Section 2 Clinical Aspects

**51**

**Chapter 4**

Mexico

**Abstract**

suspected ZIKV prenatal infection.

congenital Zika syndrome

**1. Introduction**

Clinical Manifestations in

Abnormalities in Fetus and

Transmission Period in South

*Norma Pavía-Ruz, Silvina Noemí Contreras-Capetillo,* 

*Gonzalo Vázquez-Prokopec and Pablo Manrique-Saide*

**Keywords:** Zika infection, pregnant women birth defects, pregnancy,

*Yamila Romer, Nina Valadez Gonzalez, Hector Gómez-Dantés,* 

Dengue, Chikungunya and Zika are arboviruses transmitted by *Ae. aegypti* with significant public health impact. In the first trimester of 2015, autochthonous Zika transmission was reported in Mexico. The state of Yucatan is an endemic region where pregnant women with acute infection and related congenital abnormalities in fetus and newborns were observed. We describe results from a cohort of pregnant women and their babies followed up in Yucatan during the first Zika transmission outbreak (2016–2018). Clinical manifestations of acute ZIKV infection, persistence of viral RNA in pregnant women, as well as congenital abnormalities were observed. In addition, we describe the phenotype of newborns from confirmed or

Dengue (DEN), Chikungunya (CHIK) and Zika (ZIKV) are arboviruses transmitted by the mosquito *Aedes aegypti* and known as *Aedes*-borne-diseases. These diseases are associated with high morbidity and low mortality and considered a public health problem [1]. In the 2015, the ZIKV outbreak was considered an international emergency because infection in pregnant women was related to the increase of congenital abnormalities in the fetuses [2–4]. Vertical transmission of ZIKV was demonstrated by the RNA viral detection in placenta, amniotic fluid, serum and fetal brain in products with microcephaly, abortions or in autopsies of affected newborns and offspring of symptomatic or asymptomatic mothers [5, 6].

Newborns during a Zika

Pregnant Women and Congenital

## **Chapter 4**

## Clinical Manifestations in Pregnant Women and Congenital Abnormalities in Fetus and Newborns during a Zika Transmission Period in South Mexico

*Norma Pavía-Ruz, Silvina Noemí Contreras-Capetillo, Yamila Romer, Nina Valadez Gonzalez, Hector Gómez-Dantés, Gonzalo Vázquez-Prokopec and Pablo Manrique-Saide*

## **Abstract**

Dengue, Chikungunya and Zika are arboviruses transmitted by *Ae. aegypti* with significant public health impact. In the first trimester of 2015, autochthonous Zika transmission was reported in Mexico. The state of Yucatan is an endemic region where pregnant women with acute infection and related congenital abnormalities in fetus and newborns were observed. We describe results from a cohort of pregnant women and their babies followed up in Yucatan during the first Zika transmission outbreak (2016–2018). Clinical manifestations of acute ZIKV infection, persistence of viral RNA in pregnant women, as well as congenital abnormalities were observed. In addition, we describe the phenotype of newborns from confirmed or suspected ZIKV prenatal infection.

**Keywords:** Zika infection, pregnant women birth defects, pregnancy, congenital Zika syndrome

## **1. Introduction**

Dengue (DEN), Chikungunya (CHIK) and Zika (ZIKV) are arboviruses transmitted by the mosquito *Aedes aegypti* and known as *Aedes*-borne-diseases. These diseases are associated with high morbidity and low mortality and considered a public health problem [1]. In the 2015, the ZIKV outbreak was considered an international emergency because infection in pregnant women was related to the increase of congenital abnormalities in the fetuses [2–4]. Vertical transmission of ZIKV was demonstrated by the RNA viral detection in placenta, amniotic fluid, serum and fetal brain in products with microcephaly, abortions or in autopsies of affected newborns and offspring of symptomatic or asymptomatic mothers [5, 6]. The clinical manifestations of Zika in general population and pregnant women were mild rash, conjunctivitis and low fever, although up to 80% remain asymptomatic, higher than DEN (19%) and CHIK (45%) [1, 2, 7, 8].

ZIKV is a Flavivirus with an Asian and African lineages [9, 10]. Its RNA genome (10.8 kb) encodes for a 3419-amino acid polyprotein which form a capsid (C), a membrane precursor (prM), a wrap (E) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5) [11]. ZIKV interferes with the neural development through decreased neural progenitor cells, arrest in neuronal migration and/or disruption of the maturation process of the fetus central nervous system (CNS) [12, 13]. The congenital Zika virus syndrome (CZVS) is a pattern of congenital defects associated with ZIKV infection during the pregnancy so ZIKV pathogenicity and virulence is currently studied [14–18].

The surveillance of ZIKV infection during pregnancy in endemic regions requires screening and detection of fetal morphological abnormalities [19]. An integrated intervention model for the prevention of Zika and *Aedes*-borne diseases, that includes primary health care services, gynecologists, obstetricians, pediatricians, geneticists and neurologists should be mandatory. Strategies to prevent and control the vectors and reduce the risk for diseases transmission should be strengthened, particularly for protection of women in reproductive ages [20, 21].

Here we report final the clinical manifestations observed in a cohort of pregnant women and the congenital abnormalities in fetus and newborns during a Zika transmission period (2016–2018) in South Mexico.

### **2. Methods**

We developed a prospective study to quantify the incidence of disease and infection in a cohort of pregnant women and newborns during an epidemic period of Zika (2016–2018). One of the main objectives of the study was to know the effect of prenatal exposure to ZIKV. The cohort included pregnant women, preferably in the first trimester of pregnancy. The follow up included clinical and molecular detection of ZIKV, DEN and CHIK. Obstetric ultrasound was performed to recognize morphological abnormalities in the fetuses.

During the development of this study, information on health care was provided to pregnant women and their partners, highlighting the importance of family planning and the use of condoms as a method to prevent the transmission of ZIKV, in addition to the implementation of measures to prevent the breeding of the *Aedes aegypti* and mosquito bites at home. We also provided information about general healthy habits, family planning and prevention of sexually transmitted diseases.

#### **2.1 Study population**

After the informed consent was signed, women were interviewed, and their medical records including periconceptional and pregnancy history, were collected. The recruitment included 884 families (3993 people) from the cities of Merida, Ticul, and Progreso de Castro in the Yucatan State, South-east Mexico [16]. Merida and its metropolitan area (≈1 million inhabitants), comprises ≈50% of the Yucatan population. Progreso de Castro (37,400) and Ticul (32,000) are smaller urban areas. We enrolled consenting pregnant women from these areas from July 1, 2016 to June 2018 including pregnant women referred by physicians in primary care facilities or hospitals within the areas of our cohort study.

**53**

*Clinical Manifestations in Pregnant Women and Congenital Abnormalities in Fetus…*

Patient monitoring included a monthly visit for clinical assessment and sample

collection (blood and urine for RTC DEN/CHIK/ZIKV), weekly follow-up by text messages, and complete access to a telephone to report any clinical signs in pregnant women, their newborns, or any family contact. Tissues as umbilical cord blood, placental, amniotic fluid and breastmilk were collected, when possible for assessment of RT-PCR RNA ZIKV (TRIOPLEX) [22]. Other biochemical tests were performed to rule out Toxoplasma, Rubella, Cytomegalovirus, Herpes, Syphilis and HIV [23]. Depending of the mother or/and fetus risks, other test such as biochemical serum test and karyotype in amniotic fluid were taken. Ultrasound scanning was performed at the first contact and every 2 months. At the first visit, a questionnaire was fill up to establish the clinical-epidemiologic profile. The follow-up ended when the pregnancy was completed by delivery or fetal loss, or the participant withdrew

Newborn follow up included: clinical evaluation (anthropometric measurements, APGAR score and physical exam) and sample collection for RT-PCR for DEN/CHIK/ZIKV [20–22, 24]. Patients were followed up for 24 months of life for early recognition of morphological anomalies and recorded the neurological development. These evaluations included genetic, neurologic, ophthalmologic, and audiologic evaluation. Microcephaly was defined as a cranial circumference ≥2 SDs below the mean for the age and sex of the baby, following the recommendation of

At the time when the cohort study was ongoing, in the Genetic Service in the center of Investigations Dr. Hideyo Noguchi/UADY received pregnant women with morphological abnormalities detected in their fetuses, or newborn patients in whom ZIKV prenatal infection was suspected. These patients were not integrated to the cohort, but a clinical follow-up was granted. Sample collections for RT-PCR for

The study integrated 130 pregnant women with average age of 25 years. No major differences in age distribution and socioeconomic status between ZIKVpositive and ZIKV-negative mothers were observed. Of all women, 40 (30%) were in the first trimester of pregnancy upon admission to the study, 62 (48%) in the

Positive results in *blood*/*urine* for ZIKV were found in 39 pregnant women, 31% (n = 13/39) at the first trimester, 52% (n = 20/39) in the second trimester and 15%

Of 130 pregnant women, 39 (30%) were RNA-ZIKV positive at the time of the recruitment and 91 were negative (70%). From these, 11 (12% of initially RNA-

second trimester and 28 (22%) in the third trimester (**Table 1**).

ZIKV negative) became positive during the surveillance.

*DOI: http://dx.doi.org/10.5772/intechopen.90616*

from the study.

**2.3 Clinical follow-up of newborns**

the World Health Organization [25–28].

DEN/CHIK/ZIKV were offered.

**3.1 Pregnant women cohort**

(n = 6/39) in the third trimester.

**3. Results**

**2.4 Patients not initially integrated into the cohort**

**2.2 Clinical follow-up of pregnant women**

*Clinical Manifestations in Pregnant Women and Congenital Abnormalities in Fetus… DOI: http://dx.doi.org/10.5772/intechopen.90616*

#### **2.2 Clinical follow-up of pregnant women**

*Current Concepts in Zika Research*

higher than DEN (19%) and CHIK (45%) [1, 2, 7, 8].

pathogenicity and virulence is currently studied [14–18].

transmission period (2016–2018) in South Mexico.

morphological abnormalities in the fetuses.

hospitals within the areas of our cohort study.

**2. Methods**

diseases.

**2.1 Study population**

particularly for protection of women in reproductive ages [20, 21].

The clinical manifestations of Zika in general population and pregnant women were mild rash, conjunctivitis and low fever, although up to 80% remain asymptomatic,

ZIKV is a Flavivirus with an Asian and African lineages [9, 10]. Its RNA genome (10.8 kb) encodes for a 3419-amino acid polyprotein which form a capsid (C), a membrane precursor (prM), a wrap (E) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5) [11]. ZIKV interferes with the neural development through decreased neural progenitor cells, arrest in neuronal migration and/or disruption of the maturation process of the fetus central nervous system (CNS) [12, 13]. The congenital Zika virus syndrome (CZVS) is a pattern of congenital defects associated with ZIKV infection during the pregnancy so ZIKV

The surveillance of ZIKV infection during pregnancy in endemic regions requires screening and detection of fetal morphological abnormalities [19]. An integrated intervention model for the prevention of Zika and *Aedes*-borne diseases, that includes primary health care services, gynecologists, obstetricians, pediatricians, geneticists and neurologists should be mandatory. Strategies to prevent and control the vectors and reduce the risk for diseases transmission should be strengthened,

Here we report final the clinical manifestations observed in a cohort of pregnant

We developed a prospective study to quantify the incidence of disease and infection in a cohort of pregnant women and newborns during an epidemic period of Zika (2016–2018). One of the main objectives of the study was to know the effect of prenatal exposure to ZIKV. The cohort included pregnant women, preferably in the first trimester of pregnancy. The follow up included clinical and molecular detection of ZIKV, DEN and CHIK. Obstetric ultrasound was performed to recognize

During the development of this study, information on health care was provided to pregnant women and their partners, highlighting the importance of family planning and the use of condoms as a method to prevent the transmission of ZIKV, in addition to the implementation of measures to prevent the breeding of the *Aedes aegypti* and mosquito bites at home. We also provided information about general healthy habits, family planning and prevention of sexually transmitted

After the informed consent was signed, women were interviewed, and their medical records including periconceptional and pregnancy history, were collected. The recruitment included 884 families (3993 people) from the cities of Merida, Ticul, and Progreso de Castro in the Yucatan State, South-east Mexico [16]. Merida and its metropolitan area (≈1 million inhabitants), comprises ≈50% of the Yucatan population. Progreso de Castro (37,400) and Ticul (32,000) are smaller urban areas. We enrolled consenting pregnant women from these areas from July 1, 2016 to June 2018 including pregnant women referred by physicians in primary care facilities or

women and the congenital abnormalities in fetus and newborns during a Zika

**52**

Patient monitoring included a monthly visit for clinical assessment and sample collection (blood and urine for RTC DEN/CHIK/ZIKV), weekly follow-up by text messages, and complete access to a telephone to report any clinical signs in pregnant women, their newborns, or any family contact. Tissues as umbilical cord blood, placental, amniotic fluid and breastmilk were collected, when possible for assessment of RT-PCR RNA ZIKV (TRIOPLEX) [22]. Other biochemical tests were performed to rule out Toxoplasma, Rubella, Cytomegalovirus, Herpes, Syphilis and HIV [23]. Depending of the mother or/and fetus risks, other test such as biochemical serum test and karyotype in amniotic fluid were taken. Ultrasound scanning was performed at the first contact and every 2 months. At the first visit, a questionnaire was fill up to establish the clinical-epidemiologic profile. The follow-up ended when the pregnancy was completed by delivery or fetal loss, or the participant withdrew from the study.

#### **2.3 Clinical follow-up of newborns**

Newborn follow up included: clinical evaluation (anthropometric measurements, APGAR score and physical exam) and sample collection for RT-PCR for DEN/CHIK/ZIKV [20–22, 24]. Patients were followed up for 24 months of life for early recognition of morphological anomalies and recorded the neurological development. These evaluations included genetic, neurologic, ophthalmologic, and audiologic evaluation. Microcephaly was defined as a cranial circumference ≥2 SDs below the mean for the age and sex of the baby, following the recommendation of the World Health Organization [25–28].

#### **2.4 Patients not initially integrated into the cohort**

At the time when the cohort study was ongoing, in the Genetic Service in the center of Investigations Dr. Hideyo Noguchi/UADY received pregnant women with morphological abnormalities detected in their fetuses, or newborn patients in whom ZIKV prenatal infection was suspected. These patients were not integrated to the cohort, but a clinical follow-up was granted. Sample collections for RT-PCR for DEN/CHIK/ZIKV were offered.

#### **3. Results**

#### **3.1 Pregnant women cohort**

The study integrated 130 pregnant women with average age of 25 years. No major differences in age distribution and socioeconomic status between ZIKVpositive and ZIKV-negative mothers were observed. Of all women, 40 (30%) were in the first trimester of pregnancy upon admission to the study, 62 (48%) in the second trimester and 28 (22%) in the third trimester (**Table 1**).

Positive results in *blood*/*urine* for ZIKV were found in 39 pregnant women, 31% (n = 13/39) at the first trimester, 52% (n = 20/39) in the second trimester and 15% (n = 6/39) in the third trimester.

Of 130 pregnant women, 39 (30%) were RNA-ZIKV positive at the time of the recruitment and 91 were negative (70%). From these, 11 (12% of initially RNA-ZIKV negative) became positive during the surveillance.


#### **Table 1.**

*Summary of health, medical and laboratory data collected from pregnant women in the cohort.*

Of the 28 symptomatic patients (negative or positive ZIKV), the most common symptoms were exanthema (75%), pruritus (39%) and conjunctivitis (57%). Of the 21 patients with RT-PCR ZIKV-positive, 75% were symptomatic and 25% were asymptomatic. Even so, more than half (64%) of the women had at least, more than one sign or symptom compatible with an *Aedes*-borne acute infection. Most prevalent symptoms were exanthema (100%), conjunctivitis (76%), pruritus (52%) headache (50%), retro-orbital pain (55%), arthralgia (33%), hyperemia (22%) and joint edema (6%). No hemorrhagic or systemic complications were observed in any patient (**Table 1**). Differences in the distribution of ZIKV-positive vs. ZIKVnegative women between the studied cities were not founded.

#### **3.2 Persistence of ZIKV viral RNA in serum and urine in pregnant women**

Of the 39 ZIKV-positive pregnant women, persistent RNA-ZIKV was detected in 38.5% (15/39) of the patients during 14 days after the initial symptoms or the last

**55**

**Table 2.**

*Newborn cohort follow-up.*

*Clinical Manifestations in Pregnant Women and Congenital Abnormalities in Fetus…*

PCR detection. Of these, six women were in the first trimester of gestation, eight in the second and one in the third. Within the group of symptomatic women (n = 28), nine (9/28) presented persistence of RNA-ZIKV, three in the first trimester and six

**Merida N:67 Progreso N:2 Ticul N:46 Total births** 

**End of the study**

**N (%) Alterations N (%) N (%) Alterations** 

51 (64) 30 (86) 2 (7)

**Percentile >97 N (%)**

114 (99) 0 (0) 0 (0) 115 (100)

115 (100) 0 (0) 0 (0) 115 (100)

114 (99) 0 (0) 0 (0) 115 (100)

**From mothers ZIKV positive during pregnancy N:35**

**End of the study**

**At birth**

**(%)**

**At birth**

(96)

(97)

(97)

Ophthalmology 19 (24) 31 (89) 3 (10)

NA NA 34 (97)

NA NA 22 (63)

**From mothers ZIKV negative during pregnancy N:80**

Newborn blood 29 (36) 27 (77) Newborn urine 32 (40) 14 (40) Pediatrics 39 (49) 30 (86)

Placenta NA NA 17 (49) Umbilical cord NA NA 17 (49) Genetics NA NA 35 (100)

**Age Mother ZIKV − Mother ZIKV + Total** 1–6 months 16 (22%) 0 16 (16%) 7–12 months 25 (34%) 3 (10%) 28 (27%) 13–18 months 20 (27%) 17 (59%) 37 (36%) 19–23 months 12 (17%) 9 (31%) 21 (21%) Total 73 29 102

**N:115**

**Total**

**N (%)**

*DOI: http://dx.doi.org/10.5772/intechopen.90616*

**Percentile Percentile <3 N (%) Percentile 3–97 N** 

**of the study**

5 (4) 1 (1) 110

3 (3) 0 (0) 112

2 (2) 1 (1) 112

**At birth End** 

**Newborn residence**

Birth weight percentiles

Birth height percentiles

Birth head circumference percentiles

Auditory screening

Metabolic screening

Transfontanelar and abdominal ultrasound

**Age of newborns who completed the study**

**Newborn evaluations**

PCR detection. Of these, six women were in the first trimester of gestation, eight in the second and one in the third. Within the group of symptomatic women (n = 28), nine (9/28) presented persistence of RNA-ZIKV, three in the first trimester and six


**Newborn evaluations**

*Current Concepts in Zika Research*

Signs and symptoms

Retro-orbital pain

**samples**

**Table 1.**

**Clinical profile in persistence in serum** 

Persistence (days) (interval)

**Pregnancy trimester**

**Total pregnant women**

Exanthema 21/21 (100%) Pruritus 11/21 (52%) Joint edema 7/21 (33%) Conjunctivitis 16/21 (76%)

Hyperemia 5/21 (22%)

**Positive for ZIKV in blood/urine**

21/39 (%)

10/21 (55%)

First 6 (40%) 3 3 Second 8 (53%) 6 2 Third 1 (7%) 1

*Summary of health, medical and laboratory data collected from pregnant women in the cohort.*

**Negative for ZIKV in blood/urine**

Mérida 75 (58%) 27 (69%) 47 (52%) 16 (40%) 37 (60%) 22 (79%) Progreso 4 (3%) 0 4 (4) 0 2 (3%) 2 (7%) Ticul 51 (39%) 12 (31%) 41 (44%) 24 (60%) 23 (37%) 4 (14%) 15–19 years 29 (22%) 8 (28%) 21 (72%) 6 (15%) 16 (26%) 7 (25%) 20–29 years 70 (54%) 22 (31%) 48 (69) 22 (55%) 34 (55%) 15 (54%) 30–39 years 30 (23%) 9 (23%) 21 (%) 12 (30%) 12 (19%) 6 (21%) 40–49 years 1 (1%) 0 1 (%) 0 0 1

**N:130 N:39 N:91 1st N:40 2nd N:62 3rd N:28**

**Total N:15 Symptomatic N:9 Asymptomatic p**

45.93 ± 24.4 (17–19) 50.11 ± 30.58 (17–97) 39.67 ± 9.89 (29–52) 0.363

**Trimester of pregnancy when enrolled pregnant women (130)**

Of the 28 symptomatic patients (negative or positive ZIKV), the most common symptoms were exanthema (75%), pruritus (39%) and conjunctivitis (57%). Of the 21 patients with RT-PCR ZIKV-positive, 75% were symptomatic and 25% were asymptomatic. Even so, more than half (64%) of the women had at least, more than one sign or symptom compatible with an *Aedes*-borne acute infection. Most prevalent symptoms were exanthema (100%), conjunctivitis (76%), pruritus (52%) headache (50%), retro-orbital pain (55%), arthralgia (33%), hyperemia (22%) and joint edema (6%). No hemorrhagic or systemic complications were observed in any patient (**Table 1**). Differences in the distribution of ZIKV-positive vs. ZIKV-

Age (years) 24.7 ± 4.4 24.2 ± 3.3 23.8 ± 6 0.874

negative women between the studied cities were not founded.

**3.2 Persistence of ZIKV viral RNA in serum and urine in pregnant women**

Of the 39 ZIKV-positive pregnant women, persistent RNA-ZIKV was detected in 38.5% (15/39) of the patients during 14 days after the initial symptoms or the last

**54**


#### **Table 2.**

*Newborn cohort follow-up.*


*Current Concepts in Zika Research*

*5NR: not reported.6Serum and urine were taken at born in newborns and theirs mothers.*

*4Intrauterine growth retardation.*

#### **Table 3.**

**57**

**4. Discussion**

*Clinical Manifestations in Pregnant Women and Congenital Abnormalities in Fetus…*

in the second. Of these, 100% (9/9) presented rash, 55% (5/9) conjunctivitis and 33.3% (2/9) fever. Only 22.2% (2/28) reported having three symptoms, fever, rash

All pregnancies of women in the cohort have ended the pregnancy. Two fetal losses (one in the first trimester and one in the third trimester) occurred in ZIKVnegative mothers. Of all newborns alive, 3% were preterm (two in ZIKV-negative mothers and one in a ZIKV-positive moth group). No newborns or products of conception were positive for RNA-ZIKV. Clinical evaluation of Apgar scores in the newborns did not show significant differences between positive/negative ZIKV mothers. Also, microcephaly was not founded in any newborn. One newborn of Zika-positive mother died the first days of life due to gastroschisis (**Table 2**). During the ZIKV epidemiological period in Yucatan, 10 patients attended the medical genetics clinic in CIR Hideyo Noguchi with a reference diagnosis of microcephaly, arthrogryposis and/or ventriculomegaly. Two of them were excluded from the follow up because ZIKV prenatal symptoms were absent in the mothers and microcephaly and intracranial calcifications were discarded in the patients. Preconceptional, prenatal and perinatal backgrounds were investigated in all patients. Only one woman took folic acid 6 months before the conception and none used mosquito repellent during pregnancy, even they were living in an endemic region. Of the newborns evaluated, clinical symptoms of Zika were reported only in two mothers in the first trimester of gestation, but only one was tested positive for RT-PCR Zika. One more woman reported symptoms of Zika 1 month before conception. During the pregnancy, intrauterine growth restriction in 4/8 (50%) and oligohydramnios in 2/8 (25%) were reported. Only one patient was reported prenatally with microcephaly, intracranial calcifications and ventriculomegaly (patient 5) (**Table 3**). Five pregnancies were ended by caesarean section and three by vaginal delivery between second semester of 2016 and the second semester of 2017.

All newborns were at term, except one. Of them, six were males and two were females. Three males had microcephaly with less than three standard deviations and one male with microcephaly less than two standard deviations. One female had macrocephaly. All babies from the three mothers with positive ZIKV symptoms during o before pregnancy were born with normocephaly, but were small for gestational age. One of these babies, a female, developed microcephaly within the first 6 months of life. Of all babies follow up, two had arthrogryposis, one with microcephaly and one with macrocephaly. Both of them were child from nonsymptomatic mothers. Only five patients were evaluated with axial computerized tomography with positive intracranial calcifications founded in four. All of them

All patients and their mothers were tested for RT-PCR for ZIKV/DEN/CHIK in serum and urine. TORCH was also performed. RNA-ZIKV was obtained only in serum of one male with microcephaly, arthrogryposis and intracranial calcifications. This male was from an asymptomatic mother. Antibodies IgM of toxoplasma were detected in one asymptomatic male whom has clinical symptoms of Zika

The WHO declared the ZIKV outbreak in South America and the associated increase in neurological disorders and neonatal malformations a "*public health* 

*DOI: http://dx.doi.org/10.5772/intechopen.90616*

and conjunctivitis (**Table 1**).

were from asymptomatic mothers.

during first trimester of pregnancy.

**3.3 Newborn evaluations**

*Main findings of eight patients evaluated for suspected ZIKV prenatal infection.*

*Clinical Manifestations in Pregnant Women and Congenital Abnormalities in Fetus… DOI: http://dx.doi.org/10.5772/intechopen.90616*

in the second. Of these, 100% (9/9) presented rash, 55% (5/9) conjunctivitis and 33.3% (2/9) fever. Only 22.2% (2/28) reported having three symptoms, fever, rash and conjunctivitis (**Table 1**).

#### **3.3 Newborn evaluations**

*Current Concepts in Zika Research*

**56**

**Patient/**

**Mother Zika** 

**WoG2**

**Neonatal head** 

**Birth weight for** 

**Phenotype**

**Intracranial** 

**Zika IgM InBios** 

**Final diagnosis**

**newborn/**

**mother6**

**calcification**

**gestational age**

**circumference** 

**(z score)**

**symptoms** 

**(MoG1**

**)**

**sex**

1/Male 2/Male 3/Male 4/Male 5/Male 6/Male 7/Female 8/Female *1Month of gestation.*

*2Weeks of gestation.*

*3Myelomeningocele.*

*4Intrauterine growth retardation.*

*5NR: not reported.*

**Table 3.** *Main findings of eight patients evaluated for suspected ZIKV prenatal infection.*

*6Serum and urine were taken at born in newborns and theirs mothers.*

No

38

Macrocephaly (97)

Appropriated

**Yes (2)**

40

Normocephaly (3)

No

39

**Microcephaly (**

**−3)**

Appropriated

Small

No

33

Normocephaly (10)

Appropriated

**Microcephaly** 

**Yes**

Positive in

serum/−

**Arthrogryposis**

**Microcephaly**

**Postnatal** 

**microcephaly**

**Macrocephaly** 

Normal

−/−

Amyoplasia

congenital

**Arthrogryposis**

**Yes** NR

−/−

CZS

−/−

CZS

**Yes (2)**

37

Normocephaly (3)

No

38

**Microcephaly (**

**−3**)

Appropriated

Small

**Microcephaly** Asymptomatic

**Yes (2)**

37

Normocephaly (10)

Small

No

38

**Microcephaly (**

**−3)**

Small

**Microcephaly** 

**Yes**

−/−

CZS/neural

tube defect

**MMC**3

IUGR4

NR5 **Yes** NR

−/−

IgM positive for

toxoplasma

CZS

−/−

CZS

−/−

IUGR

All pregnancies of women in the cohort have ended the pregnancy. Two fetal losses (one in the first trimester and one in the third trimester) occurred in ZIKVnegative mothers. Of all newborns alive, 3% were preterm (two in ZIKV-negative mothers and one in a ZIKV-positive moth group). No newborns or products of conception were positive for RNA-ZIKV. Clinical evaluation of Apgar scores in the newborns did not show significant differences between positive/negative ZIKV mothers. Also, microcephaly was not founded in any newborn. One newborn of Zika-positive mother died the first days of life due to gastroschisis (**Table 2**).

During the ZIKV epidemiological period in Yucatan, 10 patients attended the medical genetics clinic in CIR Hideyo Noguchi with a reference diagnosis of microcephaly, arthrogryposis and/or ventriculomegaly. Two of them were excluded from the follow up because ZIKV prenatal symptoms were absent in the mothers and microcephaly and intracranial calcifications were discarded in the patients. Preconceptional, prenatal and perinatal backgrounds were investigated in all patients. Only one woman took folic acid 6 months before the conception and none used mosquito repellent during pregnancy, even they were living in an endemic region.

Of the newborns evaluated, clinical symptoms of Zika were reported only in two mothers in the first trimester of gestation, but only one was tested positive for RT-PCR Zika. One more woman reported symptoms of Zika 1 month before conception. During the pregnancy, intrauterine growth restriction in 4/8 (50%) and oligohydramnios in 2/8 (25%) were reported. Only one patient was reported prenatally with microcephaly, intracranial calcifications and ventriculomegaly (patient 5) (**Table 3**). Five pregnancies were ended by caesarean section and three by vaginal delivery between second semester of 2016 and the second semester of 2017.

All newborns were at term, except one. Of them, six were males and two were females. Three males had microcephaly with less than three standard deviations and one male with microcephaly less than two standard deviations. One female had macrocephaly. All babies from the three mothers with positive ZIKV symptoms during o before pregnancy were born with normocephaly, but were small for gestational age. One of these babies, a female, developed microcephaly within the first 6 months of life. Of all babies follow up, two had arthrogryposis, one with microcephaly and one with macrocephaly. Both of them were child from nonsymptomatic mothers. Only five patients were evaluated with axial computerized tomography with positive intracranial calcifications founded in four. All of them were from asymptomatic mothers.

All patients and their mothers were tested for RT-PCR for ZIKV/DEN/CHIK in serum and urine. TORCH was also performed. RNA-ZIKV was obtained only in serum of one male with microcephaly, arthrogryposis and intracranial calcifications. This male was from an asymptomatic mother. Antibodies IgM of toxoplasma were detected in one asymptomatic male whom has clinical symptoms of Zika during first trimester of pregnancy.

#### **4. Discussion**

The WHO declared the ZIKV outbreak in South America and the associated increase in neurological disorders and neonatal malformations a "*public health* 

*emergency of international concern*" [2], and the CDC issued the ZIKV epidemiological alert, recommendations of high-risk Mexican territories was recognized by the National Health Service. Even so, the recognition of the ZIKV infection symptoms by patients and health workers, were underestimated [29]. In Mexico, first patients with ZIKV infection were documented early in 2016 even so, captured mosquitoes in early 2015 were recognized with ZIKV infection [30].

After the observed relationship between prenatal Zika infection and the risk of congenital defects in Brazil and Colombia, we realized a cohort with detailed evaluation of pregnant women searching ZIKV infection and congenital abnormalities [1, 31, 32].

The women in this study with the highest proportion of symptoms with ZIKV were those from 20 to 29 years, different from other studies that have reported the highest symptomatic disease ratio among women >30 years of age [33, 34]. In our studies this can be explained because the highest incidence of pregnancies in women was aged 20–29 years [1]. In clinically affected women, univariate analyzes showed that the most sensitive clinical sign was the exanthema, but it was also the least specific. The triad, conjunctival hyperemia, joint edema and exanthema had the highest level of specificity [35].

In pregnant women with exanthema without fever or other symptoms should to suspect ZIKV infection. In this study, ZIKV/DEN/CHIK co-infection was not identified neither [36].

The persistence of RNA viral in pregnant women has been described previously, reported a patient positive for RNA-ZIKV until 10 weeks after the onset of symptoms. In this study, the maximum viremia persistence was 97 days, but a quarter of positive mothers had viremia for more than 8 weeks [37]. From all RNA ZIKVpositive mothers, only 50% of the symptomatic group had persistence of ZIKV for more than 8 weeks. Other series reported longer RNA ZIKV viremia in symptomatic women than asymptomatic and other study obtained similar results in serum, in a range of 14–63 days; although in this study, we detected two pregnant women who had viremia older than 90 days [33, 34]. A study reported viral persistence in five pregnant women, of which 80% were symptomatic and only one case was asymptomatic. In this study, a higher percentage of asymptomatic viral persistence cases were found with 40%. In the symptomatic group, the average number of days of persistence after the onset of symptoms was greater than that reported, no relationship was observed between viral persistence and the presence of abnormalities in pregnancy products [38, 39].

The confirmatory tests which provide evidence for prenatal infection by ZIKV were conducted based on tests in the mother and the newborn were made with viral RNA isolated from biological fluids and placental tissues performed with the Trioplex kit of the CDC. The ZIKV genome was detected in cerebrospinal fluid, cardiac fluid, chorionic villi, fetal face of the placenta, serum and urine [26]. Vertical transmission studying the placental and fetus tissue also failed been demonstrated [40, 41].

Clinical variability in patients in whom ZIKV infection were prenatally suspected was described previously, in this cohort, congenital abnormalities associated to ZIKV were not observed in fetus, stillborn or newborns [1, 17]. Only one patient with gastroschisis was detected but the prenatal ZIKV infection in her mother was after detection of this abnormality.

Congenital Zika syndrome (CSZ) was observed in the patients evaluated from the Genetics Service out of the initial cohort. In them, Zika symptoms in mothers, microcephaly, arthrogryposis and intracranial calcifications were observed as in other reports [1, 17, 18]. Establishing the final diagnosis of ZIKV prenatal infection was difficult especially in asymptomatic mothers or in mild affected babies [31].

**59**

*Clinical Manifestations in Pregnant Women and Congenital Abnormalities in Fetus…*

In two patients, the final diagnosis was toxoplasma and congenital amyoplasia. Asymptomatic or mild symptomatic women would be a seriously limitation from early ZIKV infection. To define diagnostic of prenatal ZIKV is important: (1) to establish the follow up of the affected patient, (2) to limit the tests related to others genetic diseases that share symptoms with CSZ and (3) to establish the specific risk of recurrences of congenital abnormalities in subsequent pregnancies in the

In this study, symptomatic or asymptomatic pregnant women with a high prevalence for ZIKV are reported, however there was no positive newborn or with malformations associated with ZIKV, despite the genetic consultation, the presence of CSZ, laboratory-confirmed if present so doctors should maintain a realistic perspective of the impact of ZIKV on pregnancy. And despite the uncertainties, future mothers should receive adequate, systematic advice and the best planned obstetric surveillance, always considering the gestational moment of maternal ZIKV infection and accept that there is gestational risk for different elements of the

This research and publication was made possible through support provided by and the Canadian Institutes of Health Research (CIHR) and IDRC (preventing Zika disease with novel vector control approaches Project 108412) and the Office of Infectious Disease, Bureau for Global Health, US Agency for International Development, under the terms of an Interagency Agreement with CDC. The opinions expressed herein are those of the author(s) and do not necessarily reflect the views of the US Agency for International Development. The recipient of this support was the Yucatan Autonomous University and its affiliated Regional Research

*DOI: http://dx.doi.org/10.5772/intechopen.90616*

CZS phenotype in risk areas ZIKV transmission.

mother.

**5. Conclusions**

**Acknowledgements**

Center "Hideyo Noguchi."

*Clinical Manifestations in Pregnant Women and Congenital Abnormalities in Fetus… DOI: http://dx.doi.org/10.5772/intechopen.90616*

In two patients, the final diagnosis was toxoplasma and congenital amyoplasia. Asymptomatic or mild symptomatic women would be a seriously limitation from early ZIKV infection. To define diagnostic of prenatal ZIKV is important: (1) to establish the follow up of the affected patient, (2) to limit the tests related to others genetic diseases that share symptoms with CSZ and (3) to establish the specific risk of recurrences of congenital abnormalities in subsequent pregnancies in the mother.

## **5. Conclusions**

*Current Concepts in Zika Research*

the highest level of specificity [35].

identified neither [36].

pregnancy products [38, 39].

after detection of this abnormality.

[1, 31, 32].

*emergency of international concern*" [2], and the CDC issued the ZIKV epidemiological alert, recommendations of high-risk Mexican territories was recognized by the National Health Service. Even so, the recognition of the ZIKV infection symptoms by patients and health workers, were underestimated [29]. In Mexico, first patients with ZIKV infection were documented early in 2016 even so, captured mosquitoes

After the observed relationship between prenatal Zika infection and the risk of congenital defects in Brazil and Colombia, we realized a cohort with detailed evaluation of pregnant women searching ZIKV infection and congenital abnormalities

The women in this study with the highest proportion of symptoms with ZIKV were those from 20 to 29 years, different from other studies that have reported the highest symptomatic disease ratio among women >30 years of age [33, 34]. In our studies this can be explained because the highest incidence of pregnancies in women was aged 20–29 years [1]. In clinically affected women, univariate analyzes showed that the most sensitive clinical sign was the exanthema, but it was also the least specific. The triad, conjunctival hyperemia, joint edema and exanthema had

In pregnant women with exanthema without fever or other symptoms should to suspect ZIKV infection. In this study, ZIKV/DEN/CHIK co-infection was not

The persistence of RNA viral in pregnant women has been described previously, reported a patient positive for RNA-ZIKV until 10 weeks after the onset of symptoms. In this study, the maximum viremia persistence was 97 days, but a quarter of positive mothers had viremia for more than 8 weeks [37]. From all RNA ZIKVpositive mothers, only 50% of the symptomatic group had persistence of ZIKV for more than 8 weeks. Other series reported longer RNA ZIKV viremia in symptomatic women than asymptomatic and other study obtained similar results in serum, in a range of 14–63 days; although in this study, we detected two pregnant women who had viremia older than 90 days [33, 34]. A study reported viral persistence in five pregnant women, of which 80% were symptomatic and only one case was asymptomatic. In this study, a higher percentage of asymptomatic viral persistence cases were found with 40%. In the symptomatic group, the average number of days of persistence after the onset of symptoms was greater than that reported, no relationship was observed between viral persistence and the presence of abnormalities in

The confirmatory tests which provide evidence for prenatal infection by ZIKV were conducted based on tests in the mother and the newborn were made with viral RNA isolated from biological fluids and placental tissues performed with the Trioplex kit of the CDC. The ZIKV genome was detected in cerebrospinal fluid, cardiac fluid, chorionic villi, fetal face of the placenta, serum and urine [26]. Vertical transmission studying the placental and fetus tissue also failed been demonstrated

Clinical variability in patients in whom ZIKV infection were prenatally suspected was described previously, in this cohort, congenital abnormalities associated to ZIKV were not observed in fetus, stillborn or newborns [1, 17]. Only one patient with gastroschisis was detected but the prenatal ZIKV infection in her mother was

Congenital Zika syndrome (CSZ) was observed in the patients evaluated from the Genetics Service out of the initial cohort. In them, Zika symptoms in mothers, microcephaly, arthrogryposis and intracranial calcifications were observed as in other reports [1, 17, 18]. Establishing the final diagnosis of ZIKV prenatal infection was difficult especially in asymptomatic mothers or in mild affected babies [31].

in early 2015 were recognized with ZIKV infection [30].

**58**

[40, 41].

In this study, symptomatic or asymptomatic pregnant women with a high prevalence for ZIKV are reported, however there was no positive newborn or with malformations associated with ZIKV, despite the genetic consultation, the presence of CSZ, laboratory-confirmed if present so doctors should maintain a realistic perspective of the impact of ZIKV on pregnancy. And despite the uncertainties, future mothers should receive adequate, systematic advice and the best planned obstetric surveillance, always considering the gestational moment of maternal ZIKV infection and accept that there is gestational risk for different elements of the CZS phenotype in risk areas ZIKV transmission.

## **Acknowledgements**

This research and publication was made possible through support provided by and the Canadian Institutes of Health Research (CIHR) and IDRC (preventing Zika disease with novel vector control approaches Project 108412) and the Office of Infectious Disease, Bureau for Global Health, US Agency for International Development, under the terms of an Interagency Agreement with CDC. The opinions expressed herein are those of the author(s) and do not necessarily reflect the views of the US Agency for International Development. The recipient of this support was the Yucatan Autonomous University and its affiliated Regional Research Center "Hideyo Noguchi."

*Current Concepts in Zika Research*

## **Author details**

Norma Pavía-Ruz1 , Silvina Noemí Contreras-Capetillo1 , Yamila Romer2 , Nina Valadez Gonzalez1 , Hector Gómez-Dantés3 , Gonzalo Vázquez-Prokopec2 and Pablo Manrique-Saide1 \*

1 Autonomous University de Yucatan, Merida, Yucatan, Mexico

2 Emory University, Atlanta, GA, USA

3 Public Health Institute of Mexico, Cuernavaca, Morelos, México

\*Address all correspondence to: msaide@correo.uady.mx; pablo\_manrique2000@hotmail.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**61**

2014;**19**:1-4

2016;**16**:653-660

*Clinical Manifestations in Pregnant Women and Congenital Abnormalities in Fetus…*

et al. Epidemiology of dengue and other arboviruses in a cohort of school children and their families in Yucatan, Mexico: Baseline and first year follow-up. PLoS Neglected Tropical Diseases. 2018;**12**(11):e0006847. DOI:

10.1371/journal.pntd.0006847

[8] Pavía-Ruz N, Villanueva S, Granja P, Balam-May A, Longini IM, Halloran ME, et al. Seroprevalence of dengue antibodies in three urban settings in Yucatan, Mexico. American Journal of Tropical Medicine and Hygiene. 2018;**98**:1202-1208. DOI:

10.4269/ajtmh.17-0382

journal.pntd.0001477

Virology. 2019;**533**:59-67

10.1016/j.virusres.2019.197793

[12] Annamalai AS, Pattnaik A, Sahoo BR, Muthukrishnan E,

JVI.01348-17

[9] Haddow AD, Schuh AJ, Yasuda CY, Kasper MR, Heang V, Huy R, et al. Genetic characterization of Zika virus strains: Geographic expansion of the Asian lineage. PLoS Neglected Tropical Diseases. 2012;**6**(2):e1477. DOI: 10.1371/

[10] Rinkenberger N, Schoggins JW. Comparative analysis of viral entry for Asian and African lineages of Zika virus.

[11] Xing H, Xu S, Jia F, et al. Zika NS2B is a crucial factor recruiting NS3 to the ER and activating its protease activity. Virus Research. 2020;**275**:197793. DOI:

Natarajan SK, Steffen D, et al. Zika virus encoding nonglycosylated envelope protein is attenuated and defective in neuroinvasion. Journal of Virology. 2017;**91**:e01348-e01317. DOI: 10.1128/

[13] Leda AR, Bertrand L, Andras IE, El-Hage N, Nair M, Toborek M. Selective disruption of the blood-brain barrier by Zika virus. Frontiers in Microbiology.

2019;**10**:2158. DOI: 10.3389/

fmicb.2019.02158

*DOI: http://dx.doi.org/10.5772/intechopen.90616*

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**60**

**Author details**

Norma Pavía-Ruz1

Nina Valadez Gonzalez1

and Pablo Manrique-Saide1

2 Emory University, Atlanta, GA, USA

pablo\_manrique2000@hotmail.com

provided the original work is properly cited.

, Silvina Noemí Contreras-Capetillo1

, Hector Gómez-Dantés3

\*

1 Autonomous University de Yucatan, Merida, Yucatan, Mexico

3 Public Health Institute of Mexico, Cuernavaca, Morelos, México

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: msaide@correo.uady.mx;

, Yamila Romer2

, Gonzalo Vázquez-Prokopec2

,

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[17] Del Campo M, Feitosa IM, Ribeiro EM, Horovitz DD, Pessoa AL, França GV, et al. The phenotypic spectrum of congenital Zika syndrome. American Journal of Medical Genetics. 2017;**173**:841-857. DOI: 10.1002/

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#### *Current Concepts in Zika Research*

[40] Paz-Bailey G, Rosenberg ES, Doyle K, Munoz-Jordan J, Santiago GA, Klein L, et al. Persistence of Zika virus in body fluids—Final report. The New England Journal of Medicine. 2017;**379**(13):1234-1243. DOI: 10.1056/ NEJMoa1613108

[41] Besnard M, Lastére S, Teissier A, Cao-Lourmeau VM, Musso D. Evidence of perinatal transmission of Zika virus, French Polynesia, December 2013 and February 2014. Euro Surveillance. 2014;**19**(13):1-4

**65**

**Chapter 5**

**Abstract**

and early rehabilitation.

of patients infected with ZIKV [8–10].

conjunctivitis

**1. Introduction**

The Eye and the Zika Virus

Ocular involvement in Zika virus (ZIKV) infection can be present both in adults and infants as acquired and congenital diseases respectively. Through experimental studies, there has been clarified important mechanisms of ocular pathogenesis that allow the establishment of potential objectives for antiviral drugs development. The spread of the virus at the ocular level could be hematogenous or axonal, however the hematogenous route through the choroid is suggested as the most important initial mechanism for infection. Ocular manifestations vary according to the age of presentation, being mild and self-limited in adults and potentially devastating in children, related to congenital Zika syndrome (CZS). Ocular diagnosis is made based in clinical features and contact/travel history to countries of epidemiological importance; fundoscopy, optical coherence tomography, fluoresceinic/green indocianine angiography, cultures, serological and molecular tests are useful diagnostic tools. Ocular management is focused according to the clinical context of each patient. Prevention is carried out in a comprehensive manner and further research is directed to vaccine development and specific antiviral treatment. Proper attention requires a multidisciplinary team in order to reach complete visual evaluation

**Keywords:** Zika virus, congenital Zika syndrome, uveitis, optic nerve hypoplasia,

Zika virus (ZIKV) is a mosquito-borne viral disease caused by a flavivirus from the Flaviviridae family and transmitted by species belonging mainly to genus Aedes, discovered in 1947 in Uganda in infected rhesus monkeys [1, 2] with the first human cases reported in Africa and Asia [3]. Latin America and the Caribbean started to be affected with outbreaks, the first one reported in 2015 in Brazil [4]. Systemic symptoms include

Ocular involvement of ZIKV is not an uncommon manifestation in a patient with Zika virus infection. There are two main situations in which ocular pathology can occur: The first one is the manifestation of the virus in an adult patient, including the non-purulent conjunctivitis and more rarely ocular inflammation, especially in the anterior segment [6, 7]. Non-purulent conjunctivitis occurs between 55 and 63% of patients, as reported in outbreaks from Yap Islands and French Polineise, however according to other studies, conjunctivitis only occurs between 10 and 25%

fever, maculo-papular rash, headache, arthralgia and conjunctivitis [2, 5].

*Dayron Fernando Martínez-Pulgarín,* 

*Carlos Miguel Córdoba-Ortega* 

*and Fabio Daniel Padilla-Pantoja*

## **Chapter 5**

*Current Concepts in Zika Research*

NEJMoa1613108

2014;**19**(13):1-4

[40] Paz-Bailey G, Rosenberg ES, Doyle K, Munoz-Jordan J, Santiago GA, Klein L, et al. Persistence of Zika virus in body fluids—Final report. The New England Journal of Medicine. 2017;**379**(13):1234-1243. DOI: 10.1056/

[41] Besnard M, Lastére S, Teissier A, Cao-Lourmeau VM, Musso D. Evidence of perinatal transmission of Zika virus, French Polynesia, December 2013 and February 2014. Euro Surveillance.

**64**
