Kenny and colleagues conduct a population-based cohort study in Denmark to assess the likelihood of stillbirth, miscarriage, and ectopic pregnancy following cesarean section compared to women who gave birth by vaginal delivery.
Please see later in the article for the Editors' Summary
Background
With cesarean section rates increasing worldwide, clarity regarding negative effects is essential. This study aimed to investigate the rate of subsequent stillbirth, miscarriage, and ectopic pregnancy following primary cesarean section, controlling for confounding by indication.
Methods and Findings
We performed a population-based cohort study using Danish national registry data linking various registers. The cohort included primiparous women with a live birth between January 1, 1982, and December 31, 2010 (n = 832,996), with follow-up until the next event (stillbirth, miscarriage, or ectopic pregnancy) or censoring by live birth, death, emigration, or study end. Cox regression models for all types of cesarean sections, sub-group analyses by type of cesarean, and competing risks analyses for the causes of stillbirth were performed. An increased rate of stillbirth (hazard ratio [HR] 1.14, 95% CI 1.01, 1.28) was found in women with primary cesarean section compared to spontaneous vaginal delivery, giving a theoretical absolute risk increase (ARI) of 0.03% for stillbirth, and a number needed to harm (NNH) of 3,333 women. Analyses by type of cesarean section showed similarly increased rates for emergency (HR 1.15, 95% CI 1.01, 1.31) and elective cesarean (HR 1.11, 95% CI 0.91, 1.35), although not statistically significant in the latter case. An increased rate of ectopic pregnancy was found among women with primary cesarean overall (HR 1.09, 95% CI 1.04, 1.15) and by type (emergency cesarean, HR 1.09, 95% CI 1.03, 1.15, and elective cesarean, HR 1.12, 95% CI 1.03, 1.21), yielding an ARI of 0.1% and a NNH of 1,000 women for ectopic pregnancy. No increased rate of miscarriage was found among women with primary cesarean, with maternally requested cesarean section associated with a decreased rate of miscarriage (HR 0.72, 95% CI 0.60, 0.85). Limitations include incomplete data on maternal body mass index, maternal smoking, fertility treatment, causes of stillbirth, and maternally requested cesarean section, as well as lack of data on antepartum/intrapartum stillbirth and gestational age for stillbirth and miscarriage.
Conclusions
This study found that cesarean section is associated with a small increased rate of subsequent stillbirth and ectopic pregnancy. Underlying medical conditions, however, and confounding by indication for the primary cesarean delivery account for at least part of this increased rate. These findings will assist women and health-care providers to reach more informed decisions regarding mode of delivery.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Globally, increasing numbers of babies are being delivered by cesarean section (a surgical operation in which the baby is delivered through a cut made in the mother's abdomen and womb) instead of naturally through their mother's vagina. In England in 2010, for example, nearly 25% of all babies were delivered by cesarean section (also called C-section) compared to only 2% in the 1950s; in China and some parts of South America cesarean rates are now between 40% and 50%. A cesarean section is usually performed when a vaginal birth would endanger the life of the mother or her unborn child because, for example, the baby is in the wrong position. Some cesareans are performed as emergency procedures, but others are planned in advance when the need for the operation becomes clear during pregnancy (an elective cesarean). Some planned cesarean sections are also undertaken because the mother has requested a cesarean delivery in the absence of any medical reasons for such a delivery.
Why Was This Study Done?
Cesarean sections save lives but do they have any negative impacts on the outcome of subsequent pregnancies? With so many cesarean sections being undertaken, it is important to be sure that the procedure does not increase the rates of subsequent miscarriage, stillbirth, or ectopic pregnancy. Miscarriage—the loss of a fetus (developing baby) that is unable to survive independently—is the commonest complication of early pregnancy, affecting about one in five women who know they are pregnant. Stillbirth is fetal death after about 20–24 weeks of pregnancy; the exact definition of stillbirth varies between countries. About four million stillbirths occur each year worldwide. Ectopic pregnancy—development of the fetus outside the womb—occurs in 1%–2% of all pregnancies. In this population-based cohort study, the researchers investigate the rates of subsequent stillbirth, miscarriage, and ectopic pregnancy following a cesarean section among women living in Denmark. A population-based cohort study determines the baseline characteristics of the individuals in a population, and then follows the population over time to see whether specific characteristics are associated with specific outcomes.
What Did the Researchers Do and Find?
The researchers obtained data for 832,996 women from Danish national registers about their first live birth (including whether they had a cesarean) then followed the women (again using the registers) until they had a stillbirth, miscarriage, or ectopic pregnancy, or a second live birth. The researchers used these data and statistical models to estimate the risk of stillbirth, miscarriage, and ectopic pregnancy following a cesarean compared to a spontaneous vaginal delivery after controlling for the possibility that the cesarean was performed because of an indication that might increase the risk of a subsequent event (confounding). Women who had had a cesarean had a 14% increased risk of a stillbirth in their next pregnancy compared to women who had had a vaginal delivery, corresponding to an absolute risk increase of 0.03%. In other words, 3,333 women would need to have a cesarean to result in one extra stillbirth in subsequent pregnancy (a “number needed to harm” of 3,333). Compared to vaginal delivery, having a cesarean increased the risk of a subsequent ectopic pregnancy by 9% (an absolute risk increase of 0.1% and a number needed to harm of 1,000) but did not increase the rate of subsequent miscarriages.
What Do These Findings Mean?
These findings show that, among women living in Denmark, cesarean section is associated with a slightly increased rate of subsequent stillbirth and ectopic pregnancy. Part of this increase can be accounted for by underlying medical conditions and by confounding by the indication for the primary cesarean section. The accuracy of these findings may be affected by limitations in the study such as incomplete data on some factors (for example, the smoking history of the mother) that might have affected the risk of stillbirth, miscarriage, and ectopic pregnancy, and by misclassification or underreporting of the study outcomes. Given the global increase in cesarean rates, these findings suggest that cesarean delivery is not associated with an increased rate of subsequent stillbirth, miscarriage, or ectopic pregnancy, an important finding for both expectant mothers and health-care professionals that nonetheless needs to be confirmed in further large-scale studies. Finally, these findings highlight the need for women to consider all their options thoroughly before requesting a cesarean section on non-medical grounds.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001670.
The American Congress of Obstetricians and Gynecologists provides patient fact sheets on cesarean birth, miscarriage, and ectopic pregnancy
The US-based non-profit Nemours Foundation provides information about cesarean sections, miscarriage and stillbirth, and ectopic pregnancy (in English and Spanish)
The UK National Health Service Choices website provides information for patients about cesarean section, miscarriage, stillbirth, and ectopic pregnancy
MedlinePlus provides links to additional resources about cesarean section, miscarriage, stillbirth, and ectopic pregnancy (in English and Spanish)
The UK non-profit organization Healthtalkonline provides personal stories about cesarean delivery, miscarriage, and stillbirth
doi:10.1371/journal.pmed.1001670
PMCID: PMC4077571  PMID: 24983970
20.  Multiple sclerosis and pregnancy: experience from a nationwide database in Germany 
Objective:
The objective of this study was to evaluate exposure to disease-modifying therapies (DMTs) during pregnancy in 335 pregnancies of multiple sclerosis (MS) patients and to further determine whether exclusive breastfeeding of MS mothers has any relevant influence on postpartum relapse rate.
Background:
Only limited data are available on whether DMT exposure during pregnancy affects relapse rate during pregnancy or after birth. Currently, findings on beneficial effect of exclusive breastfeeding on MS disease course are controversially discussed.
Methods:
We enrolled pregnant women with MS who contacted us directly or via their treating physicians to be included in our nationwide MS and pregnancy database.
Results:
We identified 78 pregnancies under interferon-beta (IFNβ) preparations, 41 under glatiramer acetate (GLAT), and 216 pregnancies without DMT exposure during pregnancy. As expected, annualized relapse rate (ARR) decreased continuously during pregnancy in nonexposed mothers (p < 0.001) to then increase after birth. In IFNβ- or GLAT-exposed women this typical pattern was not as obvious. Congenital anomalies were within normal ranges in exposed pregnancies. In total, 170 women were identified who exclusively breastfed (EBF). Significantly reduced postpartum relapse rate during the first 3 months after birth were registered in the EBF group as compared with nonexclusively breastfeeding (NEBF) or nonbreastfeeding women (NBF) women with MS (p < 0.0001). Relapse rate (RR) in the year before pregnancy had been similar throughout all groups. We did not observe any significant differences in RR of NEBF and NBF women.
Conclusion:
Exclusive breastfeeding showed some beneficial effects on postpartum relapse rate in our cohort. Our data support that IFNβ and GLAT do not seem to represent a major teratogenic risk in pregnancy.
doi:10.1177/1756285612453192
PMCID: PMC3437527  PMID: 22973421
breastfeeding; disease-modifying therapy (DMT); relapse rate
21.  Tumor necrosis factor-α inhibitor therapy and fetal risk: A systematic literature review 
Tumor necrosis factor-α inhibitors (anti-TNFs) are effective in the treatment of inflammatory bowel disease (IBD) recalcitrant to conventional medical therapy. As the peak incidence of IBD overlaps with the prime reproductive years, it is crucial to establish pharmacologic regimens for women of childbearing age that achieve effective disease control without posing significant fetal harm. A systematic literature review was performed to identify all human studies with birth outcomes data after maternal exposure to infliximab, adalimumab, or certolizumab pegol within 3 mo of conception or during any trimester of pregnancy. Live births, spontaneous abortions or stillbirths, preterm or premature births, low birth weight or small for gestational age infants, and congenital abnormalities were recorded. Fifty selected references identified 472 pregnancy exposures. The subsequent review includes general information regarding anti-TNF therapy in pregnancy followed by a summary of our findings. The benefits of biologic modalities in optimizing disease control during pregnancy must be weighed against the potential toxicity of drug exposure on the developing fetus. Although promising overall, there is insufficient evidence to prove absolute safety for use of anti-TNFs during pregnancy given the limitations of available data and lack of controlled trials.
doi:10.3748/wjg.v19.i17.2591
PMCID: PMC3645377  PMID: 23674866
Tumor necrosis factor-α inhibitors; Pregnancy; Congenital abnormalities; Safety; Infliximab; Adalimumab; Certolizumab
22.  A Mechanism for the Inhibition of Neural Progenitor Cell Proliferation by Cocaine 
PLoS Medicine  2008;5(6):e117.
Background
Prenatal exposure of the developing brain to cocaine causes morphological and behavioral abnormalities. Recent studies indicate that cocaine-induced proliferation inhibition and/or apoptosis in neural progenitor cells may play a pivotal role in causing these abnormalities. To understand the molecular mechanism through which cocaine inhibits cell proliferation in neural progenitors, we sought to identify the molecules that are responsible for mediating the effect of cocaine on cell cycle regulation.
Methods and Findings
Microarray analysis followed by quantitative real-time reverse transcription PCR was used to screen cocaine-responsive and cell cycle-related genes in a neural progenitor cell line where cocaine exposure caused a robust anti-proliferative effect by interfering with the G1-to-S transition. Cyclin A2, among genes related to the G1-to-S cell cycle transition, was most strongly down-regulated by cocaine. Down-regulation of cyclin A was also found in cocaine-treated human primary neural and A2B5+ progenitor cells, as well as in rat fetal brains exposed to cocaine in utero. Reversing cyclin A down-regulation by gene transfer counteracted the proliferation inhibition caused by cocaine. Further, we found that cocaine-induced accumulation of reactive oxygen species, which involves N-oxidation of cocaine via cytochrome P450, promotes cyclin A down-regulation by causing an endoplasmic reticulum (ER) stress response, as indicated by increased phosphorylation of eIF2α and expression of ATF4. In the developing rat brain, the P450 inhibitor cimetidine counteracted cocaine-induced inhibition of neural progenitor cell proliferation as well as down-regulation of cyclin A.
Conclusions
Our results demonstrate that down-regulation of cyclin A underlies cocaine-induced proliferation inhibition in neural progenitors. The down-regulation of cyclin A is initiated by N-oxidative metabolism of cocaine and consequent ER stress. Inhibition of cocaine N-oxidative metabolism by P450 inhibitors may provide a preventive strategy for counteracting the adverse effects of cocaine on fetal brain development.
Investigating the mechanism of cocaine's effect on fetal brain development, Chun-Ting Lee and colleagues find that down-regulation of cyclin A by a cocaine metabolite inhibits neural proliferation.
Editors' Summary
Background.
Every year, cocaine abuse by mothers during pregnancy exposes thousands of unborn infants (fetuses) to this powerful and addictive stimulant. Maternal cocaine abuse during early pregnancy increases the risk of miscarriage; its use during late pregnancy slows the baby's growth and can trigger premature labor. Babies exposed to cocaine shortly before birth are often irritable and have disturbed sleep patterns. They can also be very sensitive to sound and touch and consequently hard to comfort. These problems usually resolve spontaneously within the first few weeks of life but some permanent birth defects are also associated with frequent cocaine abuse during pregnancy. In particular, babies exposed to cocaine before birth sometimes have small heads—an abnormality that generally indicates a small brain—and, although they usually have normal intelligence, the development of their thinking skills and language is often delayed, and they can have behavioral problems.
Why Was This Study Done?
Exposure to cocaine before birth clearly interferes with some aspects of brain development. More specifically, it reduces the number and position of neurons (the cells that transmit information in the form of electrical impulses around the body) within the brain. All neurons develop from neural progenitor cells, and previous research suggests that cocaine exposure before birth inhibits the proliferation of these cells in the developing brain. It would be useful to understand exactly how cocaine affects neural progenitor cells, because it might then be possible to prevent the drug's adverse effects on brain development. In this study, therefore, the researchers investigate the molecular mechanism that underlies cocaine's effect on neural progenitor cells.
What Did the Researchers Do and Find?
When the researchers investigated the effects of cocaine on AF5 cells (rat neural progenitor cells that grow indefinitely in the laboratory), they found that concentrations of cocaine similar to those measured in fetal brains after maternal drug exposure inhibited the proliferation of AF5 cells by blocking the “G1-to-S transition.” This is a stage that cells have to pass through between each round of cell division (the production of two daughter cells from one parent cell). Next, the researchers showed that cocaine-treated AF5 cells made much less cyclin A2, a protein that controls the G1-to-S transition, than untreated cells. Cocaine also decreased cyclin A2 levels in neural progenitor cells freshly isolated from human fetal brains and in fetal rat brains exposed to the drug while in their mother's womb. Treatment of AF5 cells with a cyclin A2 expression vector (a piece of DNA that directs the production of cyclin A2) counteracted the down-regulation of cyclin A2 and restored AF5 proliferation in the presence of cocaine. Other experiments indicate that the reduction of cyclin A2 by cocaine in AF5 cells involves the accumulation of “reactive oxygen species,” by-products of the breakdown of cocaine by a protein that is a member of a family of proteins called cytochrome P450. Finally, treatment of pregnant rats with cimetidine (which inhibits the action of cytochrome P450) counteracted both the inhibition of neural progenitor cell proliferation and the cyclin A2 down-regulation that cocaine exposure induced in the brains of their unborn pups.
What Do These Findings Mean?
These findings show that the cocaine-induced inhibition of neural progenitor cell proliferation involves, at least in part, interfering with the production (that is, causing down-regulation) of cyclin A2. They also show that this down-regulation is induced by the breakdown of cocaine by cytochrome P450, and that in both a rat cell line and in fetal rats, the cytochrome P450 inhibitor cimetidine (a drug that is already used clinically for stomach problems) can block the adverse effects of cocaine on the proliferation of neural progenitor cells. These findings need to be confirmed in animals more closely related to people than rats, and the long-term effects of cimetidine need to be investigated, in particular its effects on cocaine toxicity. Nevertheless these results raise the possibility that giving cimetidine or other drugs with similar effects to pregnant women who are addicted to cocaine might prevent some of the harm that their drug habit does to their unborn children, although it is not clear whether there is a dosage of cimetidine that might be both safe and adequate for this purpose.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050117.
A PLoS Medicine Perspective article by Steven Hyman further discusses this study
The US National Institute on Drug Abuse provides a fact sheet on cocaine (in English and Spanish)
The UK charity Release provides information and advice to the public and professionals about the law and drugs, including information about cocaine
MedlinePlus also provides a list of links to information about cocaine (in English and Spanish)
The March of Dimes Foundation, a US nonprofit organization for the improvement of child health, provides information about illicit drug use during pregnancy (in English and Spanish)
The Organization of Teratology Information Specialists also provides a fact sheet on cocaine and pregnancy (in English, Spanish, and French)
doi:10.1371/journal.pmed.0050117
PMCID: PMC2504032  PMID: 18593214
23.  Pregnancy outcome and neurodevelopment of children exposed in utero to psychoactive drugs: the Motherisk experience. 
This paper presents an overview of the Motherisk Program data on pregnancy outcome and neurodevelopment of children exposed in utero to selected psychoactive drugs. First, the use of cocaine during pregnancy has been associated with increased risk of spontaneous abortions, abruptio placenta, premature labor, and stillbirth. Twenty-three adopted children exposed in utero to cocaine demonstrated an 8-fold increase in risk for microcephaly compared with controls. Global intelligence quotients (IQ) did not differ between the 2 groups, but the cocaine-exposed children achieved significantly lower scores on the Reynell language test. Second, the long-term neurobehavioral effects of fetal alcohol syndrome (FAS) were studied in 384 children to show that alcohol-induced brain insults, which consist of attention and memory deficits together, and poor adaptability and organization are not attenuated with age. Third, the rates of major malformations in children exposed in utero to fluoxetine, tricyclic antidepressants, and nonteratogenic drugs did not differ or exceed the expected rates in the general population. A 2nd phase of this study established the safety of antidepressants during pregnancy by demonstrating that the mean IQ and language scores are comparable in the 3 groups. A level 2 ultrasonography is recommended in cases of in utero exposure to lithium and carbamazepine because of an increased risk of cardiac malformations and spina bifida, respectively.
PMCID: PMC1188852  PMID: 9183118
24.  The Association of Factor V Leiden and Prothrombin Gene Mutation and Placenta-Mediated Pregnancy Complications: A Systematic Review and Meta-analysis of Prospective Cohort Studies 
PLoS Medicine  2010;7(6):e1000292.
Marc Rodger and colleagues report the results of their systematic review and meta-analysis of prospective cohort studies that estimated the association of maternal factor V Leiden and prothrombin gene mutation carrier status and placenta-mediated pregnancy complications.
Background
Factor V Leiden (FVL) and prothrombin gene mutation (PGM) are common inherited thrombophilias. Retrospective studies variably suggest a link between maternal FVL/PGM and placenta-mediated pregnancy complications including pregnancy loss, small for gestational age, pre-eclampsia and placental abruption. Prospective cohort studies provide a superior methodologic design but require larger sample sizes to detect important effects. We undertook a systematic review and a meta-analysis of prospective cohort studies to estimate the association of maternal FVL or PGM carrier status and placenta-mediated pregnancy complications.
Methods and Findings
A comprehensive search strategy was run in Medline and Embase. Inclusion criteria were: (1) prospective cohort design; (2) clearly defined outcomes including one of the following: pregnancy loss, small for gestational age, pre-eclampsia or placental abruption; (3) maternal FVL or PGM carrier status; (4) sufficient data for calculation of odds ratios (ORs). We identified 322 titles, reviewed 30 articles for inclusion and exclusion criteria, and included ten studies in the meta-analysis. The odds of pregnancy loss in women with FVL (absolute risk 4.2%) was 52% higher (OR = 1.52, 95% confidence interval [CI] 1.06–2.19) as compared with women without FVL (absolute risk 3.2%). There was no significant association between FVL and pre-eclampsia (OR = 1.23, 95% CI 0.89–1.70) or between FVL and SGA (OR = 1.0, 95% CI 0.80–1.25). PGM was not associated with pre-eclampsia (OR = 1.25, 95% CI 0.79–1.99) or SGA (OR 1.25, 95% CI 0.92–1.70).
Conclusions
Women with FVL appear to be at a small absolute increased risk of late pregnancy loss. Women with FVL and PGM appear not to be at increased risk of pre-eclampsia or birth of SGA infants.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The death of a baby at any stage of pregnancy is heartbreaking and, sadly, a quarter of women lose their baby during pregnancy or birth. A pregnancy can go wrong for many reasons but complications that are caused by problems with the placenta affect more than one in 20 pregnancies. The placenta is the organ that links the mother to her baby. It is full of blood vessels that transfer oxygen and nutrients from the mother to her baby and that take carbon dioxide and waste products away from the baby. If the placenta does not circulate blood efficiently between the mother and baby (placental insufficiency), the result can be pregnancy loss (spontaneous miscarriage or still birth), pre-eclampsia (a sudden rise in blood pressure in late pregnancy that is life-threatening for both mother and baby), a small for gestational age pregnancy (the baby does not grow properly during pregnancy), or placental abruption (separation of the placenta from the wall of the womb, a condition that deprives the baby of oxygen and nutrients and can cause severe maternal blood loss).
Why Was This Study Done?
One possible cause of placental insufficiency is inherited thrombophilia, an increased tendency to form blood clots that occurs in more than 10% of people. The commonest inherited thrombophilias are factor V Leiden (FVL) and prothrombin gene mutation (PGM). Comparisons of the frequencies of these thrombophilias in women who have had placenta-mediated pregnancy complications with the frequencies in women who have not had complications (“retrospective case control studies”) have found an association between thrombophilia and pregnancy complications. As a result, doctors sometimes give heparin to women with thrombophilia who have had a poor pregnancy outcome to reduce blood clotting during subsequent pregnancies (anticoagulant therapy). However, a better way to determine whether thrombophilia and pregnancy problems are associated is to recruit groups of women with and without thrombophilia and follow them during pregnancy to see whether they develop complications —“prospective cohort studies.” In this study, the researchers undertake a systematic review (a search that uses predefined criteria to identify all the research on a given topic) and meta-analysis (a statistical method for combining the results of studies) of prospective cohort studies to estimate the risk of placenta-mediated pregnancy complications in women with FVL or PGM.
What Did the Researchers Do and Find?
The researchers identified ten prospective cohort studies that examined the association between FVL/PGM and placenta-mediated pregnancy complications and that met their predefined criteria. In their meta-analysis of these studies, they estimated that the absolute risk of pregnancy loss in women with FVL was 4.2% whereas the absolute risk of pregnancy loss in women without FVL was 3.2%. In other words, women with FVL had a 52% higher risk of pregnancy loss than women without FVL (an odds ratio of 1.52). The absolute increased risk, however, was 1%. There was no significant association (a significant association is one that is unlikely to have occurred by chance) between PGM and pregnancy loss. Similarly, there was no significant association between either of the thrombophilias and pre-eclampsia, small for gestational age pregnancies, or placental abruption. Finally, there was no significant association between either FVL or PGM and the composite outcome of any placenta-mediated pregnancy complication (pregnancy loss, pre-eclampsia, small for gestational age, and placental abruption).
What Do These Findings Mean?
These findings suggest that women with FVL have a small absolute increased risk of pregnancy loss but that neither FVL nor PGM increase a woman's risk of pre-eclampsia or of giving birth to a small for gestational age infant. Although there seems to be no increased risk of pregnancy loss with PGM, more research is needed to confirm this finding and to confirm the lack of an association between thrombophilia and placental abruption. The researchers also warn that all these reassuring findings should be treated cautiously because of variability between the studies in how complications were defined. Importantly, however, these findings suggest that the introduction of anticoagulant therapies for women with thrombophilia and a history of pregnancy complications on the basis of retrospective case control studies might have been premature. Anticoagulant therapy should be considered experimental, therefore, until controlled trials of the approach have been completed.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000292.
Womenshealth.gov, a US Department of Health and Human Services resource, provides information on pregnancy complications
Tommys, a UK charity that funds scientific research into the causes and prevention of miscarriage, premature birth, and stillbirth, has information on problems in pregnancy
The March of Dimes Foundation, a nonprofit organization for pregnancy and baby health, also has information on complications during pregnancy, including a fact sheet on thrombophilias and pregnancy
The US National Alliance for Thrombosis and Thrombophilia has detailed information on thrombophilia and an article on the evolving story of thrombophilia and pregnancy outcomes
doi:10.1371/journal.pmed.1000292
PMCID: PMC2885985  PMID: 20563311
25.  Outcomes related to 4864 pregnancies with exposure to lopinavir/ritonavir (LPV/r) 
Journal of the International AIDS Society  2014;17(4Suppl 3):19613.
Introduction
During pregnancy, LPV/r is a common anchor drug employed to treat the mother's HIV-1 infection in addition to reducing the risk of mother-to-child transmission (MTCT). The National Study of HIV in Pregnancy and Childhood (NSHPC) conducts a comprehensive population-based surveillance of HIV infection in pregnant women exposed to antiretroviral therapy (ART) in the UK and Ireland; in 2003–2012 over a third of pregnancies reported to the NSHPC involved exposure to LPV/r.
Methods
We undertook a retrospective were descriptive analysis of individual NSHPC patient data, using pregnancy as the unit of observation. Clinical outcomes for pregnancies reported by June 2013, where women were exposed to LPV/r and due to deliver between January 2003 and December 2012, are described.
Results
A total of 4864 LPV/r exposed pregnancies in 4118 women were identified. These resulted in 4702 deliveries with 4759 live and 46 stillborn infants. Seventy five percent of women were born in sub-Saharan Africa, 13% in the UK or Ireland. Median maternal age at conception was 30 years. Nine hundred and eighty (20%) pregnancies were conceived while taking LPV/r, with a median duration of LPV/r exposure of 270 days. A total of 3884 (80%) pregnancies initiated LPV/r after conception, with a median duration of LPV/r exposure of 107 days. Viral load (VL) close to delivery was available for 4083/4702 (87%) deliveries, with VL <50 c/mL in 73% and <1000 c/mL in 94% of women. VL by timing of LPV/r initiation is shown in Table 1. Sixty three percent of deliveries were by C-section, of which 62% were classified as elective and 38% as emergency. Among singleton liveborn infants, 13% were born prior to 37 weeks gestation (2.5% <32 weeks) and 15% had birth weight <2500 g (2.3% <1500 g). HIV infection status was available for 4039 (89%) singleton infants. For the periods 2003–2007 and 2008–2012, MTCT rates were 1.1% (95% CI 0.6–1.6) and 0.5% (95% CI 0.2–0.8) respectively. Hundred and thirty four live born children (2.8%) had at least one congenital abnormality reported.
Conclusions
In the NSHPC database, in women exposed to LPV/r during pregnancy in the UK and Ireland, MTCT rates are low and continue to decline, and are similar to rates in the entire NSHPC cohort of women with diagnosed HIV [1]. The congenital abnormality rate is comparable with that reported for the uninfected population in this geographic region.
doi:10.7448/IAS.17.4.19613
PMCID: PMC4224945  PMID: 25394117

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