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1.  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
2.  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
3.  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
4.  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
5.  Changes in Association between Previous Therapeutic Abortion and Preterm Birth in Scotland, 1980 to 2008: A Historical Cohort Study 
PLoS Medicine  2013;10(7):e1001481.
Gordon C. Smith and colleagues used national databases to investigate the association between previous termination of pregnancy and preterm birth in Scotland between 1980 to 2008, and whether the type of procedure was an important factor.
Please see later in the article for the Editors' Summary
Background
Numerous studies have demonstrated that therapeutic termination of pregnancy (abortion) is associated with an increased risk of subsequent preterm birth. However, the literature is inconsistent, and methods of abortion have changed dramatically over the last 30 years. We hypothesized that the association between previous abortion and the risk of preterm first birth changed in Scotland between 1 January 1980 and 31 December 2008.
Methods and Findings
We studied linked Scottish national databases of births and perinatal deaths. We analysed the risk of preterm birth in relation to the number of previous abortions in 732,719 first births (≥24 wk), adjusting for maternal characteristics. The risk (adjusted odds ratio [95% CI]) of preterm birth was modelled using logistic regression, and associations were expressed for a one-unit increase in the number of previous abortions. Previous abortion was associated with an increased risk of preterm birth (1.12 [1.09–1.16]). When analysed by year of delivery, the association was strongest in 1980–1983 (1.32 [1.21–1.43]), progressively declined between 1984 and 1999, and was no longer apparent in 2000–2003 (0.98 [0.91–1.05]) or 2004–2008 (1.02 [0.95–1.09]). A statistical test for interaction between previous abortion and year was highly statistically significant (p<0.001). Analysis of data for abortions among nulliparous women in Scotland 1992–2008 demonstrated that the proportion that were surgical without use of cervical pre-treatment decreased from 31% to 0.4%, and that the proportion of medical abortions increased from 18% to 68%.
Conclusions
Previous abortion was a risk factor for spontaneous preterm birth in Scotland in the 1980s and 1990s, but the association progressively weakened and disappeared altogether by 2000. These changes were paralleled by increasing use of medical abortion and cervical pre-treatment prior to surgical abortion. Although it is plausible that the two trends were related, we could not test this directly as the data on the method of prior abortions were not linked to individuals in the cohort. However, we speculate that modernising abortion methods may be an effective long-term strategy to reduce global rates of preterm birth.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Therapeutic termination of pregnancy is relatively common, with an estimated 40 million procedures performed worldwide every year. Until two decades ago, most terminations were performed as a surgical procedure, but now the majority of terminations are medically induced with a combination of drugs—selective progesterone receptor antagonists, such as mifepristone, and prostaglandins—that cause less damage to the woman's cervix. Although surgical terminations are still performed, nowadays prostaglandins are also used to help prevent damage to the cervix. Protecting the woman's cervix can help to reduce the risk of spontaneous preterm birth (delivery before 37 weeks gestation) in subsequent pregnancies. As many women who have abortions go on to have subsequent births, the widespread use of termination may be a significant factor in the high global rates of preterm delivery.
Why Was This Study Done?
A previous meta-analysis (a study that combines information from several studies) showed that the risk of preterm delivery was higher in women who had had a previous termination compared to women who had not. Based on this meta-analysis, UK guidelines on the care of women requesting a termination currently recommend that they be informed of the increased risk of subsequent preterm birth. However, it is biologically plausible that women undergoing medical termination or current practice for surgical termination (using prostaglandins to protect and prepare the cervix) may not have an increased risk of subsequent preterm delivery, because such approaches may cause less trauma to the cervix than traditional surgical termination. So in this study, the researchers used a large dataset from Scotland with three decades of information about previous terminations and subsequent preterm deliveries to test this possibility.
What Did the Researchers Do and Find?
The researchers linked two national databases—the Scottish Morbidity Record 02 (SMR02), which records the clinical and demographic characteristics and outcomes of all patients giving birth in Scottish maternity hospitals, and the Scottish Stillbirth and Infant Death Survey (SSBIDS), which classifies all perinatal deaths in Scotland. SMR02 data were available from 1980 onwards and also recorded each woman's self-reported total number of previous abortions, and SSBIDS data were available from 1985. Then the researchers used information from NHS National Services Scotland to examine secular trends in terminations over the past few decades, specifically, whether a recorded termination was surgical or medical, and also whether surgical abortion was preceded by cervical preparation.
Using these methods, the researchers identified that there were 757,060 live, singleton first births between 1980 and 2008 and that 56,816 women reported one previous termination, 5,790 women reported two previous terminations, and 822 women reported three previous terminations. In their analysis (adjusted for maternal characteristics) the researchers found that there was an independent association of spontaneous preterm birth, but not induced preterm birth, with previous termination. The researchers calculated that the chance (odds) of spontaneous preterm birth for one, two, and three or more previous abortions was 1.17, 1.51, and 1.64, after adjusting for maternal characteristics, including smoking. Over the time period, the researchers found that the proportion of surgical terminations without use of cervical pre-treatment decreased from 31% in 1992 to 0.4% in 2008, and over the same period the proportion of medical terminations increased from 18% to 68%. These trends are important, because in their analysis by year of delivery, the researchers found that the association between preterm delivery and previous termination was strongest in 1980–1983, progressively declined between 1984 and 1999, and was no longer present from 2000 to 2008.
What Do These Findings Mean?
These findings support the established association between previous termination and preterm delivery. But most importantly, the changes in this association over the past two decades—from strong in 1980–1983 to nonexistent in 2000–2008—a period in which the use of medical termination and pre-treatment of the cervix for surgical termination increased dramatically in Scotland, suggest that surgical termination without cervical pre-treatment is responsible for the increased risk of spontaneous preterm birth: the decrease in the proportion of this procedure over the study period may have led to the disappearance of the established association between previous termination and preterm delivery from 2000 onwards. However, these findings are limited in that the researchers could not directly test whether the two trends were related because they did not have information on the method of previous termination linked to subsequent birth outcome for individual women. However, based on the findings of this study, it is possible that using modern methods of termination of pregnancy (rather than purely surgical methods) could be a factor in reducing global rates of spontaneous preterm delivery in the future.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001481.
Wikipedia gives more information about termination of pregnancy (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
More information is available about the SMR02 dataset used in this study
The World Health Organization gives information on preterm birth
doi:10.1371/journal.pmed.1001481
PMCID: PMC3706322  PMID: 23874161
6.  Short and long term mortality rates associated with first pregnancy outcome: Population register based study for Denmark 1980–2004 
Summary
Background
There is a growing interest in examining death rates associated with different pregnancy outcomes for time periods beyond one year. Previous population studies, however, have failed to control for complete reproductive histories. In this study we seek to eliminate the potential confounding effect of unknown prior pregnancy history by examining mortality rates associated specifically with first pregnancy outcome alone. We also examine differences in mortality rates associated with early abortion and late abortions (after 12 weeks).
Material/Method
Medical records for the entire population of women born in Denmark between 1962 and 1991 and were alive in 1980, were linked to death certificates. Mortality rates associated with first pregnancy outcomes (delivery, miscarriage, abortion, and late abortion) were calculated. Odds ratios examining death rates based on reproductive outcomes, adjusted for age at first pregnancy and year of women’s births, were also calculated.
Results
A total of 463,473 women had their first pregnancy between 1980 and 2004, of whom 2,238 died. In nearly all time periods examined, mortality rates associated with miscarriage or abortion of a first pregnancy were higher than those associated with birth. Compared to women who delivered, the age and birth year adjusted cumulative risk of death for women who had a first trimester abortion was significantly higher in all periods examined, from 180 days (OR=1.84; 1.11 <95% CI <3.71) through 10 years (1.39; 1.22 <95% CI <1.61), as was the risk for women who had abortions after 12 weeks from one year (OR=4.31; 2.18 <95% CI <8.54) through 10 years (OR=2.41; 1.56 <95% CI <2.41). For women who miscarried, the risk was significantly higher for cumulative deaths through 4 years (OR=1.75; 1.34 <95% CI <2.27) and at 10 years (OR=1.48; 1.18 <95% CI <1.85).
Conclusions
Compared to women who delivered, women who had an early or late abortion had significantly higher mortality rates within 1 through 10 years. A lesser effect may also be present relative to miscarriage. Recommendations for additional research are offered.
doi:10.12659/MSM.883338
PMCID: PMC3560645  PMID: 22936199
abortion; maternal mortality; childbirth; late-term abortion; miscarriage; mortality rates
7.  Maternal age and fetal loss: population based register linkage study 
BMJ : British Medical Journal  2000;320(7251):1708-1712.
Objective
To estimate the association between maternal age and fetal death (spontaneous abortion, ectopic pregnancy, stillbirth), taking into account a woman's reproductive history.
Design
Prospective register linkage study.
Subjects
All women with a reproductive outcome (live birth, stillbirth, spontaneous abortion leading to admission to hospital, induced abortion, ectopic pregnancy, or hydatidiform mole) in Denmark from 1978 to 1992; a total of 634 272 women and 1 221 546 pregnancy outcomes.
Main outcome measures
Age related risk of fetal loss, ectopic pregnancy, and stillbirth, and age related risk of spontaneous abortion stratified according to parity and previous spontaneous abortions.
Results
Overall, 13.5% of the pregnancies intended to be carried to term ended with fetal loss. At age 42 years, more than half of such pregnancies resulted in fetal loss. The risk of a spontaneous abortion was 8.9% in women aged 20-24 years and 74.7% in those aged 45 years or more. High maternal age was a significant risk factor for spontaneous abortion irrespective of the number of previous miscarriages, parity, or calendar period. The risk of an ectopic pregnancy and stillbirth also increased with increasing maternal age.
Conclusions
Fetal loss is high in women in their late 30s or older, irrespective of reproductive history. This should be taken into consideration in pregnancy planning and counselling.
PMCID: PMC27416  PMID: 10864550
8.  Alternative Strategies to Reduce Maternal Mortality in India: A Cost-Effectiveness Analysis 
PLoS Medicine  2010;7(4):e1000264.
A cost-effectiveness study by Sue Goldie and colleagues finds that better family planning, provision of safe abortion, and improved intrapartum and emergency obstetrical care could reduce maternal mortality in India by 75% in 5 years.
Background
Approximately one-quarter of all pregnancy- and delivery-related maternal deaths worldwide occur in India. Taking into account the costs, feasibility, and operational complexity of alternative interventions, we estimate the clinical and population-level benefits associated with strategies to improve the safety of pregnancy and childbirth in India.
Methods and Findings
Country- and region-specific data were synthesized using a computer-based model that simulates the natural history of pregnancy (both planned and unintended) and pregnancy- and childbirth-associated complications in individual women; and considers delivery location, attendant, and facility level. Model outcomes included clinical events, population measures, costs, and cost-effectiveness ratios. Separate models were adapted to urban and rural India using survey-based data (e.g., unmet need for birth spacing/limiting, facility births, skilled birth attendants). Model validation compared projected maternal indicators with empiric data. Strategies consisted of improving coverage of effective interventions that could be provided individually or packaged as integrated services, could reduce the incidence of a complication or its case fatality rate, and could include improved logistics such as reliable transport to an appropriate referral facility as well as recognition of referral need and quality of care. Increasing family planning was the most effective individual intervention to reduce pregnancy-related mortality. If over the next 5 y the unmet need for spacing and limiting births was met, more than 150,000 maternal deaths would be prevented; more than US$1 billion saved; and at least one of every two abortion-related deaths averted. Still, reductions in maternal mortality reached a threshold (∼23%–35%) without including strategies that ensured reliable access to intrapartum and emergency obstetrical care (EmOC). An integrated and stepwise approach was identified that would ultimately prevent four of five maternal deaths; this approach coupled stepwise improvements in family planning and safe abortion with consecutively implemented strategies that incrementally increased skilled attendants, improved antenatal/postpartum care, shifted births away from home, and improved recognition of referral need, transport, and availability/quality of EmOC. The strategies in this approach ranged from being cost-saving to having incremental cost-effectiveness ratios less than US$500 per year of life saved (YLS), well below India's per capita gross domestic product (GDP), a common benchmark for cost-effectiveness.
Conclusions
Early intensive efforts to improve family planning and control of fertility choices and to provide safe abortion, accompanied by a paced systematic and stepwise effort to scale up capacity for integrated maternal health services over several years, is as cost-effective as childhood immunization or treatment of malaria, tuberculosis, or HIV. In just 5 y, more than 150,000 maternal deaths would be averted through increasing contraception rates to meet women's needs for spacing and limiting births; nearly US$1.5 billion would be saved by coupling safe abortion to aggressive family planning efforts; and with stepwise investments to improve access to pregnancy-related health services and to high-quality facility-based intrapartum care, more than 75% of maternal deaths could be prevented. If accomplished over the next decade, the lives of more than one million women would be saved.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, more than half a million women—most of them living in developing countries—die from pregnancy- or childbirth-related complications. About a quarter of these “maternal” deaths occur in India. In 2005, a woman's lifetime risk of maternal death in India was 1 in 70; in the UK, it was only one in 8,200. Similarly, the maternal mortality ratio (MMR; number of maternal deaths per 100,000 live births) in India was 450, whereas in the UK it was eight. Faced with the enormous maternal death toll in India and other developing countries, in September 2000, the United Nations pledged, as its fifth Millennium Development Goal (MDG 5), that the global MMR would be reduced to a quarter of its 1990 level by 2015. Currently, it seems unlikely that this target will be met. Between 1990 and 2005, global maternal deaths decreased by only 1% per annum instead of the 5% needed to reach MDG 5; in India, the decrease in maternal deaths between 1990 and 2005 was about 1.8% per annum.
Why Was This Study Done?
Most maternal deaths in developing countries are caused by severe bleeding after childbirth, infections soon after delivery, blood pressure disorders during pregnancy, and obstructed (difficult) labors. Consequently, experts agree that universal access to high-quality routine care during labor (“obstetric” care) and to emergency obstetrical care is needed to reduce maternal deaths. However, there is less agreement about how to adapt these “ideal recommendations” to specific situations. In developing countries with weak health systems and predominantly rural populations, it is unlikely that all women will have access to emergency obstetric care in the near future—so would beginning with improved access to family planning and to safe abortions (unsafe abortion is another major cause of maternal death) be a more achievable, more cost-effective way of reducing maternal deaths? How would family planning and safe abortion be coupled efficiently and cost-effectively with improved access to intrapartum care? In this study, the researchers investigate these questions by estimating the health and economic outcomes of various strategies to reduce maternal mortality in India.
What Did the Researchers Do and Find?
The researchers used a computer-based model that simulates women through pregnancy and childbirth to estimate the effect of different strategies (for example, increased family planning or increased access to obstetric care) on clinical outcomes (pregnancies, live births, or deaths), costs, and cost-effectiveness (the cost of saving one year of life) in India. Increased family planning was the most effective single intervention for the reduction of pregnancy-related mortality. If the current unmet need for family planning in India could be fulfilled over the next 5 years, more than 150,000 maternal deaths would be prevented, more than US$1 billion saved, and at least half of abortion-related deaths averted. However, increased family planning alone would reduce maternal deaths by 35% at most, so the researchers also used their model to test the effect of combinations of strategies on maternal death. They found that an integrated and stepwise approach (increased family planning and safe abortion combined with consecutively increased skilled birth attendants, improved care before and after birth, reduced home births, and improved emergency obstetric care) could eventually prevent nearly 80% of maternal deaths. All the steps in this strategy either saved money or involved an additional cost per year of life saved of less than US$500; given one suggested threshold for cost-effectiveness in India of the per capita GDP (US$1,068) per year of life saved, these strategies would be considered very cost-effective.
What Do These Findings Mean?
The accuracy of these findings depends on the assumptions used to build the model and the quality of the data fed into it. Nevertheless, these findings suggest that early intensive efforts to improve family planning and to provide safe abortion accompanied by a systematic, stepwise effort to improve integrated maternal health services could reduce maternal deaths in India by more than 75% in less than a decade. Furthermore, such a strategy would be cost-effective. Indeed, note the researchers, the cost savings from an initial focus on family planning and safe abortion provision would partly offset the resources needed to assure that every woman had access to high quality routine and emergency obstetric care. Thus, overall, these findings suggest that MDG 5 may be within reach in India, a conclusion that should help to mobilize political support for this worthy goal.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000264.
UNICEF (the United Nations Children's Fund) provides information on maternal mortality, including the WHO/UNICEF/UNFPA/The World Bank 2005 country estimates of maternal mortality
The World Health Organization also provides information on maternal health and about MDG 5 (in several languages)
The United Nations Millennium Development Goals Web site provides detailed information about the Millennium Declaration, the MDGs, their targets and their indicators, and about MDG 5.
The Millennium Development Goals Report 2009 and its progress chart provide an up-to-date assessment of progress toward all the MDGs
Computer simulation modeling as applied to health is further discussed at the Center for Health Decision Science at Harvard University
doi:10.1371/journal.pmed.1000264
PMCID: PMC2857650  PMID: 20421922
9.  Recurrent miscarriage 
Clinical Evidence  2008;2008:1409.
Introduction
Recurrent miscarriage is the spontaneous loss of three or more consecutive pregnancies with the same biological father in the first trimester, and affects 1-2% of women, half of whom have no identifiable cause. Overall, 75% of affected women will have a successful subsequent pregnancy, but this rate falls for older mothers and with increasing number of miscarriages. Antiphospholipid syndrome, with anticardiolipin or lupus anticoagulant antibodies, is present in 15% of women with recurrent first and second trimester miscarriage.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for unexplained recurrent miscarriage? What are the effects of treatments for recurrent miscarriage caused by antiphospholipid syndrome? We searched: Medline, Embase, The Cochrane Library and other important databases up to April 2007 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 14 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: aspirin (low dose), bed rest, corticosteroids, early scanning in subsequent pregnancies, heparin plus low-dose aspirin, human chorionic gonadotrophin, intravenous immunoglobulin treatment, lifestyle adaptation, oestrogen, paternal white cell immunisation, progesterone, trophoblastic membrane infusion, and vitamin supplementation.
Key Points
Recurrent miscarriage is the spontaneous loss of three or more consecutive pregnancies with the same biological father in the first trimester; it affects 1-2% of women, in half of whom there is no identifiable cause. Overall, 75% of affected women will have a successful subsequent pregnancy, but this rate falls for older mothers and with increasing number of miscarriages.Antiphospholipid syndrome, with anticardiolipin or lupus anticoagulant antibodies, is present in 15% of women with recurrent first- and second-trimester miscarriage.
We don't know whether bed rest, early scanning, lifestyle adaptation to stop smoking, reduce alcohol consumption and lose weight, low-dose aspirin, human chorionic gonadotrophin, trophoblastic membrane infusion, or vitamin supplementation increase the likelihood of a successful pregnancy in women with unexplained recurrent miscarriage.
We also don't know whether oestrogen supplementation increases the live birth rate in women with unexplained recurrent miscarriage, but it may increase the miscarriage rate and cause abnormalities in the fetus. We don't know whether progesterone supplementation or corticosteroids reduce miscarriage rates compared with placebo in women with unexplained recurrent miscarriage.
Paternal white cell immunisation and intravenous immunoglobulin treatment do not seem likely to improve live birth rates compared with placebo in women with unexplained recurrent miscarriage.
We don't know whether low-dose aspirin, alone or combined with heparin, can increase the live birth rate compared with placebo in women with antiphospholipid syndrome. Prednisolone plus aspirin may not increase live birth rates in women with antiphospholipid syndrome, and increases the risk of adverse effects compared with placebo.
PMCID: PMC2907979  PMID: 19450314
10.  Recurrent miscarriage 
Clinical Evidence  2011;2011:1409.
Introduction
Recurrent miscarriage is the spontaneous loss of three or more consecutive pregnancies with the same biological father in the first trimester, and affects 1% to 2% of women, half of whom have no identifiable cause. Overall, 75% of affected women will have a successful subsequent pregnancy, but this rate falls for older mothers and with increasing number of miscarriages. Antiphospholipid syndrome, with anticardiolipin or lupus anticoagulant antibodies, is present in 15% of women with recurrent first and second trimester miscarriage.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for unexplained recurrent miscarriage? What are the effects of treatments for recurrent miscarriage caused by antiphospholipid syndrome? We searched: Medline, Embase, The Cochrane Library, and other important databases up to January 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 14 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: aspirin (low dose), bed rest, corticosteroids, early scanning in subsequent pregnancies, heparin plus low-dose aspirin, human chorionic gonadotrophin, intravenous immunoglobulin treatment, lifestyle adaptation, oestrogen, paternal white cell immunisation, progesterone, trophoblastic membrane infusion, and vitamin supplementation.
Key Points
Recurrent miscarriage is the spontaneous loss of three or more consecutive pregnancies with the same biological father in the first trimester; it affects 1% to 2% of women, in half of whom there is no identifiable cause. Overall, 75% of affected women will have a successful subsequent pregnancy, but this rate falls for older mothers and with increasing number of miscarriages.Antiphospholipid syndrome, with anticardiolipin or lupus anticoagulant antibodies, is present in 15% of women with recurrent first- and second-trimester miscarriage.
We don't know whether bed rest, early scanning, lifestyle adaptation (to stop smoking, reduce alcohol consumption, and lose weight), low-dose aspirin, human chorionic gonadotrophin, trophoblastic membrane infusion, or vitamin supplementation increase the likelihood of a successful pregnancy in women with unexplained recurrent miscarriage.
We also don't know whether oestrogen supplementation increases the live birth rate in women with unexplained recurrent miscarriage, but it may increase the miscarriage rate and cause abnormalities in the fetus. We don't know whether progesterone supplementation or corticosteroids reduce miscarriage rates compared with placebo in women with unexplained recurrent miscarriage.
Paternal white cell immunisation and intravenous immunoglobulin treatment do not seem likely to improve live birth rates compared with placebo in women with unexplained recurrent miscarriage.
We don't know whether low-dose aspirin, alone or combined with heparin, can increase the live birth rate compared with placebo in women with antiphospholipid syndrome. Prednisolone plus aspirin does not seem to increase live birth rates, compared with placebo or aspirin alone, in women with antiphospholipid syndrome, and it increases the risk of adverse effects including hypertension, preterm birth, low birth weight, and admission to neonatal intensive care.
PMCID: PMC3275302  PMID: 21718553
11.  Influence of past reproductive performance on risk of spontaneous abortion. 
BMJ : British Medical Journal  1989;299(6698):541-545.
OBJECTIVE--To investigate the incidence of spontaneous abortion in a population of women in order to establish their risk of spontaneous abortion and the obstetric factors predisposing to it. DESIGN--Prospective study of women recruited by radio and poster appeal and from hospital outpatient clinics. SETTING--English provincial community. PATIENTS--630 Women from the general population intending to become pregnant. INTERVENTIONS--The viability of the pregnancy was assessed by abdominal ultrasonography before completion of the eighth week, and the assessment was repeated if vaginal bleeding occurred. MAIN OUTCOME MEASURE--Spontaneous abortion or live births in women with or without a previous history of spontaneous abortion. RESULTS--The overall incidence of clinically recognisable spontaneous abortion before 20 weeks of gestation was 12% (50/407 pregnancies). The risk of spontaneous abortion in each category of patient was classified with respect to the patient's past reproductive performance and found to be influenced greatly by her previous obstetric history. In primigravidas and women with a history of consistently successful pregnancies the incidences of abortion were low (5% (4/87) and 4% (3/73) respectively), whereas women with only unsuccessful histories had a much greater risk of aborting the study pregnancy (24% (24/98)), even when their sole pregnancy had ended in abortion (20% (12/59)). The outcome of the last pregnancy also influenced the outcome of the study pregnancy; only 5% of women (5/95) whose previous pregnancy had been successful aborted, whereas the incidence of loss of pregnancy among women whose last pregnancy had aborted was 19% (40/214). CONCLUSIONS--A knowledge of the patient's reproductive history is essential for the clinical assessment of her risk of spontaneous abortion. As the most important predictive factor for spontaneous abortion is a previous abortion, the outcome of a woman's first pregnancy has profound consequences for all subsequent pregnancies.
PMCID: PMC1837397  PMID: 2507063
12.  Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies) 
BMJ : British Medical Journal  1997;314(7076):253-257.
OBJECTIVE: To determine whether treatment with low dose aspirin and heparin leads to a higher rate of live births than that achieved with low dose aspirin alone in women with a history of recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies), lupus anticoagulant, and cardiolipin antibodies (or anticardiolipin antibodies). DESIGN: Randomised controlled trial. SETTING: Specialist clinic for recurrent miscarriages. SUBJECTS: 90 women (median age 33 (range 22-43)) with a history of recurrent miscarriage (median number 4 (range 3-15)) and persistently positive results for phospholipid antibodies. INTERVENTION: Either low dose aspirin (75 mg daily) or low dose aspirin and 5000 U of unfractionated heparin subcutaneously 12 hourly. All women started treatment with low dose aspirin when they had a positive urine pregnancy test. Women were randomly allocated an intervention when fetal heart activity was seen on ultrasonography. Treatment was stopped at the time of miscarriage or at 34 weeks' gestation. MAIN OUTCOME MEASURES: Rate of live births with the two treatments. RESULTS: There was no significant difference in the two groups in age or the number and gestation of previous miscarriages. The rate of live births with low dose aspirin and heparin was 71% (32/45 pregnancies) and 42% (19/45 pregnancies) with low dose aspirin alone (odds ratio 3.37 (95% confidence interval 1.40 to 8.10)). More than 90% of miscarriages occurred in the first trimester. There was no difference in outcome between the two treatments in pregnancies that advanced beyond 13 weeks' gestation. Twelve of the 51 successful pregnancies (24%) were delivered before 37 weeks' gestation. Women randomly allocated aspirin and heparin had a median decrease in lumbar spine bone density of 5.4% (range -8.6% to 1.7%). CONCLUSION: Treatment with aspirin and heparin leads to a significantly higher rate of live births in women with a history of recurrent miscarriage associated with phospholipid antibodies than that achieved with aspirin alone.
PMCID: PMC2125731  PMID: 9022487
13.  Insecticide-Treated Nets for the Prevention of Malaria in Pregnancy: A Systematic Review of Randomised Controlled Trials 
PLoS Medicine  2007;4(3):e107.
Background
Protection from malaria with insecticide-treated bednets (ITNs) during pregnancy is widely advocated, but evidence of benefit has been inconsistent. We undertook a systematic review of randomised trials.
Methods and Findings
Three cluster-randomised and two individually randomised trials met the inclusion criteria; four from Africa (n = 6,418) and one from Thailand (n = 223). In Africa, ITNs compared to no nets increased mean birth weight by 55 g (95% confidence interval [CI] 21–88), reduced low birth weight by 23% (relative risk [RR] 0.77, 95% CI 0.61–0.98), and reduced miscarriages/stillbirths by 33% (RR 0.67, 0.47–0.97) in the first few pregnancies. Placental parasitaemia was reduced by 23% in all gravidae (RR 0.77, 0.66–0.90). The effects were apparent in the cluster-randomised trials and the one individually randomised trial in Africa. The trial in Thailand, which randomised individuals to ITNs or untreated nets, showed reductions in anaemia and fetal loss in all gravidae, but not reductions in clinical malaria or low birth weight.
Conclusions
ITNs used throughout pregnancy or from mid-pregnancy onwards have a beneficial impact on pregnancy outcome in malaria-endemic Africa in the first few pregnancies. The potential impact of ITNs in pregnant women and their newborns in malaria regions outside Africa requires further research.
A systematic review of the evidence from trials shows that use of insecticide-treated mosquito nets has a beneficial impact on pregnancy outcome in malaria-endemic Africa in the first few pregnancies.
Editors' Summary
Background.
Malaria is one of the world's most important killer diseases. It is responsible for around a million deaths every year, most of them in Africa and most of them in children. Pregnant women and their unborn babies are also at high risk. Women who have malaria become extremely weak because of anemia, they are more likely to miscarry, and their babies have low birth weights. (Birth weights under 2.5 kilograms are considered to be low; low-birth-weight babies face higher risks of sickness and death than other babies.) It has been estimated that, every year, malaria during pregnancy is responsible for the deaths of about 100,000 to 200,000 babies within their first year of life.
The parasite that causes malaria is carried by certain species of mosquito. In the areas where these mosquitoes are found, taking steps to reduce the chance of being bitten can reduce one's chances of getting infected with malaria. In Africa, these mosquitoes bite mainly in the hours of darkness, so sleeping under a mosquito net helps. During the last 20 years it has been established that mosquito nets impregnated with an insecticide provide much better protection than ordinary nets. Research has shown that children who sleep under these insecticide-treated nets (ITNs) are much less likely to get malaria than other children living in the same area. The correct use of ITNs is now being heavily promoted in many national and international programs.
Why Was This Study Done?
It seems logical that pregnant women should be encouraged to sleep under ITNs, and this is recommended by the World Health Organization and other authorities. However, we cannot be sure that there are benefits, as there is a lack of clear evidence to show whether women who sleep under ITNs actually suffer less from malaria and anemia, and what the implications are for their babies.
What Did the Researchers Do and Find?
They did no new work in the field or in the laboratory. Instead, they conducted what is known as a systematic review. Working to a set of criteria carefully formulated in advance, they searched the medical literature for well-conducted “randomized controlled trials” (RCTs) involving the use of ITNs by pregnant women. RCTs are studies where one group of people receives the “treatment” under investigation and another group does not. It is decided at random who goes into which group. The authors found five trials in Africa, four of which fulfilled the entry criteria for their analysis. In three of the four studies conducted in Africa, whole villages had been “randomized” to determine which pregnant women received ITNs. In another African trial, individual women had been randomized. In total, over 6,000 women were involved in the African trials. One trial had been done outside Africa, in Thailand, where just over 400 individual women had been randomized.
In the research done in Africa, it had been found that women who slept under ITNs had lower numbers of parasites in their blood. Miscarriages were much reduced—by a third in those women who were in their first few pregnancies. The overall proportion of babies who were low birth weight went down by nearly a quarter. In the research done in Thailand, the women using ITNs were less anemic and the miscarriage rate was again lower, although there was no change in the low-birth-weight figures.
What Do These Findings Mean?
The evidence from the three trials done in Africa strongly suggests that it is a good idea for pregnant women to sleep under ITNs. With evidence available from only one trial conducted outside Africa, it is hard to be sure at this stage whether ITNs have the same beneficial effects for pregnant women in other parts of the tropics. More research is needed there.
Additional Information.
The following organizations all have useful information about malaria on their Web sites, and we have provided links to the appropriate pages below. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040107.
US Centers for Disease Control and Prevention has information specifically about malaria during pregnancy
Roll Back Malaria has information specifically about malaria during pregnancy
Wikipedia—a free online encyclopedia that anyone can edit
The World Health Organization (WHO)
The United Nations Children's Fund (UNICEF)
MedlinePlus brings together authoritative information from the US National Library of Medicine, National Institutes of Health, and other government agencies and health-related organizations
The Wellcome Trust
doi:10.1371/journal.pmed.0040107
PMCID: PMC1831739  PMID: 17388668
14.  Anti-adhesion barrier gels following operative hysteroscopy for treating female infertility: a systematic review and meta-analysis 
Gynecological Surgery  2014;11:113-127.
The aim of this study was to assess the effects of any anti-adhesion barrier gel used after operative hysteroscopy for treating infertility associated with uterine cavity abnormalities. Gynecologists might use any barrier gel following operative hysteroscopy in infertile women for decreasing de novo adhesion formation; the use of any barrier gel is associated with less severe de novo adhesions and lower mean adhesion scores. Nevertheless, infertile women should be counseled that there is at the present no evidence for higher live birth or pregnancy rates. There is a lack of data for the outcome miscarriage. Preclinical studies suggest that the use of biodegradable surgical barriers may decrease postsurgical adhesion formation. Observational studies in the human report conflicting results. We searched the Cochrane Menstrual Disorders and Subfertility Specialized Register (10 April 2013), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2013, Issue 1), MEDLINE (1950 to 4 April 2013), EMBASE (1974 to 4 April 2013), and other electronic databases of trials including trial registers, sources of unpublished literature, and reference lists. We handsearched the Journal of Minimally Invasive Gynecology (from 1 January 1992 to 13 April 2013); we also contacted experts in the field. We included the randomized comparisons between any anti-adhesion barrier gel versus another barrier gel, placebo, or no adjunctive therapy following operative hysteroscopy. Primary outcomes were live birth rates and de novo adhesion formation at second-look hysteroscopy. Secondary outcomes were pregnancy and miscarriage rates, mean adhesion scores, and severity of adhesions at second-look hysteroscopy. Two authors independently assessed eligible studies for inclusion and risk of bias, and extracted data. We contacted primary study authors for additional information or other clarification. Five trials met the inclusion criteria. There is no evidence for an effect favoring the use of any barrier gel following operative hysteroscopy for the key outcomes of live birth or clinical pregnancy (risk ratio (RR) 3.0, 95 % confidence interval (CI) 0.35 to 26, P = 0.32, one study, 30 women, very low quality evidence); there were no data on the outcome miscarriage. The use of any gel following operative hysteroscopy decreases the incidence of de novo adhesions at second-look hysteroscopy at 1 to 3 months (RR 0.65, 95 % CI 0.45 to 0.93, P = 0.02, five studies, 372 women, very low quality evidence). The number needed to treat to benefit is 9 (95 % CI 5 to 33). The use of auto-cross-linked hyaluronic acid gel in women undergoing operative hysteroscopy for fibroids, endometrial polyps, or uterine septa is associated with a lower mean adhesion score at second-look hysteroscopy at 3 months (mean difference (MD) −1.44, 95 % CI −1.83 to −1.05, P < 0.00001, one study, 24 women; this benefit is even larger in women undergoing operative hysteroscopy for intrauterine adhesions(MD −3.30, 95 % CI −3.43 to −3.17, P < 0.00001, one study, 19 women). After using any gel following operative hysteroscopy, there are more American Fertility Society 1988 stage I (mild) adhesions (RR 2.81, 95 % CI 1.13 to 7.01, P = 0.03, four studies, 79 women). The number needed to treat to benefit is 2 (95 % CI 1 to 4). Similarly there are less’ moderate or severe adhesions’ at second-look hysteroscopy (RR 0.25, 95 % CI 0.10 to 0.67, P = 0.006, four studies, 79 women). The number needed to treat to benefit is 2 (95 % CI 1 to 4) (all very low quality evidence). There are some concerns for the non-methodological quality. Only two trials included infertile women; in the remaining three studies, it is not clear whether and how many participants suffered from infertility. Therefore, the applicability of the findings of the included studies to the target population under study should be questioned. Moreover, only one small trial studied the effects of anti-adhesion barrier gels for the key outcome of pregnancy; the length of follow-up was, however, not specified. More well-designed and adequately powered randomized studies are needed to assess whether the use of any anti-adhesion gel affects the key reproductive outcomes in a target population of infertile women.
doi:10.1007/s10397-014-0832-x
PMCID: PMC4003345  PMID: 24795547
Adhesion prevention; Barrier gel; Operative hysteroscopy; Infertility; Systematic review; Meta-analysis
15.  Thyroid autoimmunity and obstetric outcomes in women with recurrent miscarriage: a case–control study 
Endocrine Connections  2013;2(2):118-124.
Objectives
Thyroid antibody positivity during pregnancy has been associated with adverse outcomes including miscarriage and preterm delivery. The aim of the study is to evaluate the obstetric outcome in pregnant women with recurrent miscarriage and their response to levothyroxine (l-T4) therapy.
Study design and methods
All pregnant and non-pregnant women between 21 and 35 years of age with a history of two or more consecutive miscarriages were included in the study. A third group comprising 100 pregnant women without a history of miscarriage were taken as healthy controls. Thyroid autoimmunity, prevalence of subclinical hypothyroidism and maternal and foetal complications were analysed in all the groups with appropriate statistical methods.
Results
The mean age of the patients included in the study was 27.0±3.1 years. Of 100 pregnant patients with previous recurrent miscarriage, thyroid autoimmunity (thyroid peroxidase antibody (TPOAb+) >34 U/ml) was found in 31% of the cases. The incidence of subclinical hypothyroidism was higher in TPOAb+ group than in TPOAb− group (52 vs 16%; P=0.0002). There was no difference in the prevalence of miscarriage or obstetric outcomes between recurrent miscarriage and healthy pregnant women group irrespective of TPO status.
Conclusions
The prevalence of thyroid autoimmunity was higher in pregnant women with a history of recurrent abortion compared with healthy pregnant control population. Following l-T4 treatment, there was no difference in prevalence of miscarriage between hypothyroid and euthyroid individuals in TPOAb+ women.
doi:10.1530/EC-13-0012
PMCID: PMC3691574  PMID: 23802061
recurrent miscarriage; thyroid peroxidase; hypothyroidism; preterm birth
16.  Clarithromycin in Early Pregnancy and the Risk of Miscarriage and Malformation: A Register Based Nationwide Cohort Study 
PLoS ONE  2013;8(1):e53327.
Background
The antibiotic clarithromycin has been associated with fetal loss in animals and a study has found a doubling in the frequency of miscarriages among women using clarithromycin in pregnancy. The aim of the study was to investigate whether clarithromycin use in early pregnancy was associated with an increased risk for miscarriages and major malformations.
Methods
We conducted a nationwide cohort study including all women in Denmark with a known conception between 1997 and 2007. The Fertility Database was used to identify all women giving birth and the National Hospital Register was used to identify all women with a record of miscarriage or induced abortion. Prescription data was obtained from the National Prescription Register. The primary outcome was the number of miscarriages and offspring with major congenital malformations among users of clarithromycin compared to non-users.
Results
We identified 931 504 pregnancies (705 837 live births, 77 553 miscarriages, and 148 114 induced abortions). 401 women redeemed a prescription of clarithromycin in the first trimester of which 40 (10.0%) experienced a miscarriage and among the live born nine (3.6%) had offspring with malformations. The hazard ratio (HR) of having a miscarriage after exposure to clarithromycin was 1.56 (CI95% 1.14–2.13). There was no increased hazard of having a miscarriage when being exposed to penicillin or erythromycin. There was no increased prevalence (OR = 1.03 (CI95% 0.52–2.00)) of having offspring with malformations after exposure to clarithromycin.
Conclusions
We found an increased hazard of miscarriage but no increased prevalance of having offspring with malformations among women redeeming a prescription of clarithromycin in early pregnancy. This is supported by previous studies in animals and humans. However, further research is required to explore the possible effect of treatment indication on the associations found.
doi:10.1371/journal.pone.0053327
PMCID: PMC3534696  PMID: 23301061
17.  Reproductive outcomes in adolescents who had a previous birth or an induced abortion compared to adolescents' first pregnancies 
Background
Recently, attention has been focused on subsequent pregnancies among teenage mothers. Previous studies that compared the reproductive outcomes of teenage nulliparae and multiparae often did not consider the adolescents' reproductive histories. Thus, the authors compared the risks for adverse reproductive outcomes of adolescent nulliparae to teenagers who either have had an induced abortion or a previous birth.
Methods
In this retrospective cohort study we used perinatal data prospectively collected by obstetricians and midwives from 1990–1999 (participation rate 87–98% of all hospitals) in Lower Saxony, Germany. From the 9742 eligible births among adolescents, women with multiple births, >1 previous pregnancies, or a previous spontaneous miscarriage were deleted and 8857 women <19 years remained. Of these 8857 women, 7845 were nulliparous, 801 had one previous birth, and 211 had one previous induced abortion. The outcomes were stillbirths, neonatal mortality, perinatal mortality, preterm births, and very low birthweight. Bivariate and multivariable logistic regression models were conducted.
Results
In bivariate logistic regression analyses, compared to nulliparous teenagers, adolescents with a previous birth had higher risks for perinatal [OR = 2.08, CI = 1.11,3.89] and neonatal [OR = 4.31, CI = 1.77,10.52] mortality and adolescents with a previous abortion had higher risks for stillbirths [OR = 3.31, CI = 1.01,10.88] and preterm births [OR = 2.21, CI = 1.07,4.58]. After adjusting for maternal nationality, partner status, smoking, prenatal care and pre-pregnancy BMI, adolescents with a previous birth were at higher risk for perinatal [OR = 2.35, CI = 1.14,4.86] and neonatal mortality [OR = 4.70, CI = 1.60,13.81] and adolescents with a previous abortion had a higher risk for very low birthweight infants [OR = 2.74, CI = 1.06,7.09] than nulliparous teenagers.
Conclusion
The results suggest that teenagers who give birth twice as adolescents have worse outcomes in their second pregnancy compared to those teenagers who are giving birth for the first time. The prevention of the second pregnancy during adolescence is an important public health objective and should be addressed by health care providers who attend the first birth or the abortion and the follow-up care. Also, health care workers should attempt to improve the pregnancy outcomes of subsequent teenage pregnancies by addressing modifiable risk factors, for example, supporting smoking cessation and utilization of prenatal care.
doi:10.1186/1471-2393-8-4
PMCID: PMC2266899  PMID: 18237387
18.  Induced abortion as an independent risk factor for breast cancer: a comprehensive review and meta-analysis. 
STUDY OBJECTIVE: To ascertain, from the published reports to date, whether or not a significantly increased risk of breast cancer is specifically attributable to a history of induced abortion, independent of spontaneous abortion and age at first full term pregnancy (or first live birth); to establish the relative magnitude of such risk increase as may be found, and to ascertain and quantify such risk increases as may pertain to particular subpopulations of women exposed to induced abortion; in particular, nulliparous women and parous women exposed before compared with after the first full term pregnancy. INCLUDED STUDIES: The meta-analysis includes all 28 published reports which include specific data on induced abortion and breast cancer incidence. Since some study data are presented in more than one report, the 28 reports were determined to constitute 23 independent studies. Overall induced abortion odds ratios and odds ratios for the different subpopulations were calculated using an average weighted according to the inverse of the variance. An overall unweighted average was also computed for comparison. No quality criteria were imposed, but a narrative review of all included studies is presented for the reader's use in assessing the quality of individual studies. EXCLUDED STUDIES: All 33 published reports including data on abortion and breast cancer incidence but either pertaining only to spontaneous abortion or to abortion without specification as to whether it was induced or spontaneous. These studies are listed for the reader's information. RESULTS: The overall odds ratio (for any induced abortion exposure; n = 21 studies) was 1.3 (95% confidence interval of 1.2, 1.4). For comparison, the unweighted overall odds ratio was 1.4 (1.3,1.6). The odds ratio for nulliparous women was 1.3 (1.0,1.6), that for abortion before the first term pregnancy in parous women was 1.5 (1.2,1.8), and that for abortion after the first term pregnancy was 1.3 (1.1,1.5). CONCLUSIONS: The results support the inclusion of induced abortion among significant independent risk factors for breast cancer, regardless of parity or timing of abortion relative to the first term pregnancy. Although the increase in risk was relatively low, the high incidence of both breast cancer and induced abortion suggest a substantial impact of thousands of excess cases per year currently, and a potentially much greater impact in the next century, as the first cohort of women exposed to legal induced abortion continues to age.
PMCID: PMC1060338  PMID: 8944853
19.  How long after a miscarriage should women wait before becoming pregnant again? Multivariate analysis of cohort data from Matlab, Bangladesh 
BMJ Open  2012;2(4):e001591.
Objective
To determine the optimum interpregnancy interval (IPI) following a miscarriage.
Design
Multivariate analysis of population-based, prospective data from a demographic surveillance system.
Setting
Pregnancies in Matlab, Bangladesh, between 1977 and 2008.
Participants
9214 women with 10 453 pregnancies that ended in a miscarriage and were followed by another pregnancy outcome.
Main outcome measures
Outcome of pregnancy following the miscarriage was singleton live birth, stillbirth, miscarriage or induced abortion. For pregnancies that ended in live birth: early neonatal, late neonatal and postneonatal mortality.
Results
Compared with IPIs of 6–12 months, pregnancies that were conceived ≤3 months after a miscarriage were more likely to result in a live birth and less likely to result in a miscarriage (adjusted relative risk ratio (RRR) 0.70, 95% CI 0.57 to 0.86) or induced abortion (0.50, 0.29 to 0.89). Induced abortions were significantly more likely following IPIs of 18–24 months (2.36, 1.48 to 3.76), 36–48 months (2.73, 1.50 to 4.94), and >48 months (3.32, 1.68 to 2.95), and miscarriages were more likely following IPIs of 12–17 months (1.25, 1.01 to 1.56) and >48 months (1.90, 1.40 to 2.58). No significant effects of IPI duration are seen on the risks of a stillbirth. However, IPIs≤3 months following a miscarriage are associated with significantly higher late neonatal mortality for the infant born at the end of the IPI (adjusted hazard ratio (HR) 1.74, 1.06 to 2.84), and IPIs of 12–18 months are associated with a significantly lower unadjusted risk of postneonatal mortality (0.54, 0.30 to 0.96).
Conclusions
The shorter the IPI following a miscarriage, the more likely the subsequent pregnancy is to result in a live birth. However, very short IPIs may not be advisable following miscarriages in poor countries like Bangladesh because they are associated with a higher risk of mortality for the infants born after them.
doi:10.1136/bmjopen-2012-001591
PMCID: PMC3425891  PMID: 22907047
Reproductive Medicine; pregnancy outcome; pregnancy spacing; miscarriage; abortion; infant mortality
20.  Multiple Miscarriages Are Associated with the Risk of Ovarian Cancer: Results from the European Prospective Investigation into Cancer and Nutrition 
PLoS ONE  2012;7(5):e37141.
While the risk of ovarian cancer clearly reduces with each full-term pregnancy, the effect of incomplete pregnancies is unclear. We investigated whether incomplete pregnancies (miscarriages and induced abortions) are associated with risk of epithelial ovarian cancer. This observational study was carried out in female participants of the European Prospective Investigation into Cancer and Nutrition (EPIC). A total of 274,442 women were followed from 1992 until 2010. The baseline questionnaire elicited information on miscarriages and induced abortions, reproductive history, and lifestyle-related factors. During a median follow-up of 11.5 years, 1,035 women were diagnosed with incident epithelial ovarian cancer. Despite the lack of an overall association (ever vs. never), risk of ovarian cancer was higher among women with multiple incomplete pregnancies (HR≥4vs.0: 1.74, 95% CI: 1.20–2.70; number of cases in this category: n = 23). This association was particularly evident for multiple miscarriages (HR≥4vs.0: 1.99, 95% CI: 1.06–3.73; number of cases in this category: n = 10), with no significant association for multiple induced abortions (HR≥4vs.0: 1.46, 95% CI: 0.68–3.14; number of cases in this category: n = 7). Our findings suggest that multiple miscarriages are associated with an increased risk of epithelial ovarian cancer, possibly through a shared cluster of etiological factors or a common underlying pathology. These findings should be interpreted with caution as this is the first study to show this association and given the small number of cases in the highest exposure categories.
doi:10.1371/journal.pone.0037141
PMCID: PMC3356371  PMID: 22623987
21.  Cross-sectional analysis of adverse outcomes in 1,029 pregnancies of Afro-Caribbean women in Trinidad with and without systemic lupus erythematosus 
The objective of the study was to examine pregnancy outcomes in women with systemic lupus erythematosus (SLE) and population controls in Trinidad. We performed a cross-sectional analysis of adverse outcomes in pregnancies of Afro-Caribbean women with SLE and without SLE. One hundred and twenty-two female adult cases of SLE and 203 neighbourhood age-matched women without SLE were interviewed concerning details of their reproductive history, and the anticardiolipin antibody (ACL) status was established for women with SLE. A total of 1,029 pregnancies were reported (356 by women with SLE, 673 by women without SLE). In women with ≥ 1 pregnancy the total number of pregnancies was similar in women with a diagnosis of SLE and women without; however, a lower proportion of women with SLE had ever been pregnant compared with women without SLE (80% versus 91%, P = 0.002). In multivariate logistic regression analyses adjusted for maternal age, district of residence, pregnancy order and smoking, SLE pregnancies were more than twice as likely to end in foetal death than non-SLE pregnancies (odds ratio (OR), 2.4; 95% confidence interval (CI), 1.2–4.7). This effect was driven by a large increase in the odds of stillbirth (OR, 8.5; 95% CI, 2.5–28.8). The odds of early miscarriage (OR, 1.4; 95% CI, 0.6–3.1) and of mid-trimester miscarriage (OR, 1.9; 95% CI, 0.4–9.5) were higher, but were not statistically significantly different, in SLE pregnancies than in non-SLE pregnancies. The odds of ectopic pregnancy (OR, 7.5; 95% CI, 0.9–62.5) and of preterm birth (OR, 3.4; 95% CI, 1.2–10.0) were higher in SLE pregnancies conceived after diagnosis than in non-SLE pregnancies. There was no evidence of raised levels of IgG or IgM ACL among the majority (93/97 women, 96%) of SLE cases who reported sporadic mid-trimester miscarriage or stillbirth, although there was evidence of high levels of IgM and IgG ACL among women reporting three or more miscarriages and three consecutive miscarriages, and of raised IgG ACL among those experiencing ectopic pregnancy. In conclusion, we found evidence for a large increase in risk of stillbirth in the pregnancies of Afro-Caribbean Trinidadian women with SLE (not accounted for by high ACL status). There was some evidence of an increased risk of preterm delivery and ectopic pregnancy in pregnancies conceived after a diagnosis of maternal SLE.
doi:10.1186/ar2332
PMCID: PMC2246243  PMID: 18042277
22.  Spontaneous abortions among women working in the pharmaceutical industry. 
A register based study was conducted on the pregnancy outcome of female workers in eight Finnish pharmaceutical factories to determine whether they had a higher risk of spontaneous abortion than the general population or matched controls. Information about all female workers who had been employed in the factories during the years 1973 or 1975 (four factories) to 1980 was obtained from the employers. The workers' pregnancy data were collected from the nation wide hospital discharge register and polyclinic data of hospitals from 1973 to 1981. The total number of 1795 pregnancies included 1179 deliveries, 142 spontaneous abortions, and 474 induced abortions. The spontaneous abortion rate (the number of spontaneous abortions X 100, divided by the number of spontaneous abortions plus the number of births) during employment was 10.9% and before/after employment 10.6%. The rate for all the women in the corresponding central hospital districts was 11.3% [corrected] during the study period. A case-control study was also carried out in which the cases were 44 women who had a spontaneous abortion during employment in the pharmaceutical factory. Three age matched female pharmaceutical factory workers who had given birth to a child were chosen as controls for every case. The information about occupational exposures was collected from questionnaires completed by the occupational physician or nurse at the factory. The response rate was 93%. Exposure to chemicals was more common among the cases than among the controls. For methylene chloride, a solvent commonly used in the pharmaceutical industry, the increase in odds ratio of borderline significance (odds ratio 2.3, p = 0.06). In a logistic regression model (which included oestrogen exposure, solvent exposure frequency of the usage, and heavy lifting) the odds ratio was increased for oestrogens (odds ratio 4.2, p = 0.05) and for continuous heavy lifting (odds ratio 5.7, p = 0.02). The odds ratio for spontaneous abortions was greater among those exposed to four or more solvents (odds ratio 3.5, p=0.05) than among those exposed to one to three solvents (odds ration 0.8, p=0.74).
PMCID: PMC1007633  PMID: 3947584
23.  Influence of bacterial vaginosis on conception and miscarriage in the first trimester: cohort study 
BMJ : British Medical Journal  1999;319(7204):220-223.
Objectives
To assess whether bacterial vaginosis affects the rates of conception and miscarriage in the first trimester.
Design
Cohort study.
Setting
Assisted conception unit of a teaching hospital in Leeds.
Participants
867 consecutive women undergoing in vitro fertilisation.
Interventions
Screening for bacterial vaginosis with a Gram stained vaginal smear before egg collection.
Main outcome measures
The presence of bacterial vaginosis or normal vaginal flora, and the rate of conception and miscarriage in the first trimester.
Results
190 of 771 (24.6%) women had bacterial vaginosis. No difference in conception rate was found between those women with bacterial vaginosis and those with normal vaginal flora: 61 women (32.1%) and 146 of 493 women (29.6%) respectively (relative risk 1.08, 95% confidence interval 0.85 to 1.39; odds ratio 1.12, 0.77 to 1.64). However, 22 women (31.6%) with bacterial vaginosis who conceived had a significantly increased risk of miscarriage in the first trimester compared with 27 women (18.5%) with normal vaginal flora (crude relative risk 1.95, 1.11 to 3.42; crude odds ratio 2.49, 1.21 to 5.12). This increased risk remained significant after adjustment for factors known to increase the rate of miscarriage: increasing maternal age, smoking, history of three or more miscarriages, no previous live birth, and polycystic ovaries (adjusted relative risk 2.03, 1.09 to 3.78; adjusted odds ratio 2.67, 1.26 to 5.63).
Conclusions
Bacterial vaginosis does not affect conception but is associated with an increased risk of miscarriage in the first trimester in women undergoing in vitro fertilisation, independent of other risk factors.
Key messagesBacterial vaginosis does not affect conception rateBacterial vaginosis is associated with a two-fold risk of miscarriage in the first trimesterThe increased miscarriage rate is equivalent to one extra miscarriage for every six pregnant women with bacterial vaginosisThe most likely cause of the miscarriages is due to pre-existing endometritis affecting implantation or early embryonic development, which could also affect naturally conceived pregnancies
PMCID: PMC28171  PMID: 10417083
24.  Diagnosing Severe Falciparum Malaria in Parasitaemic African Children: A Prospective Evaluation of Plasma PfHRP2 Measurement 
PLoS Medicine  2012;9(8):e1001297.
Arjen Dondorp and colleagues investigate whether the plasma level of Plasmodium falciparum histidine-rich protein 2 can be used to distinguish between severe malaria and other severe febrile illness in African children with malaria.
Background
In African children, distinguishing severe falciparum malaria from other severe febrile illnesses with coincidental Plasmodium falciparum parasitaemia is a major challenge. P. falciparum histidine-rich protein 2 (PfHRP2) is released by mature sequestered parasites and can be used to estimate the total parasite burden. We investigated the prognostic significance of plasma PfHRP2 and used it to estimate the malaria-attributable fraction in African children diagnosed with severe malaria.
Methods and Findings
Admission plasma PfHRP2 was measured prospectively in African children (from Mozambique, The Gambia, Kenya, Tanzania, Uganda, Rwanda, and the Democratic Republic of the Congo) aged 1 month to 15 years with severe febrile illness and a positive P. falciparum lactate dehydrogenase (pLDH)-based rapid test in a clinical trial comparing parenteral artesunate versus quinine (the AQUAMAT trial, ISRCTN 50258054). In 3,826 severely ill children, Plasmadium falciparum PfHRP2 was higher in patients with coma (p = 0.0209), acidosis (p<0.0001), and severe anaemia (p<0.0001). Admission geometric mean (95%CI) plasma PfHRP2 was 1,611 (1,350–1,922) ng/mL in fatal cases (n = 381) versus 1,046 (991–1,104) ng/mL in survivors (n = 3,445, p<0.0001), without differences in parasitaemia as assessed by microscopy. There was a U-shaped association between log10 plasma PfHRP2 and risk of death. Mortality increased 20% per log10 increase in PfHRP2 above 174 ng/mL (adjusted odds ratio [AOR] 1.21, 95%CI 1.05–1.39, p = 0.009). A mechanistic model assuming a PfHRP2-independent risk of death in non-malaria illness closely fitted the observed data and showed malaria-attributable mortality less than 50% with plasma PfHRP2≤174 ng/mL. The odds ratio (OR) for death in artesunate versus quinine-treated patients was 0.61 (95%CI 0.44–0.83, p = 0.0018) in the highest PfHRP2 tertile, whereas there was no difference in the lowest tertile (OR 1.05; 95%CI 0.69–1.61; p = 0.82). A limitation of the study is that some conclusions are drawn from a mechanistic model, which is inherently dependent on certain assumptions. However, a sensitivity analysis of the model indicated that the results were robust to a plausible range of parameter estimates. Further studies are needed to validate our findings.
Conclusions
Plasma PfHRP2 has prognostic significance in African children with severe falciparum malaria and provides a tool to stratify the risk of “true” severe malaria-attributable disease as opposed to other severe illnesses in parasitaemic African children.
Please see later in the article for the Editors' Summary.
Editors' Summary
Background
Malaria is a life-threatening disease caused by parasites that are transmitted to people through the bites of infected mosquitoes. In 2010, malaria caused an estimated 655,000 deaths worldwide, mostly in Africa, where according to the World Health Organization, one African child dies every minute from the disease. There are four Plasmodium parasite species that cause malaria in humans, with one species, Plasmodium falciparum, causing the most severe disease. However, diagnosing severe falciparum malaria in children living in endemic areas is problematic, as many semi-immune children may have the malaria parasites in their blood (described as being parasitaemic) but do not have clinical disease. Therefore, a positive malaria blood smear may be coincidental and not be diagnostic of severe malaria, and unfortunately, neither are the clinical symptoms of severe malaria, such as shock, acidosis, or coma, which can also be caused by other childhood infections. For these reasons, the misdiagnosis of falciparum malaria in severely ill children is an important problem in sub-Saharan Africa, and may result in unnecessary child deaths.
Why Was This Study Done?
Previous studies have suggested that a parasite protein—P. falciparum histidine-rich protein-2 (PfHRP2)—is a measure of the total number of parasites in the patient. Unlike the circulating parasites detected on a blood film, which do not represent the parasites that get stuck in vital organs, PfHRP2 is distributed equally through the total blood plasma volume, and so can be considered a measure of the total parasite burden in the previous 48 hours. So in this study, the researchers assessed the prognostic value of plasma PfHRP2 in African children with severe malaria and whether this protein could distinguish children who really do have severe malaria from those who have severe febrile illness but coincidental parasitaemia, who may have another infection.
What Did the Researchers Do and Find?
The researchers assessed levels of plasma PfHRP2 in 3,826 out of a possible 5,425 African children who participated in a large multinational trial (in Mozambique, The Gambia, Rwanda, Tanzania, Kenya, Uganda, and the Democratic Republic of Congo) that compared the anti-malarial drugs quinine and artesunate for the treatment of severe malaria. All children had a clinical diagnosis of severe malaria confirmed by a rapid diagnostic test, and the researchers used clinical signs to define the severity of malaria. The researchers assessed the relationship between plasma PfHRP2 concentrations and risk of death taking other well established predictors of death, such as coma, convulsions, hypoglycaemia, respiratory distress, and shock, into account.
The researchers found that PfHRP2 was detectable in 3,800/3,826 (99%) children with severe malaria and that the average plasma PfHRP2 levels was significantly higher in the 381 children who died from malaria than in children who survived (1,611 ng/mL versus 1,046 ng/mL). Plasma PfHRP2 was also significantly higher in children with severe malaria signs and symptoms such as coma, acidosis, and severe anaemia. Importantly, the researchers found that high death rates were associated with either very low or very high values of plasma PfHRP2: the odds (chance) of death were 20% higher per unit increase in PfHRP2 above a specific threshold (174 ng/ml), but below this concentration, the risk of death increased with decreasing levels, probably because at lower levels disease was caused by a severe febrile disease other than malaria, like septicemia. Finally, the researchers found that in children within the highest PfHRP2 tertile, the chance of death when treated with the antimalarial drug artesunate versus quinine was 0.61 but that there was no difference in death rates in the lowest tertile, which supports that patients with very low plasma PfHRP2 have a different severe febrile illness than malaria. The researchers use mathematical modeling to provide cut-off values for plasma PfHRP2 denoting the proportion of patients with a diagnosis other than severe malaria.
What Do These Findings Mean?
These findings suggest that in areas of moderate or high malaria transmission where a high proportion of children are parasitaemic, plasma PfHRP2 levels taken on admission to hospital can differentiate children at highest risk of death from severe falciparum malaria from those likely to have alternative causes of severe febrile illness. Therefore, plasma PfHRP2 could be considered a valuable additional diagnostic tool and prognostic indicator in African children with severe falciparum malaria. This finding is important for clinicians treating children with severe febrile illnesses in malaria-endemic countries: while high levels of plasma PfHRP2 is indicative of severe malaria which needs urgent antimalarial treatment, low levels suggest that another severe infective disease should be considered, warranting additional investigations and urgent treatment with antibiotics.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001297.
A previous small study in PLOS ONE explores the relationship between plasma PfHRP2 and severe malaria in Tanzanian children
The WHO website and the website of Malaria No More have comprehensive information about malaria
doi:10.1371/journal.pmed.1001297
PMCID: PMC3424256  PMID: 22927801
25.  Adverse effects of falciparum and vivax malaria and the safety of antimalarial treatment in early pregnancy: a population-based study 
The Lancet Infectious Diseases  2012;12(5):388-396.
Summary
Background
The effects of malaria and its treatment in the first trimester of pregnancy remain an area of concern. We aimed to assess the outcome of malaria-exposed and malaria-unexposed first-trimester pregnancies of women from the Thai–Burmese border and compare outcomes after chloroquine-based, quinine-based, or artemisinin-based treatments.
Methods
We analysed all antenatal records of women in the first trimester of pregnancy attending Shoklo Malaria Research Unit antenatal clinics from May 12, 1986, to Oct 31, 2010. Women without malaria in pregnancy were compared with those who had a single episode of malaria in the first trimester. The association between malaria and miscarriage was estimated using multivariable logistic regression.
Findings
Of 48 426 pregnant women, 17 613 (36%) met the inclusion criteria: 16 668 (95%) had no malaria during the pregnancy and 945 (5%) had a single episode in the first trimester. The odds of miscarriage increased in women with asymptomatic malaria (adjusted odds ratio 2·70, 95% CI 2·04–3·59) and symptomatic malaria (3·99, 3·10–5·13), and were similar for Plasmodium falciparum and Plasmodium vivax. Other risk factors for miscarriage included smoking, maternal age, previous miscarriage, and non-malaria febrile illness. In women with malaria, additional risk factors for miscarriage included severe or hyperparasitaemic malaria (adjusted odds ratio 3·63, 95% CI 1·15–11·46) and parasitaemia (1·49, 1·25–1·78 for each ten-fold increase in parasitaemia). Higher gestational age at the time of infection was protective (adjusted odds ratio 0·86, 95% CI 0·81–0·91). The risk of miscarriage was similar for women treated with chloroquine (92 [26%] of 354), quinine (95 [27%) of 355), or artesunate (20 [31%] of 64; p=0·71). Adverse effects related to antimalarial treatment were not observed.
Interpretation
A single episode of falciparum or vivax malaria in the first trimester of pregnancy can cause miscarriage. No additional toxic effects associated with artesunate treatment occurred in early pregnancy. Prospective studies should now be done to assess the safety and efficacy of artemisinin combination treatments in early pregnancy.
Funding
Wellcome Trust and Bill & Melinda Gates Foundation.
doi:10.1016/S1473-3099(11)70339-5
PMCID: PMC3346948  PMID: 22169409

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