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Open Access

Peer-reviewed

Research Article

Pregnant women carrying female fetuses are at higher risk of placental malaria infection

  • Ishag Adam ,

    Roles Conceptualization, Formal analysis, Project administration, Supervision, Validation, Writing – review & editing

    ishagadam@hotmail.com

    Affiliation Faculty of Medicine University of Khartoum, Sudan

    ⨯
  • Magdi M. Salih,

    Roles Data curation, Investigation, Validation, Writing – original draft

    Affiliation Faculty of Medical Laboratory Sciences, University of Khartoum, Sudan

    ⨯
  • Ahmed A. Mohmmed,

    Roles Data curation, Methodology

    Affiliation Faculty of Medicine, Ribat University, Sudan

    ⨯
  • Duria A. Rayis,

    Roles Formal analysis, Investigation, Methodology, Resources, Writing – original draft

    Affiliation Faculty of Medicine University of Khartoum, Sudan

    ⨯
  • Mustafa I. Elbashir

    Roles Conceptualization, Project administration, Supervision, Writing – review & editing

    Affiliation Faculty of Medicine University of Khartoum, Sudan

    ⨯

Abstract

Background

The pathophysiology of the placental malaria is not fully understood. If there is a fetal sex–specific susceptibility to malaria infection, this might add to the previous knowledge on the immunology, endocrinology and pathophysiology of placental malaria infections.

Aims

This study was conducted to assess whether the sex of the fetus was associated with placental malaria infections.

Subjects and methods

A cross-sectional study was performed including a secondary analysis of a cohort of women who were investigated for prevalence and risk factors (including fetal sex) for placental malaria in eastern Sudan. Placental histology was used to diagnose placental malaria infections.

Results

Among 339 women enrolled, the mean (SD) age was 25.8 (6.7) years and parity was 2.7 (2.2). Among the new born babies, 157 (46.3%) were male and 182 (53.7%) were female. Five (1.5%), 9 (2.7%) and 103 (30.4%) of the 339 placentas had active, active-chronic, past-chronic malaria infection on histopathology examination respectively, while 222 (65.5%) of them showed no malaria infection. Logistic regression analyses showed no associations between maternal age or parity and placental malaria infections. Women who have blood group O (OR = 1.95, 95% CI = 1.19–3.10; P = 0.007) and women who had female new born were at higher risk for placental malaria infections (OR = 2.55, 95% CI = 1.57–4.13; P< 0.001).

Conclusion

Fetal gender may be a novel risk factor for placental malaria. In this work the female placentas were at higher risk for malaria infections than the male placentas.

Citation: Adam I, Salih MM, Mohmmed AA, Rayis DA, Elbashir MI (2017) Pregnant women carrying female fetuses are at higher risk of placental malaria infection. PLoS ONE 12(7): e0182394. https://doi.org/10.1371/journal.pone.0182394

Editor: Claudio Romero Farias Marinho, Universidade de Sao Paulo Instituto de Ciencias Biomedicas, BRAZIL

Received: May 3, 2017; Accepted: July 17, 2017; Published: July 28, 2017

Copyright: © 2017 Adam et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper and its Supporting Information files.

Funding: The authors received no specific funding for this work.

Competing interests: The authors have declared that no competing interests exist.

Introduction

There is a great in interest in recent years in the female/male distribution during pregnancy and its interaction with maternal and perinatal health [1]. Many maternal physiological and endocrine functions are influenced in a fetal sex-specific pattern during pregnancy [2]. Various disparities between male and female fetuses in relation to a number of adverse pregnancy outcomes have been recently observed e.g. stillbirth, preeclampsia and fetal growth restriction [3–8].

Plasmodium falciparum malaria infection during pregnancy is a major public health problem especially in sub-Saharan Africa, where it is a major cause of maternal and perinatal morbidity and mortality [9,10]. The mechanisms leading to morbidity and mortality in placental malaria are incompletely understood. However, an inflammatory response in the placenta with accumulation of monocytes and macrophages in the maternal vascular bed of the placenta has been related to both severe anemia in the mother and low birth weight in the new born [11–13]. The pathophysiology of the placental malaria is not fully understood and the finding of the fetal sex–specific susceptibility of malaria infection might add to the previous knowledge on the immunology, endocrinology and pathophysiology of placental malaria infections. Pregnant women in Sudan are at higher risk for malaria and malaria during pregnancy has been reported as main cause of maternal and perinatal adverse effect [10,14]. This study was conducted to assess whether the sex of the fetus was associated with placental malaria infections where there is no published data on fetal sex and placental malaria infection.

Material and methods

This is a secondary analysis of a cohort of women who were investigated for prevalence and risk factors for placental malaria in eastern Sudan using placental histology as tool for diagnosis for placental malaria infections [15,16]. The details of the methods have been mentioned before. In summary, parturient women who delivered a singleton baby in New Half (October 2006–March 2007) and Gadarif (November 2007–January 2008) hospitals in eastern Sudan were approached to participate in the study. After signing a witnessed informed consent, socio-demographic, medical and obstetrics characteristics were gathered by questionnaires that were completed by trained medical officers in the local Arabic language. Women with antepartum haemorrhage or thyroid disease were excluded from the study. Body mass index (BMI) was computed from the woman’s weight and height (weight in kg/ height in m2 that were taken and recoded immediately. Following delivery, new born sex and weight were recorded.

Hematology

Thick blood films for malaria were prepared from the maternal, placental (small piece (0.5 cm3) excised from the centre) and cord blood and were Giemsa-stained and the number of asexual P. falciparum parasites per 200 white blood cells was recorded. Maternal blood groups were investigated by the agglutination method.

Histopathology

Around three cm3 full thickness placental blocks were taken from the placenta and kept in neutral buffered formalin for histopathology examinations. The biopsy samples were processed by embedding them in paraffin wax using standard techniques. In every case, the thick paraffin sections were stained with hematoxylin-eosin and Giemsa stains. Histology was evaluated using the criteria of Bulmer et al [17]. Placentas were identified as not infected, no evidence of parasite or pigment; active infection, parasites in maternal erythrocytes in the intervillous space, pigment in erythrocytes and monocytes in the intervillous space but no pigment in fibrin or cells within fibrin; active-chronic infection, parasites in maternal erythrocytes in the intervillous space, pigment in erythrocytes and circulating monocytes within the intervillous space and pigment in fibrin or cells within fibrin and/or chorionic villous syncytiotrophoblast or stroma; or past-chronic infection, parasites not present, pigment confined to fibrin or cells within fibrin.

The histopathology and hematology studies were performed by two independent readers namely HAH for hematology and AAM for histopathology.

Statistics

Data were entered using SPSS for windows (version 20.0). Means and proportions were compared between two groups (according to placental malaria infection and male/female new born) using Student’s t-test and X2 tests, respectively. Binary regressions were performed with placental malaria infections as a dependent variable and the independent variables age, parity, residence, education, antenatal care, maternal blood group (O versus non O) and new-born gender were entered in the model if their univariate P was <0.20. Odds ratios and 95% confidence interval were calculated and P < 0.05 was considered significant.

Ethics

The study received ethical clearance from the Research Board at the Faculty of Medicine, University of Khartoum.

Results

General characteristics

Thirty –two women were excluded from the study because they had incomplete data (18), had antepartum hemorrhage (11) or had thyroid diseases (3). Three hundred and thirty nine women had complete data include the placental malaria infections and the sex of the new born and their data were analysed. Of these women, 139 (41.0%), 265 (78.2%), 113 (33.3%) and 66 (19.55%) women were primiparae, had rural residence, were illiterate and had no antenatal care, respectively. While 32.2% of these women used bed nets, only (5.3%) used intermittent preventive treatment in the index pregnancy. The mean (SD) of the age of the enrolled women was 25.8 (6.7) years and mean (SD) parity was 2.7 (2.2), respectively. Of the participants, 79 (23.3%), 74 (21.8%), 22 (6.5%) and 164 (48.4%) had blood group A, B, AB and O, respectively.

One hundred and fifty seven (46.3%) of the new born babies were males and 182 (53.7%) were females. The mean (SD) of the birth weight was 3081.4 (530) g and it was not different between males and females [3122.7 (526.0) vs. 3045.8 (534) g, P = 0.184. There was no significant difference in the maternal age, parity, education, residence, antenatal care level, or proportion of women using bed nets in the index pregnancy between women with male and female new born babies, Table 1.

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Table 1. Comparing basic characteristics between women with male and women with female new born.

https://doi.org/10.1371/journal.pone.0182394.t001

Malaria

Maternal and placental blood films for malaria were positive in three cases. Two maternal, placental and cord settings had positive blood films for malaria. All the positive blood films for malaria were found to have a positive placental malaria infection on histology.

One hundred and seventeen placentas had malaria infection. Five (1.5%), 9 (2.7%) and 103 (30.4%) of the 339 placentas had active, active-chronic, past-chronic malaria infection on histopathology examination respectively, while 222 (65.5%) of them showed no malaria infection.

While there was no significant difference in age, parity, education, residence and antenatal care level between women with placental malaria infection and women without placental malaria infection, women with placental malaria infection had a significantly higher number of O blood group and had a female new born (78 (66.7%) vs104 (46.8%), P < 0.001), Table 2.

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Table 2. Comparing basic characteristics between women with placental malaria infection and the women without malaria infection.

https://doi.org/10.1371/journal.pone.0182394.t002

Logistic regression analyses showed no associations between the age, parity, education, antenatal care and placental malaria infections. Women who have blood group O (OR = 1.95, 95% CI = 1.19–3.10; P = 0.007) and women who had female new born were at higher risk for placental malaria infections (OR = 2.55, 95% CI = 1.57–4.13; P< 0.001), Table 3.

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Table 3. Binary logistic regression analyses of the factors associated with placental malaria infection in eastern Sudan.

https://doi.org/10.1371/journal.pone.0182394.t003

Discussion

The study showed that age and parity were not associated with placental malaria infection. This agrees with the findings of the parent studies which have been discussed in detail elsewhere [15,16].

Interestingly the current study showed that women who were pregnant with females were at 2.55 at higher risk for placental malaria infection. To the best of our knowledge this is the first study to investigate the relationship between fetal sex and the susceptibility to malaria infection. Recently Laar et al., observed that female infants of HIV infected women had an increased prevalence of cord blood malaria parasitemia [18]. On the other hand, it has previously been reported that male sex was independently associated with a baby being born with umbilical cord blood parasitemia [19]. Griffin et al. reported no significant difference between male and female sex and maternal P. falciparum parasitaemia in the first half of pregnancy.

A time may come that studies of this kind and similar cohorts or re-analyzing the previous data on malaria infection during pregnancy in different settings may conform the current observation of an association between fetal sex and susceptibility to placental malaria. If the future research yields the same results, then the expected hypothesis would be how does a female fetus render a woman more susceptible to malaria infection? The attractiveness to the mosquitoes, the hormones (cortisol and prolactin), immune system modulation and increase in the receptors mediating parasite cytoadhesion need to investigated as possible mechanisms of association between female sex and placental malaria infection [20,21]. One cellular mechanism involving glucocorticoid receptor isoforms has been identified and could explain the difference between a female versus male placenta in the response to a maternal exposure to cortisol and hence malaria infections [22].

Although the effects of fetal sex on the long-term health of the mother are still not completely understood, these are now obvious in two maternal diseases namely asthma and preeclampsia [23,24]. It is worth mentioning that, in general, male fetuses and placentas are postulated to be more susceptible to adversity in utero[25].

The placenta not only transports nutrients and oxygen from the maternal circulation and returns waste products to the maternal circulation, but also it has a major endocrine and immunological function being responsible for synthesizing many hormones and cytokines that might have effects on the physiology of both the mother and the fetus [26,27]. These hormones and cytokines, such as soluble endoglin, and insulin-like growth factor, acid labile subunit, leptin and C-peptide, might have their sex-specific characteristics [28,29]. Unfortunately, the placenta has inherently been considered an asexual organ and the sex of the embryo was not considered in research on placenta functions [30]. But it is now obvious that the placenta has a sex of the embryo it belongs to [30,31].

The pathophysiology of placental malaria is not fully understood and the finding of the sex–specific susceptibility will add to the previous knowledge on the immunology, endocrinology and pathophysiology of placental malaria infections.

Limitation of the study

The submicroscopic malaria was not investigated (through polymerase chain reaction) and this point should be considered as one of the limitation of the current study. Previous study has shown that 32.0% of pregnant women in eastern Sudan had submicroscopic malaria [32]. Many factors e.g. maternal and paternal factors that could influence fetal sex were not investigated [33]. The data that were re-analyzed in the current study were data almost 10 years back. Perhaps there are some changes in the epidemiology and transmission of malaria in the area e.g. emergence of P. vivax in the area [34].

Conclusion

The current study supported the recent findings that fetal sex might influence the maternal milieu. In this work the female placentas were at higher risk for malaria infections than the male placentas.

Ethics

The study received ethical clearance from the Research Board at the Faculty of Medicine, University of Khartoum, Sudan.

References

  1. 1. Gabory A, Roseboom TJ, Moore T, Moore LG, Junien C. Placental contribution to the origins of sexual dimorphism in health and diseases: sex chromosomes and epigenetics. Biol Sex Differ. 2013;4: 5. pmid:23514128
  2. 2. Seneviratne SN, Derraik JGB, Jiang Y, McCowan LME, Gusso S, Cutfield WS, et al. The sex of the foetus affects maternal blood glucose concentrations in overweight and obese pregnant women. J Obstet Gynaecol. 2016; 1–3.
  3. 3. Vatten LJ, Skjaerven R. Offspring sex and pregnancy outcome by length of gestation. Early Hum Dev. 2004;76: 47–54. Available: http://www.ncbi.nlm.nih.gov/pubmed/14729162 pmid:14729162
  4. 4. Edwards A, Megens A, Peek M, Wallace EM. Sexual origins of placental dysfunction. Lancet (London, England). 2000;355: 203–4.
  5. 5. Panchenko PE, Lemaire M, Fneich S, Voisin S, Jouin M, Junien C, et al. [Epigenetics and Nutrition: maternal nutrition impacts on placental development and health of offspring]. Biol Aujourdhui. 2015;209: 175–87. pmid:26514387
  6. 6. Walker MG, Fitzgerald B, Keating S, Ray JG, Windrim R, Kingdom JCP. Sex-specific basis of severe placental dysfunction leading to extreme preterm delivery. Placenta. 2012;33: 568–71. pmid:22513321
  7. 7. James WH. Offspring sex ratios and the causes of placental pathology: the case of placental abruption. Hum Reprod. 2001;16: 2031. Available: http://www.ncbi.nlm.nih.gov/pubmed/11527922 pmid:11527922
  8. 8. James WH. Sex ratios of offspring and the causes of placental pathology. Hum Reprod. 1995;10: 1403–6. Available: http://www.ncbi.nlm.nih.gov/pubmed/7593505 pmid:7593505
  9. 9. Desai M, ter Kuile FO, Nosten F, McGready R, Asamoa K, Brabin B, et al. Epidemiology and burden of malaria in pregnancy. Lancet Infect Dis. 2007;7: 93–104. pmid:17251080
  10. 10. Adam I, Elhassan EM, Haggaz AED, Ali AAA, Adam GK. A perspective of the epidemiology of malaria and anaemia and their impact on maternal and perinatal outcomes in Sudan. J Infect Dev Ctries. 2011;5: 83–7. Available: http://www.ncbi.nlm.nih.gov/pubmed/21389586 pmid:21389586
  11. 11. Reeder JC, Hodder AN, Beeson JG, Brown G V. Identification of glycosaminoglycan binding domains in Plasmodium falciparum erythrocyte membrane protein 1 of a chondroitin sulfate A-adherent parasite. Infect Immun. 2000;68: 3923–6. Available: http://www.ncbi.nlm.nih.gov/pubmed/10858204 pmid:10858204
  12. 12. Diouf I, Fievet N, Doucouré S, Ngom M, Gaye A, Dumont A, et al. Monocyte Activation and T Cell Inhibition in Plasmodium falciparum–Infected Placenta. J Infect Dis. 2004;189: 2235–2242. pmid:15181571
  13. 13. Ordi J, Ismail MR, Ventura PJ, Kahigwa E, Hirt R, Cardesa A, et al. Massive chronic intervillositis of the placenta associated with malaria infection. Am J Surg Pathol. 1998;22: 1006–11. Available: http://www.ncbi.nlm.nih.gov/pubmed/9706981 pmid:9706981
  14. 14. Bayoumi NK, Elhassan EM, Elbashir MI, Adam I. Cortisol, prolactin, cytokines and the susceptibility of pregnant Sudanese women to Plasmodium falciparum malaria. Ann Trop Med Parasitol. 2009;103: 111–117. pmid:19208295
  15. 15. Adam I, Babiker S, Mohmmed AA, Salih MM, Prins MH, Zaki ZM. ABO blood group system and placental malaria in an area of unstable malaria transmission in eastern Sudan. Malar J. 2007;6: 110. pmid:17692119
  16. 16. Adam I, Adamt GK, Mohmmed AA, Salih MM, Ibrahuim SA, Ryan CA. Placental malaria and lack of prenatal care in an area of unstable malaria transmission in eastern Sudan. J Parasitol. 2009;95: 751–2. pmid:19642807
  17. 17. Bulmer JN, Rasheed FN, Francis N, Morrison L, Greenwood BM. Placental malaria. I. Pathological classification. Histopathology. 1993;22: 211–8. Available: http://www.ncbi.nlm.nih.gov/pubmed/8495954 pmid:8495954
  18. 18. Laar AK, Grant FE, Addo Y, Soyiri I, Nkansah B, Abugri J, et al. Predictors of fetal anemia and cord blood malaria parasitemia among new borns of HIV-positive mothers. BMC Res Notes. 2013;6: 350. pmid:24007344
  19. 19. Redd SC, Wirima JJ, Steketee RW, Breman JG, Heymann DL. Transplacental transmission of Plasmodium falciparum in rural Malawi. Am J Trop Med Hyg. 1996;55: 57–60. Available: http://www.ncbi.nlm.nih.gov/pubmed/8702038 pmid:8702038
  20. 20. Himeidan YE, Elbashir MI, Adam I. Attractiveness of pregnant women to the malaria vector, Anopheles arabiensis, in Sudan. Ann Trop Med Parasitol. 2004;98: 631–633. pmid:15324469
  21. 21. Bayoumi NK, Elhassan EM, Elbashir MI, Adam I. Cortisol, prolactin, cytokines and the susceptibility of pregnant Sudanese women to Plasmodium falciparum malaria. Ann Trop Med Parasitol. 2009;103: 111–117. pmid:19208295
  22. 22. Saif Z, Hodyl NA, Hobbs E, Tuck AR, Butler MS, Osei-Kumah A, et al. The human placenta expresses multiple glucocorticoid receptor isoforms that are altered by fetal sex, growth restriction and maternal asthma. Placenta. 2014;35: 260–268. pmid:24559727
  23. 23. Schalekamp-Timmermans S, Arends LR, Alsaker E, Chappell L, Hansson S, Harsem NK, et al. Fetal sex-specific differences in gestational age at delivery in pre-eclampsia: a meta-analysis. Int J Epidemiol. 2016; 1–11.
  24. 24. Scott NM, Hodyl NA, Murphy VE, Osei-Kumah A, Wyper H, Hodgson DM, et al. Placental Cytokine Expression Covaries with Maternal Asthma Severity and Fetal Sex. J Immunol. 2009;182: 1411–1420. pmid:19155488
  25. 25. Murji A, Proctor L, Paterson A. Male sex bias in placental dysfunction. Am J. 2012;http://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.35250/full
  26. 26. John R, Hemberger M. A placenta for life. Reprod Biomed Online. 2012;25: 5–11. pmid:22578825
  27. 27. Thornburg KL, O’Tierney PF, Louey S. Review: The Placenta is a Programming Agent for Cardiovascular Disease. Placenta. 2010;31: S54–S59. pmid:20149453
  28. 28. Walsh JM, Segurado R, Mahony RM, Foley ME, McAuliffe FM. The effects of fetal gender on maternal and fetal insulin resistance. PLoS One. 2015;10: 1–8. pmid:26368559
  29. 29. Myers JE, Thomas G, Tuytten R, Van Herrewege Y, Djiokep RO, Roberts CT, et al. Mid-trimester maternal ADAM12 levels differ according to fetal gender in pregnancies complicated by preeclampsia. Reprod Sci. 2015;22: 235–241. pmid:24899472
  30. 30. Clifton VL. Review: Sex and the human placenta: mediating differential strategies of fetal growth and survival. Placenta. 2010;31 Suppl: S33–9. pmid:20004469
  31. 31. Clifton V, Osei-Kumah A, Hodyl N, Scott N. 036. Sex specific function of the human placenta: implications for fetal growth and survival. Reprod Fertil. 2009; http://www.publish.csiro.au/?paper=SRB09Abs036
  32. 32. Adam I, A-Elbasit IE, Salih I, Elbashir MI. Submicroscopic Plasmodium falciparum infections during pregnancy, in an area of Sudan with a low intensity of malaria transmission. Ann Trop Med Parasitol. 2005;99: 339–344. pmid:15949181
  33. 33. James WH. Variation in the human sex ratio at birth with maternal age, parity and placental pathology. Hum Reprod. 2001;16: 2246–7. Available: http://www.ncbi.nlm.nih.gov/pubmed/11574528 pmid:11574528
  34. 34. Rayis DA, Ahmed MA, Omer EM, Adam I. Asian Pacific Journal of Tropical Disease Plasmodium vivax malaria among pregnant women in Eastern Sudan. 2016;6: 2014–2016.