Therapeutic Options in Retinopathy of Prematurity

*Simona Delia Nicoară*

#### **Abstract**

Preterm babies may develop retinopathy of prematurity (ROP) in various stages. Most of them regress spontaneously without treatment, and a small proportion develops severe ROP that can lead to visual loss if not treated promptly. Less than 10% of the ROP cases require treatment worldwide. Before 1980, the only treatment for ROP was vitreoretinal surgery for retinal detachment in advanced stages of the disease. Around this time, cryotherapy started to be used in order to ablate the peripheral retina and interrupt the pathogenic chain in ROP, but there were no indications correlated with the severity of the disease. Few years later, cryotherapy was replaced by indirect laser photocoagulation of the nonvascular retina that became the golden standard of treatment for ROP. During the last years, efforts have been made in order to find therapeutic methods to induce the regression of new vessels with minimal side effects. Among these, intravitreal injections of anti-vascular endothelial growth factor (VEGF) became increasingly popular in the treatment of ROP worldwide. Personal experience in treating aggressive posterior ROP (APROP) with laser versus intravitreal anti-VEGF is presented. Intravitreal anti-VEGF proved its superiority in treating APROP as compared to laser, with no systemic and/or local side effects in our series.

**Keywords:** retinopathy of prematurity, laser, bevacizumab, cryotherapy, blindness

#### **1. Introduction**

All high-risk pregnancies are on the rise, and most of them result in a premature birth which is induced either due to maternal factors or fetal factors. Moreover, theoretically there could be more instances where retinopathy of prematurity (ROP) can develop because there has been a lot of development as well as success in management of preterm babies. Progress in neonatal care was associated with higher survival rates of low birth weight and low gestational age newborns.

Retinopathy of prematurity (ROP) is an important threat for the vision of the premature infants, especially for those born at low postconceptional ages (PCAs) and with low birth weights (BWs) [1, 2].

Following progress in neonatal care, the prevalence of ROP is increasing in the developing world, justifying the identification of ROP as a leading cause of visual impairment in children in the developing world, by the World Health Organization (WHO) [1].

In the developed countries, ROP accounts for 4% of childhood blindness, whereas in the developing ones, ROP generates 40% of it [1].

#### *Neonatal Medicine*

Many preterm babies will develop ROP in various stages. Most of them regress spontaneously without treatment, and a small proportion develops severe ROP that can lead to visual loss if not treated promptly [3]. ROP is one of the few largely preventable causes of visual impairment in children [3–5].

Fortunately, a treatment is available that can significantly reduce the rate of unfavorable outcomes [1]. The early detection of ROP and the prompt treatment are crucial for the prevention of blindness. Currently, there are two therapeutic methods to treat ROP: intravitreal injections with anti-vascular endothelial growth factor (VEGF) agents and indirect laser photocoagulation of the nonvascularized retina [2].

#### **2. Pathophysiology of ROP**

During the first 4 months of gestation, the retina has no blood vessels, and it is nourished by the hyaloid vasculature [6].

At 16 weeks, the angioblasts near the hyaloid artery invade the nerve fiber layer, and the first retinal vessels appear at the level of the optic nerve head. They grow progressively toward the periphery, reaching the ora serrata at 36 weeks in the nasal sector and at 40 weeks in the temporal one [6].

The development of the superficial and deep layers of the retinal vasculature depends on the delicate balance between the growth factors which are secreted by the astrocytes and the microglia: vascular endothelial growth factor (VEGF) and insulin growth factor-1 (IGF-1) [6].

During the second half of pregnancy, there is relative intrauterine hypoxia. When premature birth occurs, retinal vessels are not completely developed. Altered oxygen condition is a risk factor for the development of ROP which is a biphasic disease.

The first phase (from the moment of birth to 31- to 32-week postconceptional age) is characterized by relative environmental hyperoxia which leads to the arrest of the normal retinal development [6].

During the second phase (from 32- to 36-week postconceptional age), the retina matures, and its metabolic needs increase. By consequence, it is characterized by relative hypoxia and overexpression of VEGF, IGF-1, and oxidative damage with subsequent new vessel growth and retinal detachment [6].

The association between ROP and the administration of high doses of oxygen was demonstrated for the first time by Patz et al. in 1953 [6].

#### **3. ROP classification**

ROP was classified for the first time in 1984 by an international group of experts and updated in 2005. In classifying ROP, three criteria are used: zone, stage, and presence/absence of "plus" disease [7].

Topographically, the retina is divided into three zones. Zone 1 corresponds to a circle centered on the optic disc and with the radius equal to the double distance between the optic disc and the fovea. Zone 2 corresponds to a circle centered on the optic disc with the radius equal to the distance between the optic disc and ora serrata nasally. Zone 3 corresponds to the remaining crescent of the temporal retina up to ora serrata [7].

The stage describes the retinal changes at the limit between the vascular and nonvascular retina. Stage 1 is defined by a demarcation line, stage 2 by a nonvascular (white) ridge, and stage 3 by a vascular (red) ridge. Stage 4a corresponds to

**87**

*Therapeutic Options in Retinopathy of Prematurity DOI: http://dx.doi.org/10.5772/intechopen.80956*

**4. Diagnosis and screening for ROP**

1500 g or less or GA 30 weeks or less.

**5. Prevention and risk factors**

oxygen rate in other studies [6].

**6. Treatment of ROP**

worldwide. More than 90% regress spontaneously [1].

abnormal vascular tissue that can reactivate in zone 2 or 3.

closely monitoring.

posterior pole, as compared to a standard photograph [7].

peripheral retinal detachment, stage 4b involves also the detachment of the fovea, and stage 5 represents total retinal detachment in an open or closed funnel. "Plus" disease refers to the dilation and irregularity of retinal arteries and veins in the

Aggressive posterior ROP (APROP) is a subtype of ROP with a very unpredictable and aggressive behavior. It is always located posterior (zone 1 and posterior zone 2), with very severe "plus" disease and with flat neovascularization that progresses rapidly, without getting through the stages described above [7].

The Early Treatment for ROP (ETROP) study reclassified ROP according to the required attitude: type 1, ROP requiring treatment and type 2, ROP requiring

Fortunately, it is estimated that less than 10% of the ROP cases require treatment

Various screening criteria apply in different countries/regions. For instance, in the USA, the screening criteria updated in 2013 include all infants with BW of

Heavier and more mature babies are included in the screening at the discretion of the neonatologist, especially if other complications are present: necrotizing enterocolitis, intraventricular hemorrhage, sepsis, and bronchopulmonary dysplasia. According to our national guidelines, all premature newborns with GA of 34 weeks or less or with BW 2000 grams or less are included in the ROP screening. The first screening should be performed at 4–6 weeks after birth or at PCA 31 weeks whichever is later. When examining a premature infant, one of three situations can be identified: mature retina, immature retinal vascularization, or ROP. ROP screening can be discontinued if retinal vascularization is present in zone 3, without previous zone 1 or zone 2 disease; there is no evidence of prethreshold disease or worse ROP by 50 weeks PCA; there is regressing ROP in zone 3 without

ROP screening is made by trained ophthalmologists, using indirect ophthalmoscopy and scleral indentation in order to have access to the retinal periphery. Pupils must be dilated with a mixture of tropicamide 0.5% and phenylephrine 2.5%, and the lids are maintained open with a lid speculum throughout the examination.

The most important factor to prevent ROP is preventing premature birth [6]. The STOP-ROP multicenter study evaluated the risk for prethreshold ROP development in correlation with the oxygen saturation, and it showed no difference between maintaining an oxygen saturation level of 96–99% versus 89–94% [6]. BOOST II study showed a higher survival rate in infants younger than 28 weeks GA with 91–95% oxygen saturation levels but with an increased risk of ROP at this

Before 1980 the only treatment for ROP was vitreoretinal surgery for retinal detachment in advanced stages of the disease. Around this time cryotherapy started *Therapeutic Options in Retinopathy of Prematurity DOI: http://dx.doi.org/10.5772/intechopen.80956*

*Neonatal Medicine*

retina [2].

disease.

**2. Pathophysiology of ROP**

nourished by the hyaloid vasculature [6].

insulin growth factor-1 (IGF-1) [6].

of the normal retinal development [6].

presence/absence of "plus" disease [7].

**3. ROP classification**

up to ora serrata [7].

subsequent new vessel growth and retinal detachment [6].

was demonstrated for the first time by Patz et al. in 1953 [6].

sector and at 40 weeks in the temporal one [6].

Many preterm babies will develop ROP in various stages. Most of them regress spontaneously without treatment, and a small proportion develops severe ROP that can lead to visual loss if not treated promptly [3]. ROP is one of the few largely

Fortunately, a treatment is available that can significantly reduce the rate of unfavorable outcomes [1]. The early detection of ROP and the prompt treatment are crucial for the prevention of blindness. Currently, there are two therapeutic methods to treat ROP: intravitreal injections with anti-vascular endothelial growth factor (VEGF) agents and indirect laser photocoagulation of the nonvascularized

During the first 4 months of gestation, the retina has no blood vessels, and it is

At 16 weeks, the angioblasts near the hyaloid artery invade the nerve fiber layer, and the first retinal vessels appear at the level of the optic nerve head. They grow progressively toward the periphery, reaching the ora serrata at 36 weeks in the nasal

The development of the superficial and deep layers of the retinal vasculature depends on the delicate balance between the growth factors which are secreted by the astrocytes and the microglia: vascular endothelial growth factor (VEGF) and

During the second half of pregnancy, there is relative intrauterine hypoxia. When premature birth occurs, retinal vessels are not completely developed. Altered oxygen condition is a risk factor for the development of ROP which is a biphasic

The first phase (from the moment of birth to 31- to 32-week postconceptional age) is characterized by relative environmental hyperoxia which leads to the arrest

During the second phase (from 32- to 36-week postconceptional age), the retina matures, and its metabolic needs increase. By consequence, it is characterized by relative hypoxia and overexpression of VEGF, IGF-1, and oxidative damage with

The association between ROP and the administration of high doses of oxygen

ROP was classified for the first time in 1984 by an international group of experts and updated in 2005. In classifying ROP, three criteria are used: zone, stage, and

Topographically, the retina is divided into three zones. Zone 1 corresponds to a circle centered on the optic disc and with the radius equal to the double distance between the optic disc and the fovea. Zone 2 corresponds to a circle centered on the optic disc with the radius equal to the distance between the optic disc and ora serrata nasally. Zone 3 corresponds to the remaining crescent of the temporal retina

The stage describes the retinal changes at the limit between the vascular and nonvascular retina. Stage 1 is defined by a demarcation line, stage 2 by a nonvascular (white) ridge, and stage 3 by a vascular (red) ridge. Stage 4a corresponds to

preventable causes of visual impairment in children [3–5].

**86**

peripheral retinal detachment, stage 4b involves also the detachment of the fovea, and stage 5 represents total retinal detachment in an open or closed funnel. "Plus" disease refers to the dilation and irregularity of retinal arteries and veins in the posterior pole, as compared to a standard photograph [7].

Aggressive posterior ROP (APROP) is a subtype of ROP with a very unpredictable and aggressive behavior. It is always located posterior (zone 1 and posterior zone 2), with very severe "plus" disease and with flat neovascularization that progresses rapidly, without getting through the stages described above [7].

The Early Treatment for ROP (ETROP) study reclassified ROP according to the required attitude: type 1, ROP requiring treatment and type 2, ROP requiring closely monitoring.

#### **4. Diagnosis and screening for ROP**

Fortunately, it is estimated that less than 10% of the ROP cases require treatment worldwide. More than 90% regress spontaneously [1].

Various screening criteria apply in different countries/regions. For instance, in the USA, the screening criteria updated in 2013 include all infants with BW of 1500 g or less or GA 30 weeks or less.

Heavier and more mature babies are included in the screening at the discretion of the neonatologist, especially if other complications are present: necrotizing enterocolitis, intraventricular hemorrhage, sepsis, and bronchopulmonary dysplasia. According to our national guidelines, all premature newborns with GA of 34 weeks or less or with BW 2000 grams or less are included in the ROP screening.

The first screening should be performed at 4–6 weeks after birth or at PCA 31 weeks whichever is later. When examining a premature infant, one of three situations can be identified: mature retina, immature retinal vascularization, or ROP. ROP screening can be discontinued if retinal vascularization is present in zone 3, without previous zone 1 or zone 2 disease; there is no evidence of prethreshold disease or worse ROP by 50 weeks PCA; there is regressing ROP in zone 3 without abnormal vascular tissue that can reactivate in zone 2 or 3.

ROP screening is made by trained ophthalmologists, using indirect ophthalmoscopy and scleral indentation in order to have access to the retinal periphery. Pupils must be dilated with a mixture of tropicamide 0.5% and phenylephrine 2.5%, and the lids are maintained open with a lid speculum throughout the examination.

#### **5. Prevention and risk factors**

The most important factor to prevent ROP is preventing premature birth [6]. The STOP-ROP multicenter study evaluated the risk for prethreshold ROP development in correlation with the oxygen saturation, and it showed no difference between maintaining an oxygen saturation level of 96–99% versus 89–94% [6].

BOOST II study showed a higher survival rate in infants younger than 28 weeks GA with 91–95% oxygen saturation levels but with an increased risk of ROP at this oxygen rate in other studies [6].

#### **6. Treatment of ROP**

Before 1980 the only treatment for ROP was vitreoretinal surgery for retinal detachment in advanced stages of the disease. Around this time cryotherapy started to be used in order to ablate the peripheral retina and thus interrupt the pathogenic chain in ROP, but there were no guided indications in correlation with the severity of the disease [6].

CRYO-ROP elaborated a classification of ROP and defined "threshold" disease in which therapy was indicated: 5 contiguous hours or 8 non-contiguous hours of stage 3 ROP with plus disease in zone 1 or 2 [8].

A subsequent study, ETROP investigated whether treatment performed earlier than in threshold disease would further reduce the rate of anatomic unfavorable outcomes. Prethreshold disease was defined as type 1 and type 2 ROP. Clinically, type 1 ROP includes the following categories: zone 1 ROP of any stage with plus, zone 1 stage 3 ROP without plus, and zone 2 stage 2 or 3 disease with plus. In type 2 ROP, the following situations are included: zone 1 stage 1 or 2 without plus or zone 2 stage 3 without plus. ETROP recommends treatment in type 1 ROP and monitoring in type 2 ROP. At 6-year follow-up, the study proved 9% unfavorable structural outcomes in the early treated eyes, as compared to 15% unfavorable structural outcomes in the conventional treatment group. ETROP recommends peripheral laser ablation in type 1 ROP and frequent observation in type 2 ROP.

At this point, ablation of the peripheral retina was made by indirect laser photocoagulation that had replaced cryotherapy [9].

There are several advantages of laser over cryotherapy: laser requires less general anesthesia, it treats easier the posterior ROP, and it is associated with less systemic side effects: apnea, bradycardia, and cardiopulmonary arrest requiring resuscitation. However, ocular complications were reported after extensive indirect diode laser photocoagulation: vitreous hemorrhage, cataract, intraocular inflammation, choroidal effusion, and elevated intraocular pressure [9]. Theoretically, the risk of cataract is very low, given the fact that the infrared radiation that we use is absorbed deep into the choroid and not in the crystalline lens. Vitreous hemorrhage is rather a sign of ROP progression than a complication related to the laser itself.

Parvaresh et al. published the results of transscleral diode laser photocoagulation instead of transpupillary approach and concluded that it is technically easier, especially for retinal periphery and with fewer complications at the level of the anterior segment such as cataract formation [10].

During the last years, efforts have been made in order to find therapeutic methods to induce the regression of new vessels with minimal side effects [10].

Given the role of VEGF in angiogenesis, anti-VEGF administered intravitreally emerged as a promising tool for the treatment of ROP, alongside its use in ischemic retinopathies. Research conducted over the latest two decades proved that VEGF is one of the major factors involved in ROP pathogenesis [10].

VEGF inhibition with subsequent suppression of neovascular disease was proved by several experimental and clinical studies [10].

Clinical studies showed significantly higher levels of VEGF in the vitreous of patients with vasoproliferative ROP [11–13]. Sato et al. analyzed 27 cytokines in the vitreous of ROP eyes and found that VEGF was the most strongly correlated with vascularly active ROP [11]. This study also identified other factors elevated in ROP: fibroblast growth factor (FGF), granulocyte-colony stimulating factor (G-CSF), and granulocyte macrophage-colony stimulating factor (GM-CSF). This observation sustains the participation of an inflammatory response in the complex process of ROP development in addition to known vascular growth factors such as VEGF.

Animal ROP models showed the suppression of the vascular disease following intravitreal anti-VEGF injection [14, 15].

Nonobe et al. injected bevacizumab in the vitreous of five premature infants and showed the marked decrease of aqueous humor concentration of VEGF in four of them. Law et al. injected bevacizumab in 13 eyes of seven premature infants prior

**89**

2 ROP [10].

*Therapeutic Options in Retinopathy of Prematurity DOI: http://dx.doi.org/10.5772/intechopen.80956*

these procedures [10].

photocoagulation [10].

be performed for longer periods [10].

ment and the incidence and severity of ROP [16].

to laser or vitrectomy, and they noticed the improvement of the visualization of the retina with no systemic side effects, suggesting the role of anti-VEGF therapy prior

A retrospective study carried by Lee et al. on 15 premature infants with stage 3 ROP showed the rapid regression of plus disease with more rapid development of normal vessels toward the retinal periphery, with no significant increase in systemic or ocular complications, compared with patients treated with laser

Considerably concerns remain regarding the safety of anti-VEGF treatment in ROP, especially considering the correct dosage, timing of injection, and potential local complications such as infection, lens damage, and effect on the development of the neurosensory retina. Systemic side effects were not reported yet, but concern

persists especially regarding the development of the central nervous system. The Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity (BEATROP) study concluded that one doze of bevacizumab 0.625 mg in 0.025 ml had significantly better results in reducing the recurrence rate in zone 1 stage 3 ROP as compared to laser: 6 versus 42%, respectively. However, in posterior zone 2 ROP, the results were similar with intravitreal bevacizumab and laser. An interesting observation was that in some cases treated with intravitreal bevacizumab, late recurrence was noted: 16 ± 4.6 weeks with bevacizumab, as compared to 6.2 ± 5.7 weeks with laser. Therefore, follow-up in anti-VEGF-treated eyes should

Erythropoietin (Epo) is another growth factor that was proved to promote angiogenesis in vitro and in animal models. Recombinant Epo (rhEpo) is used to treat anemia in premature infants, as it promotes red blood cell formation. Sato et al. showed significantly elevated levels of Epo in 40 eyes from 27 premature infants with stage 4 ROP [13]. Suk et al. carried out a retrospective study in which he investigated the rhEpo treatment and ROP in 265 patients. The study concluded that high dose and later starting age for rhEpo treatment are risk factors for ROP (the phase of the disease was not taken into account). However, Shah et al. in a retrospective study on 85 patients found no correlation between the rhEpo treat-

Research in the field of angiogenesis led to a number of new ways to prevent ROP progression: targeting the insulin growth factor (IGF-1) pathway and dietary

Following preterm birth, serum IGF-1 is substantially reduced due to the interruption of fetal-maternal interaction. Animal models of ROP proved that IGF-1 is essential for vascular growth through interaction with VEGF signaling. Therefore, theoretically, supplementation of IGF-1 during phase 1 ROP would normalize vascular growth and subsequently prevent abnormal vascular proliferation in phase

Omega-3 PUFAs protect against pathologic neovascularization in ROP. They lack from the diet of premature infants because there is no transfer from the mother during the last trimester. Therefore, studies are planned to investigate the potential

Currently, laser photocoagulation of the nonvascular retina remains the only well-established, gold standard therapy to prevent ROP progression toward blindness. There is clinical and experimental research going on in order to add therapeutic strategies meant to improve the prognosis of this potentially blinding disease. Despite timely treatment, it is estimated that approximately 16% of patients with type 1 ROP develop retinal detachment. The results reported by a large series of cases showed that the reattachment rate following pars plana vitrectomy is correlated with the stage of ROP: 82% for stage 4A, 70% for stage 4B, and 43% for stage

supplementation with omega-3 polyunsaturated fatty acids (PUFAs) [10].

benefit of supplementing omega-3 PUFA intake in premature infants [10].

*Neonatal Medicine*

of the disease [6].

3 ROP with plus disease in zone 1 or 2 [8].

coagulation that had replaced cryotherapy [9].

anterior segment such as cataract formation [10].

one of the major factors involved in ROP pathogenesis [10].

proved by several experimental and clinical studies [10].

intravitreal anti-VEGF injection [14, 15].

to be used in order to ablate the peripheral retina and thus interrupt the pathogenic chain in ROP, but there were no guided indications in correlation with the severity

CRYO-ROP elaborated a classification of ROP and defined "threshold" disease in which therapy was indicated: 5 contiguous hours or 8 non-contiguous hours of stage

A subsequent study, ETROP investigated whether treatment performed earlier than in threshold disease would further reduce the rate of anatomic unfavorable outcomes. Prethreshold disease was defined as type 1 and type 2 ROP. Clinically, type 1 ROP includes the following categories: zone 1 ROP of any stage with plus, zone 1 stage 3 ROP without plus, and zone 2 stage 2 or 3 disease with plus. In type 2 ROP, the following situations are included: zone 1 stage 1 or 2 without plus or zone 2 stage 3 without plus. ETROP recommends treatment in type 1 ROP and monitoring in type 2 ROP. At 6-year follow-up, the study proved 9% unfavorable structural outcomes in the early treated eyes, as compared to 15% unfavorable structural outcomes in the conventional treatment group. ETROP recommends peripheral

At this point, ablation of the peripheral retina was made by indirect laser photo-

There are several advantages of laser over cryotherapy: laser requires less general anesthesia, it treats easier the posterior ROP, and it is associated with less systemic side effects: apnea, bradycardia, and cardiopulmonary arrest requiring resuscitation. However, ocular complications were reported after extensive indirect diode laser photocoagulation: vitreous hemorrhage, cataract, intraocular inflammation, choroidal effusion, and elevated intraocular pressure [9]. Theoretically, the risk of cataract is very low, given the fact that the infrared radiation that we use is absorbed deep into the choroid and not in the crystalline lens. Vitreous hemorrhage is rather a

Parvaresh et al. published the results of transscleral diode laser photocoagulation instead of transpupillary approach and concluded that it is technically easier, especially for retinal periphery and with fewer complications at the level of the

During the last years, efforts have been made in order to find therapeutic meth-

Given the role of VEGF in angiogenesis, anti-VEGF administered intravitreally emerged as a promising tool for the treatment of ROP, alongside its use in ischemic retinopathies. Research conducted over the latest two decades proved that VEGF is

VEGF inhibition with subsequent suppression of neovascular disease was

Clinical studies showed significantly higher levels of VEGF in the vitreous of patients with vasoproliferative ROP [11–13]. Sato et al. analyzed 27 cytokines in the vitreous of ROP eyes and found that VEGF was the most strongly correlated with vascularly active ROP [11]. This study also identified other factors elevated in ROP: fibroblast growth factor (FGF), granulocyte-colony stimulating factor (G-CSF), and granulocyte macrophage-colony stimulating factor (GM-CSF). This observation sustains the participation of an inflammatory response in the complex process of ROP development in addition to known vascular growth factors such as VEGF. Animal ROP models showed the suppression of the vascular disease following

Nonobe et al. injected bevacizumab in the vitreous of five premature infants and showed the marked decrease of aqueous humor concentration of VEGF in four of them. Law et al. injected bevacizumab in 13 eyes of seven premature infants prior

laser ablation in type 1 ROP and frequent observation in type 2 ROP.

sign of ROP progression than a complication related to the laser itself.

ods to induce the regression of new vessels with minimal side effects [10].

**88**

to laser or vitrectomy, and they noticed the improvement of the visualization of the retina with no systemic side effects, suggesting the role of anti-VEGF therapy prior these procedures [10].

A retrospective study carried by Lee et al. on 15 premature infants with stage 3 ROP showed the rapid regression of plus disease with more rapid development of normal vessels toward the retinal periphery, with no significant increase in systemic or ocular complications, compared with patients treated with laser photocoagulation [10].

Considerably concerns remain regarding the safety of anti-VEGF treatment in ROP, especially considering the correct dosage, timing of injection, and potential local complications such as infection, lens damage, and effect on the development of the neurosensory retina. Systemic side effects were not reported yet, but concern persists especially regarding the development of the central nervous system.

The Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity (BEATROP) study concluded that one doze of bevacizumab 0.625 mg in 0.025 ml had significantly better results in reducing the recurrence rate in zone 1 stage 3 ROP as compared to laser: 6 versus 42%, respectively. However, in posterior zone 2 ROP, the results were similar with intravitreal bevacizumab and laser. An interesting observation was that in some cases treated with intravitreal bevacizumab, late recurrence was noted: 16 ± 4.6 weeks with bevacizumab, as compared to 6.2 ± 5.7 weeks with laser. Therefore, follow-up in anti-VEGF-treated eyes should be performed for longer periods [10].

Erythropoietin (Epo) is another growth factor that was proved to promote angiogenesis in vitro and in animal models. Recombinant Epo (rhEpo) is used to treat anemia in premature infants, as it promotes red blood cell formation. Sato et al. showed significantly elevated levels of Epo in 40 eyes from 27 premature infants with stage 4 ROP [13]. Suk et al. carried out a retrospective study in which he investigated the rhEpo treatment and ROP in 265 patients. The study concluded that high dose and later starting age for rhEpo treatment are risk factors for ROP (the phase of the disease was not taken into account). However, Shah et al. in a retrospective study on 85 patients found no correlation between the rhEpo treatment and the incidence and severity of ROP [16].

Research in the field of angiogenesis led to a number of new ways to prevent ROP progression: targeting the insulin growth factor (IGF-1) pathway and dietary supplementation with omega-3 polyunsaturated fatty acids (PUFAs) [10].

Following preterm birth, serum IGF-1 is substantially reduced due to the interruption of fetal-maternal interaction. Animal models of ROP proved that IGF-1 is essential for vascular growth through interaction with VEGF signaling. Therefore, theoretically, supplementation of IGF-1 during phase 1 ROP would normalize vascular growth and subsequently prevent abnormal vascular proliferation in phase 2 ROP [10].

Omega-3 PUFAs protect against pathologic neovascularization in ROP. They lack from the diet of premature infants because there is no transfer from the mother during the last trimester. Therefore, studies are planned to investigate the potential benefit of supplementing omega-3 PUFA intake in premature infants [10].

Currently, laser photocoagulation of the nonvascular retina remains the only well-established, gold standard therapy to prevent ROP progression toward blindness. There is clinical and experimental research going on in order to add therapeutic strategies meant to improve the prognosis of this potentially blinding disease.

Despite timely treatment, it is estimated that approximately 16% of patients with type 1 ROP develop retinal detachment. The results reported by a large series of cases showed that the reattachment rate following pars plana vitrectomy is correlated with the stage of ROP: 82% for stage 4A, 70% for stage 4B, and 43% for stage

5 ROP. Scleral buckles can also be used for stage 4A ROP. A small case series showed that the association of a scleral buckle to pars plana vitrectomy did not improve the reattachment rate as compared cu PPV alone [10].

Because the therapeutic results in stage 5 ROP are extremely poor, the goal is to screen and treat type 1 ROP before the occurrence of retinal detachment.

In some circumstances, exudative retinal detachment is present, as a result of leakage from the vascular structures. This type of detachment is usually located posterior to the ridge, and it is convex in shape. Favorable results were reported in some of these cases after intravitreal administration of bevacizumab [10].

#### **7. Personal experience in the treatment of aggressive posterior ROP (APROP)**

#### **7.1 Background**

APROP is a particularly severe form of ROP defined by the following characteristics: posterior location (zone I or posterior zone II), very dilated and tortuous vessels, and development of arteriovenous shunts [17]. The evolution of APROP toward retinal detachment is very rapid, without the stages described in the "classic" form of ROP.

Laser treatment of ROP became available in the Ophthalmology Department ("Iuliu Hatieganu" University of Medicine and Pharmacy from Cluj-Napoca, Romania) in 2006, whereas intravitreal bevacizumab injections started to be used in 2009 (Avastin; Genentech Inc., San Francisco, California, USA).

In this study, we aimed to establish the relative effectiveness and safety of intravitreal bevacizumab (IVB) as compared to laser photocoagulation in APROP.

#### **7.2 Method**

We analyzed retrospectively all the files of the consecutive infants with APROP that we treated either by laser photocoagulation or with IVB between January 1, 2006 and December 31, 2013 and were followed for at least 60 weeks (for the laser group) and 80 weeks (for the IVB group). The overall follow-up ranged between 60 and 144 weeks from the treatment. The study was in agreement with the declaration of Helsinki (1964), and it has the approval of the ethics committee of our university.

Main outcome measures are represented by APROP regression, and the structural outcome associated either with laser photocoagulation or with IVB.

#### *7.2.1 Medical intervention*

In APROP we perform treatment (laser or IVB) within 24 hours from diagnosis. Before the intervention, a mixture of tropicamide 0.5% and phenylephrine 2.5% was instilled four times, every 15 minutes in order to obtain pupil dilatation. All laser treatments were performed under analgesia and sedation in the neonatology unit. Laser energy was delivered transpupillary from a portable diode laser having the emission of 810 nm, through the indirect ophthalmoscope. The lids were maintained open with a lid speculum, and the light and laser energy were focalized on the retina with the help of a + 28 diopters lens. We started laser photocoagulation of the retina with a power of 150 mW which we increased gradually up to the obtaining of the desired effect (whitish burn on the retina). We did not exceed 300 mW, the exposure time was 200 ms, and the spot dimension was 200 microns in all circumstances. We applied between 4000 and

**91**

*Therapeutic Options in Retinopathy of Prematurity DOI: http://dx.doi.org/10.5772/intechopen.80956*

course of the disease.

*7.2.2 Follow-up*

anti-VEGF therapy.

*7.2.3 Anatomical outcome*

*7.2.4 Statistical analysis*

*7.3.1 Evolution following treatment*

p = 0.412, respectively.

(version 23.0).

**7.3 Results**

stances, laser photocoagulation was added if possible.

6000 burns per eye in 1 or 2 sessions, according to the amount of the nonvascularized retina. The first postlaser checkup took place at 6–7 days and continued every 6–7 days, until there was evidence of APROP regression. If APROP failed to regress, re-treatment was carried out immediately. The frequency of checkups was determined by the clinical

We injected bevacizumab intravitreally for APROP according to the following guidelines: topical anesthesia with 0.5% proparacaine hydrochloride administered three times, every 2 minutes, topical administration of betadine 5%, fixation of the lid speculum, and injection of 0.025 ml (0.625 mg) bevacizumab at 1.5–1.75 mm from the limbus (in the pars plicata), with a 30G needle, perpendicularly on the globe, aiming the center of the eyeball. For the next 3 days, topical tobramycin eye drops were instilled five times/day. The first checkup took place the next day (for the risk of endophthalmitis) and then 7 days following the injection. The follow-up continued every week and then according to the clinical course of the disease.

The infants treated by laser were followed for at least 60 weeks, every month,

The anatomical outcome was evaluated by indirect ophthalmoscopy. The following signs were considered positive outcome: good pupil dilation and the decrease/ disappearance of retinal vessel tortuosity and of the neovascularization. In the IVB group, normal development of the retinal vessels toward periphery was noted. The aggravation of APROP was defined if "plus disease" and/or neovascularization persisted/reappeared, and there were signs of retinal detachment. In these circum-

Statistical analysis was performed using Microsoft Excel and IBM SPSS

Between January 1, 2006 and December 31, 2013, we treated 23 infants with APROP. The laser group includes 6 APROP infants and the intravitreal bevacizumab (IVB group) and 17 APROP infants. In both groups, the treatment was bilateral.

APROP treated by laser totalized 24 eyes and by bevacizumab, 34 eyes. Among the laser-treated eyes, the outcome was favorable in 18 eyes (75%), and within the IVB-treated eyes, result was favorable in 29 eyes (85.29%). Chi-square test and Fisher exact test prove no statistically significant difference: p = 0.419 and

whereas the ones treated with IVB were followed for at least 80 weeks, every 2 weeks for the first 3 months and then every month. The follow-up was discontinued when full vascularization of the retina was noticed. The exams were performed by three ophthalmologists trained in ROP. In the same time, the patients were followed by pediatricians for the risk of systemic complications related to intravitreal

#### *Therapeutic Options in Retinopathy of Prematurity DOI: http://dx.doi.org/10.5772/intechopen.80956*

6000 burns per eye in 1 or 2 sessions, according to the amount of the nonvascularized retina. The first postlaser checkup took place at 6–7 days and continued every 6–7 days, until there was evidence of APROP regression. If APROP failed to regress, re-treatment was carried out immediately. The frequency of checkups was determined by the clinical course of the disease.

We injected bevacizumab intravitreally for APROP according to the following guidelines: topical anesthesia with 0.5% proparacaine hydrochloride administered three times, every 2 minutes, topical administration of betadine 5%, fixation of the lid speculum, and injection of 0.025 ml (0.625 mg) bevacizumab at 1.5–1.75 mm from the limbus (in the pars plicata), with a 30G needle, perpendicularly on the globe, aiming the center of the eyeball. For the next 3 days, topical tobramycin eye drops were instilled five times/day. The first checkup took place the next day (for the risk of endophthalmitis) and then 7 days following the injection. The follow-up continued every week and then according to the clinical course of the disease.

#### *7.2.2 Follow-up*

*Neonatal Medicine*

**(APROP)**

**7.1 Background**

sic" form of ROP.

**7.2 Method**

university.

*7.2.1 Medical intervention*

5 ROP. Scleral buckles can also be used for stage 4A ROP. A small case series showed that the association of a scleral buckle to pars plana vitrectomy did not improve the

Because the therapeutic results in stage 5 ROP are extremely poor, the goal is to

In some circumstances, exudative retinal detachment is present, as a result of leakage from the vascular structures. This type of detachment is usually located posterior to the ridge, and it is convex in shape. Favorable results were reported in

screen and treat type 1 ROP before the occurrence of retinal detachment.

some of these cases after intravitreal administration of bevacizumab [10].

**7. Personal experience in the treatment of aggressive posterior ROP** 

APROP is a particularly severe form of ROP defined by the following characteristics: posterior location (zone I or posterior zone II), very dilated and tortuous vessels, and development of arteriovenous shunts [17]. The evolution of APROP toward retinal detachment is very rapid, without the stages described in the "clas-

Laser treatment of ROP became available in the Ophthalmology Department ("Iuliu Hatieganu" University of Medicine and Pharmacy from Cluj-Napoca, Romania) in 2006, whereas intravitreal bevacizumab injections started to be used

In this study, we aimed to establish the relative effectiveness and safety of intra-

We analyzed retrospectively all the files of the consecutive infants with APROP that we treated either by laser photocoagulation or with IVB between January 1, 2006 and December 31, 2013 and were followed for at least 60 weeks (for the laser group) and 80 weeks (for the IVB group). The overall follow-up ranged between 60 and 144 weeks from the treatment. The study was in agreement with the declaration of Helsinki (1964), and it has the approval of the ethics committee of our

Main outcome measures are represented by APROP regression, and the struc-

In APROP we perform treatment (laser or IVB) within 24 hours from diagnosis. Before the intervention, a mixture of tropicamide 0.5% and phenylephrine 2.5% was instilled four times, every 15 minutes in order to obtain pupil dilatation. All laser treatments were performed under analgesia and sedation in the neonatology unit. Laser energy was delivered transpupillary from a portable diode laser having the emission of 810 nm, through the indirect ophthalmoscope. The lids were maintained open with a lid speculum, and the light and laser energy were focalized on the retina with the help of a + 28 diopters lens. We started laser photocoagulation of the retina with a power of 150 mW which we increased gradually up to the obtaining of the desired effect (whitish burn on the retina). We did not exceed 300 mW, the exposure time was 200 ms, and the spot dimension was 200 microns in all circumstances. We applied between 4000 and

tural outcome associated either with laser photocoagulation or with IVB.

vitreal bevacizumab (IVB) as compared to laser photocoagulation in APROP.

in 2009 (Avastin; Genentech Inc., San Francisco, California, USA).

reattachment rate as compared cu PPV alone [10].

**90**

The infants treated by laser were followed for at least 60 weeks, every month, whereas the ones treated with IVB were followed for at least 80 weeks, every 2 weeks for the first 3 months and then every month. The follow-up was discontinued when full vascularization of the retina was noticed. The exams were performed by three ophthalmologists trained in ROP. In the same time, the patients were followed by pediatricians for the risk of systemic complications related to intravitreal anti-VEGF therapy.

#### *7.2.3 Anatomical outcome*

The anatomical outcome was evaluated by indirect ophthalmoscopy. The following signs were considered positive outcome: good pupil dilation and the decrease/ disappearance of retinal vessel tortuosity and of the neovascularization. In the IVB group, normal development of the retinal vessels toward periphery was noted. The aggravation of APROP was defined if "plus disease" and/or neovascularization persisted/reappeared, and there were signs of retinal detachment. In these circumstances, laser photocoagulation was added if possible.

#### *7.2.4 Statistical analysis*

Statistical analysis was performed using Microsoft Excel and IBM SPSS (version 23.0).

#### **7.3 Results**

Between January 1, 2006 and December 31, 2013, we treated 23 infants with APROP. The laser group includes 6 APROP infants and the intravitreal bevacizumab (IVB group) and 17 APROP infants. In both groups, the treatment was bilateral.

#### *7.3.1 Evolution following treatment*

APROP treated by laser totalized 24 eyes and by bevacizumab, 34 eyes. Among the laser-treated eyes, the outcome was favorable in 18 eyes (75%), and within the IVB-treated eyes, result was favorable in 29 eyes (85.29%). Chi-square test and Fisher exact test prove no statistically significant difference: p = 0.419 and p = 0.412, respectively.

We needed to repeat laser treatment in 10 of the 24 eyes with APROP (41.66%) with good outcome in 8 of them. Supplementary laser spots were applied on the skipped areas toward the macula.

APROP regressed in 29 eyes (85.29%) from the IVB-treated group and failed to regress in five eyes (14.71%). In three of the five eyes, laser photocoagulation was carried out, with favorable outcome in all of them. In the remaining two eyes, laser treatment could not be performed due to the lack of visualization.

#### *7.3.2 Comparative evolution after treatment between the two groups*

The observed differences between the two groups are statistically significant, as proved by McNemar's test (p < 0.001). Global success rate (bilateral or unilateral regression) versus unsuccessful treatment was higher for IVB (94, 12% of cases) against laser photocoagulation (66, 66%), but no statistically significance higher (Chi-square test p = 0.420, Fisher exact test p = 0.462).

After excluding the infants with bad outcome, who came from the same NICU, the difference between the two groups regarding regression rate is no longer significant: 85.29% in the IVB group and 81.25% in the laser photocoagulation group (p > 0.05).

Treatment worked quicker within the IVB group, as compared to the laser photocoagulation group.

The bad outcome was identified 1 week after treatment, in all the 16 eyes within this series (11 from the laser photocoagulation group and 5 from the IVB group). We had no late recurrence in this series.

#### **7.4 Discussion**

#### *7.4.1 Indirect diode laser photocoagulation for APROP*

Laser photocoagulation of the retina is the gold standard in the treatment of ROP, and it proved its efficacy in more than 90% of ROP cases [18]. On the other hand, laser destroys the retina, and complications were cited in relation to it: cornea, iris and lens burns, hyphema, uveitis, retinal hemorrhages, and choroidal ruptures [19]. In our series, we report two cases of mild anterior uveitis following laser photocoagulation for APROP, with prompt resolution following mydriatic and anti-inflammatory eye drops.

Laser photocoagulation does not address the underlying cause of the disease [18]. Zone 1 APROP is known to have worse prognosis following laser photocoagulation, as compared to the classical form of the disease [20].

Because of the lack of landmarks in APROP, laser photocoagulation of the retina toward the posterior pole is difficult, and sometimes untreated areas of the avascular retina remain as a source of VEGF explaining the progression of the disease. By consequence, one single session of laser treatment is often insufficient in APROP.

Within the laser photocoagulation group, APROP final failure rate was 45.83%, represented by 11 eyes from 7 infants (four, bilaterally and three, unilaterally). From these seven cases, five came from the same neonatal unit and totalize eight eyes with bad outcome (three, bilaterally and two, unilaterally). This observation can lead us to the supposition that the inadequate neonatal care and oxygen administration might be at the origin of the severity and unresponsiveness to the laser treatment in these cases.

If we exclude these eight eyes from our analysis, the success rate following laser photocoagulation for APROP becomes 81.25% (in 13 of the remaining 16 cases, APROP could be stopped by laser treatment).

**93**

*Therapeutic Options in Retinopathy of Prematurity DOI: http://dx.doi.org/10.5772/intechopen.80956*

APROP regression rate following IVB was 85.29% in our series (29 of the 34 eyes). We added laser photocoagulation in all the five eyes with lack of regression following IVB, with good outcome in three of them. The two eyes with final poor

We did not identify any local complication subsequent to IVB in our group. No

The main reason that determined us to replace laser photocoagulation with IVB in APROP was the high failure rate in this form of ROP, following laser treatment, in our practice, which is in agreement with data in the literature (45.83%) [21]. Besides, there are other disadvantages of laser treatment for APROP: the need to apply many laser spots during long and laborious sessions and the need to repeat laser because often at the moment of treatment there are no well-defined landmarks between the vascularized and the nonvascularized retina (typical feature of APROP). Often pupils do not dilate well in these severe cases, and vitreous hemorrhage can be associated, making laser treatment inadequate. The general status of the infant is often severe in APROP cases, making laser treatment risky for the patient's life. Finally, IVB does not destroy the retina as opposed to laser which ablates the nonvascularized retina in order to keep alive its vascular part. [21].

APROP regression rate was significantly better following IVB as compared with

Another major advantage of IVB over laser is the continuation of retinal vascularization following treatment up to the periphery [20]. This observation was verified in our series. Anti-VEGF and laser act by different mechanisms in stopping the progression of ROP toward retinal detachment. Whereas laser photocoagulation destroys the source of VEGF (ischemic retina), anti-VEGF annihilates also the VEGF already present in the vitreous. This explains the quicker response and higher

According to our experience, all bad outcomes were identified 1 week after treatment. Therefore, we consider them as unresponsiveness to treatment, not late

We identified asymmetric response to treatment in six cases: three from the laser group and three from the IVB group. The possible explanation of this outcome might be the unequal development of the eyes which also explains the rare situation

The main issue related to IVB treatment is its safety. There is proof that following IVB injections the serum VEGF levels decrease and anti-VEGF was found in the systemic circulation [21]. It is known that in ROP the blood-retinal barrier is broken down, allowing the exit of anti-VEGF in the systemic circulation, while the infant is still during the process of organogenesis. Concern comes from the fact that VEGF is necessary for the development of the lungs, brain, kidneys, and skeleton. VEGF also

laser photocoagulation in our series. However, when we remove from the laser photocoagulation group, the infants with bad outcome, who came from the same

*7.4.2 IVB for APROP in our series*

outcome belonged to different infants.

late reactivation of the disease was present.

NICU, the difference is no longer significant.

efficacy of IVB as compared to laser in APROP.

*7.4.5 Safety issues related to anti-VEGF therapy*

*7.4.4 Asymmetric response to treatment*

recurrences [21].

of unilateral ROP.

*7.4.3 IVB versus laser photocoagulation in the treatment of APROP*

#### *7.4.2 IVB for APROP in our series*

*Neonatal Medicine*

(p > 0.05).

**7.4 Discussion**

photocoagulation group.

had no late recurrence in this series.

anti-inflammatory eye drops.

treatment in these cases.

APROP could be stopped by laser treatment).

skipped areas toward the macula.

We needed to repeat laser treatment in 10 of the 24 eyes with APROP (41.66%) with good outcome in 8 of them. Supplementary laser spots were applied on the

APROP regressed in 29 eyes (85.29%) from the IVB-treated group and failed to regress in five eyes (14.71%). In three of the five eyes, laser photocoagulation was carried out, with favorable outcome in all of them. In the remaining two eyes, laser

The observed differences between the two groups are statistically significant, as proved by McNemar's test (p < 0.001). Global success rate (bilateral or unilateral regression) versus unsuccessful treatment was higher for IVB (94, 12% of cases) against laser photocoagulation (66, 66%), but no statistically significance higher

After excluding the infants with bad outcome, who came from the same NICU, the difference between the two groups regarding regression rate is no longer significant: 85.29% in the IVB group and 81.25% in the laser photocoagulation group

The bad outcome was identified 1 week after treatment, in all the 16 eyes within this series (11 from the laser photocoagulation group and 5 from the IVB group). We

Laser photocoagulation of the retina is the gold standard in the treatment of ROP, and it proved its efficacy in more than 90% of ROP cases [18]. On the other hand, laser destroys the retina, and complications were cited in relation to it: cornea, iris and lens burns, hyphema, uveitis, retinal hemorrhages, and choroidal ruptures [19]. In our series, we report two cases of mild anterior uveitis following laser photocoagulation for APROP, with prompt resolution following mydriatic and

Laser photocoagulation does not address the underlying cause of the disease [18]. Zone 1 APROP is known to have worse prognosis following laser photocoagu-

Because of the lack of landmarks in APROP, laser photocoagulation of the retina toward the posterior pole is difficult, and sometimes untreated areas of the avascular retina remain as a source of VEGF explaining the progression of the disease. By consequence, one single session of laser treatment is often insufficient in APROP. Within the laser photocoagulation group, APROP final failure rate was 45.83%, represented by 11 eyes from 7 infants (four, bilaterally and three, unilaterally). From these seven cases, five came from the same neonatal unit and totalize eight eyes with bad outcome (three, bilaterally and two, unilaterally). This observation can lead us to the supposition that the inadequate neonatal care and oxygen administration might be at the origin of the severity and unresponsiveness to the laser

If we exclude these eight eyes from our analysis, the success rate following laser photocoagulation for APROP becomes 81.25% (in 13 of the remaining 16 cases,

Treatment worked quicker within the IVB group, as compared to the laser

treatment could not be performed due to the lack of visualization.

*7.3.2 Comparative evolution after treatment between the two groups*

(Chi-square test p = 0.420, Fisher exact test p = 0.462).

*7.4.1 Indirect diode laser photocoagulation for APROP*

lation, as compared to the classical form of the disease [20].

**92**

APROP regression rate following IVB was 85.29% in our series (29 of the 34 eyes). We added laser photocoagulation in all the five eyes with lack of regression following IVB, with good outcome in three of them. The two eyes with final poor outcome belonged to different infants.

We did not identify any local complication subsequent to IVB in our group. No late reactivation of the disease was present.

#### *7.4.3 IVB versus laser photocoagulation in the treatment of APROP*

The main reason that determined us to replace laser photocoagulation with IVB in APROP was the high failure rate in this form of ROP, following laser treatment, in our practice, which is in agreement with data in the literature (45.83%) [21]. Besides, there are other disadvantages of laser treatment for APROP: the need to apply many laser spots during long and laborious sessions and the need to repeat laser because often at the moment of treatment there are no well-defined landmarks between the vascularized and the nonvascularized retina (typical feature of APROP). Often pupils do not dilate well in these severe cases, and vitreous hemorrhage can be associated, making laser treatment inadequate. The general status of the infant is often severe in APROP cases, making laser treatment risky for the patient's life. Finally, IVB does not destroy the retina as opposed to laser which ablates the nonvascularized retina in order to keep alive its vascular part. [21].

APROP regression rate was significantly better following IVB as compared with laser photocoagulation in our series. However, when we remove from the laser photocoagulation group, the infants with bad outcome, who came from the same NICU, the difference is no longer significant.

Another major advantage of IVB over laser is the continuation of retinal vascularization following treatment up to the periphery [20]. This observation was verified in our series. Anti-VEGF and laser act by different mechanisms in stopping the progression of ROP toward retinal detachment. Whereas laser photocoagulation destroys the source of VEGF (ischemic retina), anti-VEGF annihilates also the VEGF already present in the vitreous. This explains the quicker response and higher efficacy of IVB as compared to laser in APROP.

According to our experience, all bad outcomes were identified 1 week after treatment. Therefore, we consider them as unresponsiveness to treatment, not late recurrences [21].

#### *7.4.4 Asymmetric response to treatment*

We identified asymmetric response to treatment in six cases: three from the laser group and three from the IVB group. The possible explanation of this outcome might be the unequal development of the eyes which also explains the rare situation of unilateral ROP.

#### *7.4.5 Safety issues related to anti-VEGF therapy*

The main issue related to IVB treatment is its safety. There is proof that following IVB injections the serum VEGF levels decrease and anti-VEGF was found in the systemic circulation [21]. It is known that in ROP the blood-retinal barrier is broken down, allowing the exit of anti-VEGF in the systemic circulation, while the infant is still during the process of organogenesis. Concern comes from the fact that VEGF is necessary for the development of the lungs, brain, kidneys, and skeleton. VEGF also acts as a neural survivor factor inside the eye, and its suppression might prevent the development of neural components in the retina [21].

#### *7.4.6 Comparison between laser and IVB in the treatment of ROP*

The advantages of IVB over laser photocoagulation in the treatment of ROP are related to its simplicity; short duration; lack of retinal destruction, conducting under topical anesthesia; lower price; and possibility to be performed in the eyes with small pupils and hazy media and in infants with poor general condition in which laser treatment under general anesthesia would be risky [21]. As proved by our series, IVB allows further development of retinal normal vascularization up to periphery, as opposed to laser. However, IVB is not risk free as far as local complications are considered. Lens injury, intraocular hemorrhage, retinal detachment, and endophthalmitis are possible, but they were not reported in the literature so far.

According to our experience, the most important advantage of IVB as compared to laser treatment is the better outcome in APROP, as published by other authors [21]. In this context, IVB represents our first therapeutic indication for APROP, even if the systemic safety issues were not fully addressed [21].

In a study that compared laser with bevacizumab in ROP and published in 2015, similar results were reported in the two groups, but it included all ROP cases, not just the severe ones (APROP) [22].

Other authors found higher recurrence rate of ROP following IVB as compared to laser, but within the laser group, macular ectopia had a higher incidence [23]. This observation is in agreement with our study that identified macular ectopia only in one case from the laser treated group.

In a previously published study, we showed that in the IVB-treated eyes, the retinal vascularization continued up to the periphery, unlike with laser [24].

Another observation of this comparative study is that the response to IVB was quicker than following laser. The explanation is represented by the fact that anti-VEGF suppresses not only the VEGF in the retina (such as laser does) but also the VEGF which is already released in the vitreous.

#### **8. Conclusion**

#### **8.1 Personal experience**

Intravitreal bevacizumab has emerged as a very useful tool in the treatment of ROP. We found a statistically significant higher APROP regression rate after IVB, as compared to laser photocoagulation in our series. IVB is much shorter, easier, accessible, and less expensive than laser photocoagulation. We could perform IVB in the eyes with small pupils and hazy media. By consequence, bevacizumab given intravitreally replaced laser in APROP, becoming the standard of care in this severe form of ROP, in our practice.

#### **8.2 General**

Progress in neonatal care was associated with higher survival rates of low birth weight and low gestational age newborns.

ROP is a biphasic disease: the first phase (from the moment of birth to 31–32 weeks postconceptional age) is called hyperoxic and it leads to the arrest of the normal retinal development, and the second phase (from 32- to 36-week

**95**

provided the original work is properly cited.

*Therapeutic Options in Retinopathy of Prematurity DOI: http://dx.doi.org/10.5772/intechopen.80956*

complete vascularization of the retina.

advantages.

**Acknowledgements**

**Conflict of interest**

**Author details**

Simona Delia Nicoară

Pharmacy, Cluj-Napoca, Romania

chapter.

postconceptional age) is called hypoxic with overexpression of VEGF, IGF-1, and oxidative damage with subsequent new vessel growth and retinal detachment. The Early Treatment for ROP study (ETROP) reclassified ROP according to the required attitude: type 1, ROP requiring treatment and type 2, ROP requiring closely monitoring. APROP is a very severe type 1 ROP characterized by rapid

ROP screening should be made by trained ophthalmologists and started at 4–6 weeks after birth or at PCA 31 weeks whichever is later and continued up to the

The most important factor to prevent ROP is preventing premature birth. The gold standard for the treatment of ROP is indirect laser photocoagulation of the nonvascularized retina. Clinical studies conducted during the last years proved the superior efficacy of IVB over laser in APROP as well as its other

Research in the field of angiogenesis led to a number of new ways to prevent ROP progression: targeting the insulin growth factor (IGF-1) pathway and dietary

This study was funded by grant number PED 156, Executive Agency for Higher

The author declares no conflict of interest related to the publication of this

evolution toward retinal detachment if not addressed accordingly.

supplementation with omega-3 polyunsaturated fatty acids (PUFA).

Education, Research, Development, and Innovation Funding, Romania.

© 2018 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,

Department of Ophthalmology, "Iuliu Hațieganu" University of Medicine and

\*Address all correspondence to: simonanicoara1@gmail.com

*Therapeutic Options in Retinopathy of Prematurity DOI: http://dx.doi.org/10.5772/intechopen.80956*

*Neonatal Medicine*

literature so far.

**8. Conclusion**

**8.2 General**

**8.1 Personal experience**

form of ROP, in our practice.

weight and low gestational age newborns.

just the severe ones (APROP) [22].

only in one case from the laser treated group.

VEGF which is already released in the vitreous.

acts as a neural survivor factor inside the eye, and its suppression might prevent the

The advantages of IVB over laser photocoagulation in the treatment of ROP are related to its simplicity; short duration; lack of retinal destruction, conducting under topical anesthesia; lower price; and possibility to be performed in the eyes with small pupils and hazy media and in infants with poor general condition in which laser treatment under general anesthesia would be risky [21]. As proved by our series, IVB allows further development of retinal normal vascularization up to periphery, as opposed to laser. However, IVB is not risk free as far as local complications are considered. Lens injury, intraocular hemorrhage, retinal detachment, and endophthalmitis are possible, but they were not reported in the

According to our experience, the most important advantage of IVB as compared to laser treatment is the better outcome in APROP, as published by other authors [21]. In this context, IVB represents our first therapeutic indication for APROP,

In a study that compared laser with bevacizumab in ROP and published in 2015, similar results were reported in the two groups, but it included all ROP cases, not

Other authors found higher recurrence rate of ROP following IVB as compared to laser, but within the laser group, macular ectopia had a higher incidence [23]. This observation is in agreement with our study that identified macular ectopia

In a previously published study, we showed that in the IVB-treated eyes, the retinal vascularization continued up to the periphery, unlike with laser [24].

Another observation of this comparative study is that the response to IVB was quicker than following laser. The explanation is represented by the fact that anti-VEGF suppresses not only the VEGF in the retina (such as laser does) but also the

Intravitreal bevacizumab has emerged as a very useful tool in the treatment of ROP. We found a statistically significant higher APROP regression rate after IVB, as compared to laser photocoagulation in our series. IVB is much shorter, easier, accessible, and less expensive than laser photocoagulation. We could perform IVB in the eyes with small pupils and hazy media. By consequence, bevacizumab given intravitreally replaced laser in APROP, becoming the standard of care in this severe

Progress in neonatal care was associated with higher survival rates of low birth

ROP is a biphasic disease: the first phase (from the moment of birth to 31–32 weeks postconceptional age) is called hyperoxic and it leads to the arrest of the normal retinal development, and the second phase (from 32- to 36-week

development of neural components in the retina [21].

*7.4.6 Comparison between laser and IVB in the treatment of ROP*

even if the systemic safety issues were not fully addressed [21].

**94**

postconceptional age) is called hypoxic with overexpression of VEGF, IGF-1, and oxidative damage with subsequent new vessel growth and retinal detachment.

The Early Treatment for ROP study (ETROP) reclassified ROP according to the required attitude: type 1, ROP requiring treatment and type 2, ROP requiring closely monitoring. APROP is a very severe type 1 ROP characterized by rapid evolution toward retinal detachment if not addressed accordingly.

ROP screening should be made by trained ophthalmologists and started at 4–6 weeks after birth or at PCA 31 weeks whichever is later and continued up to the complete vascularization of the retina.

The most important factor to prevent ROP is preventing premature birth.

The gold standard for the treatment of ROP is indirect laser photocoagulation of the nonvascularized retina. Clinical studies conducted during the last years proved the superior efficacy of IVB over laser in APROP as well as its other advantages.

Research in the field of angiogenesis led to a number of new ways to prevent ROP progression: targeting the insulin growth factor (IGF-1) pathway and dietary supplementation with omega-3 polyunsaturated fatty acids (PUFA).

#### **Acknowledgements**

This study was funded by grant number PED 156, Executive Agency for Higher Education, Research, Development, and Innovation Funding, Romania.

#### **Conflict of interest**

The author declares no conflict of interest related to the publication of this chapter.

#### **Author details**

Simona Delia Nicoară Department of Ophthalmology, "Iuliu Hațieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania

\*Address all correspondence to: simonanicoara1@gmail.com

© 2018 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.

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[9] Kieselbach GF, Ramharter A, Baldissera I, Kralinger MT. Laser photocoagulation for retinopathy of prematurity: Structural and functional outcome. Acta Ophthalmologica Scandinavica. 2006;**84**(1):21-26. DOI: 10.1111/j.1600-0420.2005.00548.x

[10] Jing C, Stahl A, Hellstrom A, Smith LS. Current update on retinopathy of prematurity: Screening and treatment. Current Opinion in Pediatrics. 2011;**23**(2):173-178. DOI: 10.1097/ mop.0b013e3283423f35

[11] Sato T, Kusaka S, Shimojo H, Fujikado T. Simultaneous analyses of vitreous levels of 27 cytokines in eyes with retinopathy of prematurity. Ophthalmology. 2009;**116**(11):2165-2169. DOI: 10.1016/j.ophtha.2009.04.026

[12] Sonmez K, Drenser KA, Capone A Jr, Trese MT. Vitreous levels of stromal cell-derived factor 1 and vascular endothelial growth factor in patients with retinopathy of prematurity. Ophthalmology. 2008;**115**(6):1065-1070. DOI: 10.1016/j.ophtha.2007.08.050

[13] Sato T, Kusaka S, Shimojo H, Fujikado T. Vitreous levels of erythropoietin and vascular endothelial growth factor in eyes with retinopathy of prematurity. Ophthalmology. 2009;**116**(9):1599-1603. DOI: 10.1016/j. ophtha.2008.12.023

[14] Aiello LP, Pierce EA, Foley ED, et al. Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins. Proceedings of

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Monitor. 2016;**22**:1192-1209. DOI:

[22] Maram I, Kamiar M, Nasrin T. Treatment of type 1 retinopathy of prematurity with bevacizumab versus laser. JAAPOS. 2015;**19**:140-144. DOI:

10.12659/MSM.897095

10.12659/MSM.897095

MSM.897095

[23] Hwang KC, Hubbard GB,

after intravitreal bevacizumab versus laser photocoagulation for retinopathy of prematurity: A 5-year retrospective analysis. Ophthalmology. 2015;**122**:1008-1015. DOI: 10.12659/

[24] Nicoară SD, Nascutzy C, Cristian C, et al. Outcomes and prognostic factors of intravitreal bevacizumab monotherapy in zone I stage 3+ and aggressive posterior retinopathy of prematurity. Journal of Ophthalmology. 2015;**2015**:102582. DOI:

10.1155/2015/102582

Hutchinson AK, Lambert SR. Outcomes

the National Academy of Sciences of the United States of America. 1995;**92**(23):10457-10461

[15] Smith LE, Shen W, Perruzzi C, et al. Regulation of vascular endothelial growth factor-dependent retinal neovascularization by insulin-like growth factor-1 receptor. Nature Medicine. 1999;**5**(12):1390-1395. DOI:

[16] Shah N, Jadav P, Jean-Baptiste D, Weedon J, Cohen LM, Kim MR. The effect of recombinant human

erythropoietin on the development of retinopathy of prematurity. American Journal of Perinatology. 2010;**27**(1):67-71.

[18] Hellström A, Smith LEH, Dammann O. Retinopathy of prematurity. Lancet. 2013;**382**(9902):1445-1457. DOI: 10.1016/S0140-6736(13)60178-6

[19] Laser ROP Study Group. Laser therapy for retinopathy of prematurity.

[21] Nicoara SD, Stefanut AC, Nascutzy C, Zaharie G, Toader LE, Drugan T. Regression rates following the treatment of aggressive posterior retinopathy of prematurity with bevacizumab versus laser: 8 year retrospective analysis. Medical Science

Archives of Ophthalmology.

[20] Nicoara SD, Nascutzy C, Cristian C, et al. Outcomes and prognostic factors of intravitreal bevacizumab monotherapy in zone I stage 3+ and aggressive posterior retinopathy of prematurity. Journal of Ophthalmology. 2015;**2015**:1-8. DOI:

1994;**112**(2):154-156

10.1155/2015/102582

DOI: 10.1055/s-0029-1224872

[17] Drenser KA, Trese MT, Capone A Jr. Aggressive posterior retinopathy of prematurity. Retina. 2010;**30**(suppl):S37-S40. DOI: 10.1097/

IAE.0b013e3181cb6151

10.1038/70963

*Therapeutic Options in Retinopathy of Prematurity DOI: http://dx.doi.org/10.5772/intechopen.80956*

the National Academy of Sciences of the United States of America. 1995;**92**(23):10457-10461

[15] Smith LE, Shen W, Perruzzi C, et al. Regulation of vascular endothelial growth factor-dependent retinal neovascularization by insulin-like growth factor-1 receptor. Nature Medicine. 1999;**5**(12):1390-1395. DOI: 10.1038/70963

[16] Shah N, Jadav P, Jean-Baptiste D, Weedon J, Cohen LM, Kim MR. The effect of recombinant human erythropoietin on the development of retinopathy of prematurity. American Journal of Perinatology. 2010;**27**(1):67-71. DOI: 10.1055/s-0029-1224872

[17] Drenser KA, Trese MT, Capone A Jr. Aggressive posterior retinopathy of prematurity. Retina. 2010;**30**(suppl):S37-S40. DOI: 10.1097/ IAE.0b013e3181cb6151

[18] Hellström A, Smith LEH, Dammann O. Retinopathy of prematurity. Lancet. 2013;**382**(9902):1445-1457. DOI: 10.1016/S0140-6736(13)60178-6

[19] Laser ROP Study Group. Laser therapy for retinopathy of prematurity. Archives of Ophthalmology. 1994;**112**(2):154-156

[20] Nicoara SD, Nascutzy C, Cristian C, et al. Outcomes and prognostic factors of intravitreal bevacizumab monotherapy in zone I stage 3+ and aggressive posterior retinopathy of prematurity. Journal of Ophthalmology. 2015;**2015**:1-8. DOI: 10.1155/2015/102582

[21] Nicoara SD, Stefanut AC, Nascutzy C, Zaharie G, Toader LE, Drugan T. Regression rates following the treatment of aggressive posterior retinopathy of prematurity with bevacizumab versus laser: 8 year retrospective analysis. Medical Science

Monitor. 2016;**22**:1192-1209. DOI: 10.12659/MSM.897095

[22] Maram I, Kamiar M, Nasrin T. Treatment of type 1 retinopathy of prematurity with bevacizumab versus laser. JAAPOS. 2015;**19**:140-144. DOI: 10.12659/MSM.897095

[23] Hwang KC, Hubbard GB, Hutchinson AK, Lambert SR. Outcomes after intravitreal bevacizumab versus laser photocoagulation for retinopathy of prematurity: A 5-year retrospective analysis. Ophthalmology. 2015;**122**:1008-1015. DOI: 10.12659/ MSM.897095

[24] Nicoară SD, Nascutzy C, Cristian C, et al. Outcomes and prognostic factors of intravitreal bevacizumab monotherapy in zone I stage 3+ and aggressive posterior retinopathy of prematurity. Journal of Ophthalmology. 2015;**2015**:102582. DOI: 10.1155/2015/102582

**96**

*Neonatal Medicine*

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[1] Good WV, Carden SM. Retinopathy of prematurity. British Journal of Ophthalmology. 2006;**90**(3):254-255.

Multicenter trial of cryotherapy for retinopathy of prematurity: Preliminary results. Archives of Ophthalmology. 1988;**106**(4):471-479. DOI: 10.1001/ archopht.1988.01060130517027

[9] Kieselbach GF, Ramharter A, Baldissera I, Kralinger MT. Laser photocoagulation for retinopathy of prematurity: Structural and functional outcome. Acta Ophthalmologica Scandinavica. 2006;**84**(1):21-26. DOI: 10.1111/j.1600-0420.2005.00548.x

[10] Jing C, Stahl A, Hellstrom A, Smith LS. Current update on retinopathy of prematurity: Screening and treatment.

Current Opinion in Pediatrics. 2011;**23**(2):173-178. DOI: 10.1097/

[11] Sato T, Kusaka S, Shimojo H, Fujikado T. Simultaneous analyses of vitreous levels of 27 cytokines in eyes with retinopathy of prematurity. Ophthalmology. 2009;**116**(11):2165-2169. DOI: 10.1016/j.ophtha.2009.04.026

[12] Sonmez K, Drenser KA, Capone A Jr, Trese MT. Vitreous levels of stromal cell-derived factor 1 and vascular endothelial growth factor in patients with retinopathy of prematurity.

Ophthalmology. 2008;**115**(6):1065-1070. DOI: 10.1016/j.ophtha.2007.08.050

erythropoietin and vascular endothelial growth factor in eyes with retinopathy of prematurity. Ophthalmology. 2009;**116**(9):1599-1603. DOI: 10.1016/j.

neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins. Proceedings of

[13] Sato T, Kusaka S, Shimojo H, Fujikado T. Vitreous levels of

[14] Aiello LP, Pierce EA, Foley ED, et al. Suppression of retinal

ophtha.2008.12.023

mop.0b013e3283423f35

[2] Salgado CM, Celik Y, Vanderveen DK. Anterior segment complications after diode laser photocoagulation for prethreshold retinopathy of prematurity. American Journal of Ophthalmology. 2010;**150**(1):6-9. DOI:

[3] Wilkinson AR, Haines L, Head K, Fielder AR. UK retinopathy of prematurity guideline. Early Human Development. 2008;**84**(2):71-74. DOI: 10.1016/j.earlhumdev.2007.12.004

[4] Jalali S, Matalia J, Hussain A, Anand R. Modification of screening criteria for retinopathy of prematurity in India and other middle-income countries. American Journal of Ophthalmology. 2006;**141**(5):966-968. DOI: 10.1016/j.

[5] Gilbert C, Rahi J, Eckstein M, O'Sullivan J, Foster A. Retinopathy of prematurity in middle-income countries. Lancet. 1997;**350**(9070):12-14. DOI: 10.1016/S0140-6736(97)01107-0

[6] Suelves AM, Shulman JP. Current screening and treatments in retinopathy of prematurity in the US. Eye and Brain. 2016;**8**(1):37-43. DOI: 10.2147/

[7] International Committee for the Classification of Retinopathy of Prematurity. The International Classification of Retinopathy of Prematurity revisited. Archives of Ophthalmology. 2005;**123**(7):991-999. DOI: 10.1001/archopht.123.7.991

[8] Cryotherapy for Retinopathy of Prematurity Cooperative Group.

DOI: 10.1136/bjo.2005.081166

10.1016/j.ajo.2009.12.017

ajo.2005.12.016

EB.S94439

Chapter 6

Abstract

mortality.

1. Introduction

maternal education.

99

Mortality

Thillagavathie Pillay

Parent-Carer Education: Reducing

the Risks for Neonatal and Infant

In this chapter, the role of engaging parents, family members, partners, significant others and carers (subsequently referred to as parent-carers) as key partners in targeted strategies for reducing the risks associated with neonatal mortality is discussed, especially within the context of less resource-constrained environments. Parent-carer education, sharing information on regionally prevalent risk factors and associations with death in the first 28 days of life and in infancy, can be potentially impactful and could drive behavioural changes, while promoting acquisition of newer life-saving skills such as basic life support training. Such education can be considered participatory learning and action. It affords parent-carers the confidence and knowledge on measures to key risks in infancy, such as the risk of sudden infant death, and how to recognize when their baby may be ill, facilitating timely access to appropriate healthcare services. Potentially, these then empower parent-carers to work with health services proactively in measures to reduce the risks for neonatal

Keywords: parent-carer education, reducing risks, neonatal mortality

Neonatal mortality refers to deaths in the first 28 days after birth and contributes to the total burden of mortality in children. Globally, 5.4 million children under 5 years of age died in 2017, of which 2.5 million were neonates [1]. In this millennium alone, there have been overall improvements in survival in children under 5, but the greatest reduction in mortality is seen in those between 1 and 4 years of age. Between 2000 and 2017, there was a 60% worldwide reduction in mortality in this age group. In contrast, neonatal mortality reduced by 41% [1, 2]. Two key factors have influenced this improvement in outcomes: access to healthcare services and

A faster rate of decline in childhood mortality rates compared to neonatal death

rate results in the latter assuming a higher proportion of the overall burden of deaths in children. This is especially obvious in more developed economies such as in England, where, with relatively lower child and infant death profiles, the proportion of neonatal deaths to those in infancy and childhood is much higher (70%) [3]. As a result, here, the spotlight has now readjusted towards addressing neonatal mortality [4–6]. In this chapter, the potential for further reductions in neonatal

#### Chapter 6

## Parent-Carer Education: Reducing the Risks for Neonatal and Infant Mortality

Thillagavathie Pillay

#### Abstract

In this chapter, the role of engaging parents, family members, partners, significant others and carers (subsequently referred to as parent-carers) as key partners in targeted strategies for reducing the risks associated with neonatal mortality is discussed, especially within the context of less resource-constrained environments. Parent-carer education, sharing information on regionally prevalent risk factors and associations with death in the first 28 days of life and in infancy, can be potentially impactful and could drive behavioural changes, while promoting acquisition of newer life-saving skills such as basic life support training. Such education can be considered participatory learning and action. It affords parent-carers the confidence and knowledge on measures to key risks in infancy, such as the risk of sudden infant death, and how to recognize when their baby may be ill, facilitating timely access to appropriate healthcare services. Potentially, these then empower parent-carers to work with health services proactively in measures to reduce the risks for neonatal mortality.

Keywords: parent-carer education, reducing risks, neonatal mortality

#### 1. Introduction

Neonatal mortality refers to deaths in the first 28 days after birth and contributes to the total burden of mortality in children. Globally, 5.4 million children under 5 years of age died in 2017, of which 2.5 million were neonates [1]. In this millennium alone, there have been overall improvements in survival in children under 5, but the greatest reduction in mortality is seen in those between 1 and 4 years of age. Between 2000 and 2017, there was a 60% worldwide reduction in mortality in this age group. In contrast, neonatal mortality reduced by 41% [1, 2]. Two key factors have influenced this improvement in outcomes: access to healthcare services and maternal education.

A faster rate of decline in childhood mortality rates compared to neonatal death rate results in the latter assuming a higher proportion of the overall burden of deaths in children. This is especially obvious in more developed economies such as in England, where, with relatively lower child and infant death profiles, the proportion of neonatal deaths to those in infancy and childhood is much higher (70%) [3]. As a result, here, the spotlight has now readjusted towards addressing neonatal mortality [4–6]. In this chapter, the potential for further reductions in neonatal

mortality is explored, especially in less resource-constrained environments, by focusing on parent-carer education around risks for neonatal mortality, while using learning points from around the world. Potentially, these initiatives empower parent-carers to acquire the necessary skills to manage their baby at risk and also engage in risk-reducing behaviours for the benefit of their baby.

infancy and beyond. Data on this as a package of care, however, are very limited. Maternal education improves infant, child and maternal mortality globally [15–17]. These relate to mothers' general awareness through education, which empowers women to make better decisions on the care of their baby and themselves. Engaging them in understanding the regional mortality risks for their baby, and their future babies, and what they could do to minimise these where possible may be of value. This kind of awareness of risk factors for infant mortality could provide parents and carers with knowledge that could drive longer term behavioural change that could influence the outcome of current baby, subsequent pregnancies and, in a cascade

Parent-Carer Education: Reducing the Risks for Neonatal and Infant Mortality

A recent project on parent education around the risks of mortality in a region in the West Midlands [8] in England revealed that parental uptake for the education on understanding risks for mortality was well accepted and supported (Table 1). Educating parents and carers on the basics of life support, how to manage their choking child and how to recognise that their baby is ill may empower parents and carers, enabling them to initiate preventative intervention earlier, which may be life-saving. Evidence that this can affect short-term behavioural change and empowerment through confidence building in parents appears to be possible [8],

I think this should be available to all parents. Found it really useful even after having three babies

Include grandparents/relatives; make it compulsory for first-time parents. Make nursing staff more

I can truly say this service has made me feel 100% confident in taking my baby home! Could not be

This made me feel at ease about taking my baby Harry home knowing about the ways to safe sleep.

Trainer very informative and helpful. Additional advice given on other topics; reassurance given

Selected parent feedback comments for parent/carer training on a neonatal unit in the West Midlands,

Very good. Helped put my mind at ease should the need arise. Felt very comfortable

Was very useful and has made me aware now as I did not have a clue about any Absolutely I think all parents should go through this not just ones on neonates unit

effect, those of close family members.

DOI: http://dx.doi.org/10.5772/intechopen.82786

but more studies are needed in this regard.

Very informative and should be offered to all parents

Really useful—should be available to all parents

Really appreciate eagerness of staff to come and help us

It is good to help save babies' life. Every parent should do

It is a great programme and all parents will benefit from it. I know I have!

Very useful and helpful instructor. Wish all mums had this opportunity. Really helpful. Get to know things you did not before and understand it better

All parents should be offered this!

aware for STORK referrals

more grateful. Thank you!

Very informative, thank you

Brilliant today. Thank you very much!

Covered a lot I wasn't even aware of

Brilliant!!

England. Extracted from [8].

Table 1.

101

#### 2. Reducing neonatal mortality through parent-carer education

Before embarking on parent education, understanding the risk factors for neonatal mortality is important. In poorly resourced areas, key risk factors and associations are infection, hypothermia, lack of breastfeeding, failure to recognise signs of illness in their baby and failure to provide adequate basic resuscitation at birth. Education packages focused on improving neonatal mortality therefore include information on maintaining warmth; drying; wrapping; skin-to-skin contact; supporting breastfeeding; infection prevention including handwashing, cord care, recognising signs of illness in their newborn baby and infant and basic life support [7].

For neonatal teams in relatively higher resourced environments, where access to public health facilities and general maternal education are less of an issue, and most of the above are routinely adopted, what are other key risk factors and what other kinds of initiatives are needed in order to make a difference to current neonatal mortality rates, and can they work?

In attempting to address this, the key risk factors here for neonatal mortality need to be identified. The most significant of these is prematurity [8–10]. In a report on perinatal mortality from MBRRACE on 2016 deaths, approximately 70% of all extended perinatal deaths occurred preterm, and almost 40% were in less than 28 weeks' gestation [9]. Optimising place of birth for the most vulnerable preterm births less than 26 weeks gestation at birth does reduce their mortality rates [11] and optimising nurse staffing for the care of especially preterm babies in neonatal intensive care units appears to be crucial [12]. Evidence-based or consensus medical and nursing care, robust reviews of mortalities and complex morbidities and sound clinical governance are instinctively important. But, simply improving clinical care provided, and in the correct place, is probably not enough.

By virtue of these babies being born prematurely, much of the potential factors that could influence outcome predate the birth of baby. These include obstetric, maternal health and social factors [13] and are usually out of the bounds of care of neonatal teams. For example, in the risk factors for neonatal mortality in a region in the West Midlands in England, prematurity, being born with low birth weight, congenital abnormalities, born at the extremes of maternal age, late maternal presentation for antenatal care, smoking, not breastfeeding and sudden infant death syndrome (SIDS) were the key associations with infant mortality [8]. All of these are influenced by upstream issues, that is, before birth (except SIDS). Just focusing on care pathways and postnatal care for these babies on neonatal units and in the community will have little impact on their mortality rate. A more multidisciplinary, lateral approach is needed, and there are lessons too, from developments in parent education in resource-limited environments.

Apart from optimising clinical care, what else can neonatal teams do? An area of focus for neonatal units could potentially be enhanced primary preventive care [4]. There is evidence that early parental interventions in preterm births are effective in promoting child health [14], and there is possible value in targeting parent-carer empowerment in reducing the risks of mortality for their newly born baby in

#### Parent-Carer Education: Reducing the Risks for Neonatal and Infant Mortality DOI: http://dx.doi.org/10.5772/intechopen.82786

infancy and beyond. Data on this as a package of care, however, are very limited. Maternal education improves infant, child and maternal mortality globally [15–17]. These relate to mothers' general awareness through education, which empowers women to make better decisions on the care of their baby and themselves. Engaging them in understanding the regional mortality risks for their baby, and their future babies, and what they could do to minimise these where possible may be of value. This kind of awareness of risk factors for infant mortality could provide parents and carers with knowledge that could drive longer term behavioural change that could influence the outcome of current baby, subsequent pregnancies and, in a cascade effect, those of close family members.

A recent project on parent education around the risks of mortality in a region in the West Midlands [8] in England revealed that parental uptake for the education on understanding risks for mortality was well accepted and supported (Table 1). Educating parents and carers on the basics of life support, how to manage their choking child and how to recognise that their baby is ill may empower parents and carers, enabling them to initiate preventative intervention earlier, which may be life-saving. Evidence that this can affect short-term behavioural change and empowerment through confidence building in parents appears to be possible [8], but more studies are needed in this regard.


Table 1.

mortality is explored, especially in less resource-constrained environments, by focusing on parent-carer education around risks for neonatal mortality, while using learning points from around the world. Potentially, these initiatives empower parent-carers to acquire the necessary skills to manage their baby at risk and also

engage in risk-reducing behaviours for the benefit of their baby.

support [7].

Neonatal Medicine

100

mortality rates, and can they work?

provided, and in the correct place, is probably not enough.

education in resource-limited environments.

2. Reducing neonatal mortality through parent-carer education

Before embarking on parent education, understanding the risk factors for neonatal mortality is important. In poorly resourced areas, key risk factors and associations are infection, hypothermia, lack of breastfeeding, failure to recognise signs of illness in their baby and failure to provide adequate basic resuscitation at birth. Education packages focused on improving neonatal mortality therefore include information on maintaining warmth; drying; wrapping; skin-to-skin contact; supporting breastfeeding; infection prevention including handwashing, cord care, recognising signs of illness in their newborn baby and infant and basic life

For neonatal teams in relatively higher resourced environments, where access to public health facilities and general maternal education are less of an issue, and most of the above are routinely adopted, what are other key risk factors and what other kinds of initiatives are needed in order to make a difference to current neonatal

In attempting to address this, the key risk factors here for neonatal mortality need to be identified. The most significant of these is prematurity [8–10]. In a report on perinatal mortality from MBRRACE on 2016 deaths, approximately 70% of all extended perinatal deaths occurred preterm, and almost 40% were in less than 28 weeks' gestation [9]. Optimising place of birth for the most vulnerable preterm births less than 26 weeks gestation at birth does reduce their mortality rates [11] and optimising nurse staffing for the care of especially preterm babies in neonatal intensive care units appears to be crucial [12]. Evidence-based or consensus medical and nursing care, robust reviews of mortalities and complex morbidities and sound clinical governance are instinctively important. But, simply improving clinical care

By virtue of these babies being born prematurely, much of the potential factors that could influence outcome predate the birth of baby. These include obstetric, maternal health and social factors [13] and are usually out of the bounds of care of neonatal teams. For example, in the risk factors for neonatal mortality in a region in the West Midlands in England, prematurity, being born with low birth weight, congenital abnormalities, born at the extremes of maternal age, late maternal presentation for antenatal care, smoking, not breastfeeding and sudden infant death syndrome (SIDS) were the key associations with infant mortality [8]. All of these are influenced by upstream issues, that is, before birth (except SIDS). Just focusing on care pathways and postnatal care for these babies on neonatal units and in the community will have little impact on their mortality rate. A more multidisciplinary, lateral approach is needed, and there are lessons too, from developments in parent

Apart from optimising clinical care, what else can neonatal teams do? An area of focus for neonatal units could potentially be enhanced primary preventive care [4]. There is evidence that early parental interventions in preterm births are effective in promoting child health [14], and there is possible value in targeting parent-carer empowerment in reducing the risks of mortality for their newly born baby in

Selected parent feedback comments for parent/carer training on a neonatal unit in the West Midlands, England. Extracted from [8].

#### 3. The benefits of overall maternal education on infant mortality

Method Example

DOI: http://dx.doi.org/10.5772/intechopen.82786

Parent-Carer Education: Reducing the Risks for Neonatal and Infant Mortality

Home visit by community-based worker after birth in India: information shared included breastfeeding, basic care of the baby—temperature control, hygiene, care of the umbilical cord stump, danger signs in the baby and how to use the healthcare system, especially for the sick, or preterm, or low-birth weight baby. There was a significant reduction in neonatal mortality rate in those who received the education [35.7 deaths per 1000 live births compared to those who did not (53.8 per 1000 live births)]

Group sessions by lady health workers in Pakistan included sharing information on immediate newborn care, cord care (cleaning and avoiding the use of traditional materials, such as ash and lead powder), and promotion of exclusive breastfeeding. There was also additional sharing of information on early breastfeeding (within the first hour) use of colostrum, thermoregulation, home care of low-birth weight infants, treatment of neonatal pneumonia, recognising the sick baby and danger signs needing treatment. Here the neonatal mortality rate significantly decreased from 57.3 to 41.3 per 1000 live births.

In India, this package included birth preparedness, clean delivery and cord care, thermal care (including skin-to-skin care), breastfeeding promotion, and danger sign recognition, and in

Compared with controls, neonatal mortality rate was

This was a meta-analysis of seven trials in India, Bangladesh, Nepal, Malawi, estimating the effect of women's group interventions on behavioural outcomes. Women's groups practising PLA showed improved behaviours during and after home deliveries, including the use of safe birthing kits, sterile blade to cut the cord, birth attendant washing hands before delivery, delayed bathing of baby for at least 24 hours and wrapping baby within 10 minutes of birth. Here, neonatal mortality was 32% lower in the clusters that had the intervention.

face-to-face, via telephone, social media or social engagement and include online and physical resources for training and guidance to parents on antenatal, birth and child issues. E.g.: Child birth peer support groups, supporting antenatal, birth and parenting in the UK (NCT); https://www.nct.org.uk/ E.g.: BLISS charity for sick and preterm babies; https://www.

E.g.: Breastfeeding support may be delivered on one-to-one or group format, at the bedside while in hospital and in the home. Breastfeeding support workers, nurses and breastfeeding buddies may be local and regional and hospital or community based. There also exists international organisational support through La Leche League International; https://www.llli.org/

These are usually groups based on national or international need and include for example the national Down syndrome group in the UK, and its international counterpart—Down syndrome international, which co-ordinates working with and advocating the case for children with Down syndrome in over 136 countries

one group a hypothermia indicator.

significantly reduced by 54%.

Organised support groups Peer support groups may work on one-to-one or group basis,

bliss.org.uk/

around the world.

Examples of parent-carer engagement: examples from around the world.

Home visits by community health

Regular community group sessions by Lady Health Workers [70]

Community-based package of care in

Participatory learning and action via

In resource-richer environments

Support groups: local, regional, national and international [72]

Support for specialised conditions/

congenital anomalies

Table 2.

103

women's groups [25]

[71]

care workers [69]

The most significant factor globally in reducing mortality for young children under 5 years of age is maternal education, and universal primary education for mothers is an established key focus of the United Nations Millennium Development Goal [17]. Better maternal education decreases not only childhood mortality but also maternal mortality [18] and is evident across resource-constrained and resourcericher environments. This is most striking in the former, where lower levels of maternal education (i.e., less than secondary school education) are significantly associated with neonatal mortality. In resource-richer environments, this effect is less noticeable [19] but prevalent in pockets with lower socio-economic status and lower levels of maternal education [19, 20]. While not easy to tease out, it is assumed that the impact of general maternal education on infant and childhood outcomes relates to empowerment of women to make better decisions over the care of their baby and care of themselves. Therefore, any targeted education, through providing parents and carers with knowledge of risks and associations with neonatal mortality, may contribute to empowering them into making decisions in the best interest of their baby, in an attempt to reduce risks for mortality.

#### 4. Methods of delivering targeted parent-carer education

A synopsis of this can be found in Table 2.

#### 4.1 One-to-one point-of-care education

This refers to education around a reason for a healthcare visit, usually in the home, or a visiting point. This has its benefits, providing an opportunity for maternal and family engagement with health services and focused learning and behavioural change. It is best reported in resource-constrained environments, as evidenced by the impact of health visits and education on behavioural changes and infant mortality, in women who have recently given birth [21]. Keeping baby warm, dry and wrapped to prevent hypothermia, skin-to-skin contact, breastfeeding and infection prevention, including delivering in a clean environment, handwashing, cord care and knowing what the signs of illness are in their baby, are key aspects of shared knowledge [21]. Guidelines for postnatal care of the mother and newborn, especially in resource-limited environments, were produced by the World Health Organisation ([22], Table 3), and these include parent education via home visits in the first week after birth and at least three additional postnatal contact points in the first 6 weeks of life.

In resource-richer environments, for example, England, similar 1:1 point-of-care visits at home usually occur post-delivery, initially by midwives and later by healthcare workers. NICE Guidelines on 1:1 postnatal care [23] guide the basic requirements for routine postnatal care for women and their babies and their partners and families. Support for feeding, advice on safe sleeping, recognising and dealing with health problems for both mother and baby are included in the quality standard, but there are limitations to its success to date [24]. These are usually delivered by midwives or health visitors, as the primary healthcare contacts for a mother and family with a newly born baby.

Educational engagement with parents and carers on the neonatal unit occurs as per unit policy and can include a wide variety of information supported by online

Parent-Carer Education: Reducing the Risks for Neonatal and Infant Mortality DOI: http://dx.doi.org/10.5772/intechopen.82786


#### Table 2.

3. The benefits of overall maternal education on infant mortality

interest of their baby, in an attempt to reduce risks for mortality.

4. Methods of delivering targeted parent-carer education

This refers to education around a reason for a healthcare visit, usually in the home, or a visiting point. This has its benefits, providing an opportunity for mater-

breastfeeding and infection prevention, including delivering in a clean environment, handwashing, cord care and knowing what the signs of illness are in their baby, are key aspects of shared knowledge [21]. Guidelines for postnatal care of the mother and newborn, especially in resource-limited environments, were produced by the World Health Organisation ([22], Table 3), and these include parent educa-

tion via home visits in the first week after birth and at least three additional

visits at home usually occur post-delivery, initially by midwives and later by healthcare workers. NICE Guidelines on 1:1 postnatal care [23] guide the basic requirements for routine postnatal care for women and their babies and their partners and families. Support for feeding, advice on safe sleeping, recognising and dealing with health problems for both mother and baby are included in the quality standard, but there are limitations to its success to date [24]. These are usually delivered by midwives or health visitors, as the primary healthcare contacts for a

In resource-richer environments, for example, England, similar 1:1 point-of-care

Educational engagement with parents and carers on the neonatal unit occurs as per unit policy and can include a wide variety of information supported by online

nal and family engagement with health services and focused learning and behavioural change. It is best reported in resource-constrained environments, as evidenced by the impact of health visits and education on behavioural changes and infant mortality, in women who have recently given birth [21]. Keeping baby warm, dry and wrapped to prevent hypothermia, skin-to-skin contact,

A synopsis of this can be found in Table 2.

postnatal contact points in the first 6 weeks of life.

mother and family with a newly born baby.

102

4.1 One-to-one point-of-care education

Neonatal Medicine

The most significant factor globally in reducing mortality for young children under 5 years of age is maternal education, and universal primary education for mothers is an established key focus of the United Nations Millennium Development Goal [17]. Better maternal education decreases not only childhood mortality but also maternal mortality [18] and is evident across resource-constrained and resourcericher environments. This is most striking in the former, where lower levels of maternal education (i.e., less than secondary school education) are significantly associated with neonatal mortality. In resource-richer environments, this effect is less noticeable [19] but prevalent in pockets with lower socio-economic status and lower levels of maternal education [19, 20]. While not easy to tease out, it is assumed that the impact of general maternal education on infant and childhood outcomes relates to empowerment of women to make better decisions over the care of their baby and care of themselves. Therefore, any targeted education, through providing parents and carers with knowledge of risks and associations with neonatal mortality, may contribute to empowering them into making decisions in the best

Examples of parent-carer engagement: examples from around the world.


Support groups work through community engagement, in which mothers develop and implement their own strategies for improvement, through shared peer group learning with a facilitator. The women are empowered to make improvements for their own communities, which result in behavioural changes that were more effective than simple traditional teacher/student model. In a trial in India, neonatal mortality reduced by 45%, with behavioural changes towards better hygiene practices and better newborn care, such as cord care, delivering in a clean environment

Parent-Carer Education: Reducing the Risks for Neonatal and Infant Mortality

In higher resourced environments, participatory learning and action can apply as well, with parents being offered information on risks for neonatal and infant mortality, knowledge on basic life support and choking, reducing the risks for sudden infant death and promoting safe sleeping and recognising signs of illness in

In resource-richer environments, peer groups supporting the new mother may be driven by health care or by the community. Mother and baby peer groups or new parent groups are a useful way of engaging parents and family members [27] and can be local, regional or national such as BLISS, which is a national charity for sick and premature babies [28] in England. These may be one-to-one engagements or group interaction depending on resources and availability and include online resources for learning and communicating. Examples of these are shown in Table 2. The benefits of these kinds of educational thrust on reducing mortality may be

less obvious where health care is equitable to all [19], but still of value as such environments do have pockets of poorer educational levels [20], linked with greater mortality. It may be appropriate to extrapolate that the benefits of maternal peer and group education in contributing to behavioural changes that reduce the risk of mortality can possibly also apply to resource-richer environments. In the USA, an Advisory Committee on Infant Mortality identified the value of a multimedia approach in the preventive campaign needed to reduce infant mortality [29]. They suggest a life course perspective on infant mortality reduction, urging an approach that includes health promotion and optimisation throughout the course of life, in a clinical and population-based manner. Such a perspective should include focused parent-carer education and empowerment through education on risks for infant mortality. This could mean that parents have a better idea of how best and when to seek help for their baby who may be getting ill, that is, early initiation of preventative care. Although widely prevalent in higher resourced economies, very little has been studied in this regard, and this is being mapped better in more resource-

5. What should a parent-carer education package aimed at reducing the

depending on societal needs. In resource-limited environments with poor access to health care, basic hygiene around delivery, cord care, keeping baby dry, wrapped and warm, immunizations, basic life support and breastfeeding may be key [21, 22]. In less resource-constrained environments, where most of the above are standard practice, other areas may be relevant. In the sections below, some of these are

areas that do adopt a primary prevention package the contents will change

Key parameters are driven by local epidemiological needs. It is likely that even in

and early breastfeeding [26].

DOI: http://dx.doi.org/10.5772/intechopen.82786

constrained settings [30].

described.

105

risks for infant mortality comprise?

4.3 Local, regional and national support groups

their infant [8].

Table 3.

WHO recommendation on postnatal care for newborn babies, 2013 [22].

resources and paper reading material. Guidance on basic life support is offered by some, but specific packages of information targeting knowledge around key risk factors on neonatal mortality are usually not presented in such a format to parents and carers. These may, however, be a useful point-of-care opportunity for education and training [8].

#### 4.2 Centre-based peer group education

Participatory learning and action programmes promoted by the World Health Organization drive behavioural change through parent and community engagement [25].

#### Parent-Carer Education: Reducing the Risks for Neonatal and Infant Mortality DOI: http://dx.doi.org/10.5772/intechopen.82786

Support groups work through community engagement, in which mothers develop and implement their own strategies for improvement, through shared peer group learning with a facilitator. The women are empowered to make improvements for their own communities, which result in behavioural changes that were more effective than simple traditional teacher/student model. In a trial in India, neonatal mortality reduced by 45%, with behavioural changes towards better hygiene practices and better newborn care, such as cord care, delivering in a clean environment and early breastfeeding [26].

In higher resourced environments, participatory learning and action can apply as well, with parents being offered information on risks for neonatal and infant mortality, knowledge on basic life support and choking, reducing the risks for sudden infant death and promoting safe sleeping and recognising signs of illness in their infant [8].

#### 4.3 Local, regional and national support groups

In resource-richer environments, peer groups supporting the new mother may be driven by health care or by the community. Mother and baby peer groups or new parent groups are a useful way of engaging parents and family members [27] and can be local, regional or national such as BLISS, which is a national charity for sick and premature babies [28] in England. These may be one-to-one engagements or group interaction depending on resources and availability and include online resources for learning and communicating. Examples of these are shown in Table 2.

The benefits of these kinds of educational thrust on reducing mortality may be less obvious where health care is equitable to all [19], but still of value as such environments do have pockets of poorer educational levels [20], linked with greater mortality. It may be appropriate to extrapolate that the benefits of maternal peer and group education in contributing to behavioural changes that reduce the risk of mortality can possibly also apply to resource-richer environments. In the USA, an Advisory Committee on Infant Mortality identified the value of a multimedia approach in the preventive campaign needed to reduce infant mortality [29]. They suggest a life course perspective on infant mortality reduction, urging an approach that includes health promotion and optimisation throughout the course of life, in a clinical and population-based manner. Such a perspective should include focused parent-carer education and empowerment through education on risks for infant mortality. This could mean that parents have a better idea of how best and when to seek help for their baby who may be getting ill, that is, early initiation of preventative care. Although widely prevalent in higher resourced economies, very little has been studied in this regard, and this is being mapped better in more resourceconstrained settings [30].

#### 5. What should a parent-carer education package aimed at reducing the risks for infant mortality comprise?

Key parameters are driven by local epidemiological needs. It is likely that even in areas that do adopt a primary prevention package the contents will change depending on societal needs. In resource-limited environments with poor access to health care, basic hygiene around delivery, cord care, keeping baby dry, wrapped and warm, immunizations, basic life support and breastfeeding may be key [21, 22]. In less resource-constrained environments, where most of the above are standard practice, other areas may be relevant. In the sections below, some of these are described.

resources and paper reading material. Guidance on basic life support is offered by some, but specific packages of information targeting knowledge around key risk factors on neonatal mortality are usually not presented in such a format to parents and carers. These may, however, be a useful point-of-care opportunity for educa-

existing WHO guidelines.

WHO recommendation on postnatal care for newborn babies, 2013 [22].

After an uncomplicated vaginal birth in a health facility, healthy mothers and babies should receive care in the facility for at least

If birth is at home, the first postnatal contact should be as early as possible within 24 hours of birth. At least three additional postnatal contacts are recommended for all mothers and babies, on day 3, between days 7 and 14 after birth, and 6 weeks after birth.

postnatal care in the facility for at least 24 hours after birth. Home visits in the first week after birth are recommended for care

contact and the baby should be referred for further evaluation if

stopped feeding well, history of convulsions, fast breathing (breathing rate 60 per minute), severe chest in-drawing, no spontaneous movement, fever (temperature 37.5°C), low body temperature (temperature < 35.5°C), any jaundice in first 24 hours of life, or yellow palms and soles at any age. The family should be encouraged to seek health care early if they identify any of the above danger signs in

of age. Mothers should be counselled and provided support for

the first week of life is recommended for babies who are born at home in settings with high neonatal mortality (30 or more neonatal

Clean, dry cord care is recommended for babies born in health facilities and at home in low neonatal mortality settings. Use of chlorhexidine in these situations may be considered only to replace application of a harmful traditional substance to the cord stump.

possible, bathing should be delayed for at least 6 hours. Appropriate clothing of the baby for ambient temperature is recommended. This means one to two layers of clothes more than adults, and use of hats/caps. The mother and baby should not be separated and should

Communication and play with the baby should be encouraged. Immunisation should be promoted as per existing WHO guidelines. Preterm and low-birth weight babies should be identified immediately after birth and should be provided special care as per

exclusive breastfeeding at each postnatal contact.

24 hours after birth.

3: Home visits for postnatal care If birth is in a health facility, mothers and babies should receive

of the mother and her baby. 4: Assessment of the baby The following signs should be assessed during each postnatal care

any of the signs is present:

between postnatal care visits. 5: Exclusive breastfeeding All babies should be exclusively breastfed from birth until 6 months

6: Cord care Daily chlorhexidine application to the umbilical cord stump during

deaths per 1000 live births).

7: Other postnatal care Bathing should be delayed until 24 hours after birth. If this is not

stay in the same room 24 hours a day.

Participatory learning and action programmes promoted by the World Health Organization drive behavioural change through parent and community engagement [25].

tion and training [8].

Table 3.

104

1: Timing of discharge from a health facility after birth

2: Number and timing of postnatal contacts

Neonatal Medicine

4.2 Centre-based peer group education

#### 5.1 Breastfeeding education and infant mortality

The benefits of breastfeeding on reducing infant mortality and morbidity are widely accepted. In 2003, the Lancet published data [31] that of all children who died under the age of 5 years, 12% of these deaths could have been prevented if they were effectively breastfed as infants. This amounted to roughly 800,000 lives in low- and middle-income countries per year. In their systematic review, Sankar et al. [32] showed that the relative risk for all-cause mortality in infants under 6 months of age and not breastfed was 14.4, 4.8 in those partially breastfed and 1.5 in those completely breastfed. For children 6–23 months of age, they demonstrated up to a two-fold higher mortality (RR 1.97 [1.45–2.67]) if not breastfed, when compared to those who were. Exclusive breastfeeds are also associated with lower mortality and infection rates [33], and this impact can be seen as early as with breastfeeds given within the first hour of life [34–36]. Maternal awareness, education and support for breastfeeding to improve breastfeeding rates are therefore a critical part of the parent empowerment, in reducing infant mortality.

support, willingness to change smoking behaviour and the smoking dynamics within relationships mattered, and delivery of information is a key barrier than can potentially be overcome with the appropriate educational drives. At the same time, it is important to note that up to 50% of women who stop smoking during their pregnancy resume within 6 months after birth [46]. There may be a hard core of individual mothers/parents who are unable to stop smoking, even knowing the risks to their baby. Some evidence exists that specific behavioural techniques may have an impact on prenatal smoking cessation [47–49], but the complexities around cessation in relation to pregnancy and childbirth need further interventional analysis. Despite these limitations, there may still be the benefit of incorporating smoking cessation information into parent awareness packages [8], while awaiting more

Parent-Carer Education: Reducing the Risks for Neonatal and Infant Mortality

DOI: http://dx.doi.org/10.5772/intechopen.82786

Safe sleep programmes can make a difference to the risks of sudden infant death syndrome. In parts of the USA, interventions such as these halved the rate of infant deaths from 1.08/1000 to 0.48/1000. Research suggests that education of caregivers does result in improved understanding of behaviours that promote safe sleep and reduce the risk of SIDS [50]. Simple measures such as position of sleeping have changed SIDS rates dramatically [51]. And parent and carer education is a key directive for future reductions in this area [52]. Evidence that discharge from hospital programmes do make a difference is also emerging [53] in a pilot trial of promoting safe sleep patterns in mothers of preterm babies, who have a doubled risk of SIDS; and there is also acknowledgement that this group especially should be targeted for educational interventions to reduce the risk of SIDS. Simple educational campaigns en masse may not have the desired effect [54, 55] and additional measures may be needed such as 1:1 educational drives. These can comfortably be delivered in 1:1 or peer group packages supported by neonatal units, midwives and health care visitors as part of the point-of-care programme of education for parents

Basic life support at birth is critical, and a standard practice in higher income settings where healthcare support exists at the time of birth. However, even for home births and births outside of healthcare facilities, this skill is essential. In their review on neonatal resuscitation in low-income settings, Wall et al. [56] noted that the major burden of resuscitation at birth (approximately 10 million babies do not breathe at birth, of which 6 million require basic life support) is in low-income settings. Here, they suggest that local education of community health workers can make a difference to the rate of deaths at the time of birth (termed intrapartum

In higher income settings, where there are healthcare workers trained in basic life support, there still exists a need for parent-carer education and awareness. Acute life-threatening events in infancy are the next area of concern and can affect babies as young as 0–3 months of age [57]. Bystander CPR with and without dispatcher instructions improved 1-month neurological outcomes favourably (adjusted OR 1.81 and 1.68) when compared to no bystander CPR in children with out-of-hospital cardiac arrests [58], and survival after shockable arrests was higher when delivered by a first responder or public AED rather than a paramedic (83.3 vs. 40% p = 0.04) [59]. In reporting on the Committee on Pediatric Emergency Medicine in the USA, Callahan and colleagues advocate that paediatricians should

effective interventions and primary preventive packages.

5.3 Safe sleep

and carers.

deaths).

107

5.4 Basic life support training

These benefits exist in all resource settings. For example, in Washington, Alaska, Maine, Nebraska and Ohio, promotion of the Baby Friendly Hospital Initiative saw benefits of this for mothers of lower education which were significant, increasing the breastfeeding rates for >4 weeks of life here (p = 0.02) [37]. These provide evidence for the continued thrust for promoting breastfeeding as a potential protective factor against the risk of neonatal and infant mortality, even in resource-richer environments. The Baby Friendly Initiative, developed by UNICEF, promotes breastfeeding as part of its thrust to support families with feeding, enabling the development of close relationships for the best start in life for babies.

#### 5.2 Smoking cessation and infant mortality

The negative effects of prenatal, natal and postnatal smoking on morbidity and mortality in infants are widely described [38, 39] and include premature births, low-birth weight babies which are themselves at risk for mortality and an increased risk for sudden infant death. Smoking cessation in pregnancy or prenatally, or even postnatally, is complex. Risk factors for smoking include having a smoking partner, with a lower risk where there is higher maternal education level [40]. Mass campaigns can potentially influence smoking cessation rates in pregnancy [41]. In three states in the USA, those smokers exposed to a CDC smoking cessation campaign in pregnancy had a reduction in smoking by the third trimester compared to those who were not exposed to the campaign (34.7 vs. 32.9%; p < 0.001). In a systematic review and meta-analysis of 54 studies encompassing 55,584 women who smoked before their pregnancy, Riaz et al. [42] noted that higher educational level, higher socio-economic status, low exposure to second-hand smoke and planned breastfeeding were associated with cessation of smoking during pregnancy. So, there is potential value, extrapolating from these that an awareness programme could influence smoking cessation rates in association with pregnancy/after birth, targeting not only mothers, but their partners, significant others and family members.

Education versus incentive-based systems to reduce smoking may work to different degrees. These modern alternatives to conventional educational and awareness campaigns could include mobile apps, ipad programmes and text messages [43, 44]. But simply offering education may not be adequate, and there is much more to be done to understand this. Barriers to smoking cessation are multi-fold and may exceed support pathways. In an NIHR HTA assessment of these [45], partners' Parent-Carer Education: Reducing the Risks for Neonatal and Infant Mortality DOI: http://dx.doi.org/10.5772/intechopen.82786

support, willingness to change smoking behaviour and the smoking dynamics within relationships mattered, and delivery of information is a key barrier than can potentially be overcome with the appropriate educational drives. At the same time, it is important to note that up to 50% of women who stop smoking during their pregnancy resume within 6 months after birth [46]. There may be a hard core of individual mothers/parents who are unable to stop smoking, even knowing the risks to their baby. Some evidence exists that specific behavioural techniques may have an impact on prenatal smoking cessation [47–49], but the complexities around cessation in relation to pregnancy and childbirth need further interventional analysis. Despite these limitations, there may still be the benefit of incorporating smoking cessation information into parent awareness packages [8], while awaiting more effective interventions and primary preventive packages.

#### 5.3 Safe sleep

5.1 Breastfeeding education and infant mortality

parent empowerment, in reducing infant mortality.

5.2 Smoking cessation and infant mortality

for babies.

Neonatal Medicine

members.

106

The benefits of breastfeeding on reducing infant mortality and morbidity are widely accepted. In 2003, the Lancet published data [31] that of all children who died under the age of 5 years, 12% of these deaths could have been prevented if they were effectively breastfed as infants. This amounted to roughly 800,000 lives in low- and middle-income countries per year. In their systematic review, Sankar et al. [32] showed that the relative risk for all-cause mortality in infants under 6 months of age and not breastfed was 14.4, 4.8 in those partially breastfed and 1.5 in those completely breastfed. For children 6–23 months of age, they demonstrated up to a two-fold higher mortality (RR 1.97 [1.45–2.67]) if not breastfed, when compared to those who were. Exclusive breastfeeds are also associated with lower mortality and infection rates [33], and this impact can be seen as early as with breastfeeds given within the first hour of life [34–36]. Maternal awareness, education and support for breastfeeding to improve breastfeeding rates are therefore a critical part of the

These benefits exist in all resource settings. For example, in Washington, Alaska, Maine, Nebraska and Ohio, promotion of the Baby Friendly Hospital Initiative saw benefits of this for mothers of lower education which were significant, increasing the breastfeeding rates for >4 weeks of life here (p = 0.02) [37]. These provide evidence for the continued thrust for promoting breastfeeding as a potential protective factor against the risk of neonatal and infant mortality, even in resource-richer environments. The Baby Friendly Initiative, developed by UNICEF, promotes breastfeeding as part of its thrust to support families with feeding, enabling the development of close relationships for the best start in life

The negative effects of prenatal, natal and postnatal smoking on morbidity and mortality in infants are widely described [38, 39] and include premature births, low-birth weight babies which are themselves at risk for mortality and an increased risk for sudden infant death. Smoking cessation in pregnancy or prenatally, or even postnatally, is complex. Risk factors for smoking include having a smoking partner, with a lower risk where there is higher maternal education level [40]. Mass campaigns can potentially influence smoking cessation rates in pregnancy [41]. In three states in the USA, those smokers exposed to a CDC smoking cessation campaign in pregnancy had a reduction in smoking by the third trimester compared to those who were not exposed to the campaign (34.7 vs. 32.9%; p < 0.001). In a systematic review and meta-analysis of 54 studies encompassing 55,584 women who smoked before their pregnancy, Riaz et al. [42] noted that higher educational level, higher

socio-economic status, low exposure to second-hand smoke and planned breastfeeding were associated with cessation of smoking during pregnancy. So, there is potential value, extrapolating from these that an awareness programme could influence smoking cessation rates in association with pregnancy/after birth, targeting not only mothers, but their partners, significant others and family

Education versus incentive-based systems to reduce smoking may work to different degrees. These modern alternatives to conventional educational and awareness campaigns could include mobile apps, ipad programmes and text messages [43, 44]. But simply offering education may not be adequate, and there is much more to be done to understand this. Barriers to smoking cessation are multi-fold and may exceed support pathways. In an NIHR HTA assessment of these [45], partners'

Safe sleep programmes can make a difference to the risks of sudden infant death syndrome. In parts of the USA, interventions such as these halved the rate of infant deaths from 1.08/1000 to 0.48/1000. Research suggests that education of caregivers does result in improved understanding of behaviours that promote safe sleep and reduce the risk of SIDS [50]. Simple measures such as position of sleeping have changed SIDS rates dramatically [51]. And parent and carer education is a key directive for future reductions in this area [52]. Evidence that discharge from hospital programmes do make a difference is also emerging [53] in a pilot trial of promoting safe sleep patterns in mothers of preterm babies, who have a doubled risk of SIDS; and there is also acknowledgement that this group especially should be targeted for educational interventions to reduce the risk of SIDS. Simple educational campaigns en masse may not have the desired effect [54, 55] and additional measures may be needed such as 1:1 educational drives. These can comfortably be delivered in 1:1 or peer group packages supported by neonatal units, midwives and health care visitors as part of the point-of-care programme of education for parents and carers.

#### 5.4 Basic life support training

Basic life support at birth is critical, and a standard practice in higher income settings where healthcare support exists at the time of birth. However, even for home births and births outside of healthcare facilities, this skill is essential. In their review on neonatal resuscitation in low-income settings, Wall et al. [56] noted that the major burden of resuscitation at birth (approximately 10 million babies do not breathe at birth, of which 6 million require basic life support) is in low-income settings. Here, they suggest that local education of community health workers can make a difference to the rate of deaths at the time of birth (termed intrapartum deaths).

In higher income settings, where there are healthcare workers trained in basic life support, there still exists a need for parent-carer education and awareness. Acute life-threatening events in infancy are the next area of concern and can affect babies as young as 0–3 months of age [57]. Bystander CPR with and without dispatcher instructions improved 1-month neurological outcomes favourably (adjusted OR 1.81 and 1.68) when compared to no bystander CPR in children with out-of-hospital cardiac arrests [58], and survival after shockable arrests was higher when delivered by a first responder or public AED rather than a paramedic (83.3 vs. 40% p = 0.04) [59]. In reporting on the Committee on Pediatric Emergency Medicine in the USA, Callahan and colleagues advocate that paediatricians should

encourage training of basic life support to parents, children, caregivers, school personnel and lay members of the public [60]. Many neonatal units do offer basic life support training for parents and carers when their baby is due to leave their unit; these boost parent confidence in being able to cope with their infant after discharge from hospital.

6. Conclusion

DOI: http://dx.doi.org/10.5772/intechopen.82786

programmes.

Acknowledgements

Conflict of interest

Author details

109

Thillagavathie Pillay1,2\*

Wolverhampton, United Kingdom

Leicester, United Kingdom

for supporting this programme.

There is no conflict of interest.

Parent education programmes, targeted around understanding and, thereby, empowering parents with knowledge around the risks of neonatal and infant mortality, are an intuitively important adjunct to neonatal clinical care. Its role in preventive neonatal care may be strong, for its potential benefits on behavioural changes that enable reduced risks for the current and subsequent pregnancies. Getting parents actively engaged in programmes that work with them for the betterment of their baby, their subsequent babies and their communities may be the key to change for the future. This embraces patient and public (i.e., parents/family members/significant others and carers) involvement in taking ownership of, and making a greater contribution to their overall health, and to that of their families. What is now needed are focused thrusts around parent education and empow-

Parent-Carer Education: Reducing the Risks for Neonatal and Infant Mortality

erment, based on local risk factors and associations with neonatal mortality, combined with robust scientific research to assess the impact, if any, of such

To the Royal Wolverhampton NHS Trust, its Neonatal Unit, parents and babies who participated, Wolverhampton Public Health and to its commissioning group

1 School of Medicine and Clinical Practice, Faculty of Science and Engineering,

2 Department of Health Sciences, College of Life Sciences, University of Leicester,

© 2019 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,

University of Wolverhampton, Royal Wolverhampton NHS Trust,

\*Address all correspondence to: tilly.pillay@nhs.net

provided the original work is properly cited.

#### 5.5 Kangaroo care and infant mortality

Skin-to-skin contact via Kangaroo care [61] is also an important part of a care package especially for preterm births. When compared to conventional care, Kangaroo mother care was associated with 36% lower mortality (RR 0.64), a lower risk of neonatal sepsis (RR 0.53), hypothermia (RR 0.22), hypoglycaemia (RR 0.12), hospital readmission (RR 0.42) and increased rate of exclusive breastfeeding (RR 1.50; 95% CI 1.26, 1.78) [62]. Educating and empowering mothers, on the value of such care packages, is important in reducing morbidities especially in low-birth weight infants.

#### 5.6 Reducing the risks for congenital abnormalities

Congenital abnormalities are a major cause of infant mortality in higher resource environments, with variation between ethnic groups and a strong association with consanguinity [63, 64]. Reducing the risks for life-threatening congenital abnormalities [65] (either through the condition itself, or through its association with preterm birth) is dependent on parental awareness regarding the risks of congenital abnormality pre-conceptually, availability and uptake of screening for major congenital abnormalities, the potential for intervention, and parent perspectives on termination of pregnancy, should they carry a baby with a lethal/potentially lethal condition in utero. Where possible, parent education to raise awareness regarding the likelihood of a congenital abnormality should be discussed in the context of consanguinity and the elderly mother.

#### 5.7 Reducing the risk of preterm birth

Risk factors for preterm birth include, among a wide array of clinical scenarios, poor maternal health, maternal infections, smoking and alcohol use in pregnancy, multiple births and extremes of maternal age [66]. The World Health Organisation [67] has set out basic advice to reduce preterm births and these include promoting a healthy pregnancy by supporting: (a) a healthy diet, (b) optimal nutrition, (c) advice on tobacco use in pregnancy, (d) advice on alcohol use in pregnancy,

(e) antenatal support and scanning to detect gestational age and multiple births,

(f) better access to contraceptives, (g) management of risk factors such as infections and (h) increased maternal empowerment.

In higher resource settings, strategies for prevention of preterm births include: (a) prevention of non-medically indicated late preterm/early term births, (b) progesterone supplementation, (c) cervical cerclage, (d) tobacco control and prevention of smoking in pregnancy, (e) judicious use of fertility treatments and (f) dedicated preterm birth prevention clinics [68].

All of these aspects relate to upstream events prior to birth of the baby, but still hold benefit in parent-carer education, for the ripple effect that it may have on communities, and also for guiding care around the subsequent pregnancy.

Parent-Carer Education: Reducing the Risks for Neonatal and Infant Mortality DOI: http://dx.doi.org/10.5772/intechopen.82786

#### 6. Conclusion

encourage training of basic life support to parents, children, caregivers, school personnel and lay members of the public [60]. Many neonatal units do offer basic life support training for parents and carers when their baby is due to leave their unit; these boost parent confidence in being able to cope with their infant after

Skin-to-skin contact via Kangaroo care [61] is also an important part of a care package especially for preterm births. When compared to conventional care, Kangaroo mother care was associated with 36% lower mortality (RR 0.64), a lower risk of neonatal sepsis (RR 0.53), hypothermia (RR 0.22), hypoglycaemia (RR 0.12), hospital readmission (RR 0.42) and increased rate of exclusive breastfeeding (RR 1.50; 95% CI 1.26, 1.78) [62]. Educating and empowering mothers, on the value of such care packages, is important in reducing morbidities especially in low-birth

Congenital abnormalities are a major cause of infant mortality in higher resource environments, with variation between ethnic groups and a strong association with consanguinity [63, 64]. Reducing the risks for life-threatening congenital abnormalities [65] (either through the condition itself, or through its association with preterm birth) is dependent on parental awareness regarding the risks of congenital abnormality pre-conceptually, availability and uptake of screening for major congenital abnormalities, the potential for intervention, and parent perspectives on termination of pregnancy, should they carry a baby with a lethal/potentially lethal condition in utero. Where possible, parent education to raise awareness regarding the likelihood of a congenital abnormality should be discussed in the context of consanguinity and the elderly

Risk factors for preterm birth include, among a wide array of clinical scenarios, poor maternal health, maternal infections, smoking and alcohol use in pregnancy, multiple births and extremes of maternal age [66]. The World Health Organisation [67] has set out basic advice to reduce preterm births and these include promoting a

In higher resource settings, strategies for prevention of preterm births include: (a) prevention of non-medically indicated late preterm/early term births, (b) progesterone supplementation, (c) cervical cerclage, (d) tobacco control and preven-

All of these aspects relate to upstream events prior to birth of the baby, but still hold benefit in parent-carer education, for the ripple effect that it may have on communities, and also for guiding care around the subsequent

healthy pregnancy by supporting: (a) a healthy diet, (b) optimal nutrition, (c) advice on tobacco use in pregnancy, (d) advice on alcohol use in pregnancy, (e) antenatal support and scanning to detect gestational age and multiple births, (f) better access to contraceptives, (g) management of risk factors such as infec-

tion of smoking in pregnancy, (e) judicious use of fertility treatments and

discharge from hospital.

Neonatal Medicine

weight infants.

mother.

pregnancy.

108

5.5 Kangaroo care and infant mortality

5.7 Reducing the risk of preterm birth

tions and (h) increased maternal empowerment.

(f) dedicated preterm birth prevention clinics [68].

5.6 Reducing the risks for congenital abnormalities

Parent education programmes, targeted around understanding and, thereby, empowering parents with knowledge around the risks of neonatal and infant mortality, are an intuitively important adjunct to neonatal clinical care. Its role in preventive neonatal care may be strong, for its potential benefits on behavioural changes that enable reduced risks for the current and subsequent pregnancies. Getting parents actively engaged in programmes that work with them for the betterment of their baby, their subsequent babies and their communities may be the key to change for the future. This embraces patient and public (i.e., parents/family members/significant others and carers) involvement in taking ownership of, and making a greater contribution to their overall health, and to that of their families.

What is now needed are focused thrusts around parent education and empowerment, based on local risk factors and associations with neonatal mortality, combined with robust scientific research to assess the impact, if any, of such programmes.

#### Acknowledgements

To the Royal Wolverhampton NHS Trust, its Neonatal Unit, parents and babies who participated, Wolverhampton Public Health and to its commissioning group for supporting this programme.

#### Conflict of interest

There is no conflict of interest.

#### Author details

Thillagavathie Pillay1,2\*

1 School of Medicine and Clinical Practice, Faculty of Science and Engineering, University of Wolverhampton, Royal Wolverhampton NHS Trust, Wolverhampton, United Kingdom

2 Department of Health Sciences, College of Life Sciences, University of Leicester, Leicester, United Kingdom

\*Address all correspondence to: tilly.pillay@nhs.net

© 2019 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.

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[59] Goto Y, Maeda T, Goto Y. Impact of dispatcher-assisted bystander cardiopulmonary resuscitation on neurological outcomes in children with out-of-hospital cardiac arrests: A prospective, nationwide, populationbased cohort study. Journal of the American Heart Association. 2014;3(3): e000499. DOI: 10.1161/JAHA.113. 000499

[60] Callahan JM, Fuchs SM, Committee on Paediatric Emergency Medicine. Advocating for life support training of children, parents, caregivers, school personnel, and the public. Pediatrics 2018;141(6). pii: e20180704. DOI: 10.1542/peds.2018-0704

[61] Chan GJ, Valsangkar B, Kajeepeta S, Boundy EO, Wall S. What is kangaroo mother care? Systematic review of the literature. Journal of Global Health. 2016;6(1):010701. DOI: 10.7189/ jogh.06.010701

[62] Boundy EO, Dastjerdi R, Spiegelman D, et al. Kangaroo mother care and neonatal outcomes: A metaanalysis. Pediatrics. 2016;137(1): e20152238. DOI: 10.1542/peds.2015-2238 [63] Sheridan E, Wright J, Small N, et al. Risk factors for congenital anomaly in a multiethnic birth cohort: An analysis of the Born in Bradford study. Lancet. 2013;382(9901):1350-1359. DOI: 10.1016/S0140-6736(13)61132-0. Epub 2013 Jul 4

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[72] Shealy KR, Li R, Benton-Davis S, Grummer-Strawn LM. The CDC Guide to Breastfeeding Interventions. Atlanta: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention; 2005. Available from: https://www.cdc.gov/breastfeeding/ pdf/breastfeeding\_interventions.pdf

MS, Cousens S, Martines J. Implementing community-based perinatal care: Results from a pilot study in rural Pakistan. Bulletin of the World Health Organization. 2008;86:452-459

372(9644):1151-1162

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[64] Kapurubandara S, Melov S, Shalou E, Alahakoon I. Consanguinity and associated perinatal outcomes, including stillbirth. The Australian & New Zealand Journal of Obstetrics & Gynaecology. 2016;56(6):599-604. DOI: 10.1111/ajo.12493. Epub 2016 Jul 11

[65] Institute of Medicine (US) Committee on Improving Birth Outcomes, Bale JR, Stoll BJ, Lucas AO, editors. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington (DC): National Academies Press (US); 2003. 3. Interventions to Reduce the Impact of Birth Defects. Available from: https://www.ncbi.nlm. nih.gov/books/NBK222083/

[66] Up to date—Preterm Birth: Risk Factors, Interventions for Risk Reduction and Maternal Prognosis. Available from: https://www.uptodate. com/contents/preterm-birth-risk-fac tors-interventions-for-risk-reduction-a nd-maternal-prognosis [Accessed: 15-10-2018]

[67] World Health Organization: Preterm Births. Available from: http:// www.who.int/news-room/fact-sheets/ detail/preterm-birth [Accessed 15-10- 2018]

[68] Newnham JP, Dickinson JE, Hart RJ, Pennell CE, Arresse CA, Keelan JA. Strategies to prevent preterm birth. Frontiers in Immunology. 2014;5:584

[69] Baqui AH, Williams EK, Rosecrans AM, Agrawal PK, Ahmed S, Darmstadt GL, et al. Impact of an integrated nutrition and health programme on neonatal mortality in rural northern India. Bulletin of the World Health Organization. 2008;86:796-804

Parent-Carer Education: Reducing the Risks for Neonatal and Infant Mortality DOI: http://dx.doi.org/10.5772/intechopen.82786

[70] Bhutta ZA, Memon ZA, Sooi S, Salat MS, Cousens S, Martines J. Implementing community-based perinatal care: Results from a pilot study in rural Pakistan. Bulletin of the World Health Organization. 2008;86:452-459

Neonatal resuscitation in low-resource settings: What, who, and how to overcome challenges to scale up? International Journal of Gynaecology and Obstetrics. 2009;107(Supp. 1):

[63] Sheridan E, Wright J, Small N, et al. Risk factors for congenital anomaly in a multiethnic birth cohort: An analysis of the Born in Bradford study. Lancet. 2013;382(9901):1350-1359. DOI: 10.1016/S0140-6736(13)61132-0. Epub

[64] Kapurubandara S, Melov S, Shalou E, Alahakoon I. Consanguinity and associated perinatal outcomes, including

Gynaecology. 2016;56(6):599-604. DOI: 10.1111/ajo.12493. Epub 2016 Jul 11

stillbirth. The Australian & New Zealand Journal of Obstetrics &

[65] Institute of Medicine (US) Committee on Improving Birth Outcomes, Bale JR, Stoll BJ, Lucas AO, editors. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington (DC): National Academies Press (US); 2003. 3. Interventions to Reduce the Impact of Birth Defects. Available from: https://www.ncbi.nlm.

nih.gov/books/NBK222083/

15-10-2018]

2018]

[66] Up to date—Preterm Birth: Risk Factors, Interventions for Risk Reduction and Maternal Prognosis. Available from: https://www.uptodate. com/contents/preterm-birth-risk-fac tors-interventions-for-risk-reduction-a nd-maternal-prognosis [Accessed:

[67] World Health Organization: Preterm Births. Available from: http:// www.who.int/news-room/fact-sheets/ detail/preterm-birth [Accessed 15-10-

[68] Newnham JP, Dickinson JE, Hart RJ, Pennell CE, Arresse CA, Keelan JA. Strategies to prevent preterm birth. Frontiers in Immunology. 2014;5:584

[69] Baqui AH, Williams EK, Rosecrans AM, Agrawal PK, Ahmed S, Darmstadt GL, et al. Impact of an integrated nutrition and health programme on neonatal mortality in rural northern India. Bulletin of the World Health Organization. 2008;86:796-804

2013 Jul 4

[57] McGovern MC, Smith MBH. Causes of apparent life threatening events in infants: A systematic review. Archives of Disease in Childhood. 2004;89:

[58] Nehme Z, Namachivayam S, Forrest A, Butt W, Bernard S, Smith K. Trends in the incidence and outcome of

paediatric out-of-hospital cardiac arrest:

Resuscitation. 2018 Jul;128:43-50. DOI: 10.1016/j.resuscitation.2018.04.030.

[59] Goto Y, Maeda T, Goto Y. Impact of

[60] Callahan JM, Fuchs SM, Committee on Paediatric Emergency Medicine. Advocating for life support training of children, parents, caregivers, school personnel, and the public. Pediatrics 2018;141(6). pii: e20180704. DOI:

[61] Chan GJ, Valsangkar B, Kajeepeta S, Boundy EO, Wall S. What is kangaroo mother care? Systematic review of the literature. Journal of Global Health. 2016;6(1):010701. DOI: 10.7189/

10.1542/peds.2018-0704

[62] Boundy EO, Dastjerdi R,

Spiegelman D, et al. Kangaroo mother care and neonatal outcomes: A metaanalysis. Pediatrics. 2016;137(1):

e20152238. DOI: 10.1542/peds.2015-2238

jogh.06.010701

114

A 17-year observational study.

dispatcher-assisted bystander cardiopulmonary resuscitation on neurological outcomes in children with out-of-hospital cardiac arrests: A prospective, nationwide, populationbased cohort study. Journal of the American Heart Association. 2014;3(3): e000499. DOI: 10.1161/JAHA.113.

Epub 2018 Ap. 25

000499

S47-S64

Neonatal Medicine

1043-1048

[71] Kumar V, Mohanty S, Kumar A, et al. Effect of community based behaviour change management on neonatal mortality in Shivgarh, Uttar Pradesh, India: A cluster randomised controlled trial. Lancet. 2008; 372(9644):1151-1162

[72] Shealy KR, Li R, Benton-Davis S, Grummer-Strawn LM. The CDC Guide to Breastfeeding Interventions. Atlanta: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention; 2005. Available from: https://www.cdc.gov/breastfeeding/ pdf/breastfeeding\_interventions.pdf

### *Edited by Antonina I. Chubarova*

Neonatology is a new and quickly developing medical specialty. The rate of child and infant mortality and the incidence of adult diseases on life expectancy in any country are strongly dependent on the quality of medical aid to neonates. This is an area of medicine where a lot of new industrial innovations are used in combination with the humanizing of technologies.

This book includes information on several aspects of neonatal care beginning with resuscitation in the delivery room and culminating with methods of constructing a parent-friendly atmosphere. It is addressed to neonatologists, obstetricians, pediatricians, nurses, and social workers.

Published in London, UK © 2019 IntechOpen © RusN / iStock

Neonatal Medicine

Neonatal Medicine

*Edited by Antonina I. Chubarova*