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1.  Comprehensive Reference Ranges for Hematology and Clinical Chemistry Laboratory Parameters Derived from Normal Nigerian Adults 
PLoS ONE  2014;9(5):e93919.
Background
Interpretation of laboratory test results with appropriate diagnostic accuracy requires reference or cutoff values. This study is a comprehensive determination of reference values for hematology and clinical chemistry in apparently healthy voluntary non-remunerated blood donors and pregnant women.
Methods and findings
Consented clients were clinically screened and counseled before testing for HIV, Hepatitis B, Hepatitis C and Syphilis. Standard national blood donors’ questionnaire was administered to consented blood donors. Blood from qualified volunteers was used for measurement of complete hematology and chemistry parameters. Blood samples were analyzed from a total of 383 participants, 124 (32.4%) males, 125 (32.6%) non-pregnant females and 134 pregnant females (35.2%) with a mean age of 31 years. Our results showed that the red blood cells count (RBC), Hemoglobin (HB) and Hematocrit (HCT) had significant gender difference (p = 0.000) but not for total white blood count (p>0.05) which was only significantly higher in pregnant verses non-pregnant women (p = 0.000). Hemoglobin and Hematocrit values were lower in pregnancy (P = 0.000). Platelets were significantly higher in females than men (p = 0.001) but lower in pregnant women (p = 0.001) with marked difference in gestational period. For clinical chemistry parameters, there was no significant difference for sodium, potassium and chloride (p>0.05) but gender difference exists for Bicarbonate (HCO3), Urea nitrogen, Creatinine as well as the lipids (p<0.05). Total bilirubin was significantly higher in males than females (p = 0.000). Significant differences exist for all chemistry parameters between pregnant and non-pregnant women in this study (p<0.05), except Amylase and total cholesterol (p>0.05).
Conclusions
Hematological and Clinical Chemistry reference ranges established in this study showed significant gender differences. Pregnant women also differed from non-pregnant females and during pregnancy. This is the first of such comprehensive study to establish reference values among adult Nigerians and difference observed underscore the need to establish reference values for different populations.
doi:10.1371/journal.pone.0093919
PMCID: PMC4022493  PMID: 24832127
2.  Neither Folic Acid Supplementation nor Pregnancy Affects the Distribution of Folate Forms in the Red Blood Cells of Women1–3 
The Journal of nutrition  2014;144(9):1364-1369.
It is not known whether folate metabolism is altered during pregnancy to support increased DNA and RNA biosynthesis. By using a state-of-the-art LC tandem mass spectrometry technique, the aim of this study was to investigate differences in RBC folate forms between pregnant and nonpregnant women and between nonpregnant women consuming different concentrations of supplemental folic acid. Forms of folate in RBCs were used to explore potential shifts in folate metabolism during early erythropoiesis. Total RBC folate and folate forms [tetrahydrofolate; 5-methyltetrahydrofolate (5-methyl-THF); 4α-hydroxy-5-methyl-tetrahydrofolate (an oxidation product of 5-methyl-THF); 5-formyl-tetrahydrofolate; and 5,10-methenyl-tetrahydrofolate] were measured in 4 groups of women (n = 26): pregnant women (PW) (30–36 wk of gestation) consuming 1 mg/d of folic acid, and nonpregnant women consuming 0 mg/d (NPW-0), 1 mg/d (NPW-1), and 5 mg/d (NPW-5) folic acid. The mean ± SD RBC folate concentration of the NPW-0 group (890 ± 530 nmol/L) was lower than the NPW-1 (1660 ± 350 nmol/L) and NPW-5 (1980 ± 570 nmol/L) groups as assessed by microbiologic assay (n = 26, P < 0.0022). No difference was found between the NPW-1 and NPW-5 groups. We detected 5-methyl-THF [limit of detection (LOD) = 0.06 nmol/L] in all groups and tetrahydrofolate (LOD = 0.2 nmol/L) in most women regardless of methylenetetrahydrofolate reductase genotype. Most women consuming folic acid supplements had detectable concentrations of 5,10-methenyl-tetrahydrofolate (LOD = 0.31 nmol/L). However, there was no difference in the relative distribution of 5-methyl-THF (83–84%), sum of non-methyl folates (0.6–3%), or individual non-methyl folate forms in RBCs across groups. We conclude that although folic acid supplementation in nonpregnant women increases RBC total folate and the concentration of individual folate forms, it does not alter the relative distribution of folate forms. Similarly, distribution of RBC folate forms did not differ between pregnant and nonpregnant women. This trial was registered at clinicaltrials.gov as NCT01741077.
doi:10.3945/jn.113.189233
PMCID: PMC4811356  PMID: 24991041
3.  Epidemiology of nausea and vomiting of pregnancy: prevalence, severity, determinants, and the importance of race/ethnicity 
Background
Studies that contributed to the epidemiology of nausea and vomiting of pregnancy have reported conflicting findings, and often failed to account for all possible co-variables necessary to evaluate the multidimensional associations. The objectives of this study were to: 1) Estimate the prevalence and the severity of nausea and vomiting of pregnancy during the 1st and the 2nd trimester of pregnancy, and 2) Identify determinants of presence and severity of nausea and vomiting of pregnancy during the 1st and 2nd trimesters separately, with a special emphasis on the impact of race/ethnicity.
Methods
A prospective study including pregnant women attending the Centre Hospitalier Universitaire (CHU) Sainte-Justine or René-Laennec clinics for their prenatal care was conducted from 2004 to 2006. Women were eligible if they were ≥ 18 years of age, and ≤ 16 weeks of gestation. Women were asked to fill out a 1st trimester self-administered questionnaire and were interviewed over the telephone during their 2nd trimester of pregnancy. Presence of nausea and vomiting of pregnancy was based on the reporting of pregnant women (yes/no); severity of symptoms was measured by the validated modified-PUQE index.
Results
Of the 367 women included in the study, 81.2% were Caucasians, 10.1% Blacks, 4.6% Hispanics, and 4.1% Asians. Multivariate analyses showed that race/ethnicity was significantly associated with a decreased likelihood of reporting nausea and vomiting of pregnancy (Asians vs. Caucasians OR: 0.13; 95%CI 0.02–0.73; and Blacks vs. Caucasians OR: 0.29; 95%CI 0.09–0.99).
Conclusion
Our study showed that race/ethnicity was associated with the reporting of nausea and vomiting of pregnancy in the 1st trimester of pregnancy.
doi:10.1186/1471-2393-9-26
PMCID: PMC2713199  PMID: 19573237
4.  Ethnic differences in lipid and lipoprotein metabolism in pregnant women of African and Caucasian origin. 
Journal of Clinical Pathology  1994;47(12):1105-1107.
AIMS--To investigate differences in serum lipid, lipoprotein and apolipoprotein concentrations in pregnant women of different ethnic origin. METHODS--Serum lipid, lipoprotein and apolipoprotein concentrations were measured in 232 women (114 Caucasians, 118 Africans/Afro-Caribbeans), who presented consecutively for screening for gestational diabetes in the third trimester of pregnancy. RESULTS--African/Afro-Caribbean pregnant women had lower serum concentrations of total cholesterol, low density lipoprotein cholesterol, triglycerides, and apolipoprotein B and higher high density lipoprotein cholesterol and Lp(a) lipoprotein concentrations compared with Caucasian women. Apolipoprotein A1 concentrations were similar in the two groups. The differences were not attributable to differences in weight, age, parity, or postload plasma glucose levels. CONCLUSION--Ethnic origin is an important determinant of serum lipid, lipoprotein and apolipoprotein concentrations during pregnancy.
PMCID: PMC502203  PMID: 7876384
5.  RESISTIN: A HORMONE WHICH INDUCES INSULIN RESISTANCE IS INCREASED IN NORMAL PREGNANCY 
Journal of perinatal medicine  2007;35(6):513-521.
Aims
Resistin, a newly discovered adipokine, is thought to play a key role in the regulation of insulin resistance. The objectives of this study were to develop a nomogram of maternal plasma concentrations of resistin from 11 weeks of gestation to term and to determine whether resistin concentrations differ between normal and overweight pregnant women.
Methods
In this cross-sectional study, plasma concentrations of resistin were determined in normal pregnant women of normal body mass index (BMI 18.5–24.9; n=261), overweight pregnant women (BMI ≥25; n=140), and non-pregnant women of normal weight (n=40). Blood samples were collected once from each woman between the first trimester and term. Percentiles for resistin concentration were determined for five pre-specified windows of gestational age. Plasma resistin concentration was determined by immunoassay. Non-parametric statistics were used for analysis.
Results
The median maternal plasma concentration of resistin between 11 to 14 weeks of gestation in women of normal weight was significantly higher than non-pregnant women; The plasma concentration of resistin increased with gestational age.
Conclusions
Normal pregnant women have a higher median plasma concentration of resistin than non-pregnant women and the concentration of this adipokine increases with advancing gestation. Alterations in the maternal plasma concentration of resistin during pregnancy may contribute to metabolic changes of pregnancy.
doi:10.1515/JPM.2007.122
PMCID: PMC2413054  PMID: 17919114
Adipokines; Resistin; Pregnancy; Obesity; Nomogram
6.  Gestational diabetes mellitus: Challenges for different ethnic groups 
World Journal of Diabetes  2015;6(8):1024-1032.
Ethnicity is defined as “belonging to a social group that has a common national or cultural tradition”. Membership of certain ethnic groups has long been associated with increased risk of gestational diabetes mellitus (GDM). Studies that examined ethnic differences amongst women with GDM were often conducted in western countries where women from various ethnic backgrounds were represented. The prevalence of GDM appears to be particularly high among women from South Asia and South East Asia, compared to Caucasian, African-American and Hispanic communities. For some, but not all ethnic groups, the body mass index is a risk factor for the development of GDM. Even within a particular ethnic group, those who were born in their native countries have a different risk profile for GDM compared to those born in western countries. In terms of treatment, medical nutrition therapy (MNT) plays a key role in the management of GDM and the prescription of MNT should be culturally sensitive. Limited studies have shown that women who live in an English-speaking country but predominantly speak a language other than English, have lower rates of dietary understanding compared with their English speaking counterparts, and this may affect compliance to therapy. Insulin therapy also plays an important role and there appears to be variation as to the progression of women who progress to requiring insulin among different ethnicities. As for peri-natal outcomes, women from Pacific Islander countries have higher rates of macrosomia, while women from Chinese backgrounds had lower adverse pregnancy outcomes. From a maternal outcome point of view, pregnant women from Asia with GDM have a higher incidence of abnormal glucose tolerance test results post-partum and hence a higher risk of future development of type 2 diabetes mellitus. On the other hand, women from Hispanic or African-American backgrounds with GDM are more likely to develop hypertension post-partum. This review highlights the fact that management needs to be individualised and the clinician should be mindful of the impact that differences in ethnicity may have on the clinical characteristics and pregnancy outcomes in women affected by GDM, particularly those living in Western countries. Understanding these differences is critical in the delivery of optimal antenatal care for women from diverse ethnic backgrounds.
doi:10.4239/wjd.v6.i8.1024
PMCID: PMC4515442  PMID: 26240699
Gestational diabetes mellitus; Ethnicity; Peri-natal outcomes; Medical nutrition therapy; Prevalence
7.  Association of Tumor Growth Factor-β and Interferon-γ Serum Levels with Insulin Resistance in Normal Pregnancy 
Pregnancy is related to change in glucose metabolism and insulin production. The aim of our study was to determine the association of serum IFN-γ and TGF-β levels with insulin resistance during normal pregnancy. This cross sectional study was carried out on 97 healthy pregnant (in different trimesters) and 28 healthy non-pregnant women. Serum TGF-β and IFN-γ level were measured by ELISA method. Pregnant women had high level TGF-β and low level IFN-γ as compared non-pregnant women. Maternal serum TGF-β concentration significantly increased in third trimester as compared first and second trimester of pregnancy. Maternal serum IFN-γ concentration significantly decreased in third trimester as compared first and second trimester of pregnancy. Pregnant women exhibited higher score of HOMA IR as compared non-pregnant women. There were association between gestational age with body mass index (r=0.28, P=0.005), TGF-β (r=0.45, P<0.001) and IFN-γ (r=-0.50, P<0.001). There was significant association between Insulin resistance and TGF-β (r=0.17, p=0.05). Our findings suggest that changes in maternal cytokine level in healthy pregnant women were anti-inflammatory. Furthermore, Tumor Growth Factor-β appears has a role in induction insulin resistance in healthy pregnant women. However, further studies needed to evaluate role of different cytokines on insulin resistance in normal pregnancy.
doi:10.5539/gjhs.v8n6p25
PMCID: PMC4954908  PMID: 26755467
IFN-γ; TGF-β; Insulin resistance; normal pregnancy
8.  Elevation in D-dimer concentrations is positively correlated with gestation in normal uncomplicated pregnancy 
Background
D-dimer levels have been reported to increase progressively during pregnancy, but how this affects Nigerian women is not well known.
Objective
This study aims to determine the D-dimer concentration and its relationship to other coagulation parameters among pregnant women in Port Harcourt, Nigeria.
Method
In a cross-sectional observational study conducted in Port Harcourt, Nigeria, 120 pregnant women and 60 nonpregnant controls, drawn from a tertiary health institution in the Niger Delta, Nigeria, were assessed, using the standard procedures, for the following parameters: D-dimer concentration, prothrombin time, activated partial thromboplastin time, platelet count, hemoglobin, and packed cell volume.
Results
The median D-dimer concentration of 153.1 ng/mL in the pregnant group was found to be significantly elevated when compared with the control value of 118.5 ng/mL (t = 2.348, P = 0.021). Conversely, there was a marked depression in the platelet count among pregnant women (193.5 × 109/L) when compared with 229.0 × 109/L in the control group (t = 3.424; P = 0.001). There was no statistically significant difference in the values for the prothrombin time and the activated partial thromboplastin time between pregnant and nonpregnant women. D-dimer values correlated positively and significantly with gestation (r = 0.36; P < 0.01) and negatively with international normalized ratio values (r = −0.281; P < 0.05). About 63.3% of the pregnant women had normal D-dimer values (0–200 ng/mL), 26.7% of the pregnant women had elevated D-dimer levels (201–499 ng/mL), while 10.0% of the pregnant women were found to be at risk of thrombosis (D-dimer > 500 ng/mL). A linear relationship was found to exist between D-dimer and gestation (y = 8.355x + 36.55; R2 = 0.130; P < 0.005).
Conclusion
10% of the pregnant women in this population had elevated D-dimer levels over 500 ng/mL, and through comparison with what has been reported in the literature, there is the possibility that this group may be at risk of thrombosis. Further studies, incorporating other diagnostic parameters, may be needed before a more logical conclusion can be drawn, since the D-dimer is not a specific test.
doi:10.2147/IJWH.S32655
PMCID: PMC3469224  PMID: 23071413
D-dimer; prothrombin time; activated partial thromboplastin time; pregnancy; Nigeria
9.  Plasma Fibronectin Concentration in Obese/Overweight Pregnant Women: A Possible Risk Factor for Preeclampsia 
Plasma fibronectin (FN) levels in obese/overweight and non-obese pregnant women were evaluated as a possible risk factor for preeclampsia. A total of one hundred and sixty three pregnant women attending antenatal clinic at University of Calabar Teaching Hospital participated in the study and sixty non-pregnant women served as control. About 77 (47.24%) of the pregnant women were followed up for any subsequent development of preeclampsia during the pregnancy. Fibronectin levels in plasma were measured by ELISA assay and serum total protein, urea and creatinine were determined spectrophotometrically. The mean plasma FN concentration of non-obese pregnant women in first trimester was lower than those of the non-pregnant women by 24%, but however, increased to the non-pregnant level in second and third trimesters. Obese/overweight pregnant women had significantly (P < 0.05) higher values than non-obese pregnant women in second and third trimesters. FN in obese/overweight pregnant women correlated positively with mean arterial blood pressure (MAP: r = 0.414, P = 0.04). About 28.57% of the pregnant women with FN above cut off point of 330 μg/ml at 18–24 weeks of gestation developed preeclampsia. This value increased to 40.0% when only the obese/overweight women were considered. On analysis of both fibronectin >330 μg/ml and MAP > 90, the predictive value increased to 66.7%. We therefore conclude that elevated FN may be regarded as a risk factor of preeclampsia especially among the obese women.
doi:10.1007/s12291-011-0127-1
PMCID: PMC3107410  PMID: 22468048
Fibronectin; Obesity; Arterial pressure; Risk factor; Pregnancy; Preeclampsia
10.  Folic acid use in pregnant patients presenting to the emergency department 
Background
The US Preventive Services Task Force has recommended daily folic acid supplementation for women planning on becoming pregnant in an effort to prevent fetal neural tube defects. We evaluated pregnant patients presenting to the emergency department to determine rates of folic acid supplementation.
Methods
We surveyed a convenience sample of pregnant patients who presented to the University of Utah Emergency Department (ED) between 1 January 2008, and 30 April 2009, regarding pregnancy history and prior medical care.
Results
One hundred thirty-five patients participated in the study. Eighty-four patients (62.2%) reported current folic acid supplementation. Sixty-six patients identified themselves as Caucasian and 69 as non-Caucasian race. There was a significant difference in folic acid use between Caucasian and non-Caucasian women (p = 0.035). The majority of Caucasian women (71.2%) reported daily folic acid use versus approximately one-half of non-Caucasian women (53.6%). Both groups were similar in accessing a primary care provider (PCP) for pregnancy care prior to the ED visit (53% vs. 49.3%, p = 0.663), and rates of folic acid use were similar in those who had seen a PCP (85.7% vs. 76.5%, p = 0.326). Language did not have a significant association with folic acid use.
Conclusion
A large percentage of pregnant ED patients did not report current folic use, and there was a significant difference between Caucasian and non-Caucasian women in rates of folic acid supplementation. This study highlights the potential role of the ED in screening patients for folic acid supplementation.
doi:10.1186/1865-1380-4-38
PMCID: PMC3145558  PMID: 21702941
11.  Is Pregnancy Associated with Severe Dengue? A Review of Data from the Rio de Janeiro Surveillance Information System 
Background
Dengue is a reportable disease in Brazil; however, pregnancy has been included in the application form of the Brazilian notification information system only after 2006. To estimate the severity of maternal dengue infection, the available data that were compiled from January 2007 to December 2008 by the official surveillance information system of the city of Rio de Janeiro were reviewed.
Methods and Principal Findings
During the study period, 151,604 cases of suspected dengue infection were reported. Five hundred sixty-one women in their reproductive age (15–49 years) presented with dengue infection; 99 (18.1%) pregnant and 447 (81.9%) non-pregnant women were analyzed. Dengue cases were categorized using the 1997 WHO classification system, and DHF/DSS were considered severe disease. The Mann-Whitney test was used to compare maternal age, according to gestational period, and severity of disease. A chi-square test was utilized to evaluate the differences in the proportion of dengue severity between pregnant and non-pregnant women. Univariate analysis was performed to compare outcome variables (severe dengue and non-severe dengue) and explanatory variables (pregnancy, gestational age and trimester) using the Wald test. A multivariate analysis was performed to assess the independence of statistically significant variables in the univariate analysis. A p-value<0.05 was considered statistically significant.
A higher percentage of severe dengue infection among pregnant women was found, p = 0.0001. Final analysis demonstrated that pregnant women are 3.4 times more prone to developing severe dengue (OR: 3.38; CI: 2.10–5.42). Mortality among pregnant women was superior to non-pregnant women.
Conclusion
Pregnant women have an increased risk of developing severe dengue infection and dying of dengue.
Author Summary
Dengue represents a major worldwide public health problem. According to the WHO, up to 50 million dengue infections occur each year. The occurrence of dengue fever and dengue hemorrhagic fever has increased in Brazil, in part due to the simultaneous circulation of DENV-1, DENV-2 and DENV-3. Although a primary infection with one serotype confers a partial or transient immunity against other serotypes, any subsequent infections harbor the risk of increased morbidity/mortality. Several case reports have been published regarding maternal and fetal outcomes from dengue infection, but it is still inconclusive if pregnancy is associated with severity. To estimate the severity of maternal dengue infection, available data that were compiled from 2007 to 2008 by the official surveillance information system of the city of Rio de Janeiro were reviewed. The cases of dengue were analyzed using the 1997 WHO classification. Pregnant women were 3.4 times more prone to developing severe dengue than non-pregnant women. Mortality among pregnant women was superior to non-pregnant women. The increased risk of severe outcomes in pregnant women merits further attention to effective public health and medical interventions that will aid in avoiding morbidity/fatalities within this population.
doi:10.1371/journal.pntd.0002217
PMCID: PMC3649957  PMID: 23675548
12.  The Effect of Intermittent Antenatal Iron Supplementation on Maternal and Infant Outcomes in Rural Viet Nam: A Cluster Randomised Trial 
PLoS Medicine  2013;10(6):e1001470.
Beverley-Anne Biggs and colleagues conduct a community-based cluster randomized trial in rural Viet Nam to compare the effect of antenatal iron-folic acid supplementation taken daily or twice weekly on maternal and infant outcomes.
Please see later in the article for the Editors' Summary
Background
Anemia affects over 500 million women, and in pregnancy is associated with impaired maternal and infant outcomes. Intermittent antenatal iron supplementation is an attractive alternative to daily dosing; however, the impact of this strategy on infant outcomes remains unclear. We compared the effect of intermittent antenatal iron supplementation with daily iron supplementation on maternal and infant outcomes in rural Viet Nam.
Methods and Findings
This cluster randomised trial was conducted in Ha Nam province, Viet Nam. 1,258 pregnant women (<16 wk gestation) in 104 communes were assigned to daily iron–folic acid (IFA), twice weekly IFA, or twice weekly multiple micronutrient (MMN) supplementation. Primary outcome was birth weight. Mean birth weight was 3,148 g (standard deviation 416). There was no difference in the birth weights of infants of women receiving twice weekly IFA compared to daily IFA (mean difference [MD] 28 g; 95% CI −22 to 78), or twice weekly MMN compared to daily IFA (MD −36.8 g; 95% CI −82 to 8.2). At 32 wk gestation, maternal ferritin was lower in women receiving twice weekly IFA compared to daily IFA (geometric mean ratio 0.73; 95% CI 0.67 to 0.80), and in women receiving twice weekly MMN compared to daily IFA (geometric mean ratio 0.62; 95% CI 0.57 to 0.68), but there was no difference in hemoglobin levels. Infants of mothers who received twice weekly IFA had higher cognitive scores at 6 mo of age compared to those who received daily IFA (MD 1.89; 95% CI 0.23 to 3.56).
Conclusions
Twice weekly antenatal IFA or MMN did not produce a clinically important difference in birth weight, when compared to daily IFA supplementation. The significant improvement in infant cognitive outcomes at 6 mo of age following twice weekly antenatal IFA requires further exploration, and provides additional support for the use of intermittent, rather than daily, antenatal IFA in populations with low rates of iron deficiency.
Trial registration
Australia New Zealand Clinical Trials Registry 12610000944033
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Anemia is a common condition in which the blood does not supply the body with enough oxygen because of a low number of red blood cells or low levels of hemoglobin—the iron-containing pigment that enables red blood cells to carry oxygen. Iron deficiency is the most common cause of anemia worldwide and, according to the World Health Organization, affects over 2 billion people: half of all pregnant women and 40% of preschool children in low- and middle-income countries are thought to be anemic. Anemia contributes to 20% of all maternal deaths and is also linked to increased maternal morbidity, higher rates of preterm birth and low birth weight, and reduced infant survival, with potential long-term consequences for child growth and development. Identifying and treating iron deficiency anemia is therefore a global health priority.
Why Was This Study Done?
Daily iron–folic acid supplementation given from early in pregnancy is the standard recommended approach to prevent and treat anemia in pregnant women, but recently the World Health Organization recommended intermittent use because of poor compliance with daily regimes (because of side effects) and poor bowel absorption. However, the evidence from many of the studies used to support this recommendation was of poor quality, and so it remains unclear whether intermittent supplementation is as, or more, effective than daily supplementation, especially in lower income settings where antenatal testing for anemia is not readily available. So in this study, the researchers conducted a community-based cluster randomized trial (where groups of people are randomized, rather than individuals) in rural Viet Nam to compare the effect of antenatal iron–folic acid supplementation taken twice weekly (either alone, or in combination with other micronutrients) with daily iron–folic acid supplementation, on maternal and infant outcomes during the first six months of life.
What Did the Researchers Do and Find?
The researchers randomized 104 communes in Ha Nam Province, Viet Nam, and enrolled 1,258 women who were less than 16 weeks pregnant into the study between September and November 2010. Although the researchers intended to register the trial before the study started, registration was delayed by a month because the supplements arrived earlier than the researchers anticipated, and they thought it best to start recruiting at that time to avoid the Vietnamese New Year, when women might be travelling. Each woman was interviewed and had blood taken for hemoglobin and iron indices (ferritin) before receiving daily iron–folic acid supplementation (426 women), twice weekly iron–folic acid supplementation (425 women), or twice weekly iron–folic acid supplementation plus micronutrients (407 women). The women had follow-up assessments at 32 weeks gestation, delivery, and at six months postpartum: their infants were assessed at birth and at six months old.
The researchers found that at enrollment, the women's average hemoglobin concentration was 123 g/l, and 12.6% of the women were anemic. At 32 weeks gestation, 10.8% of the women were anemic, but there was no difference in hemoglobin levels between the three supplement groups. The average ferritin level was 75.6 µg/l at enrollment, with 2.2% of women iron deficient. Ferritin levels decreased from enrollment to 32 weeks gestation in all supplement groups but were lower in women who took twice weekly supplements. The researchers also found that birth weight (the primary outcome) was similar in all supplement groups, and there were also no differences in gestational age or in the risk of prematurity, stillbirth, or early neonatal death. At six months, there were also no differences in the levels of infant hemoglobin, prevalence of anemia, or growth rates. However, infants born to mothers in the twice weekly iron–folic acid group had improved cognitive development compared to infants born to mothers in the daily supplement group. Finally, the researchers found that adherence rates were significantly higher in the twice weekly iron–folic acid supplement group compared to the once daily regime.
What Do These Findings Mean?
These findings suggest that in an area of Southeast Asia with low anemia prevalence, once daily antenatal supplementation with iron–folic acid did not provide any benefits in birth weight or improved infant growth over twice weekly supplementation. Furthermore, twice weekly supplementation with iron–folic acid was associated with improved maternal adherence rates and also improved cognitive development in infants aged six months—a finding that requires further study and provides added support for the use of intermittent iron–folic acid supplementation over daily supplementation.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001470.
The World Health Organization website has comprehensive information on anemia, including a report of global estimates and the guideline Intermittent Iron and Folic Acid Supplementation in Non-Anaemic Pregnant Women
Wikipedia provides information on iron supplementation (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001470
PMCID: PMC3708703  PMID: 23853552
13.  A Randomised Controlled Trial of Artemether-Lumefantrine Versus Artesunate for Uncomplicated Plasmodium falciparum Treatment in Pregnancy 
PLoS Medicine  2008;5(12):e253.
Background
To date no comparative trials have been done, to our knowledge, of fixed-dose artemisinin combination therapies (ACTs) for the treatment of Plasmodium falciparum malaria in pregnancy. Evidence on the safety and efficacy of ACTs in pregnancy is needed as these drugs are being used increasingly throughout the malaria-affected world. The objective of this study was to compare the efficacy, tolerability, and safety of artemether-lumefantrine, the most widely used fixed ACT, with 7 d artesunate monotherapy in the second and third trimesters of pregnancy.
Methods and Findings
An open-label randomised controlled trial comparing directly observed treatment with artemether-lumefantrine 3 d (AL) or artesunate monotherapy 7 d (AS7) was conducted in Karen women in the border area of northwestern Thailand who had uncomplicated P. falciparum malaria in the second and third trimesters of pregnancy. The primary endpoint was efficacy defined as the P. falciparum PCR-adjusted cure rates assessed at delivery or by day 42 if this occurred later than delivery, as estimated by Kaplan-Meier survival analysis. Infants were assessed at birth and followed until 1 y of life. Blood sampling was performed to characterise the pharmacokinetics of lumefantrine in pregnancy. Both regimens were very well tolerated. The cure rates (95% confidence interval) for the intention to treat (ITT) population were: AS7 89.2% (82.3%–96.1%) and AL 82.0% (74.8%–89.3%), p = 0.054 (ITT); and AS7 89.7% (82.6%–96.8%) and AL 81.2% (73.6%–88.8%), p = 0.031 (per-protocol population). One-third of the PCR-confirmed recrudescent cases occurred after 42 d of follow-up. Birth outcomes and infant (up to age 1 y) outcomes did not differ significantly between the two groups. The pharmacokinetic study indicated that low concentrations of artemether and lumefantrine were the main contributors to the poor efficacy of AL.
Conclusion
The current standard six-dose artemether-lumefantrine regimen was well tolerated and safe in pregnant Karen women with uncomplicated falciparum malaria, but efficacy was inferior to 7 d artesunate monotherapy and was unsatisfactory for general deployment in this geographic area. Reduced efficacy probably results from low drug concentrations in later pregnancy. A longer or more frequent AL dose regimen may be needed to treat pregnant women effectively and should now be evaluated. Parasitological endpoints in clinical trials of any antimalarial drug treatment in pregnancy should be extended to delivery or day 42 if it comes later.
Trial Registration: Current Controlled Trials ISRCTN86353884
Rose McGready and colleagues show that an artemether-lumefantrine regimen is well tolerated and safe in pregnant Karen women with uncomplicated falciparum malaria, but efficacy is inferior to artesunate, probably because of low drug concentrations in later pregnancy.
Editors' Summary
Background.
Plasmodium falciparum, a mosquito-borne parasite that causes malaria, kills nearly one million people every year. Although most deaths occur among young children, malaria during pregnancy is also an important public-health problem. In areas where malaria transmission is high (stable transmission), women acquire a degree of immunity. Although less symptomatic than women who lack natural protection, their babies are often small and sickly because malaria-related anemia (lack of red blood cells) and parasites in the placenta limit the nutrients supplied to the baby before birth. By contrast, in areas where malaria transmission is low (unstable transmission or sporadic outbreaks), women have little immunity to P. falciparum. If these women become infected during pregnancy, “uncomplicated” malaria (fever, chills, and anemia) can rapidly progress to “severe” malaria (in which vital organs are damaged), which can be fatal to the mother and/or her unborn child unless prompt and effective treatment is given.
Why Was This Study Done?
Malaria parasites are now resistant to many of the older antimalarial drugs (for example, quinine). So, since 2006, the World Health Organization (WHO) has recommended that uncomplicated malaria during the second and third trimester of pregnancy is treated with short course (3 d) fixed-dose artemisinin combination therapy (ACT; quinine is still used in early pregnancy because it is not known whether ACT damages fetal development, which mainly occurs during the first 3 mo of pregnancy). Artemisinin derivatives are fast-acting antimalarial agents that are used in combination with another antimalarial drug to reduce the chances of P. falciparum becoming resistant to either drug. The most widely used fixed-dose ACT is artemether–lumefantrine (AL) but, although several trials have examined the safety and efficacy of this treatment in non-pregnant women, little is known about how well it works in pregnant women. In this study, the researchers compare the efficacy, tolerability, and safety of AL with a 7-d course of artesunate monotherapy (AS7; another artemisinin derivative) in the treatment of uncomplicated malaria in pregnancy in northwest Thailand, an area with unstable but highly drug resistant malaria transmission.
What Did the Researchers Do and Find?
The researchers enrolled 253 women with uncomplicated malaria during the second and third trimesters of pregnancy into their open-label trial (a trial in which the patients and their health-care workers know who is receiving which drug regimen). Half the women received each type of treatment. The trial's main outcome was the “PCR-adjusted cure rate” at delivery or 42 d after treatment if this occurred after delivery. This cure rate was assessed by examining blood smears for parasites and then using a technique called PCR to determine which cases of malaria were new infections (classified as treatment successes along with negative blood smears) and which were recurrences of an old infection (classified as treatment failures). The PCR-adjusted cure rates were 89.7% and 81.2% for AS7 and AL, respectively. Both treatments were well tolerated, few side effects were seen with either treatment, and infant health and development at birth and up to 1 y old were similar with both regimens. Finally, an analysis of blood samples taken 7 d after treatment with AL showed that blood levels of lumefantrine were below those previously associated with treatment failure in about a third of the women tested.
What Do These Findings Mean?
Although these findings indicate that the AL regimen is a well tolerated and safe treatment for uncomplicated malaria in pregnant women living in northwest Thailand, the efficacy of this treatment was lower than that of artesunate monotherapy. In fact, neither treatment reached the 90% cure rate recommended by WHO for ACTs and it is likely that cure rates in a more realistic situation (that is, not in a trial where efforts are made to make sure everyone completes their treatment) would be even lower. The findings also suggest that the reduced efficacy of the AL regimen in pregnant women compared to the efficacy previously seen in non-pregnant women may be caused by lower drug blood levels during pregnancy. Thus, a higher-dose AL regimen (or an alternative ACT) may be needed to successfully treat uncomplicated malaria during pregnancy.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050253.
The MedlinePlus encyclopedia contains a page on malaria (in English and Spanish)
Information is available from the World Health Organization on malaria (in several languages), and their 2006 Guidelines for the Treatment of Malaria includes specific recommendations for the treatment of pregnant women
The US Centers for Disease Control and Prevention provide information on malaria and on malaria during pregnancy (in English and Spanish)
Information is available from the Roll Back Malaria Partnership on malaria during pregnancy, on artemisinin-based combination therapies, and on malaria in Thailand
doi:10.1371/journal.pmed.0050253
PMCID: PMC2605900  PMID: 19265453
14.  What accounts for ethnic differences in newborn skinfold thickness comparing South Asians and White Caucasians? Findings from the START and FAMILY Birth Cohorts 
Objective:
South Asians are a high-risk group for type 2 diabetes and coronary heart disease. We sought to determine ethnic differences in newborn adiposity comparing South Asians (SA) to White Caucasians (Whites).
Methods:
Seven hundred ninety pregnant women (401 SA, 389 Whites) and their full-term offspring from two birth cohorts in Canada were analyzed. Pregnant women completed a health assessment including a 75-g oral glucose tolerance test to assess for dysglycemia. Birthweight, length, waist and hip circumference, and triceps and subscapular skinfold thickness (a surrogate measure of body adiposity) were measured in all newborns. Multivariate regression was used to identify maternal factors associated with newborn skinfold measurements.
Results:
South Asian women were younger (30.1 vs 31.8 years, P<0.001), their prepregnancy body mass index was lower (23.7 vs 26.2, P<0.0001) and gestational diabetes was substantially higher (21% vs 13%, P=0.005) compared with Whites. Among full-term newborns, South Asians had lower birthweight (3283 vs 3517 g, P=0.0001), had greater skinfold thickness (11.7 vs 10.6 mm; P=0.0001) and higher waist circumference (31.1 vs 29.9 cm, P=0.0001) compared with Whites. Risk factors for newborn skinfold thickness included South Asian ethnicity (standardized estimate (s.e.): 0.24; P<0.0001), maternal glucose (s.e.: 0.079; P=0.04) and maternal body fat (s.e.: 0.14; P=0.0002).
Conclusions:
South Asian newborns are lower birthweight and have greater skinfold thickness, compared with White newborns, and this is influenced by maternal body fat and glucose. Interventions aimed at reducing body fat prior to pregnancy and gestational diabetes during pregnancy in South Asians may favorably alter newborn body composition and require evaluation.
doi:10.1038/ijo.2015.171
PMCID: PMC4753357  PMID: 26315840
15.  Objectively recorded physical activity in pregnancy and postpartum in a multi-ethnic cohort: association with access to recreational areas in the neighbourhood 
Background
Physical activity may reduce the risk of adverse pregnancy outcomes; however, compared to non-pregnant women, a lower proportion of pregnant women meet the physical activity guidelines. Our objectives were to explore overall changes and ethnic differences in objectively recorded moderate-to-vigorous intensity physical activity (MVPA) during pregnancy and postpartum and to investigate the associations with objective and perceived access to recreational areas.
Methods
We analysed 1,467 person-observations from 709 women in a multi-ethnic population-based cohort, with MVPA data recorded with the SenseWear™ Pro3 Armband in early pregnancy (mean gestational week (GW) 15), mid-pregnancy (mean GW 28) and postpartum (mean postpartum week 14). MVPA was limited to bouts ≥10 min. Women were nested within 56 neighbourhoods defined by postal code area. We derived neighbourhood-level objective access to recreational areas (good vs limited) by geographic information systems. We collected information about perceived access (high vs low perception) to recreational areas in early pregnancy. We treated ethnicity, objective and perceived access as explanatory variables in separate models based on linear mixed effects regression analyses.
Results
Overall, MVPA dropped between early and mid-pregnancy, followed by an increase postpartum. Western women performed more MVPA than women in other ethnic groups across time points, but the differences increased postpartum. Women residing in neighbourhoods with good objective access to recreational areas accumulated on average nine additional MVPA minutes/day (p < 0.01) compared with women in neighbourhoods with limited access. Women with perceptions of high access to recreational areas accumulated on average five additional MVPA minutes/day (p < 0.01) compared with women with perceptions of low access. After mutual adjustments, perceived and objective access to recreational areas remained significantly associated with MVPA. The association between MVPA and access to recreational areas did not differ by time point, ethnic group or socio-economic position.
Conclusions
In all ethnic groups, we observed a decline in MVPA between early and mid-pregnancy. However, at both time points during pregnancy, and especially three months postpartum, Western women were more physically active than ethnic minority women. In all ethnic groups, and at all three time points, both objective and perceived access to recreational areas were positively associated with MVPA levels.
Electronic supplementary material
The online version of this article (doi:10.1186/s12966-016-0401-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s12966-016-0401-y
PMCID: PMC4936091  PMID: 27386943
Physical activity; Urban planning; Neighbourhoods; Pregnancy; Geographic information systems; Ethnic groups
16.  Extracellular chromosome 21-derived microRNAs in euploid & aneuploid pregnancies 
Background & objectives:
Trisomy 21 is the most common chromosomal aneuploidy in live born infants. Recently, the over expression of chromosome 21-derived microRNAs (miR-99a, let-7c, miR-125b-2, miR-155 and miR-802) in human fetal hippocampus and heart samples from individuals with Down syndrome was observed. Therefore, concentrations and expression profile of extracellular chromosome 21-derived microRNAs were studied to verify their ability to distinguish noninvasively between pregnancies bearing euploid fetuses and those affected with Down syndrome.
Methods:
RNA enriched for small RNAs was isolated from plasma samples of 12 pregnant women with high risk of bearing Down syndrome foetuses (median gestation 18.5 wk), 12 women with normal course of gestation and 10 non-pregnant women. MicroRNA transcribed into cDNA using specific stem-loop primer was detected using real-time PCR assay. Simulation experiments using RNA pools of healthy non-pregnant individuals and aneuploid amniotic fluid samples in descending dilution ratio ranging from 1:1 to 1000:1 were used to test the detection limit of the technique for overexpressed chromosome 21-derived microRNAs specific for Down syndrome. The expression profile of the gene encoding microRNA was studied through the relative gene expression using the comparative Ct (threshold cycle) method. Concentrations of individual microRNAs were subtracted from the calibration curves in the course of analyses and expressed as pg of total RNA per milliliter of plasma.
Results:
Four of the five extracellular chromosome 21-derived microRNAs (miR-99a, let-7c, miR-125b-2 and miR-155) were reliably detected in plasma samples. Simulation experiments revealed the detection limit of aneuploidy at a ratio 100:1 for let-7c, miR-125b-2 and miR-155, and a ratio of 1000:1 for miR-99a. Overexpression of extracellular miR-99a, miR-125b-2 and miR-155 was observed in pregnant women compared to non-pregnant women. Similarly, increased concentrations of extracellular miR-99a and miR-125b-2 were detected in pregnant women than in non-pregnant women. The concentrations and relative gene expression of extracellular chromosome 21-derived microRNAs did not differ between the cohorts of pregnancies bearing euploid foetuses and those affected with Down syndrome.
Interpretation & conclusions:
Analysis of extracellular chromosome 21-derived microRNAs has no benefit for screening programmes and non-invasive diagnosis of Down syndrome.
PMCID: PMC3978985  PMID: 24521639
Aneuploidy; chromosome 21; Down syndrome; maternal plasma; microRNAs; real-time PCR; screening
17.  Intermittent Preventive Treatment of Malaria in Pregnancy with Mefloquine in HIV-Infected Women Receiving Cotrimoxazole Prophylaxis: A Multicenter Randomized Placebo-Controlled Trial 
PLoS Medicine  2014;11(9):e1001735.
Clara Menéndez and colleagues conducted a randomized controlled trial among HIV-positive pregnant women in Kenya, Mozambique, and Tanzania to investigate the safety and efficacy of mefloquine as intermittent preventative therapy for malaria in women receiving cotrimoxazole prophylaxis and long-lasting insecticide treated nets.
Please see later in the article for the Editors' Summary
Background
Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is recommended for malaria prevention in HIV-negative pregnant women, but it is contraindicated in HIV-infected women taking daily cotrimoxazole prophylaxis (CTXp) because of potential added risk of adverse effects associated with taking two antifolate drugs simultaneously. We studied the safety and efficacy of mefloquine (MQ) in women receiving CTXp and long-lasting insecticide treated nets (LLITNs).
Methods and Findings
A total of 1,071 HIV-infected women from Kenya, Mozambique, and Tanzania were randomized to receive either three doses of IPTp-MQ (15 mg/kg) or placebo given at least one month apart; all received CTXp and a LLITN. IPTp-MQ was associated with reduced rates of maternal parasitemia (risk ratio [RR], 0.47 [95% CI 0.27–0.82]; p = 0.008), placental malaria (RR, 0.52 [95% CI 0.29–0.90]; p = 0.021), and reduced incidence of non-obstetric hospital admissions (RR, 0.59 [95% CI 0.37–0.95]; p = 0.031) in the intention to treat (ITT) analysis. There were no differences in the prevalence of adverse pregnancy outcomes between groups. Drug tolerability was poorer in the MQ group compared to the control group (29.6% referred dizziness and 23.9% vomiting after the first IPTp-MQ administration). HIV viral load at delivery was higher in the MQ group compared to the control group (p = 0.048) in the ATP analysis. The frequency of perinatal mother to child transmission of HIV was increased in women who received MQ (RR, 1.95 [95% CI 1.14–3.33]; p = 0.015). The main limitation of the latter finding relates to the exploratory nature of this part of the analysis.
Conclusions
An effective antimalarial added to CTXp and LLITNs in HIV-infected pregnant women can improve malaria prevention, as well as maternal health through reduction in hospital admissions. However, MQ was not well tolerated, limiting its potential for IPTp and indicating the need to find alternatives with better tolerability to reduce malaria in this particularly vulnerable group. MQ was associated with an increased risk of mother to child transmission of HIV, which warrants a better understanding of the pharmacological interactions between antimalarials and antiretroviral drugs.
Trial registration
ClinicalTrials.gov NCT 00811421; Pan African Clinical Trials Registry PACTR 2010020001813440
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Malaria, a mosquito-borne parasitic disease, kills about 600,000 people every year. Most of these deaths occur among young children living in sub-Saharan Africa but pregnant women living in Africa are also very vulnerable to malaria. Infection with malaria during pregnancy can cause severe maternal anemia (reduced red blood cell numbers), stillbirths, and pre-term and low-birthweight babies, and is responsible for the deaths of many African women and their babies. To reduce the loss of life from malaria in pregnancy, the World Health Organization (WHO) recommends that pregnant women living in Africa receive the antimalarial drug sulfadoxine-pyrimethamine (SP) at each scheduled antenatal care visit given at least a month apart (intermittent preventive treatment in pregnancy [IPTp]). In addition, WHO advises pregnant women to sleep under insecticide-treated bed nets to protect themselves from the bites of infected mosquitoes and recommends effective case management of pregnant women with malarial illness.
Why Was This Study Done?
Pregnant women living in Africa are often infected with HIV, the virus that causes AIDS. HIV infection increases both the risk and severity of malaria infection during pregnancy, and at least one million pregnancies are complicated by co-infection with malaria and HIV in sub-Saharan Africa every year. WHO recommends that HIV-positive pregnant women take cotrimoxazole (CTX) daily to prevent opportunistic infections (CTX prophylaxis [CTXp]). Unfortunately, both CTX and SP are antifolate drugs and taking two drugs of this type increases a woman's risk of developing a severe skin reaction. Moreover, although CTXp protects children and HIV-infected adults against malaria, it is not known whether CTXp alone protects HIV-infected pregnant women adequately against malaria. Thus, evaluations of alternative drugs for use in IPTp in HIV-positive pregnant women are needed. In this randomized placebo-controlled trial, the researchers study the safety and efficacy of the antimalarial drug mefloquine (MQ) in HIV-infected women receiving CTXp. A randomized, placebo-controlled trial compares outcomes among people chosen through the play of chance to receive either the drug under investigation or a “dummy” (placebo) drug.
What Did the Researchers Do and Find?
The researchers allocated 1,071 HIV-infected pregnant women from Kenya, Mozambique, and Tanzania to receive three doses of MQ (IPTp-MQ), given at least one month apart, or three doses of placebo. All the women received CTXp and were given an insecticide-treated bed net. In an intention-to-treat analysis (an analysis that considers the outcomes of all trial participants irrespective of whether they receive their allocated treatment), the prevalence of parasitemia (parasites in the blood) at delivery among women given IPTp-MQ was 3.5% whereas the prevalence among women given the placebo was 6.9%. In other words, compared to placebo, IPTp-MQ was associated with a reduced risk of maternal parasitemia. IPTp-MQ was also associated with a reduced rate of placental malaria (parasites in the placenta) and a reduced incidence of hospital admissions for non-pregnancy related causes. There was no difference in adverse pregnancy outcomes such as stillbirth between the intervention groups but drug tolerability was poorer in the MQ group than in the placebo group. Finally, in an exploratory (unplanned) according-to-protocol analysis (an analysis that only considers outcomes in trial participants who receive their allocated intervention), women in the MQ group had a higher HIV viral load at delivery than women in the control group and were nearly twice as likely to transmit HIV to their child around the time of birth.
What Do These Findings Mean?
These findings suggest that the addition of IPTp-MQ to CTXp and the use of insecticide-treated bed nets can improve malaria prevention and maternal health in HIV-infected pregnant women in Africa. However, the poor tolerability of MQ and the association of MQ treatment with both an increased HIV viral load at delivery and a higher frequency of mother-to-child-transmission of HIV when compared to placebo raise concerns about the use of MQ in IPTp. Because these last two findings came from an exploratory analysis, which is more likely to throw up a chance finding than a pre-planned analysis further studies are needed to confirm these unexpected but potentially important findings. Nevertheless, overall, the findings of this study suggest that MQ should not be recommended for IPTp in HIV-infected pregnant women in Africa and highlight the need to find alternative drugs for malaria prevention in this group of women who are particularly vulnerable to malaria.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001735.
This study is further discussed in a PLOS Medicine Perspective by Richard Steketee.
A related PLOS Medicine Research Article by González et al. compares the efficacy of IPTp-MQ and IPTp-SP in HIV-negative women
Information is available from the World Health Organization on malaria (in several languages) and on malaria in pregnancy; information on IPTp and the current WHO policy recommendation on IPTp with SP are available; the 2013 World Malaria Report provides details of the current global malaria situation
The US Centers for Disease Control and Prevention also provides information on malaria; a personal story about malaria in pregnancy is available
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
MedlinePlus provides links to additional information on malaria (in English and Spanish)
More information about the trial protocol is available
doi:10.1371/journal.pmed.1001735
PMCID: PMC4172537  PMID: 25247995
18.  Retaining women in a prenatal care randomized controlled trial in Canada: implications for program planning 
BMC Public Health  2007;7:148.
Background:
Challenges to retention in prenatal care seem to exist under both universal systems of care, as in Canada, and non-universal systems of care, as in the United States. However, among populations being served by a system of publicly funded health care, the barriers are less well understood and universal uptake of prenatal services has not been realized. Determining the characteristics of women who dropped out of a prenatal care randomized controlled trial can help identify those who may need alternate retention and service approaches.
Methods:
In this study, pregnant women were randomized to: a) current standard of care; b) 'a' plus nursing support; or c) 'b' plus a paraprofessional home visitor. 16% of 2,015 women did not complete all three telephone interviews (197 dropped out and 124 became unreachable). Responders were compared to non-responders on demographics, lifestyle, psychosocial factors, and life events using chi-squared tests. Logistic regression models were constructed using stepwise logistic regression to determine the probability of not completing the prenatal program.
Results:
Completion rates did not differ by intervention. In comparison to responders, non-responders were more likely to be younger, less educated, have lower incomes, smoke, have low social support, have a history of depression, and have separated or divorced parents (all p < 0.05). Unreachable women were more likely to be single, use drugs, report distress and adverse life events (all p < 0.05). Non-Caucasian women were more likely to drop out (p = 0.002). Logistic regression modeling indicated that independent key risk factors for dropping out were: less than high school education, separated or divorced parents, lower social support, and being non-Caucasian. Pregnant women who were single/separated/divorced, less than 25 years old, had less than high school education, earned less than $40,000 in annual household income, and/or smoked had greater odds of becoming unreachable at some point during pregnancy and not completing the study.
Conclusion:
Women at risk due to lifestyle and challenging circumstances were difficult to retain in a prenatal care study, regardless of the intervention. For women with complex health, lifestyle and social issues, lack of retention may reflect incongruence between their needs and the program.
Trial registration:
Current Controlled Trials ISRCTN64070727
doi:10.1186/1471-2458-7-148
PMCID: PMC1939989  PMID: 17617914
19.  Soluble TRAIL in Normal Pregnancy and Acute Pyelonephritis: a Potential Explanation for the Susceptibility of Pregnant Women to Microbial Products and Infection 
Objective
Pregnancy is characterized by activation of the innate immune response demonstrated by phenotypic and metabolic changes in granulocytes and monocytes. This state of activation has been implicated in the pathophysiology of multiorgan dysfunction of pregnant women with acute viral or bacterial infection. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is one of the mediators responsible for neutrophil apoptosis. Gene deletion of TRAIL results in delayed neutrophil apoptosis and resolution of inflammation after the administration of bacterial endotoxin. The aim of this study was to determine if maternal plasma concentrations of the soluble form of TRAIL (sTRAIL) differ in women with uncomplicated pregnancy and those with acute pyelonephritis.
Method
A cross-sectional study was conducted to include women in the following groups: 1) non-pregnant (n=23); 2) uncomplicated pregnancies (n=93); and 3) pregnancies with acute pyelonephritis (n=23). Plasma concentrations of sTRAIL were determined by ELISA.
Results
1) Women with uncomplicated pregnancies had a lower mean plasma sTRAIL concentration (pg/mL) than non-pregnant women (31.5 ± 10.1 vs. 53.3 ± 12.5; p < 0.001); 2) plasma sTRAIL concentrations did not change as a function of gestational age (Pearson correlation = −0.1; p=0.4); 3) the mean plasma sTRAIL concentration (pg/mL) was significantly lower in pregnant women with acute pyelonephritis than in those with uncomplicated pregnancies (20.5 ± 6.6 vs. 31.5 ± 10.1; p<0.001); and 4) among patients with acute pyelonephritis, patients with bacteremia had a significantly lower mean plasma concentration of sTRAIL (pg/mL) than those without bacteremia (15.1 ± 4.8 vs. 24.7 ± 4.6; p< 0.001).
Conclusion
Women with uncomplicated pregnancies are associated with a significantly lower mean maternal plasma concentration of sTRAIL than that observed in non-pregnant women. Moreover, a further decrease of plasma sTRAIL concentration was observed in pregnant women with acute pyelonephritis, and this could account, at least in part, for the exaggerated intravascular inflammatory response previously reported in pyelonephritis during pregnancy.
doi:10.3109/14767058.2013.783811
PMCID: PMC4100917  PMID: 23480056
innate immunity; neutrophil apoptosis; non-pregnant; normal pregnancy; plasma; tumor necrosis factor-related apoptosis-inducing ligand
20.  Clinical Profile, Maternal and Fetal Outcomes of Acute Hepatitis E in Pregnancy 
Background:
Pregnant women are at increased risk of complications in hepatitis E virus (HEV) infection, with the risk increasing as the pregnancy progresses, often leading to fulminant hepatic failure and adverse fetal outcome.
Aims:
The primary objective of the following study is to evaluate the maternal and fetal complications of this infection and secondary aim is to compare the clinical features of hepatitis E in pregnant women to those in non-pregnant women.
Subjects and Methods:
This was a hospital based case-controls study, carried out from July 2008 to June 2010. Over a period of 2 years, cases were serologically confirmed pregnant women with hepatitis E, selected by screening in antenatal clinic. Controls were serologically confirmed non-pregnant women with hepatitis E, selected by screening in Medicine Outpatient Department. We studied 96 women with HEV infection, of which 52 were pregnant and 44 were non-pregnant. Clinical and laboratory profile of patients in both groups were studied. Patients were treated as per protocol and the outcome was studied in both groups. Pregnant women were followed-up for fetal and maternal outcome. We used t-test and z-test to compare normally distributed data and non-normally distributed data, respectively. Chi-square test was used to compare discrete values between groups.
Results:
Mean (standard deviation [SD]) age in pregnant patients was 24.1 (3.3) years while 32.6 (10.5) years in non-pregnant patients. 71.1% (37/52) of the patients were primigravida and 28.8% (15/52) patients were multigravida, by natural occurrence. Mean (SD) gestational age when infection occurred was 27.5 (7.2) weeks. Among pregnant women, 63.4% (33/52) were in 3rd trimester. Jaundice 1-5 days before presentation was seen in 51.9% (27/52) pregnant and 44.2% (23/44) non-pregnant women. Myalgia/arthralgia, fever, nausea/vomiting, right upper quadrant pain, jaundice, dark urine, light-colored stools, pruritus, diarrhea, altered sensorium and hematemesis/melena were presenting features. In pregnant group, 46.1% (24/52) patients developed encephalopathy while in non-pregnant group 34% (15/44) developed this complication. Among pregnant cases, 67.3% (35/52) survived and 32% (17/52) cases died. In non-pregnant group, nearly 90% (40/44) patients survived and only 9% (4/44) patients died. This difference was statistically significant (P < 0.01). Adverse fetal outcome was seen in 71.1% (37/52) pregnant women with acute hepatitis E, including pre-term delivery in 23% (12/52), stillbirth in 23% (12/52), abortion in 3.8% (2/52) and intra-uterine fetal death in 21.1% (11/52) patients.
Conclusions:
There is significantly higher occurrence of hepatitis E infection in pregnant women than in non-pregnant women, which increases with gestation, with associated fulminant hepatic failure, maternal mortality and worse fetal outcome.
doi:10.4103/2141-9248.138033
PMCID: PMC4145510  PMID: 25184080
Fetal outcome; Hepatitis E; Jaundice; Pregnancy
21.  Gestational thrombocytopaenia among pregnant women in Lagos, Nigeria 
Background:
Thrombocytopaenia is a common haematologic abnormality during pregnancy. Pregnant women with thrombocytopenia have a higher risk of bleeding excessively during or after childbirth, particularly if they need to have a caesarean section or other surgical intervention during pregnancy, labour or in the puperium. The aim of this study was to determine the prevalence of gestational thrombocytopaenia among pregnant women reporting for antenatal care at tertiary health care centres in Lagos.
Materials and Methods:
Platelet count was analyzed in 274 consecutive pregnant women who gave informed consent and 70 non-pregnant female staff of the hospitals. Platelet count was performed on each sample using the Sysmex KN-21N automated haematology analyzer. The study design was cross-sectional, proportions were analyzed for statistical significance with the chi-square, and Odds ratio was also calculated. Thrombocytopaenia is classically defined as a platelet count of less than 150 × 109/L.34 Counts from 100 to 150 × 109/L are considered mildly depressed, 50 to 100 × 109/L are moderately depressed and less than 50 × 109/L are severely depressed.
Results:
Thirty-four (13.5%) pregnant women were thrombocytopaenic compared with three (4.3%) non-pregnant women. This was statistically significant; P = 0.03; Odds ratio: 3.5 (95% CI 1.03-11.82). Out of the 37 pregnant women who were thrombocytopaenic, most of them (78%) had mild thrombocytopenia, only 6% had severe thrombocytopaenia.
Conclusion:
The prevalence of gestational thrombocytopaenia in this study was 13.5%. Although majority of the pregnant women had mild thrombocytopaenia, healthcare providers should screen all pregnant women routinely for thrombocytopaenia to avoid excessive bleeding during or after childbirth.
doi:10.4103/0300-1652.129647
PMCID: PMC4003717  PMID: 24791048
Gestational thrombocytopaenia; platelet count; haemorrhage
22.  Exercise Training and Weight Gain in Obese Pregnant Women: A Randomized Controlled Trial (ETIP Trial) 
PLoS Medicine  2016;13(7):e1002079.
Background
The effectiveness of exercise training for preventing excessive gestational weight gain (GWG) and gestational diabetes mellitus (GDM) is still uncertain. As maternal obesity is associated with both GWG and GDM, there is a special need to assess whether prenatal exercise training programs provided to obese women reduce the risk of adverse pregnancy outcomes. Our primary aim was to assess whether regular supervised exercise training in pregnancy could reduce GWG in women with prepregnancy overweight/obesity. Secondary aims were to examine the effects of exercise in pregnancy on 30 outcomes including GDM incidence, blood pressure, blood measurements, skinfold thickness, and body composition.
Methods and Findings
This was a single-center study where we randomized (1:1) 91 pregnant women with a prepregnancy body mass index (BMI) ≥ 28 kg/m2 to exercise training (n = 46) or control (standard maternity care) (n = 45). Assessments were done at baseline (pregnancy week 12–18) and in late pregnancy (week 34–37), as well as at delivery. The exercise group was offered thrice weekly supervised sessions of 35 min of moderate intensity endurance exercise and 25 min of strength training. Seventeen women were lost to follow-up (eight in the exercise group and nine in the control group). Our primary endpoint was GWG from baseline testing to delivery. The principal analyses were done as intention-to-treat analyses, with supplementary per protocol analyses where we assessed outcomes in the women who adhered to the exercise program (n = 19) compared to the control group. Mean GWG from baseline to delivery was 10.5 kg in the exercise group and 9.2 kg in the control group, with a mean difference of 0.92 kg (95% CI −1.35, 3.18; p = 0.43). Among the 30 secondary outcomes in late pregnancy, an apparent reduction was recorded in the incidence of GDM (2009 WHO definition) in the exercise group (2 cases; 6.1%) compared to the control group (9 cases; 27.3%), with an odds ratio of 0.1 (95% CI 0.02, 0.95; p = 0.04). Systolic blood pressure was significantly lower in the exercise group (mean 120.4 mm Hg) compared to the control group (mean 128.1 mm Hg), with a mean difference of −7.73 mm Hg (95% CI −13.23, −2.22; p = 0.006). No significant between-group differences were seen in diastolic blood pressure, blood measurements, skinfold thickness, or body composition in late pregnancy. In per protocol analyses, late pregnancy systolic blood pressure was 115.7 (95% CI 110.0, 121.5) mm Hg in the exercise group (significant between-group difference, p = 0.001), and diastolic blood pressure was 75.1 (95% CI 71.6, 78.7) mm Hg (significant between-group difference, p = 0.02). We had planned to recruit 150 women into the trial; hence, under-recruitment represents a major limitation of our results. Another limitation to our study was the low adherence to the exercise program, with only 50% of the women included in the intention-to-treat analysis adhering as described in the study protocol.
Conclusions
In this trial we did not observe a reduction in GWG among overweight/obese women who received a supervised exercise training program during their pregnancy. The incidence of GDM in late pregnancy seemed to be lower in the women randomized to exercise training than in the women receiving standard maternity care only. Systolic blood pressure in late pregnancy was also apparently lower in the exercise group than in the control group. These results indicate that supervised exercise training might be beneficial as a part of standard pregnancy care for overweight/obese women.
Trial Registration
ClinicalTrials.gov NCT01243554
Moholdt and colleagues show that exercise training in pregnancy reduces incidence of gestational diabetes and blood pressure, but not weight gain.
Author Summary
Why Was This Study Done?
Maternal obesity is associated with increased risk of several adverse pregnancy outcomes.
The aim of our study was to investigate whether exercise training during pregnancy can reduce gestational weight gain and prevent negative health outcomes, such as gestational diabetes mellitus and high blood pressure, among overweight/obese pregnant women.
What Did the Researchers Do and Find?
Ninety-one overweight/obese pregnant women were randomly allocated to an exercise group or a control group in early pregnancy (starting in pregnancy week 12–18).
Women in the exercise group were asked to attend supervised sessions of combined endurance and resistance training three times weekly.
Women in both groups gained on average about 10 kg. In late pregnancy, there seemed to be fewer women in the exercise group with gestational diabetes mellitus, and the exercising women had lower systolic blood pressure compared to those in the control group.
What Do These Findings Mean?
Providing an exercise program to overweight/obese pregnant women did not reduce gestational weight gain compared to standard pregnancy care.
Exercise training might reduce the incidence of gestational diabetes mellitus and lower systolic blood pressure in late pregnancy in this population.
doi:10.1371/journal.pmed.1002079
PMCID: PMC4961392  PMID: 27459375
23.  Adiponectin Multimers in Normal Pregnancy 
Objective
Adiponectin is an anti-diabetic, anti-atherogenic, anti-inflammatory and angiogenic adipokine that circulates in oligomeric complexes including: low-molecular-weight (LMW) trimers, medium-molecular-weight (MMW) hexamers and high-molecular-weight (HMW) isoforms. The aim of this study was to determine whether there are changes in adiponectin multimers in pregnancy and as a function of maternal weight.
Study design
In this cross-sectional study, serum concentrations of total, HMW, MMW and LMW adiponectin were determined in women included in three groups: 1) normal pregnant women of normal body mass index (BMI) (n=466); 2) overweight/obese pregnant women (BMI ≥25; n=257); and 3) non-pregnant women of normal weight (n=40). Blood samples were collected once from each pregnant woman between 11 and 42 weeks of gestation. Serum adiponectin multimers concentrations were determined by ELISA. Non-parametric statistics were used for analysis.
Results
1) The median HMW adiponectin concentration and the median HMW/Total adiponectin ratio were significantly higher and the median LMW adiponectin concentration was significantly lower in pregnant than in non-pregnant women; 2) among pregnant women, the median serum concentration of total, HMW and MMW adiponectin was significantly higher in normal weight women than in overweight/obese patients; 3) HMW adiponectin was the most prevalent multimer in maternal serum regardless of gestational age or BMI status; 4) there were no significant differences in the median concentration of total, MMW, LMW adiponectin, and their relative distribution with advancing gestation.
Conclusion
Human pregnancy is characterized by quantitative and qualitative changes in adiponectin multimers, especially of the most active isoform, HMW adiponectin.
doi:10.1080/14767050802266881
PMCID: PMC2729195  PMID: 19031276
Adiponectin; Adipokines; Pregnancy; High molecular weight (HMW) adiponectin; Medium molecular weigh (MMW) adiponectin; Low molecular weight (LMW) adiponectin; BMI
24.  Physical activity, sedentary behaviors, and estimated insulin sensitivity and secretion in pregnant and non-pregnant women 
Background
Overweight and obesity during pregnancy raise the risk of gestational diabetes and birth complications. Lifestyle factors like physical activity may decrease these risks through beneficial effects on glucose homeostasis. Here we examined physical activity patterns and their relationships with measures of glucose homeostasis in late pregnancy compared to non-pregnant women.
Methods
Normal weight and overweight women without diabetes (N = 108; aged 25-35 years) were studied; 35 were pregnant (in gestational weeks 28-32) and 73 were non-pregnant.
Insulin sensitivity and β-cell response were estimated from an oral glucose tolerance test. Physical activity was measured during 10-days of free-living using a combined heart rate sensor and accelerometer. Total (TEE), resting (REE), and physical activity (PAEE) energy expenditure were measured using doubly-labeled water and expired gas indirect calorimetry.
Results
Total activity was associated with reduced first-phase insulin response in both pregnant (Regression r2 = 0.11; Spearman r = -0.47; p = 0.007) and non-pregnant women (Regression r2 = 0.11 Spearman; r = -0.36; p = 0.002). Relative to non-pregnant women, pregnant women were estimated to have secreted 67% more insulin and had 10% lower fasting glucose than non-pregnant women. Pregnant women spent 13% more time sedentary, 71% less time in moderate-to-vigorous intensity activity, had 44% lower objectively measured total activity, and 12% lower PAEE than non-pregnant women. Correlations did not differ significantly for any comparison between physical activity subcomponents and measures of insulin sensitivity or secretion.
Conclusions
Our findings suggest that physical activity conveys similar benefits on glucose homeostasis in pregnant and non-pregnant women, despite differences in subcomponents of physical activity.
doi:10.1186/1471-2393-11-44
PMCID: PMC3130709  PMID: 21679399
pregnancy; physical activity; sedentary time; β-cell response; insulin sensitivity
25.  Pulse Wave Analysis in Normal Pregnancy: A Prospective Longitudinal Study 
PLoS ONE  2009;4(7):e6134.
Background
Outside pregnancy, arterial pulse wave analysis provides valuable information in hypertension and vascular disease. Studies in pregnancy using this technique show that vascular stiffness is raised in women with established pre-eclampsia. We aimed to establish normal ranges for parameters of pulse wave analysis in normal pregnancy and to compare different ethnic groups.
Methodology/Principal Findings
This prospective study was conducted at The Homerton University Hospital, London between January 2006 and March 2007. Using applanation tonometry, the radial artery pulse waveform was recorded and the aortic waveform derived. Augmentation pressure (AP) and Augmentation Index at heart rate 75/min (AIx-75), measures of arterial stiffness, were calculated.
We recruited 665 women with singleton pregnancies. Women who developed pre-eclampsia (n = 24, 3.6%) or gestational hypertension (n = 36, 5.4%) were excluded. We also excluded 47 women with other pregnancy complications or incomplete follow-up, leaving 541 healthy normotensive pregnant women for subsequent analysis. In the overall group of 541 women, there were no significant changes in AP or AIx-75 as pregnancy progressed. In 45 women followed longitudinally, AP and AIx-75 fell significantly from the first to the second trimester, then rose again in the third (P<0.001). The two main ethnic groups represented were Caucasian (n = 229) and Afrocaribbean (n = 216). There were no significant differences in AP or AIx-75 in any trimester between these two ethnic groups.
Conclusions
This study is the largest to date of pulse wave analysis in normal pregnancy, the first to report on a subset of women studied longitudinally, and the first to investigate the effect of ethnicity. These data provide the foundation for further investigation into the potential role of this technique in vascular disorders in pregnancy.
doi:10.1371/journal.pone.0006134
PMCID: PMC2700961  PMID: 19578538

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